Substituted (piperidin-4-yl)-1,5-naphthyridine and (piperidin-4-yl)quinoline derivatives and uses thereof

Abstract

The present disclosure provides a Compound of Formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein R1, R2a, R2b, R2c, R2d, R6, R7a, R7b, R7c, R7d, R7e, R8, X1, X2, X3, X4, X5, X6, X7, o, p, r and subvariables thereof are as defined herein.

Description

SUBSTITUTED (PIPERIDIN-4-YL)-l,5-NAPHTHYRIDINE AND (PIPERIDIN-4-YDQUINOLINE DERIVATIVES AND USES THEREOFCLAIM OF PRIORITYThe present application claims priority to U.S. Application No. 63 / 547,059, filed November 2, 2023, and U.S. Application No. 63 / 547,060, filed November 2, 2023. The entire contents of each of the foregoing applications are incorporated by reference in their entirety.FIELD OF THE DISCLOSUREThe present disclosure relates to substituted (piperidin-4-yl)-l,5-naphthyridine and (piperidin-4- yl)quinoline compounds and compositions for modulation of hypoxia inducible factor 1 beta (HIF-lb) and their use for the treatment of HIF-lb-dependent diseases or disorders or where reduction of HIF-lb protein levels can ameliorate a disease or disorder.BACKGROUND OF THE DISCLOSUREThe HIE transcription factors are master regulators of the cellular response to hypoxia. The HIE transcriptional regulator acts as a heterodimeric complex consisting of the constitutively expressed hypoxia inducible factor 1 beta (HIF-lb, also known as ARNT) and either of the two HIF-a isoforms, HIF-la orHIF-2a. HIF-lb is a key player in both the hypoxic-response pathway and the aryl hydrocarbon receptor (AHR) pathway. The first evidence provided that the HIF heterodimer not only activates the erythropoietin gene but is also part of a widespread oxygen-sensing and signal transduction mechanism was demonstrated when HIF activity was detected in various non-erythropoietin-producing cell lines cultured under hypoxic conditions (Wang and Semenza, Proc. Natl. Acad. Set. USA, 1993, 90, 4304-4308; Maxwell et al., Proc. Natl. Acad. Set. USA, 1993, 90, 2423-2427).Oxygen supply to tissues is essential in maintaining mammalian cell function and physiology and a deficiency in oxygen supply to tissues is a characteristic of a number of conditions in which there is insufficient blood flow to provide adequate oxygenation. Examples of diseases affected by inadequate oxygen supply include ischemic disorders, cancer, and atherosclerosis. Activation of a signaling cascade occurs in response to this hypoxic environment in tissues which drives the induction or repression of the transcription of a multitude of genes implicated in events such as angiogenesis (neo- vascularization), glucose metabolism, and cell survival / death. A key to this hypoxic transcriptional response lies in the transcription factors, the hypoxia inducible factors (HIF).It has been shown that both HIF-a isoforms are rapidly degraded under normoxic conditions due to the oxygen-dependent hydroxylation of specific proline residues that mark the proteins for proteasomal degradation (Jewell, et al., Faseb. J., 2001, 15, 1312-1314; Gorlach, et al., Biochim. BioPhase. Acta, 2000,1493, 125-134) and that under hypoxic conditions this hydroxylation is reversed, and the protein is further stabilized by phosphorylation (Wang et al., Biochip. Biophys. Res. Comrnun, 1995, 216, 669-675). Consequently, the HIF-a proteins are then translocated to the nucleus, where they interact with HIF-lb to form a heterodimeric transcription factor (Kallio et al., Embo J, 1998, 17, 6573-65, 86). The dimerization step has been shown in HIF-lb deficient cells to be an absolute requirement for the transcriptional activation of hypoxia response element genes (Wood et al., J. Biol. Chem., 1996, 271, 15117-15123). As a result, there are categories of genes that are activated by the HIF dimer which include oxygen transport genes, such as erythropoietin (Semenza, et al., J. Biol. Chem., 1994, 269, 23757- 23763) and transferrin (Rolfs et al., J. Biol. Chem., 1997, 272, 20055-20062); as well as genes involved in angiogenesis, such as VEGF (Levy et al., J. Biol. Chem., 1995, 270, 13333-13340); and genes involved in anaerobic metabolism, such as glucose transporter 1 (Ebert et al., J. Biol. Chem., 1995, 270, 29083-29089). It is thought that hypoxia- induced genes such as VEGF play a role in promoting angiogenesis and subsequent tumor growth (Harris, Nat. Rev. Cancer, 2002, 2, 38-47).Cellular oxygen concentration precisely regulates HIF transcriptional activity. While changes in oxygen levels do not affect HIF-lb protein levels, the abundance of the HIF-a subunits is markedly increased upon exposure of cells to hypoxia, primarily due to stabilization of the alpha subunits (Safran and Kaelin, J. Clin. Invest., 2003, 111, 779-783). The HIF-2a / HIF-lb heterodimer protein, which contains the core recognition sequence 5’-TACGTG-3’, binds to the hypoxic response element and is found in the cis- regulatory regions of hypoxia-regulated genes (Ema, et al., Proc. Natl. Acad. Sci. U.S.A., 1997, 94, 4273- 4278; Hogenesch, et al., J. Biol. Chem., 1997, 272, 8581-8593). It has been shown that binding of the heterodimer to the hypoxia-responsive element (HRE) induces gene expression (Wiesener, et al., Blood, 1998, 92, 2260-2268).A range of other genes regulated by the dioxin response element (DRE) can also be activated by HIF dimers resulting in some of the toxic and carcinogenic effects associated with many of the AHR ligands, such as immunotoxicity, developmental and reproductive toxicity, disruption of endocrine pathways, wasting syndrome, and tumor promotion (Safe Toxicol. Lett., 2001, 120, 1-7). It has been demonstrated that the AHR / HIF-lb heterodimer directly associates with the estrogen receptors ER-a and ER-b and that this association results in the recruitment of unliganded estrogen receptor and coactivator p300 to estrogen-responsive gene promoters. This association has been shown to lead the activation of transcription and estrogenic effects and to give rise to the adverse estrogen-related actions of dioxin-type environmental contaminants (Ohtake et al., Nature, 2003, 423, 545-550).In summary, HIF-lb plays an important role in both the hypoxia-induced and AHR signaling pathways, which have been linked to various forms of malignancies (Harris, Nat. Rev. Cancer, 2002, 2, 8- 47; Safe Toxicol. Lett., 2001, 120 1-7) The angiogenic promoting capabilities of HIF-lb also make it apotential therapeutic target for a variety of angiogenic disorders, such as arthritis, cardiovascular diseases, skin conditions, aberrant wound healing and ocular conditions (e.g., macular degeneration, diabetic retinopathy, diabetic macular edema and retinopathy of prematurity). Reduction of HIF-lb levels with small molecule modulators therefore has the potential to be a treatment for a range of diseases, including cancers, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases and other HIF-related diseases. For this reason, there remains a considerable need for novel and potent small molecule modulators of HIF-lb.SUMMARY OF THE DISCLOSUREThe compounds of the disclosure have use as therapeutic agents, particularly for cancers, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary disorders (e.g., pulmonary arterial hypertension (PAH)), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases, and other HIF-lb-related diseases. In one aspect, the compounds of the disclosure have HIF-lb degrader activity. In some embodiments, the HIF-lb degrader activity is at or below the 50 pM level, and more preferably at or below the 10 pM level, when administered to a cell or subject. The compounds of the disclosure have usefulness in treating cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases, and other diseases for which such degrader activity would be beneficial.A first aspect of the present disclosure relates to compounds of Formula (I):pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Xi is N or CRp X2is N, N(O), or CR5;X3 is N or CR4a; X4 is N or CR4bi X5 is N or CR4b-; Xe is N or CR5; X? is N or N(O); wherein no more than three of X2, X2, X4, X5, Xe and X? is simultaneously N; Ri is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRI2, -CH2OC(O)OR]2, -P(O)(ORI2)2, -CH2OP(O)(ORI2)2, -CH2OP(O)(OH)ORI2,CH2OP(O)(R12)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(RI2-)NHRI2-, -CH2OC(O)(CH2)q-C(0)0Ri2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S); R2a, R2b, R2c, and R2d are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, or -OH, wherein two of R2a, R2b, R2c, and R2d may be taken together with the carbon atom to which they are attached form a (Cs-Cvlcarbocyclyl or (C3-C7)spirocarbocyclyl; R3 is H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, halogen, or -OH, wherein R3 may be taken together with one of R2a, R2b, R2c, and R2d with the carbon atom to which they are attached to form a (C3-C7)carbocyclyl or (C3-C7)spirocarbocyclyl; Rda, R4b, and R4b' are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)deuteroalkoxy, (C1-C6)haloalkoxy, (C3-C7)carbocyclyl, O(C3-C7)carbocyclyl, 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or - NR9R10; wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, and carbocyclyl is optionally substituted with one or more R4oR4a- are each independently H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, or halogen; R5 and Rs- are each independently H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)deuteroalkoxy, (C1-C6)haloalkoxy, (C3- C7)carbocyclyl, O(C3-C7)carbocyclyl, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or -NR9R10; wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, and carbocyclyl is optionally substituted with one or more R4oR4a' are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, or halogen; R()is H, D, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, (C1-C6) aminoalkyl, (C1-C6)alkyl-0-(Ci- C6)hydroxyalkyl, -C(0)Rn, -CH20C(0)Rn, -CH2OC(O)NHR,2, -CH2OC(O)OR,2, -P(O)(OR,2)2, - CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2; R?a, R?b, R?c, and R?d are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, or (Ci-C2)haloalkyl; or two of R2a, R?b, R?c, and R?d are taken together with the carbon atoms to which they are attached form a (C3-C7)carbocyclyl, (C3-C7)spirocarbocyclyl, or a 4- to 7- membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB', -C(0)Ri3, and -C(O)NRi3'Ri3'; each R2eis independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -0-(Ci-Cb)hydroxy alkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one or more R19, the aryl and heteroaryl are optionally substituted with one or more R21, and the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; or two R2etogether with the carbon atom to which they are attached form a (C3-C7)carbocyclyl, (C3- C7)spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from0, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0Ri3 , -C(0)RB, and -C(O)NRi3'Ri3-; one Rveis taken together with any one of Rva, R?b, R?c, and R?d and the atoms to which they are attached form a (Cs-Cvlcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; Rs is (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxy alkyl, or (C3-C7)carbocyclyl, wherein alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, and carbocyclyl are optionally substituted with one or more substituents independently selected from R21, D, (C1-C6)alkoxy, - SF5, -SRua, -NR14R14', -C(O)NR32R33, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15 and the carbocyclyl and heterocyclyl are optionally substituted with one or more R 15 ; R9 and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, or (Ci- C6)haloalkyl; Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-Cio)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (Cs-Cio)aryl, (C1-C6)alkoxy, ((C1-Cj6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (Ci-Gjalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R12’ is independently at each occurrence H or (C1-C6)alkyl; R13 is independently at each occurrence (C1-C6)alkyl or (C1-C6)haloalkyl; R13’ is independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl; Ru and Ru- are each independently at each occurrence H or (C1-C6)alkyl; Ruais H, (Ci- C6)alkyl or (C1-C6)haloalkyl; R15 and Riv are each independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein alkyl, alkoxy,”" phenyl, heteroaryl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R3s, -C(O)Rs7, - C(O)OR37, -SF5, -SR29, SO2NR30R31, -CN, and R19; or two R15, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Rn; two R 15 , when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Rn; or two Rn- together with the atoms to which they are attached form a (Cs-C-icarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; or two R 15 when on the same carbon atom form C=(0); Rie is H, (C1-C6)alkyl or (C1-C6)haloalkyl; Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN; Rn is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci-Cjhaloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R23 and the aryl and heteroaryl are optionally substituted with one or more R24; or R19 when on the same carbon atom form C=(0); or two R19 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; R20and R20’ are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Crjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 togetherwith the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6lhaloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3- C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl, or (C1-C6)haloalkyl; R30 and R31 are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)carbocyclyl, -C(O)R34, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl or heteroaryl can be substituted with one or more Rp; R32, R33, and R34 are each independently at each occurrence H or (C1-C6)alkyl; R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -C(0)Rs9; R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl; R40 is D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, - 0(C3-C7)carbocyclyl, phenyl; o is 1 or 2; p is 0, 1, 2, 3 or 4; q is 1, 2, or 3; and r is 0 or 1.In one aspect of the disclosure, the hydrogens in the Compound of Formula (I) are present in the normal isotopic abundances. In a preferred aspect of the disclosure, the hydrogens are isotopically enriched in deuterium (D), as discussed in more detail concerning isotopes and isotopic enrichment below.Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is useful in the treatment of HIF-lb-dependent diseases or disorders. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.In another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient for use in the treatment of an HIF-lb-dependent disease or disorder by reducing HIF-lb protein levels wherein reduction of HIF-lb protein levels treats the HIF-lb-dependent disease or disorder. Thepharmaceutical composition is useful in the treatment of HIF-lb-dependent diseases or disorders. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is useful in the treatment of diseases or disorders affected by the reduction of HIF-lb protein levels. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.In another aspect, the present disclosure relates to a method of degrading HIF-lb, comprising administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.Another aspect of the present disclosure relates to a method of modulating HIF-lb levels comprising administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.In another aspect, the present disclosure relates to an in vitro method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.Another aspect of the present disclosure relates to a method of treating a disease or disorder that is affected by the modulation of HIF-lb levels, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from renal cell carcinoma (RCC), von Hippel-Lindau disease (VHL), pulmonary arterial hypertension (PAH), glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease.In another aspect, the present disclosure relates to a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the cancer is VHL-deficient cancer. In another embodiment, the cancer is selected from renalcell carcinoma (RCC), glioblastoma, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or nonHodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), and myeloid leukemia.Another aspect of the present disclosure relates to a method for reducing HIF-lb levels, comprising administering to a subject in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.In another aspect, the present disclosure relates to a method of treating von Hippel-Lindau (VHL) disease, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.Another aspect of the present disclosure relates to a method of treating a neoplastic condition, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.In another aspect, the present disclosure relates to a method of treating renal cell carcinoma (RCC), comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC).The present disclosure provides degraders of HIF-lb that are therapeutic agents in the treatment of diseases such as cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases, in the treatment of diseases affected by the modulation of HIF-lb protein levels, and in the treatment HIF- Ib-dependent diseases or disorders.In one embodiment, the disease or disorder that can be treated by the compounds of the present disclosure is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases, including but not limited to, renal cell carcinoma (RCC), von Hippel-Lindau disease (VHL), pulmonary arterial hypertension (PAH), glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC),microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease.The present disclosure provides agents with novel mechanisms of action toward HIE- lb proteins in the treatment of various types of diseases including cancer von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases, in the treatment of diseases affected by the modulation of HIF- 1b protein levels, and in the treatment HIF-lb-dependent diseases or disorders. Ultimately the present disclosure provides the medical community with a novel pharmacological strategy for the treatment of diseases and disorders associated with HIF-lb proteins.DETAILED DESCRIPTION OF THE DISCLOSUREThe present disclosure relates to compounds and compositions that are capable of modulating HIF- lb protein levels. The disclosure features methods of treating, preventing, or ameliorating a disease or disorder in which HIF-lb plays a role by administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The methods of the present disclosure can be used in the treatment of a variety of HIF-lb-dependent diseases and disorders by modulating HIF-lb protein levels. Modulation of HIF-lb protein levels through degradation provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis, and other HIF- lb-dependent diseases or disorders.In one aspect, the compounds of the disclosure have use as therapeutic agents, particularly for cancers, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases and other HIF-lb-related diseases. In one aspect, the compounds of the disclosure have HIF-lb degradation activity, preferably having such activity at or below the 50 pM level, and more preferably having such activity at or below the 10 pM level. The compounds of the disclosure have usefulness in treating cancer and other diseases for which such degradation activity would be beneficial for the patient. In summary, the present disclosure provides novel HIF-lb degraders useful for the treatment of cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections,parasitic infections, metabolic diseases, allergic and genetic diseases and other disease related to the modulation of HIF-lb-related diseases.In a first aspect of the disclosure, the compounds of Formula (I) are described:pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein Ri, R2a, R2b, R2c, R2d, Re, R?a, R?b, R?c, R7d, R7e, Rs, Xi, X2, X3, X4, X5, X6, X7, o, p, r and subvariables thereof are as defined herein.The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. 