1. A method for treating, preventing, or ameliorating one or more symptoms of an endoplasmic reticulum stress-caused disease in a subject, comprising administering to the subject a compound of Formula I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

i. R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10

cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a,

-S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly

attached form heteroaryl or heterocyclyl;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a,

-OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C₃_i₀ cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

2. The method of claim 1, wherein the endoplasmic reticulum stress-caused disease is a cardiovascular disease, cancer, diabetes, an inflammatory disease, a metabolic disease, or a neurological disease.

3. The method of claim 1, wherein the endoplasmic reticulum stress-caused disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, muscular dystrophy, polyglutamine disease, prion disease, stroke, bipolar disorder, heart disease, atherosclerosis, cancer, diabetes, obesity, muscle degeneration, an inflammatory disease, an ischemic disease, or an autoimmune disease.

4. The method of claim 1, wherein the endoplasmic reticulum stress-caused disease is diabetes.

5. The method of claim 1, wherein the endoplasmic reticulum stress-caused disease is Alzheimer's disease.

6. The method of claim 1, wherein the endoplasmic reticulum stress-caused disease is cancer.

7. A method for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a sarcoplasmic/endoplasmic reticulum calcium ATP- ase in a subject, comprising administering to the subject a compound of Formula I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

1. R is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10

cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c,

-NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly attached form heteroaryl or heterocyclyl;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d, -NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C_3-10 cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

8. The method of claim 7, wherein the disorder, disease, or condition mediated by a sarcoplasmic/endoplasmic reticulum calcium ATP-ase is a cardiovascular disease, cancer, diabetes, an inflammatory disease, a metabolic disease, or a neurological disease.

9. The method of claim 7, wherein the disorder, disease, or condition mediated by a sarcoplasmic/endoplasmic reticulum calcium ATP-ase is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, muscular dystrophy, polyglutamine disease, prion disease, stroke, bipolar disorder, heart disease, atherosclerosis, cancer, diabetes, obesity, muscle degeneration, an inflammatory disease, an ischemic disease, or an autoimmune disease.

10. The method of claim 7, wherein the disorder, disease, or condition mediated by a sarcoplasmic/endoplasmic reticulum calcium ATP-ase is diabetes.

11. The method of claim 7, wherein the disorder, disease, or condition mediated by a sarcoplasmic/endoplasmic reticulum calcium ATP-ase is Alzheimer's disease.

12. The method of claim 7, wherein the disorder, disease, or condition mediated by a sarcoplasmic/endoplasmic reticulum calcium ATP-ase is cancer.

13. A method for treating, preventing, or ameliorating one or more symptoms of diabetes in a subject, comprising administering to the subject a compound of Formula I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

i. R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂-6 alkynyl, C_3-10

cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a,

-S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly attached form heteroaryl or heterocyclyl;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a,

-OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C_3-10 cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl; wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

14. The method of any one of claims 4, 10, and 13, wherein the diabetes is type 1.

15. The method of any one of claims 4, 10, and 13, wherein the diabetes is type 2.

16. A method for increasing glucose tolerance in a subject, comprising administering to the subject a compound of Formula I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

i. R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10

cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c,

-NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a,

-S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly attached form heteroaryl or heterocyclyl;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C_3-10 cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

17. A method for treating, preventing, or ameliorating one or more symptoms of hepatosteatosis in a subject, comprising administering to the subject a compound of Formula I or IB:

(I)

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

i. R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀

cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c,

-NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a,

-S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly attached form heteroaryl or heterocyclyl; each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a,

-OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C₃_₁₀ cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C₆-i4 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

18. A method for treating, preventing, or ameliorating one or more symptoms of Alzheimer's disease in a subject, comprising administering to the subject a compound of I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

i. R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀

cycloalkyl, C₆_i4 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d, -