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 disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.Definition of Terms and Conventions UsedTerms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification and appended claims, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.A. Chemical Nomenclature, Terms, and ConventionsIn the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, (C1-C10)alkyl means an alkyl group or radical having 1 to 10 carbon atoms. In general, for groups comprising two or more subgroups, the last named group is the radical attachment point, for example, "alkylaryl" means a monovalent radical of the formula alkyl-aryl-, while "arylalkyl" means a monovalent radical of the formula aryl-alkyl-. Furthermore, the use of a term designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the respective divalent radical and vice versa. Unless otherwise specified, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups. Thearticles "a" and "an" refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.The term "and / or" means either "and" or "or" unless indicated otherwise.The term "optionally substituted" means that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g. , heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (Ci- C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-Cg)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. "Optionally substituted" as used herein also refers to substituted or unsubstituted whose meaning is described below.The term "substituted" means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.The term "unsubstituted" means that the specified group bears no substituents.Unless otherwise specifically defined, "aryl" means a cyclic, aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group are optionally joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group is optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -CN, -O-(C1-C6)alkyl, (Cl-CS)alkyl, -O-(C2-C5)alkenyl, -O-(C2- C6)alkynyl, (C2-C5)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(Ci-C5)alkyl, -C(O)(C1-C6)alkyl, - OC(O)O(C1-C6) alkyl, NH2, NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl)2. The substituents are themselves optionally substituted. Furthermore, when containing two fused rings, the aryl groups optionally have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these aryl groups include, butare not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from N, 0, or S, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, 0, or S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno [3 ,2-b] thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1 ,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b ][l,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3- ajpyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[l ,2-a]pyrimidinyl, tetrahydropyrrolo[l ,2-a]pyrimidinyl, 3,4-dihydro-2H- lA2-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3- c]pyridinyl, lH-pyrido[3,4-b][l,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo[l,2,3]triazolyl, imidazo[l,2a]pyrimidinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, benzo[c] [l,2,5]thiadiazolyl, benzo[c] [1,2,5] oxadiazole, l,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H- pyrazolo [1,5-b] [l,2]oxazinyl,4,5,6, 7-tetrahydropyrazolo [l,5-a]pyridinyl, thiazolo[5,4d]thiazolyl, imidazo[2,l-b] [ 1 ,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl."Alkyl" means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1-C6)alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl."Alkoxy" means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal "0" in the chain, e.g., -O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups."Alkenyl" means a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted and may be straight or branched."Alkynyl" means a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted."Alkylene" or "alkylenyl" means a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a (C1-C6)alkylene. An alkylene may further be a (Ci -Chalky lene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH-, and the like."Amino" means a substituent containing at least one nitrogen atom (e.g., NH2)."Cyano" means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C=N"Cycloalkyl" or "carbocyclyl" means a monocyclic or polycyclic saturated or partially unsaturated non-aromatic carbon ring containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof. A (C3-Cs)cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkyl group can be fused (e.g. , decalin) or bridged (e.g., norbornane)."Deuteroalkyl" means an alkyl group substituted with one or more deuterium (“D”). Examples of deuteroalkyl groups include -CDH2, -CD3, -CHD2, -CD2CH3, -CD2CD3, CH2CD3, -CHDCH3, - CD2CH2CD3, etc.“Halogen” or "halo" mean fluorine, chlorine, bromine, or iodine."Haloalkyl" means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc."Haloalkoxy" means an alkoxy group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.“Halohydroxyalkyl” means an alkyl group substituted with at least one halogen and at least one - OH group. Examples of halohydroxyalkyl groups include, but are not limited to, HO-C(H)F-, HO-CH(F)- CH2-, CF3-CH(OH)-CH2-, and CH3-CH(OH)-, etc."Heterocyclyl" or "heterocycloalkyl" means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, or sulfur (0, N, or S) and wherein there is not delocalized n electrons (aromaticity) shared among the ring carbon or heteroatoms. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocycloalkyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1 ,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, dithiolanyl, and homotropanyl."Hydroxyalkyl" means an alkyl group substituted with one or more -OH groups. Examples of hydroxyalkyl groups include H0-CH2-, HO-CH2CH2-, and CH3-CH(0H)-."Spirocarbocyclyl " or "spirocycloalkyl" means carbogenic bicyclic ring systems with both rings connected through a single atom. The rings can be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. A (C3-Ci2)spirocarbocyclyl is a spirocycle containing between 3 and 12 carbon atoms."Spiroheterocyclyl" or "spiroheterocycloalkyl" means a spirocycle wherein at least one of the rings is a heterocycle one or more of the carbon atoms can be substituted with a heteroatom (e.g. , one or more of the carbon atoms can be substituted with a heteroatom in at least one of the rings). One or both of the rings in a spiroheterocyclyl can be fused to another ring, e.g., carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.B. Salt, Prodrug, Derivative, and Solvate Terms and Conventions"Prodrug" or "prodrug derivative" means a covalently-bonded derivative or carrier of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s). In general, such prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to yield the parent compound for example by hydrolysis in blood and generallyinclude esters and amide analogs of the parent compounds. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased aqueous solubility), and / or decreased side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: "Design and Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396; Burger’s Medicinal Chemistry and Drug Discovery, Sth Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, E.B. Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in their entireties."Pharmaceutically acceptable prodrug" as used herein means a prodrug of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible."Salt" means an ionic form of the parent compound or the product of the reaction between the parent compound with a suitable acid or base to make the acid salt or base salt of the parent compound. Salts of the compounds of the present disclosure can be synthesized from the parent compounds which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid parent compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents."Pharmaceutically acceptable salt" means a salt of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. As the compounds of the present disclosure are useful in both free base and salt form, in practice, the use of the salt form amounts to use of the base form. Lists of suitable salts are found in, e.g., S.M. Birge et al., J. Pharm. Sei., 1977, 66, pp. 1-19, which is hereby incorporated by reference in its entirety."Pharmaceutically-acceptable acid addition salt" means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, heptanoic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2- naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3 -phenylpropionic acid, picric acid, pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, and the like."Pharmaceutically-acceptable base addition salt" means those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically-acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine, N,N’ -dibenzylethylenediamine, polyamine resins, and the like. Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine."Solvate" means a complex of variable stoichiometry formed by a solute, for example, a Compound of Formula (I)) and solvent, for example, water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporatedin the crystal lattice of the crystalline solid. In general, such solvents selected for the purpose of the disclosure do not interfere with the biological activity of the solute. Solvates encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like."Hydrate" means a solvate wherein the solvent molecule(s) is / are water.The compounds of the present disclosure as discussed below include the free base or acid thereof, their salts, solvates, and prodrugs and may include oxidized sulfur atoms or quaternized nitrogen atoms in their structure, although not explicitly stated or shown, particularly the pharmaceutically acceptable forms thereof Such forms, particularly the pharmaceutically acceptable forms, are intended to be embraced by the appended claims.C. Isomer Terms and Conventions"Isomers" means compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms in space. The term includes stereoisomers and geometric isomers."Stereoisomer" or "optical isomer" mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well known in the art.“Enantiomers" means a pair of stereoisomers that are non-superimposable mirror images of each other."Diastereoisomers" or "diastereomers" mean optical isomers, which are not mirror images of each other."Racemic mixture" or "racemate" mean a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" means a mixture containing unequal parts of individual enantiomers."Geometrical isomer" means a stable isomer, which results from restricted freedom of rotation about double bonds (e.g., cis-2-butene and trans-2-butene) or in a cyclic structure (e.g., cis- 1,3- dichlorocyclobutane and trans-l,3-dichlorocyclobutane). Because carbon-carbon double (olefinic) bonds, C=N double bonds, cyclic structures, and the like may be present in the compounds of the disclosure, the disclosure contemplates each of the various stable geometric isomers and mixtures thereof resulting from the arrangement of substituents around these double bonds and in these cyclic structures. The substituents and the isomers are designated using the cis / trans convention or using the E or Z system, wherein the term "E" means higher order substituents on opposite sides of the double bond, and the term "Z" means higher order substituents on the same side of the double bond. A thorough discussion of E and Z isomerism is provided in J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons, 1992, which is hereby incorporated by reference in its entirety. Several of the following examples represent single E isomers, single Z isomers, and mixtures of E / Z isomers. Determination of the E and Z isomers can be done by analytical methods such as x-ray crystallography, *H NMR, and13C NMR.Some of the compounds of the disclosure can exist in more than one tautomeric form. As mentioned above, the compounds of the disclosure include all such tautomers.It is well known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the ait will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the disclosure from this disclosure and the knowledge of the prior art.Thus, although the racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the S -isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the drug is less thanthat of the pure S-isomer). Furthermore, the pharmacological activities of enantiomers may have distinct biological activity. For example, S -penicillamine is a therapeutic agent for chronic arthritis, while inactive, R-penicillamine is toxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos. 5,114,946 and 4,818,541.Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way, the patient undergoing treatment would be exposed to a lower total dose of the drug and to a lower dose of an enantiomer that is possibly toxic or an inhibitor of the other enantiomer.Preparation of pure enantiomers or mixtures of desired enantiomeric excess (ee) or enantiomeric purity are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof. These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R.P.W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc., 2000. Furthermore, there are equally well-known methods for the quantitation of enantiomeric excess or purity, for example, GC, HPLC, CE, or NMR, and assignment of absolute configuration and conformation, for example, CD ORD, X-ray crystallography, or NMR.In general, all tautomeric forms and isomeric forms and mixtures, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, of a chemical structure or compound is intended, unless the specific stereochemistry or isomeric form is specifically indicated in the compound name or structure.D. Pharmaceutical Administration and Treatment Terms and ConventionsA "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or nonhuman primate, such as a monkey, chimpanzee, baboon or, rhesus. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.An "effective amount" or "therapeutically effective amount" when used in connection with a compound means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.The terms "pharmaceutically effective amount" or "therapeutically effective amount" means an amount of a compound according to the disclosure which, when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue, system, or patient that is sought by a researcher or clinician. The amount of a compound of according to the disclosure which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the disclosure, and the age, body weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.As used herein, the term "pharmaceutical composition" refers to a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration."Carrier" encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject. A subject is "in need of’ a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably, a human).As used herein, the term "inhibit", "inhibition", or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.As used herein, the term "treat", "treating", or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.As used herein, the term "prevent", "preventing", or "prevention" of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder."Pharmaceutically acceptable" means that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith."Disorder" means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated."Administer", "administering", or "administration" means to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body."Prodrug" means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound. "Compounds of the present disclosure", "compounds of the disclosure", and equivalent expressions (unless specifically identified otherwise) refer to compounds of Formulae (I), (la), (lb), (le), (Id), (le), (If), (1g), (Ih), (li), (Ij), (Ik), (II), (Im), (Io), (Ip) (Iq), (Ir), (lu), (Iv), (Iw), (lx), (ly), (Iz), (laa), (Ibb), (Icc), (Idd), (lee), (Iff), (Igg), (Ihh), (lii), (Ijj), (Ikk), (Imm), (loo), (Ipp), (Iqq), (Irr), (Iss), (Itt), (luu), (Ivv), (Iww), (Ixx), (Iyy), (Izz), (laaa), (Ibbb), (Iccc), (Iddd), (leee), (Ifff), (Iggg), (Ihhh), (liii), (Ijjj), and (Ikkk), as herein described including the tautomers, the prodrugs, salts particularly the pharmaceutically acceptable salts, and the solvates and hydrates thereof, where the context so permits thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labelled compounds (including deuterium substitutions), as well as inherently formed moieties (e.g., polymorphs, solvates and / or hydrates). For the purposes of this disclosure, solvates and hydrates are generally considered compositions. In general and preferably, the compounds of the disclosure and the formula designating the compounds of the disclosure are understood to only include stable compounds thereof and exclude unstable compounds, even if an unstable compound might be considered to be literally embraced by the compound formula. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative, and it is not intended to exclude other instances when the context so permits."Stable compound" or "stable structure" means a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic or diagnostic agent. For example, a compound, which would have a "dangling valency" or is a carbanion is not a compound contemplated by the disclosure.In a specific embodiment, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield."Simultaneously n" or "simultaneous" when referring to a method of treating or a therapeutic use means with a combination of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s) means administration of the compound and the one or more second agent(s) by the same route and at the same time."Separately" or "separate" when referring to a method of treating or a therapeutic use means with a combination of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s) means administration of the compound and the one or more second agent(s) by different routes and at approximately the same time.By therapeutic administration "over a period of time" means, when referring to a method of treating or a therapeutic use with a combination of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s), administration of the compound and the one or more second agent(s) by the same or different routes and at different times. In some embodiments, the administration of the compound or the one or more second agent(s) occurs before the administration of the other begins. In this way, it is possible to administer a one of the active ingredients (i.e., a compound of the Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or one or more second agent(s)) for several months before administering the other active ingredient or ingredients. In this case, no simultaneous administration occurs. Another therapeutic administration over a period of time consists of the administration over time of the two or more active ingredients of the combination using different frequencies of administration for each of the active ingredients, whereby at certain time points in time simultaneous administration of all of the active ingredients takes place whereas at other time points in time only a part of the active ingredients of the combination may be administered (e.g., for example, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and the one or more second agents the therapeutic administration over a period of time could be such that a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is administered once a day and the one or more second agent(s) is administered once every four weeks).The compounds can be administered simultaneously (as a single preparation or separate preparation), sequentially, separately, or over a period of time to the other drug therapy or treatment modality. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy."HIF-lb-dependent disease or disorder" means any disease or disorder which is directly or indirectly affected by the modulation of HIF-lb protein levels.The term “von Hippel-Lindau disease” or “VHL disease” or “VHL syndrome” or “von Hippel- Lindau syndrome”, as used herein, refers to a rare disease caused by a mutation in the von Hippel-Lindau (VHL) tumor suppressor leading to an aberrant non-functional VHL protein and to an absence of VHL protein. VHL gene mutations associated with this condition either prevent the production of any VHL protein or lead to the production of an abnormal version of the protein, with more than 370 inherited mutations in the VHL gene having been identified in people with von Hippel-Lindau disease (http: / / www.umd.be / VHL / ). VHL disease is characterized by the formation of multiple benign and malignant tumors and fluid-filled sacs (cysts) in many different parts of the body, including: retinal hemangioblastoma, CNS hemangioblastoma, clear cell renal cell carcinoma (CCRCC), pheochromocytoma, pancreatic islet tumor, endolymphatic sac tumors and cysts in testes and broad ligament."Colitis" is an inflammation of the colon. The colitis may be acute or chronic. As used herein, colitis includes ulcerative colitis, microscopic colitis, lymphocytic colitis, collagenous colitis, diversion colitis, chemical colitis, ischemic colitis, infections colitis, pancolitis, left-sided colitis, extensive colitis, segmental colitis, microscopic colitis, radiation-induced colitis, medication-induced colitis and proctitis.E. CompoundsThe present disclosure relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of modulating HIF-lb protein levels, which are useful for the treatment of diseases and disorders associated with modulation of HIF-lb protein levels. The disclosure further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for reducing or decreasing HIF-lb protein levels.The present disclosure features compounds of Formula (I):pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein X] is N or ClRsh: X2 is N, N(O), or CR5; X3 is N or CR4a; X4 is N or CR4t>; X5 is N or CR4b-; Xe is N or CR5; X? is N or N(O); wherein no more than three of X2, X3, X4, X5, Xe and X? is simultaneously N; Ri is H, D, -C(O)Rn, -CH20C(0)Rn, - CH2OC(O)NHRi2, -CH2OC(O)ORi2, -P(O)(ORI2)2, -CH2OP(O)(ORi2)2, -CH2OP(O)(OH)ORi2, -CH2OP(O)(R12)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R12-)NHR12 , -CH2OC(O)(CH2)q-C(0)0Ri2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S); R2a, R2b, R2c, and R2d are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, or -OH, wherein two of R2a, R2b, R2c, and R2<I may be taken together with the carbon atom to which they are attached form a (C3-C7)carbocyclyl or (C3-C7)spirocarbocyclyl; R3 is H, D, (Ci-Cb)alkyl, (C1-C6)deuteroalkyl, halogen, or -OH, wherein Runay be taken together with one of R2a, R2b, R2c, and R2<I with the carbon atom to which they are attached to form a (C3-C7)carbocyclyl or (C3-C7)spirocarbocyclyl; Rda, Rdb, and R*' are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (Ci-Cb)deuteroalkoxy, (C1-C6)haloalkoxy, (C3-C7)carbocyclyl, O(C3-C7)carbocyclyl, 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or - NR9R10; wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, and carbocyclyl is optionally substituted with one or more R^Rto- are each independently H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, or halogen; R5 and Rs- are each independently H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)deuteroalkoxy, (C1-C6)haloalkoxy, (C3- C7)carbocyclyl, O(C3-C7)carbocyclyl, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or -NR9R10;, wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, and carbocyclyl is optionally substituted with one or more RdoRra' are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, or halogen; Rg is H, D, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, (C1-C6)aminoalkyl, , (C1-C6)alkyl-0- (C1-C6)hydroxyalkyl, -C(0)Rn, -CH20C(0)RH, -CH2OC(O)NHR,2, -CH2OC(O)ORI2, -P(O)(ORI2)2, - CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2; R?a, R?b, R?c, and R?ci are each independently H, D, (Ci- Cs)alkyl, (C1-C6)deuteroalkyl, or(Ci-C2)haloalkyl; or two of R?a, R?b, R?c, and Rg.i are taken together with the carbon atoms to which they are attached form a (C3-C7)carbocyclyl, (C3-C7)spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB', -C(0)RB, and -C(O)NRi3'Ri3’; each R7e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -0-(Ci-Cb)hydroxyalkyl, (Ce- C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one or more Rig, the aryl and heteroaryl are optionally substituted with one or more R21, and the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; or two R?e together with the carbon atom to which they are attached form a (C3-C7)carbocyclyl, (C3-C7)spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRi3'Ri3’; one R?eis taken together with any one of R7a, R?b, R?c, and Rva and the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; Rs is (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxy alkyl, or (C3-C7)carbocyclyl, wherein alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, and carbocyclyl are optionally substituted with one or more substituents independently selected from R21, D, (C1-C6)alkoxy, -SF5, -SRua, -NRuRir, -C(O)NR32R33, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15 and the carbocyclyl and heterocyclyl are optionally substituted with one or more R15’ ; R9 and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, (Ci-G,)dcutcroalkyl, or (C1-C6)haloalkyl; Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl,-N((C1-C6)alkyl)2, (Ci- C6)alkyl optionally substituted with one or more substituents independently selected from (C6-Cio)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; Rm is independently at each occurrence H or (C1-C6)alkyl; R13 is independently at each occurrence (Ci- C6)alkyl or (C1-C6)haloalkyl; Rm is independently at each occurrence H, (C1-C6)alkyl or (C1-C6) haloalkyl; Ru and Rm are each independently at each occurrence H or (C1-C6)alkyl; Rmais H, (Ci- C6)alkyl or (C1-C6)haloalkyl; R15 and Rm are each independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4heteroatoms selected from 0, N, NH, and S), wherein alkyl, alkoxy,”" phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci-Cgjhydroxyalkyl, halogen, -OH, -NR35R36, - C(O)NR37R38, -C(O)R37, -C(O)OR37, -SFS, -SR29, SO2NR30R31, -CN, and R19; or two Ris, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (O-C-Jcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Rn; two Ri5', when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Rn; or two Ris- together with the atoms to which they are attached form a (C s-C- Jcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Ri? ; or two Ris- when on the same carbon atom form C=(0); Rie is H, (Ci- C6)alkyl or (C1-C6)haloalkyl; Rn is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - OH, -NH2, -SF5, -SR18, or -CN; Ris is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each Rn is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (Cs-Cvjcarbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R23 and the aryl and heteroaryl are optionally substituted with one or more R24; or R19 when on the same carbon atom form C=(0); or two R19 together with the atoms to which they are attached form a (Cs-Cvjcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; R20and R20' are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SFs, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Ris; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy,(C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3- C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; R25, R2e, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl, or (C1-C6)haloalkyl; R30 and R31 are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)carbocyclyl, -C(O)R34, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl or heteroaryl can be substituted with one or more RJ7; R32, R33, and R34 are each independently at each occurrence H or (C1-C6)alkyl; R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -C(0)Rs9; R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl; R40 is D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, - 0(C3-C7)carbocyclyl, phenyl; o is 1 or 2; p is 0, 1, 2, 3 or 4; q is 1, 2, or 3; and r is 0 or 1.In some embodiments, the compound of Formula (I) is a compound of Formula (La):pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Xi is N or CR3; X2 is N or CR4a-; X3 is N or CR4a; X4 is N or CR4t>; X5 is N or CR4b-; Xe is N or CR5; X? is N or CRv; wherein no more than three of X2, X3, X4, X5, Xe and X? is simultaneously N; Ri is H, D, -C(0)Rn, -CH20C(0)Rn, - CH2OC(O)NHRi2, -CH2OC(O)ORi2, -P(O)(ORI2)2, -CH2OP(O)(ORI2)2, -CH2OP(O)(OH)ORi2, -CH2OP(O)(RI2)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(RI2-)NHRI2■, -CH2OC(O)(CH2)q- C(O)ORI2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,N, NH, and S); R2a, RM, R2c, and RM are each independently H or D; Rs is H, D, (C1-C6)alkyl, or (Ci- Cs)deuteroalkyl; Rgaand R» are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NRgRio; R4a' are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, or halogen; R4t>’ is H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NRgRio; Rs is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NRgRio; Rs- is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NRgRio; Re is H, D, -C(0)R„, -CH20C(0)Rn, -CH2OC(O)NHR,2, - CH2OC(O)ORI2, -P(O)(ORI2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2; R7a, R7b, Rvc, and R7dare each independently H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl; each R7eis independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, O-(C1-C6)hydroxy alkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one or more Rig, the aryl and heteroaryl are optionally substituted with one or more R2I , and the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; or two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected fromO, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)Ri3, and -C(O)NRi3’Ri3’; Rs is (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, - NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R 15 and the carbocyclyl and heterocyclyl are optionally substituted with one or more R15S Rg and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, or (C1-C6)deuteroalkyl; Rn is independently at each occurrence H, (C1-C6) alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6) alkoxy, (Ci- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (Ci-Gjhydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R 12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (Ce- Cio)aryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Cio)aryl optionally substituted with one or more substituents independently selected from (Ci-Cgjalkyl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R12' is independently at each occurrence H or (C1-C6)alkyl; RB is independently at each occurrence (C1-C6)alkyl or (Ci- C6)haloalkyl; RB' is independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl; R14 and Ru- are each independently at each occurrence H or (Ci-Cgjalkyl; Rua is H, (C1-C6)alkyl or (Ci-Cft)haloalkyl; RB and RB- are each independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl,(C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -OtGs-Cvjcarbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -O-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from (Ci -C6)alkyl, (C1-C6)haloalkyl, (Ci-Crjalkoxy, (Ci-Qjhaloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)Rs7, -C(O)OR3?, -SF5, -SR29, and -CN; or two RB, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Ri?; two RB’, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Rn; or two RB1together with the atoms to which they are attached form a (Cs-C-lcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; or two RB- when on the same carbon atom form C=(O); Rie is H, (C1-C6)alkyl or (C1-C6)haloalkyl; Rn is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (Ci-G>)haloalkyl, (C1-C6)alkoxy, (G-G>)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN; Rn is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (G-Cdcarbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R23 and the aryl and heteroaryl are optionally substituted with one or more R24; R20and R20' are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, - CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S; or two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected fromO, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3- C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, ICi-Gjhaloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl, or (C1-C6)haloalkyl; R30 and R31 are each independently at each occurrence H, (C1-C6)alkyl, or -C(O)R34; R32, R33, and R34 are each independently at each occurrence H or (Ci -C6)alkyl; R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -C(O)R,u; R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl; o is 1 or 2; p is 0, 1, 2, 3 or 4; and q is 1, 2, or 3.In some embodiments, the compound of Formula (I) is a compound of Formula (I-b):or a pharmaceutically accept-able salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Xi is N or CR3; X2is N or CR5’ ; Ri is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRI2,-CH2OC(O)OR12, -P(O)(OR12)2, -CH2OP(O)(OR12)2, -CH2OP(O)(OH)OR12, -CH2OP(O)(RI2)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R12’)NHR12’, -CH2OC(O)(CH2)qC(O)ORi2’, or-CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S); R2a, R2b, Ric. and R2d are each independently H or D; R3 is H, D, (Ci-C3)alkyl, or (Ci-C3)deuteroalkyl; each R4 is independently at each occurrence D, (Ci-Celalkyl, (Ci- C6)deuteroalkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, (Ci-C6)haloalkoxy, halogen, -OH, or -NR9R10; each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10; Rs- is H, D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10; Re is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR,2, - CH2OC(O)OR,2, -P(O)(OR,2)2, -CH2OP(O)(OH)OR,2, or -CH2OP(O)(R,2)2; R7a, R7b, R7c, and R7dare each independently H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl; each R7eis independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci-Gjhaloalkyl, ((C1-Cj6)alkoxy, (C1-C6lhaloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one or more R 19, the aryl and heteroaryl are optionally substituted with one or more R2I , and the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; or two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci-Cb)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0Ri3', -C(0)RB, and -C(O)NRi3'Ri3’; Rs is (C1-C6)haloalkyl, (Ci-Cjhydroxyalkyl, (C1-C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from D, (C1-C6)alkoxy, -SFs, -SRua,-NRuRu', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15 and the carbocyclyl and heterocyclyl are optionally substituted with one or more Rir; Rg and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, or (C1-C6)deuteroalkyl; Rn is independently at each occurrence H, (C1-C6) alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6) alkoxy, (Ci- Gjhydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (Ci- Gjhydroxyalkyl. (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (Ce- Ciolaryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Ciolaryl optionally substituted with one or more substituents independently selected from (Ci-Cgjalkyl, (Ci- C6)alkoxy, (G-Gjhydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R, 2 is independently at each occurrence H or (C1-C6)alkyl; R13 is independently at each occurrence (C1-C6)alkyl or (Ci- Gjhaloalkyl; Ri v is independently at each occurrence H, (C1-C6)alkyl or (Ci-Cgjhaloalkyl; R14 and Ru- are each independently at each occurrence H or (C1-C6)alkyl; Ri4ais H, (C1-C6)alkyl or (Ci-Cgjhaloalkyl; R15 and Ri5' are each independently at each occurrence D, (C1-C6)alkyl, (G-G>)deuteroalkyl, (C1-C6)haloalkyl, (‘G-Gjalkoxy, (G-Gjhaloalkoxy, (G-Gjhydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, - C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -OIGnGjcaiFocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (G-Gjalkoxy, (C1-C6)haloalkoxy, (Ci- Gjhydroxyalkyl, halogen, -OH, -NR35R36, -GOiNRnRsx, -C(0)Rs7, -C(O)OR37, -SF5, -SR29, and -CN; or two R15, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Rn; two Ri5', when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and SO, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Rn; or two Rn- together withthe atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; or two Ris- when on the same carbon atom form C=(0); Rie is H, (C1-C6)alkyl or (C1-C6)haloalkyl; Rn is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR18, or -CN; Ris is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each R19 is independently at each occurrence (C1-C6) alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R23 and the aryl and heteroaryl are optionally substituted with one or more R24; R20and R20' are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- Cv)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, ((C1-CJ6)alkoxy, (Cj-Gjhaloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl; R30 and R31 are each independently at each occurrence H, (C1-C6)alkyl, or -QOjRu: R32, R33, and R34 are each independently ateach occurrence H or (C1-C6)alkyl; R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -C(0)R3p; R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl; o is 1 or 2; m and n are each independently 0, 1 or 2; p is 0, 1, 2, 3 or 4; and q is 1, 2, or 3.In one embodiment, the compounds of Formula (I) have the structure of Formula (I-c):or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula(I-d), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (I-e):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In yet another embodiment, the compounds of Formula (I) have the structure of Formula (I-f):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (I-g)pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (I-h):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (I-i):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds ofFormula (I) have the structure of Formula (pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (I-k):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formulapharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (I-m):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formulapharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (I-o):or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds ofFormula (I) have the structure of Formulapharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (I-q):or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (I-r):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formulapharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (lu):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formulapharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Iw):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formulapharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the ssttrruuccttuurree of Formula (ly):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Iz):(Iz), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formula (laa)(laa), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ibb):or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds ofFormula (I) have the structure of Formulapharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Idd):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formula (lee):(lee), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Iff):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formulapharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Ihh):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) havethe structure of Formula (lii):(lii), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Ijj):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formulapharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Imm):(Imm), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formula (loo)(loo), or pharmaceutically acceptable salts hydrates solvates prodrugs stereoisomers and tautomers thereofIn another embodiment, the compounds of Formula (I) have the structure of Formula (Ipp):(Ipp), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formulapharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (In):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formulapharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Itt):pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (luu)(luu), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Ivv):(Ivv), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formula (pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Ixx):(Ixx), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formula (pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Izz):(Izz), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formula (laaa)(laaa), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Ibbb):(Ibbb), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formula (Iccc)(Iccc), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Iddd):(Iddd), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formula (leee)(leee), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Ifff):(Ifff), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formula (Iggg):(Iggg),orpharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In yet another embodiment, the compounds of Formula (I) have the structure of Formula (Ihhh):(Ihhh), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formula (liii)(liii), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In another embodiment, the compounds of Formula (I) have the structure of Formula (Ijjj):(Ijjj), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds ofFormula (I) have the structure of Formula (Ikkk):(Ikkk), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.In some embodiments of the formulae above (e.g. , Formula (I), Formula (la), Formula (lb) Formula (le), or Formula (Id) Formula (le), Formula (If), Formula (Ig), Formula (Ih), Formula (li), Formula (Ij), Formula (Ik), Formula (II), Formula (Im), Formula (Io), Formula (Ip), Formula (Iq), Formula (Ir), Formula (lu), Formula (Iv), Formula (Iw), Formula (lx), Formula (ly), Formula (Iz), Formula (laa), Formula (Ibb), Formula (Icc), Formula (Idd), Formula (lee), Formula (Iff), Formula (Igg), Formula (Ihh), Formula (lii), Formula (Ijj), Formula (Ikk), Formula (Imm), Formula (loo), Formula (Ipp), Formula (Iqq), Formula (hr), Formula (Iss), Formula (Itt), Formula (luu), Formula (Ivv), Formula (Iww), Formula (Ixx), Formula (Iyy), Formula (Izz), Formula (laaa), Formula (Ibbb), Formula (Iccc), Formula (Iddd), Formula (leee), Formula(Ifff), Formula (Iggg), Formula (Ihhh), Formula (liii), Formula (Ijjj), and / or Formula (Ikkk)), wherein: Xi is N or CR2;X2is N or CR5-;Ri is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(ORI2)2,-CH2OP(O)(OR12)2, -CH2OP(O)(OH)OR12, -CH2OP(O)(R12)2, -CH2OC(O)CH2NHC(O)CH2NH2,-CH2OC(O)CH(RI2')NHRI2', -CH2OC(O)(CH2)qC(O)ORi2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S);R2a, R2t>, R2C, and R2d are each independently H or D;Ra is H, D, (Ci-Ca)alkyl, or (C1-C6)deuteroalkyl; each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, ((C1-CJ6)alkoxy. (Ci-Gjhaloalkoxy, halogen, -OH, or -NR9R10; each R5 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl,(C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10;Rs- is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10;Re is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRI2, -CH2OC(O)OR12, -P(O)(OR)2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2;R?a, R?b, R?c, and R?d are each independently H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl; each R?eis independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxyalkyl, -CN, -OH, -O-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to four R19, the aryl and heteroaryl are optionally substituted with one to four R2I, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22; or two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (Cj-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0Ri3', -C(0)RB, and -C(O)NRi3'Ri3’;Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6) alkoxy, -SF5, -SRua, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris1;R9 and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, or (C1-C6)deuteroalkyl;Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN;RI2is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to foursubstituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN;R12- is independently at each occurrence H or (C1-C6)alkyl;R13 is independently at each occurrence (C1-C6)alkyl or (C1-C6)haloalkyl;Ro- is independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl;R14 and R M are each independently at each occurrence H or (C1-C6)alkyl;Ri4a is H, (C1-C6)alkyl or (C1-C6)haloalkyl;R15 and Rn- are each independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(0)0R3?, -SF5, -SR29, and -CN; or two R15, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- Cvjcarbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four Rn; two Ris’, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and SO, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Rn; or two Ris- together with the atoms to which they are attached form a (Cs-C-Jcarbocyclyl or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn; or two Ris- when on the same carbon atom form C=(0);Rie is H, (C1-C6)alkyl or (C1-C6)haloalkyl;Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN;Ris is H, (C1-C6)alkyl, or (C1-C6)haloalkyl;each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24; R20and R20' are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Crjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci-Gjalkoxy, (C1-C6)haloalkoxy, (Ci-Gjhydroxyalkyl. halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Czjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (G-Gjalkoxy, (C1-C6)haloalkoxy, (G-Gjhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci-Cjalkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Crjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S;R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl;R30 and R31 are each independently at each occurrence H, (C1-C6)alkyl, or -CiOjRxi;R32, R33, and R34 are each independently at each occurrence H or (C1-C6)alkyl;R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -GOjRsj;R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl;o is 1 or 2; m and n are each independently 0, 1 or 2; p is 0, 1, 2, 3 or 4; and q is 1, 2, or 3.In some embodiments of the formulae above, Xi is N. In another embodiment, Xi is CR3. In yet another embodiment, Xi is CD. In another embodiment, Xi is CH.In some embodiments of the formulae above, X2is N. In another embodiment, X2is CR51.In some embodiments of the formulae above, R, is H, D, -C(0)Rn, -CH20C(0)Ru,CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(ORI2)2, -CH2OP(O)(ORI2)2, -CH2OP(O)(OH)OR12,CH2OP(O)(RI2)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(Ri2-)NHRi2-,CH2OC(O)(CH2)qC(O)ORi2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S). In another embodiment, Ri is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(ORI2)2, -CH2OP(O)(ORI2)2, -CH2OP(O)(OH)OR12, or -CH2OP(O)(RI2)2. In yet another embodiment, Ri is H, D, -CH2OC(O)CH2NHC(O)CH2NH2, - CH2OC(O)CH(Ri2-)NHRi2', -CH2OC(O)(CH2)qC(O)ORi2-, or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S).In some embodiments of the formulae above, Ri is -C(O)Rn, -CH2OC(O)Ru, -CH2OC(O)NHRI2, -CH2OC(O)OR12, -P(O)(OR]2)2, -CH2OP(O)(OR12)2, -CH2OP(O)(OH)OR12, -CH2OP(O)(R,2)2, - CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R12')NHR12', -CH2OC(O)(CH2)qC(O)ORi2', orCH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S). In yet another embodiment, Ri is -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRi2, -CH2OC(O)ORi2, - P(O)(OR|2)2, -CH2OP(O)(OR12)2, -CH2OP(O)(OH)OR12, or -CH2OP(O)(R|2)2, In another embodiment, R, is -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(Ri2)NHRi2-, -CH2OC(O)(CH2)qC(O)ORi2-, or - CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S). In another embodiment, Ri is H or D. In yet another embodiment, Ri is D. In another embodiment, Ri is H.In some embodiments of the formulae above, R2ais H or D. In another embodiment, R2ais D. In yet another embodiment, R2ais H.In some embodiments of the formulae above, R2b is H or D. In another embodiment, R2b is D. In yet another embodiment, R2b is H.In some embodiments of the formulae above, R2cis H or D. In another embodiment, R2cis D. In yet another embodiment, R2cis H.In some embodiments of the formulae above, R2d is H or D. In another embodiment, R2d is D. In yet another embodiment, R2d is H.In some embodiments of the formulae above, R3 is H, D, (C3-C7)alkyl, or (C3-C7)deuteroalkyl. In another embodiment, R3 is D, (C1-C6)alkyl, or (C3-C7)deuteroalkyl. In yet another embodiment, R3 is H, (C3-C7)alkyl, or (C3-C7)deuteroalkyl. In another embodiment, R3 is H, D, or (C3-C7)alkyl. In yet another embodiment, R3 is H, D, or (C3-C7)deuteroalkyl. In another embodiment, R3 is (C3-C7)alkyl or (Ci- C3)deuteroalkyl. In another embodiment, R3 is D or (C3-C7)deuteroalkyl. In another embodiment, R3 is H or (C3-C7)deuteroalkyl. In another embodiment, R3 is D or (C3-C7)alkyl. In another embodiment, R3 is H or (C3-C7)alkyl. In another embodiment, R3 is H or D. In yet another embodiment, R3 is D. In another embodiment, R3 is H.In some embodiments of the formulae above, each R4 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci-Gjhaloalkoxy. halogen, -OH, or - NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6lalkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH. In yet another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, -OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (Ci-Crjdcutcroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, -OH, or - NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6lalkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10.In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (Ci- Cs)deuteroalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (Ci- C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10.In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy. In yet another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, - OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)alkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci-C6)alkoxy, halogen, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, iCi-C,)alkoxy, halogen, or -NR9R10.In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy. In yet another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C3-C7)alkyl, (C3-C7)alkoxy, halogen, or -NR9R10.In another embodiment, each R4 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy. In yet another embodiment, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, - OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)alkoxy, halogen, or -NR9R10. In another embodiment, each R4 is independently at each occurrence (Ci- C3)alkyl, (C3-C7)alkoxy, halogen, or -NR9R10.In some embodiments of the formulae above, each Rs is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6lhaloalkoxy, halogen, -OH, or - NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH. In yet another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, -OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, -OH, or - NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C1-C6lalkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10.In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (Ci- C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or-NR9R10. In yet another embodiment, each Rs is independently at each occurrence (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10.In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy. In yet another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, - OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)alkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)alkoxy, halogen, or -NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C3-C7)alkyl, (C1-C6)deuteroalkyl, (C1-C3) alkoxy, halogen, or -NR9R10.In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy. In yet another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (Ci-Qjalkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10. In another embodiment, each R$ is independently at each occurrence D, (C3-C7)alkyl, (C3-C7)alkoxy, halogen, or -NR9R10.In another embodiment, each R$ is independently at each occurrence (C1-C6)alkyl, (Ci- Cs)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy. In yet another embodiment, each Rs is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, - OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence (C1-C6)alkyl, (Ci- C6)alkoxy, halogen, or -NR9R10. In another embodiment, each Rs is independently at each occurrence (Ci- C3)alkyl, (C3-C7)alkoxy, halogen, or -NR9R10.In some embodiments of the formulae above, Rs- is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, Rs’ is H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, or -OH. In yet another embodiment, Rs- is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, or -NR9R10. In another embodiment, Rs- is H, D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, -OH, or -NR9R10. In yet another embodiment, Rs- is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, -OH, or -NR9R10. In another embodiment, Rs- is H, D, (Ci- C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In yet another embodiment, Rs1is H, D, (Ci-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, Rs- is H, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In yet another embodiment, Rs- is D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, R5' is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, or -NR9R10. In yet another embodiment, Rs- is H, D, (C3-C7)alkyl, (C1-C6)deuteroalkyl, halogen, or -NR9R10. In another embodiment, Rs- is H, D, (Ci-Cft)alkyl, halogen, or -NR9R10. In yet another embodiment, Rs- is H, D, (C3-C7)alkyl, halogen, or -NR9R10. In another embodiment, Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10. In yet another embodiment, Rs- is H, (C3-C7)alkyl, halogen, or -NR9R10.In some embodiments of the formulae above, Re is H, D, -C(O)Rn, -CH2OC(O)Rn, - CH2OC(O)NHR12, -CH2OC(O)OR]2, -P(O)(OR12)2, -CH2OP(O)(OH)OR12, or -CH2OP(O)(RI2)2. In another embodiment, Re is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR,2, -CH2OC(O)OR,2, -P(O)(OR,2)2, or -CH2OP(O)(OH)ORI2. In yet another embodiment, Re is H, D, -C(O)Rn, -CH2OC(O)Rn, - CH2OC(O)NHR,2, -CH2OC(O)ORI2, -P(O)(ORI2)2, or -CH2OP(O)(R,2)2. In another embodiment, Re is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR,2, -CH2OC(O)ORI2, -CH2OP(O)(OH)ORI2, or - CH2OP(O)(RI2)2. In yet another embodiment, Re is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR]2, - P(O)(ORI2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2. In another embodiment, Re is H, D, -C(O)Rn, - CH2OC(O)Rn, -CH2OC(O)ORI2, -P(O)(ORI2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(R12)2. In yet another embodiment, Re is H, D, -C(O)Rn, -CH2OC(O)NHR,2, -CH2OC(O)ORI2, -P(O)(OR,2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2. In another embodiment, Re is H, D, -CH2OC(O)Rn, -CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(ORI2)2, -CH2OP(O)(OH)OR12, or -CH2OP(O)(RI2)2. In yet another embodiment, Re is H, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRI2, -CH2OC(O)ORI2, -P(O)(ORI2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2. In another embodiment, Re is D, -C(O)Rn, -CH2OC(O)R11, -CH2OC(O)NHRI2, -CH2OC(O)ORI2, -P(O)(OR12)2, -CH2OP(O)(OH)OR12, orCH2OP(O)(R,2)2. In yet another embodiment, Re is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRI2, or -CH2OC(O)ORI2. In another embodiment, Re is H, D, -P(O)(ORI2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2. In yet another embodiment, Re is -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRI2, - CH2OC(O)ORI2, -P(O)(ORI2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2. In another embodiment, Re isH or D. In yet another embodiment, Re is D. In another embodiment, Re is H.In some embodiments of the formulae above, R?ais H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Cr C2)haloalkyl. In another embodiment, R2ais H, D, (Ci-C2)alkyl, or (Ci-C2)deuteroalkyl. In yet another embodiment, R2ais H, D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In another embodiment, R2ais H, D, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R2ais H, (Ci-C2)alkyl, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In another embodiment, R2ais D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment R?ais H D or (Ci-C2)alkyl In another embodiment R2ais H, D, or (Ci-C2)deuteroalkyl. In yet another embodiment, R?ais H, D, or (Ci-C2)haloalkyl. In another embodiment, R?ais H, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?ais D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?ais (Ci-C2)alkyl or (Ci-C2)haloalkyl. In another embodiment, R?ais H or D. In yet another embodiment, R?ais D. In another embodiment, R?ais H.In some embodiments of the formulae above, R?b is H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl. In another embodiment, R?b is H, D, (Ci-C2)alkyl, or (Ci-C2)deuteroalkyl. In yet another embodiment, R?b is H, D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In another embodiment, Rvb is H, D, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?b is H, (Ci-C2)alkyl, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In another embodiment, R?b is D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?b is H, D, or (Ci-C2)alkyl. In another embodiment, R?b is H, D, or (Ci-C2)deuteroalkyl. In yet another embodiment, R?b is H, D, or (Ci-C2)haloalkyl. In another embodiment, R?b is H, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?b is D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?b is (Ci-C2)alkyl or (Ci-C2)haloalkyl. In another embodiment, R?b is H or D. In yet another embodiment, R?b is D. In another embodiment, R?b is H.In some embodiments of the formulae above, R?cis H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Cr C2)haloalkyl. In another embodiment, R?Lis H, D, (Ci-C2)alkyl, or (Ci-C2)deuteroalkyl. In yet another embodiment, R?Lis H, D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In another embodiment, R?cis H, D, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?cis H, (Ci-C2)alkyl, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In another embodiment, Rvcis D, (Ci-C2)alkyl, (Cj-Cdidcutcroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?cis H, D, or (Ci-C2)alkyl. In another embodiment, R?cis H, D, or (Ci-C2)deuteroalkyl. In yet another embodiment, Rvcis H, D, or (Ci-C2)haloalkyl. In another embodiment, R?c is H, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?c is D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?c is (Ci-C2)alkyl or (Ci-C2)haloalkyl. In another embodiment, R?c is H or D. In yet another embodiment, R?cis D. In another embodiment, R?cis H.In some embodiments of the formulae above, Rva is H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl. In another embodiment, R?d is H, D, (Ci-C2)alkyl, or (Ci-C2)deuteroalkyl. In yet another embodiment, R?d is H, D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In another embodiment, Rvd is H, D, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?d is H, (Ci-C2)alkyl, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In another embodiment, R?d is D, (Ci-Cdlalkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?<i is H, D, or (Ci-C2)alkyl. In another embodiment, R?d is H, D, or (Ci-C2)deuteroalkyl. In yet another embodiment, R?d is H, D, or (Ci-C2)haloalkyl. In another embodiment, R?<i is H, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?d is D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?d is (Ci-C2)alkyl or (Ci-C2)haloalkyl. In another embodiment, Rv<i is H or D. In yet another embodiment, R?d is D. In another embodiment, R?d is H.In some embodiments of the formulae above, each R?eis independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (Ci- C6)hydroxyalkyl, -CN, -OH, -0-(C1-C6)hydroxy alkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six Rig, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In another embodiment, each R?eis independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or (C3- C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six Rig, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl is optionally substituted with one to four R22.In another embodiment, each R?eis independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(C1-C6)hydroxy alkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one or more Rig, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In another embodiment, each R?eis independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -0-(C1-C6)hydroxy alkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six Rig, the aryl and heteroaryl are optionally substituted with one to six R21, and the heterocyclyl is optionally substituted with one to four R22.In another embodiment, each R?eis independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -0-(C1-C6)hydroxy alkyl, (C6-C10) aryl, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one or more Rig, the aryl is optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In yet another embodiment, each R?eis independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(C1-C6)hydroxy alkyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one to six Rig, the heteroaryl is optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In yet another embodiment, each R?eis independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (Ci- C6)hydroxyalkyl, -CN, -O-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.In another embodiment, each R?eis independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, -0-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In yet another embodiment, each R?eis independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -CN, - OH, -O-(C1-C6)hydroxy alkyl, (Cg-Cio) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, -CN, -OH, -0- (C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl andheteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In yet another embodiment, each R?eis independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -CN, -OH, -O-(C1-C6)hydroxy alkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.In another embodiment, each R?eis independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(Ci- C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In yet another embodiment, each Rveis independently at each occurrence D, (C1-C6)deuteroalkyl, (C1-C6)alkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, - CN, -OH, -0-(C1-C6)hydroxyalkyl, (Cg-Cio) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. wherein the alkyl is optionally substituted with one six R19, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In another embodiment, each R?eis independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.In another embodiment, each R?eis independently at each occurrence D, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxyalkyl, -CN, -OH, -O-(Ci- C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the aryl and heteroaryl are optionally substituted with one to four R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In yet another embodiment, each R?eis independently at each occurrence (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxyalkyl, -CN, -OH, -O-(Ci- C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(C1-C6)hydroxyalkyl, wherein the alkyl is optionally substituted with one to six R19. In another embodiment, each R?eis independently at each occurrence (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.In another embodiment, each Rveis independently at each occurrence D, (C1-C6ialkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to six R21 , and the carbocyclyl is optionally substituted with one to four R22. In yet another embodiment, each R?eis independently at each occurrence (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (Cj-CoJalkoxy, halogen, (C1-C6)hydroxy alkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to six R21 , and the carbocyclyl is optionally substituted with one to four R22.In some embodiments of the formulae above, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB', -C(0)RB, and -C(0)NRB'RB'. In another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRI3'RB'. In yet another embodiment, two R?e, when on the same carbon atom, together with thecarbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spirocarbocyclyl is optionally substituted with one to four substituents independently selected from D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci-Gjhaloalkoxy, (C1-C6)hydroxyalkyl, halogen, -C(0)0RB', -C(0)RB, and -C(0)NRB’RB’. In another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spiroheterocyclyl is optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRB-RB'. In yet another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7) spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.In another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 6-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB'. In yet another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C?) spirocarbocyclyl or a 4- to 6-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB’.In another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- or 5-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB', -C(0)RB, and -C(0)NRB’RB'. In yet another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7) spirocarbocyclyl or a 4- or 5 -membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to foursubstituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB'RB’.In another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRB-RB'. In yet another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C?) spirocarbocyclyl or a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRB-RB’.In another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 5- or 6-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB'. In yet another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7) spirocarbocyclyl or a 5- or 6-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB’.In another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 6- or 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB', -C(0)RB, and -C(0)NRB'RB'. In yet another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7) spirocarbocyclyl or a 6- or 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to foursubstituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB'RB’.In another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB RB'. In yet another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7) spirocarbocyclyl, wherein the spirocarbocyclyl is substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(O)ORB-, -C(O)RB, and -C(O)NRB'RB-. In another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl. In yet another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C?)spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one to four halogen.In another embodiment, two R76, when on the same carbon atom, together with the carbon atom to which they are attached form a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spiroheterocyclyl is optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(O)ORB’, -C(O)RB, and -C(O)NRB’RB’- In yet another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spiroheterocyclyl is substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(O)NRi3'Ri3’. In another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a 5- to 7- membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spiroheterocyclyl is optionally substituted with one to four halogen.In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (Ci-Gjalkoxy, -SF5, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl areoptionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15'. In another embodiment, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, -NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four RD-.In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxyalkyl, or (C1-C6)alkyl substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Riy. In yet another embodiment, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or (Cr C6)halohydroxy alkyl. In another embodiment, Rg is (C1-C6)haloalkyl or (C1-C6)hydroxy alkyl. In yet another embodiment, Rg is (C1-C6)haloalkyl or (C1-C6)halohydroxyalkyl. In another embodiment, Rg is (Ci- C6)hydroxy alkyl or (C1-C6)halohydroxy alkyl.In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRi4a, - NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15’. In yet another embodiment, Rg is iC 1 -C(,) hydroxy alky I or (C1-C6) alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ru-.In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C1-C6)alkoxy, -SF5, -SRua, -NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclylcomprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15'. In another embodiment, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, -SF5, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvKarbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R 15 . In yet another embodiment, Rg is (C1-C6)haloalkyl, (Ci-Gjhydroxyalkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ri v.In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15-. In yet another embodiment, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ru-.In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, -NRuRu-, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl is optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one tofour Ris'. In yet another embodiment, Rg is (Ci-Cjhaloalkyl, (C1-C6)hydroxyalkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRi4a, -NR14R14', phenyl, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the heteroaryl is optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R 15 .In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (Ci-G,)alkoxy, -SF5, -SRi4a, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the heterocyclyl is optionally substituted with one to four Ris-. In yet another embodiment, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, - SRi4a, -NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, and (C3-C7)carbocyclyl, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl is optionally substituted with one to four R15'.In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15’. In yet another embodiment, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxyalkyl, or (C1-C6)alkyl substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ru-.In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)halohydroxyalkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R 15 and the carbocyclyl andheterocyclyl are optionally substituted with one to four Ris-. In yet another embodiment, Rg is (Ci-C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7Karbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Ris and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris-.In some embodiments of the formulae above, Rg is (C1-C6lhaloalkyl or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvKarbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Ris and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris-. In yet another embodiment, Rg is (C1-C6)hydroxy alkyl or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Ris and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris-. In another embodiment, Rg is (C1-C6)halohydroxy alkyl or (Ci- Coialkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, and 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Ris and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris1.In some embodiments of the formulae above, Rg is independently at each occurrence H, D, (Ci- C6)alkyl, or (C1-C6ldeuteroalkyl. In another embodiment, Rg is independently at each occurrence D, (Ci- C6)alkyl, or (C1-C6)deuteroalkyl. In yet another embodiment, Rg is independently at each occurrence H, D, or (C1-C6)deuteroalkyl. In another embodiment, Rg is independently at each occurrence H, D, or (Ci- C6)alkyl. In yet another embodiment, Rg is independently at each occurrence H or D. In another embodiment, Rg is independently at each occurrence D or (C1-C6)alkyl. In yet another embodiment, Rg is independently at each occurrence H or (C3-C7)alkyl. In another embodiment, Rg is independently at each occurrence H or (C1-C6)deuteroalkyl. In yet another embodiment, Rg is independently at each occurrence D or (C1-C6)deuteroalkyl. In another embodiment, Rg is independently at each occurrence (C1-C3) alkyl or (C1-C6)deuteroalkyl. In yet another embodiment, Rg is independently at each occurrence D or (C3-C7)alkyl. In another embodiment, Rg is independently at each occurrence (C1-C6)deuteroalkyl. In yet anotherembodiment, R9 is independently at each occurrence (C1-C6)alkyl. In another embodiment, Rg is independently at each occurrence D. In yet another embodiment, Rg is independently at each occurrence H.In some embodiments of the formulae above, Rio is independently at each occurrence H, D, (Ci- C6)alkyl, or (C1-C6)deuteroalkyl. In another embodiment, Rio is independently at each occurrence D, (Ci- C6)alkyl, or (C1-C6)deuteroalkyl. In yet another embodiment, Rio is independently at each occurrence H, D, or (C1-C6)deuteroalkyl. In another embodiment, Rio is independently at each occurrence H, D, or (Ci- C6)alkyl. In yet another embodiment, Rio is independently at each occurrence H or D. In another embodiment, Rio is independently at each occurrence D or (C1-C6)alkyl. In yet another embodiment, Rio is independently at each occurrence H or (C3-C7)alkyl. In another embodiment, Rio is independently at each occurrence H or (C1-C6)deuteroalkyl. In yet another embodiment, Rio is independently at each occurrence D or (C1-C6)deuteroalkyl. In another embodiment, Rio is independently at each occurrence (C3-C7)alkyl or (C1-C6)deuteroalkyl. In yet another embodiment, Rio is independently at each occurrence D or (C3-C7)alkyl. In another embodiment, Rio is independently at each occurrence (C1-C6)deuteroalkyl. In yet another embodiment, Rio is independently at each occurrence (C1-C6)alkyl. In another embodiment, Rio is independently at each occurrence D. In yet another embodiment, Rio is independently at each occurrence H.In some embodiments of the formulae above, Rn is independently at each occurrence H, (Ci- C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-Cio)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (Ci- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (Ci- C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, or (C6-Cio)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.In another embodiment, Ri 1 is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(Ci- C6)alkyl, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (Ce- Ciolaryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Ciolaryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet anotherembodiment, Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N((C1-C6)alkyl)2, (Ci- C6)alkyl optionally substituted with one to four substituents independently selected from (C6-Cio)aryl, (Ci- C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Cg-Cio)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.In another embodiment, Rn is independently at each occurrence H, (C1-C6)alkoxy, -N(H)(Ci- C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, Rn is independently at each occurrence H, -NH2, -N(H)(C1-C6)alkyl, -N((Ci- C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Ciolaryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.In another embodiment, Rn is independently at each occurrence (C1-C6)alkoxy, -NH2, -N(H)(Ci- C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-Cio)aryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, Rn is independently at each occurrence H, (C1-C6)alkoxy, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (Ci- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (Ci-Gjalkoxy. (Ci- C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.In some embodiments of the formulae above, R12 is independently at each occurrence H, (Ci- C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (Ci- C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Cg-Cio)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, R12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, or (C1-C6)hydroxy alkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, R12 is independently at each occurrence H, (C1-C6)alkyl substituted with one to four substituents independently selected from (Ce-Ciolaryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Ciolaryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.In another embodiment, RB is independently at each occurrence H, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (Ci- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, RB is independently at each occurrence H. In another embodiment, RB is independently at each occurrence (Ci- C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, RB is independently at each occurrence (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.In another embodiment, R12 is independently at each occurrence (C1-C6)alkyl substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, RB is independently at each occurrence (C6-Cio)aryl substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.In some embodiments of the formulae above, RB' is independently at each occurrence H or (Ci- C6)alkyl. In another embodiment, RB’ is independently at each occurrence H or (C3-C7)alkyl. In another embodiment, RB’ is independently at each occurrence (C1-C6)alkyl. In another embodiment, RB’ is independently at each occurrence H.In some embodiments of the formulae above, R B is independently at each occurrence (C1-C6) alkyl or (C1-C6)haloalkyl. In another embodiment, R B is independently at each occurrence (C3-C7)alkyl or (Ci- C3)haloalkyl. In another embodiment, RB is independently at each occurrence (C1-C6)haloalkyl. In another embodiment, RB is independently at each occurrence (C1-C6)alkyl. In another embodiment, RB is independently at each occurrence (C3-C7)haloalkyl. In another embodiment, RB is independently at each occurrence (C3-C7)alkyl.In some embodiments of the formulae above, R B- is independently at each occurrence H, (Ci- C6)alkyl or (C1-C6)haloalkyl. In another embodiment, RB- is independently at each occurrence H, (Ci- C3)alkyl or (C3-C7)haloalkyl. In yet another embodiment, RB- is independently at each occurrence H or (Ci- C6)alkyl. In another embodiment, RB- is independently at each occurrence H or (C1-C6)haloalkyl. In yet another embodiment, RB' is independently at each occurrence (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, RB- is independently at each occurrence (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, RBV is independently at each occurrence (C1-C6)alkyl. In another embodiment, RB- isindependently at each occurrence (C3-C7)alkyl. In another embodiment, Ruv is independently at each occurrence (C1-C6)haloalkyl. In another embodiment, Ru is independently at each occurrence (Ci- C3)haloalkyl. In another embodiment, R u is independently at each occurrence H.In some embodiments of the formulae above, Ru is independently at each occurrence H or (Ci- C6)alkyl. In another embodiment, Ru is independently at each occurrence H or (C3-C7)alkyl. In yet another embodiment, Ru is independently at each occurrence (C1-C6)alkyl. In another embodiment, Ru is independently at each occurrence (C3-C7)alkyl. In another embodiment, Ru is independently at each occurrence H.In some embodiments of the formulae above, Ru- is independently at each occurrence H or (Ci- C6)alkyl. In another embodiment, Ru- is independently at each occurrence H or (C3-C7)alkyl. In yet another embodiment, Ru- is independently at each occurrence (C1-C6)alkyl. In another embodiment, Ru- is independently at each occurrence (C3-C7)alkyl. In another embodiment, Ru- is independently at each occurrence H.In some embodiments of the formulae above, Rua is H, (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, Ruais H, (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, Ruais H or (Cr C6)alkyl. In another embodiment, Ruais H or (C1-C6)haloalkyl. In yet another embodiment, Ruais (Ci- C6)alkyl or (C1-C6)haloalkyl. In another embodiment, Ruais (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, Ruais (C1-C6)alkyl. In another embodiment, Ruais (C3-C7)alkyl. In another embodiment, Ruais (C1-C6)haloalkyl. In another embodiment, Ruais (C3-C7)haloalkyl. In another embodiment, Ruais H.In some embodiments of the formulae above, R 15 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -O-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R3s, -C(O)R37, - C(O)OR37, -SF5, -SR29, and -CN. In another embodiment, R15 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, - SF5, -SR29, and -CN.In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, - C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3- C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), or -0-(4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - OH, -NR35R36, -C(O)NR37R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- Cs)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH,-NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, - 0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN.In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected fromO, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selectedfrom O, N, NH, and S or -O-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN.In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substitutedwith one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6lalkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, -OH, - NR30R31, -SFs, -SR16, -CN, -C(O)NRS2R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl,monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN.In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6lhydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, - C(O)NR3ZR33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)Rs7, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (Ci-Co.idcutcroalkyl. (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6lhydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, - C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R3s, -C(0)Rs7, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, R15 is independently at each occurrence (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selectedfrom O, N, NH, and S or -O-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, or -C(O)OR32- In yet another embodiment, R15 is independently at each ooccccuurrrreennccee (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, or -C(O)OR32.In another embodiment, R15 is independently at each occurrence (C3-C7)carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, - C(O)OR37, -SF5, -SR29, and -CN.In yet another embodiment, R15 is independently at each occurrence (C3-C7)carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)Rs7, -C(O)OR37, - SF5, -SR29, and -CN.In some embodiments of the formulae above, R 15 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (Ci-Cjhaloalkoxy. (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R3s, -C(O)R37, - C(O)OR37, -SF5, -SR29, and -CN. In another embodiment, Ris- is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR37R3s, -C(O)R37, -C(O)OR37, - SF5, -SR29, and -CN.In another embodiment, Riv is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, - C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRis, -CN, -C(O)NR32R33, -C(O)OR32, (C3- C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), or -0-(4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - OH, -NR35R36, -C(O)NR37R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -O-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR37R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, R15’ is independently at each occurrence D, (C1-C6)alkyl, (Ci- Cs)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatomsselected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SFs, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, - □-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Cr C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, R15' is independently at each occurrence D, (C1-C6)alkyl, (Cj-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci-G,)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)Rs7, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected fromO, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substitutedwith one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15' is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, Riv is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR37R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, R15’ is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci-Gjalkoxy. (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, -OH, - NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl,-O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN.In another embodiment, Riv is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR37R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -ClOjNRuRx -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, R15' is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatomsselected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(0)0R3?, -SF5, -SR29, and -CN.In another embodiment, R45’ is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6lhydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, - C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci-G,)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6lhydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRis, -CN, - C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to foursubstituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci-Cjalkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R3s, -C(O)Rs7, -C(O)OR37, -SF5, -SR29, and -CN.In another embodiment, Ris- is independently at each occurrence (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, or -C(O)OR32- In yet another embodiment, Riv is independently at each ooccccuurrrreennccee (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, or -C(O)OR32-In another embodiment, R15- is independently at each occurrence (C3-C7)carbocyclyl, -O(Cs- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, - C(O)OR37, -SF5, -SR29, and -CN.In yet another embodiment, Ris- is independently at each occurrence (C3-C7)carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy,(C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -ClOjNRnR^, -C(0)Rs7, -C(O)OR37, - SF5, -SR29, and -CN.In some embodiments of the formulae above, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four R17. In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C -Cv.icarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four Rn. In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or (Cs-Cvjcarbocyclyl, wherein the phenyl, heteroaryl, and carbocyclyl are optionally substituted with one to four Rn.In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, and heterocyclyl are optionally substituted with one to four Rn. In yet another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, (C3-C7jcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, carbocyclyl, and heterocyclyl are optionally substituted with one to four Rn- In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Ca-Cvjcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four Rn.In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Rn- In yet another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected fromO, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn. In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or (C3-C7)carbocyclyl, wherein the phenyl and carbocyclyl are optionally substitutedwith one to four Rn. In yet another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl and heterocyclyl are optionally substituted with one to four R n.In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, wherein the phenyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl is optionally substituted with one to four Rn. In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a (C3-C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn.In some embodiments of the formulae above, two Rn-, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Rn- In another embodiment, two R15’ , when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are substituted with one to four Rn- In yet another embodiment, two Rn-, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl is optionally substituted with one to four Rn and the heteroaryl is substituted with one to four Rn- In another embodiment, two R iv. when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl is substituted with one to four Rn and the heteroaryl is optionally substituted with one to four Rn.In another embodiment, two Rn-, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, wherein the phenyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn-, when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl is optionally substituted with one to four R17. In another embodiment, two Rn-, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, wherein the phenyl is substituted with one to four Rn. In yet another embodiment, two Ris- , when on adjacent atoms, together with the atomsto which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl is substituted with one to four Rn.In some embodiments of the formulae above, two R15' together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn. In yet another embodiment, two Riv together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn. In another embodiment, two Rm together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is to optionally substituted with one to four Rn. In yet another embodiment, two Rm together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is to optionally substituted with one to four Rn- In another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn- In yet another embodiment, two Ris- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn.In another embodiment, two R15’ together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 4- or 5-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R17. In yet another embodiment, two R15’ together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R17. In another embodiment, two R15- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 6- or 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn. In another embodiment, two Rm together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- or 5-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn. In another embodiment, two Rm together with the atoms to which theyare attached form a (Cs-Cvjcarbocyclyl or 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Riv. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn.In another embodiment, two R 15 together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 4- or 5-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn. In another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn-In another embodiment, two R15' together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 4- or 5-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four R17. In yet another embodiment, two Ris- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn. In another embodiment, two R15’ together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four R17.In another embodiment, two Riv together with the atoms to which they are attached form a (C3- C6)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn- In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C5)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn- In another embodiment, two R iv together with the atoms to which they are attached form a (C3-C4)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to whichthey are attached form a (C4-C7)carbocyclyl or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn-In another embodiment, two Rn- together with the atoms to which they are attached form a (C5- C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn- In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C6-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn. In another embodiment, two R iv together with the atoms to which they are attached form a (C5-C6)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn.In another embodiment, two Rn together with the atoms to which they are attached form a (C3- C6)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two R15' together with the atoms to which they are attached form a (Ca-Cslcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn- In another embodiment, two Ris- together with the atoms to which they are attached form a (C3-C4)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two R n together with the atoms to which they are attached form a (C4-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn.In another embodiment, two Ris- together with the atoms to which they are attached form a (C5- C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (Ce-Cvlcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn. In another embodiment, two Rn- together with the atoms to which they are attached form a (C5-C6)carbocyclyl or 4- to 7-membered heterocyclylcomprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn-In another embodiment, two R 15 together with the atoms to which they are attached form a (C3- C6)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (Cs-Cslcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn. In another embodiment, two Rn- together with the atoms to which they are attached form a (Cs-C^carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C4-Cv)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn-In another embodiment, two R15' together with the atoms to which they are attached form a (C5- C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four R17. In yet another embodiment, two Ris- together with the atoms to which they are attached form a (C6-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn- In another embodiment, two R15’ together with the atoms to which they are attached form a (G-Gjcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn-In another embodiment, two Riv together with the atoms to which they are attached form a (C3- C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C7)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn- In another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn.In another embodiment, two Rn together with the atoms to which they are attached form a (C3- C5)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn. In yet anotherembodiment, two Ris- together with the atoms to which they are attached form a (C3-Cs)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn- In another embodiment, two R iv together with the atoms to which they are attached form a (C3-C4)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four R 17. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C4)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn.In another embodiment, two R 15 together with the atoms to which they are attached form a (C4- C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C4-C7)carbocyclyl, wherein the carbocyclyl is substituted with one to four R17. In another embodiment, two Rn- together with the atoms to which they are attached form a (C5-C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C5-C7)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn.In another embodiment, two Rn together with the atoms to which they are attached form a (Ce- C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C6-C7)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn- In another embodiment, two R15' together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two R15' together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn- In another embodiment, two R 15' together with the atoms to which they are attached form a (C4-C6)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two R15’ together with the atoms to which they are attached form a ('Cn-Cjcarbocyclyl. wherein the carbocyclyl is substituted with one to four Rn-In another embodiment, two Ris- together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Rm together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn- In another embodiment, two R i v together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two Rn- together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn.In another embodiment, two Ris- together with the atoms to which they are attached form a 6- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two Rn- together with the atoms to which they are attached form a 6- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn- In another embodiment, two Ris- together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Ris- together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn.In another embodiment, two Rn- together with the atoms to which they are attached form a 4- to 5- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Ri, together with the atoms to which they are attached form a 4- to 5 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn- In another embodiment, two Ri v together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two Ris- together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn.In some embodiments of the formulae above, two Ris’ when on the same carbon atom form C=(0);In some embodiments of the formulae above, Ris is independently at each occurrence H, (Ci- Cs)alkyl or (C1-C6)haloalkyl. In another embodiment, Ris is independently at each occurrence H, (Ci- C3)alkyl or (C3-C7)haloalkyl. In yet another embodiment, Ris is independently at each occurrence H or (Ci- Cs)alkyl. In another embodiment, Ris is independently at each occurrence H or (C1-C6)haloalkyl. In yet another embodiment, Ris is independently at each occurrence (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, Ris is independently at each occurrence (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, Ris is independently at each occurrence (C1-C6)alkyl. In another embodiment, Ris is independently at each occurrence (C3-C7)alkyl. In another embodiment, Ris is independently at each occurrence (C1-C6)haloalkyl. In another embodiment, Ris is independently at each occurrence (Ci- C3)haloalkyl. In another embodiment, Ris is independently at each occurrence H.In some embodiments of the formulae above, Rn is independently at each occurrence D, (Ci- Cs)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN. In another embodiment, Rn is independently at each occurrenceD, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, or -SRis. In yet another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, or -CN. In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SRis, or -CN. In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -NH2, -SF5, -SRis, or -CN. In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, -OH, -NH2, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NH2, -SF5, -SRis, or -CN.In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NHj, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence D, (C1-C6ialkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, - SRis, or -CN. In another embodiment, R17 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN. In another embodiment, Rn is independently at each occurrence D, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SRis, or -CN.In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, or halogen. In yet another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN. In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, or -CN. Inanother embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)hydroxyalkyl, halogen, or -CN. In yet another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, or -CN.In another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, or halogen. In yet another embodiment, Rn is independently at each occurrence halogen, -OH, -NH2, -SF5, -SRn, or -CN. In another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, halogen, -OH, - NH2, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, -SF5, -SRn, or -CN. In another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, or -CN. In yet another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)hydroxyalkyl, halogen, or -CN. In another embodiment, Rn is independently at each occurrence (Ci- C6)alkyl, (C1-C6)haloalkyl, halogen, or -CN.In some embodiments of the formulae above, Rn is H, (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, Rn is H, (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, Rn is H or (Ci- C6)alkyl. In another embodiment, Ris is H or (C1-C6)haloalkyl. In yet another embodiment, Ris is (Ci- C6)alkyl or (C1-C6)haloalkyl. In another embodiment, Ris is (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, Ris is (C1-C6)alkyl. In another embodiment, Rn is (C3-C7)alkyl. In another embodiment, Rn is (C1-C6)haloalkyl. In another embodiment, Rn is (C3-C7)haloalkyl. In another embodiment, Rn is H.In some embodiments of the formulae above, each Rig is independently at each occurrence (Ci- Cs)alkoxy, (C1-C6)haloalkoxy, -NR20R20’, -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In another embodiment, each R19 is independently at each occurrence (C1-C6) alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S,wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are substituted with one to four R24.In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20’, -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or (C6-C10) aryl, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl is optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, - NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the heteroaryl is optionally substituted with one to four R24.In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20’, -CN, (C3-C7)carbocyclyl, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein carbocyclyl is optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20', -CN, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In another embodiment, each Rig is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20’, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl andheterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.In another embodiment, each Rig is independently at each occurrence (C1-C6)haloalkoxy, - NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20', or -CN. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -NR20R20'.In another embodiment, each R19 is independently at each occurrence (C3-C7)carbocyclyl, 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10), wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23.In another embodiment, each R19 is independently at each occurrence ((C1-CJ6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20’, -CN, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20’, -CN, (C3-C7)carbocyclyl, or (C6-C10) aryl, wherein the carbocyclyl is optionally substituted with one to four R23 and the aryl is optionally substituted with one to four R24. In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20', -CN, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four R23 and the heteroaryl is optionally substituted with one to four R24.In another embodiment, each Rig is independently at each occurrence (C1-C6)alkoxy, -NR20R20', - CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, or (C6-C10) aryl, wherein the carbocyclyl is substituted with one to four R23 and the aryl is optionally substituted with one to four R24.In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20’, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', (C3-C7)carbocyclyl, or (C6-C10) aryl, wherein the carbocyclyl is optionally substituted with one to four R23 and the aryl is optionally substituted with one to four R24. In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, - NR20R20', 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four R23 and the heteroaryl is optionally substituted with one to four R24.In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, -NR20R20', (C3-C7)carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6ialkoxy, -NR20R20’, (C3-C7)carbocyclyl, or (C6-C10) aryl, wherein the carbocyclyl is substituted with one to four R23 and the aryl is optionally substituted with one to four R24.In some embodiments of the formulae above, R20is independently at each occurrence H or (Ci- C6)alkyl. In another embodiment, R20is independently at each occurrence H or (C3-C7)alkyl. In yet another embodiment, R20is independently at each occurrence (C1-C6)alkyl. In another embodiment, R20is independently at each occurrence (C3-C7)alkyl. In yet another embodiment, R20is independently at each occurrence H.In some embodiments of the formulae above, R20' is independently at each occurrence H or (Ci- C6alkyl. In another embodiment, R2o- is independently at each occurrence H or (C3-C7)alkyl. In yet another embodiment, R20' is independently at each occurrence (C1-C6)alkyl. In another embodiment, R20' is independently at each occurrence (C3-C7)alkyl. In yet another embodiment, R20' is independently at each occurrence H.In some embodiments of the formulae above, each R21 is independently at each occurrence (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2,-SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or (C3-C7)carbocyclyl. In yet another embodiment, each R21 is independently at each occurrence (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, - CN, phenyl, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R21 is independently at each occurrence (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci-Cojhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -SF5, -SR25, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R21 is independently at each occurrence (C1-C6lalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR25, or -CN. In yet another embodiment, each R21 is independently at each occurrence halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-me...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I’):pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:Xi is N or CR3;X2is N, N(0), or CR5;X7is N and N(0);Ri is H, D, -C(0)Rn, -CH20C(0)RH, -CH2OC(O)NHRI2, -CH2OC(O)OR12, -P(O)(ORI2)2, - CH2OP(O)(OR12)2, -CH2OP(O)(OH)OR12, -CH2OP(O)(R12)2, -CH2OC(O)CH2NHC(O)CH2NH2, - CH2OC(O)CH(RI2')NHRI2', -CH2OC(O)(CH2)q-C(O)ORi2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S);R2a, RM, RM, and RM are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, or -OH, wherein two of R2a, RM, RM, and RM may be taken together with the carbon atom to which they are attached form a (Cs-C7)carbocyclyl or (Cs-C7)spirocarbocyclyl optionally substituted with one or more R40;Rs is H, D, (C1-C6)alkyl, (Ci-Cb)deuteroalkyl, or halogen, wherein Rs may be taken together with one of Rsa, RM, RM, and RM with the carbon atom to which they are attached to form a (Cs-CsXarbocyclyl or (Cs-C7)spirocarbocyclyl optionally substituted with one or more R40;R4s D (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (Ci- C6)deuteroalkoxy, (C1-C6)haloalkoxy, (C3-C7)carbocyclyl, -O(Cs-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or -NR9R10; wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more R40;R5is D, (C,-C6)alkyl, (C1-C6)deuteroalkyl, (C,-C6)haloalkyl, (C,-C6)alkoxy, (C,- C6)deuteroalkoxy, (C1-C6)haloalkoxy, (Cs-C7)carbocyclyl, O(Cs-C7)carbocyclyl, (Cs-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or-NR9R10, wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more R40;Re is H, D, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxy alkyl, (C1-C6)aminoalkyl, (C1-C6)alkyl-O- (C1-C6)hydroxyalkyl, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(OR12)2, - CH2OP(O)(OH)OR12, or -CH2OP(O)(Ri2)2;R?a, R?b, R?c, and R?d are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, or (Ci-C2)haloalkyl; or two of R?a, R?b, R?c, and R?d are taken together with the carbon atoms to which they are attached form (C3-C7)carbocyclyl, (C3-C7)spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(O)ORB', -C(0)Ri3, and -C(O)NRi3'Ri3-; each R7eis independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxyalkyl, -CN, -OH, -O-(Ci- C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one or more R19, the aryl and heteroaryl are optionally substituted with one or more R2I , and the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; or two R?etogether with the carbon atom to which they are attached form a (C3-C7)carbocyclyl, (C3- C7)spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (Ci-Cb)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0Ri3-, -C(0)Ri3, and -C(O)NRi3’Ri3’; one R?eis taken together with any one of R?a, R?b, R?c, and R?d and the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R22;Rs is (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxy alkyl, or (C3- C7)carbocyclyl, wherein alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, and carbocyclyl are optionally substituted with one or more substituents independently selected from R21, D, (C1-C6)alkoxy, -SF5, -SRua, -NR14R14', -C(O)NR32R33, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selectedfrom O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15 and the carbocyclyl and heterocyclyl are optionally substituted with one or more R 15' ;R9 and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, or (C1-C6)haloalkyl;Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((Ci-Cft)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10jaryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (Ci-Gjhydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN;R12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci-Gjhaloalkyl, halogen, -OH, -NH2, and -CN;R12' is independently at each occurrence H or (C1-C6)alkyl; R13 is independently at each occurrence (C,-C6)alkyl or (C1-C6)haloalkyl;R13' is independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl;R14 and G are each independently at each occurrence H or (C1-C6)alkyl;Ri4a is H, (C1-C6)alkyl or (Ci-Gjhaloalkyl;R15 and R15’ are each independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (G-Gjalkoxy, (Ci-Gjhaloalkoxy. (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -O-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, hydroalkyl, phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - OH, -NR35R36, -C(O)NR37R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, SO2NR30R31, -CN, and Rig; or two R15, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH,and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Rn; two R15-, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Rn; or two Rn- together with the atoms to which they are attached form a (CnC-Jcarbocyclyl or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; or two Rn- when on the same carbon atom form C=(0);Rie is H, (C1-C6)alkyl or (C1-C6)haloalkyl;Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN;Ris is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (Ca-Cvjcarbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cg-Cio) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R23 and the aryl and heteroaryl are optionally substituted with one or more R24; or two R19 when on the same carbon atom form C=(0); or two R19 together with the atoms to which they are attached form a (C3-C7jcarbocyclyl or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; R20and R20’ are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7jcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15 ; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7jcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; ortwo R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S;R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl, or (Ci- C6)haloalkyl; R30 and Rsi are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3- C?)carbocyclyl, -C(O)R34, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl or heteroaryl can be substituted with one or more R17;R32, R33, and R34 are each independently at each occurrence H or (C1-C6) alkyl;R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -C(O)R39;R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl;R40 is D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SRis, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl; m and n are each independently 0, 1 or 2; o is 0, 1 or 2; p is 0, 1, 2, 3 or 4; q is 1, 2, or 3; and r is 0 or 1.

2. The compound according to claim 1, wherein Ri is H.

3. The compound according to claim 1 , wherein R2a is H.

4. The compound according to claim 1 , wherein R2bis H.

5. The compound according to claim 1 , wherein R2Cis H.

6. The compound according to claim 1 , wherein R2d is H.

7. The compound according to claim 1, wherein one to four members of R2a, R2b, R2c, and R2d is CH3.

8. The compound according to claim 1, wherein Xi is CR3.

9. The compound according to claim 1, wherein Xi is N.

10. The compound according to claim 1 , wherein X2 is N.

11. The compound according to claim 1 , wherein X2 is CR5.

12. The compound according to claim 1 , wherein R3 is H.

13. The compound according to claim 1 , wherein R3 is D.

14. The compound according to claim 1 , wherein R3 is CH3.

15. The compound according to claim 1, wherein R4 is independently in each instance (C1-C6)alkyl, (C1-C6)haloalkyl, -OH, -O-(C1-C6)alkyl, -NR9R10, or halogen.

16. The compound according to claim 1, wherein R4 is independently in each instance -CH3, -C2H5, - CF3, -OH, -OCH3, -NH2, -NHCH3, or -Cl.

17. The compound according to claim 1, wherein R5 is independently in each instance (C1-C6)alkyl or halogen.

18. The compound according to claim 1, wherein R5 is independently in each instance -CH3, -F.

19. The compound according to claim 1, wherein R5 is independently in each instance (C1-C6)alkyl, (C3-C7)carbocyclyl, -OH, -O-(C1-C6)alkyl, -NR9R10, or halogen.

20. The compound according to claim 1, wherein R5 is independently in each instance -CH3, cyclopropyl, -OH, -OCH3, -NH2, -F, -Cl.

21. The compound according to claim 1, wherein n is 0.

22. The compound according to claim 1, wherein n is 1.

23. The compound according to claim 1, wherein m is 0.

24. The compound according to claim 1, wherein m is 1.

25. The compound according to claim 1, wherein m is 2.

26. The compound according to claim 1 wherein R is H27. The compound according to claim 1, wherein R?ais H, or (C1-C6)alkyl.

28. The compound according to claim 1 , wherein R?ais -H, -CH3, or -CH(CH3h.

29. The compound according to claim 1 , wherein R?b is H.

30. The compound according to claim 1 , wherein R?cis H.

31. The compound according to claim 1 , wherein R?d is H.

32. The compound according to claim 1, wherein each R?eis independently at each occurrence (Ci- Cs)alkyl, (C1-C6)deuteroalkyl, halogen, -OH, -O-(C1-C6)alkyl, (C3-C7)carbocyclyl, or phenyl wherein the alkyl is optionally substituted with one to six R19 and the carbocyclyl is optionally substituted with one to five R22 and the phenyl is optionally substituted with one to five R22; or two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or 4- to 7- membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB’.

33. The compound according to claim 1, wherein each R?eis independently at each occurrencetwo R?e, when on the same carbon atom, together with the carbon atom to which they are attached, form, whereinR in each instance is independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB , -C(0)RB, and -C(0)NRB’RI3S andR21, R22, and R24 are defined as in claim 1.

34. The compound according to claim 1, wherein each R?eis independently at each occurrence / ,_ Dtwo R?e, when on the same carbon atom, together with the carbon atom to which they are attached,35. The compound according to claim 1 , wherein o is 2.

36. The compound according to claim 1 , wherein o is 1.

37. The compound according to claim 1 , wherein p is 0.

38. The compound according to claim 1 , wherein p is 1.

39. The compound according to claim 1 , wherein p is 2.

40. The compound according to claim 1 , wherein p is 4.

41. The compound according to claim 1, having a Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (If), Formula (Ig), Formula (Ih), Formula (li), Formula (Ij), Formula (Ik), or Formula (II):or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

42. The compound according to claim 1, having a Formula (Im), Formula (Io), Formula (Ip), Formula (Iq), Formula (Ir), Formula (lu), Formula (Iv), Formula (Iw), Formula (lx), Formula (ly), Formula (Iz), Formula (laa), Formula (Ibb), or Formula (Icc):

43. The compound according to claim 1, wherein Rs is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)alkyl optionally substituted with one to three substituents independently selected from D, (C1-C6)alkoxy, -SRi4a, -NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl optionally substituted with one to three R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to three R15'.

44. The compound according to claim 1 , wherein Rs is selected from:each of X t, and X si-> is independently selected from 0, S, NH, and NR15;X4is 0, S, NH, and NRLV;R is selected from (Ci-C5)alkyl and (C3-C7)cycloalkyl, and is optionally substituted with one or more of D, hydroxy, halogen, alkoxy, imidazol-2-yl, and -ClOjNR^R^; andR15, Ri5', R32, and R33 are as defined in claim 1.

45. The compound according to claim 1 , wherein Rg is selected from:0NI H2N0N UXA46. The compound according to claim 1, wherein each R19 is independently at each occurrence (Ci- C6)alkoxy, -NR20R20', or (C3-C7)carbocyclyl wherein carbocyclyl is optionally substituted with two to four R23.

47. The compound according to claim 1, wherein the compound is selected from any compound provided in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

48. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

49. The pharmaceutical composition according to claim 48, further comprising at least one additional pharmaceutical agent.

50. The pharmaceutical composition according to claim 48 for use in the treatment of a disease or disorder that is affected by the reduction of HIF-1 P levels.

51. A method of degrading HIF-ip, comprising administering to a patient in need thereof an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

52. A method of modulating HIF- 1 [3 levels comprising administering to a patient in need thereof an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

53. An in vitro method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

54. A method of treating a disease or disorder that is affected by the modulation of HIF-ip levels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

55. The method according to claim 54, wherein the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary diseases, autoimmune and inflammatory -related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, neovascular diseases, retinal vascular diseases, fibrosis, endometriosis, preeclampsia, and allergic and genetic diseases.

56. The method according to claim 54, wherein the disease or disorder is selected from renal cell carcinoma (RCC), von Hippel-Lindau disease (VHL), advanced pheochromocytoma / paraganglioma (PPGL), pancreatic neuroendocrine tumor (pNET), pulmonary arterial hypertension (PAH), glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’ s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer(TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease.

57. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

58. The method according to claim 57, wherein the cancer is VHL-deficient cancer.

59. The method according to claim 57, wherein the cancer is selected from renal cell carcinoma (RCC), glioblastoma, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), and myeloid leukemia.

60. A method for reducing HIF-ip levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

61. A method of treating von Hippel-Lindau (VHL) disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

62. A method of treating a neoplastic condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

63. A method of treating renal cell carcinoma (RCC), comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

64. The method of claim 63, wherein the renal cell carcinoma is clear cell renal cell carcinoma(ccRCC).

65. The method according to claim 54, wherein the administration is oral, parenteral, subcutaneous, by injection, or by infusion.

66. A compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the reduction of HIF- I |3 levels.

67. A compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder associated with the reduction of HIF-1 P levels.

68. Use of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of HIF-1 P levels.

69. Use of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with the reduction of HIF- 1 P levels.

70. The compound for use according to claim 68 or 69 or the use according to claim 52 or 53, wherein the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases.

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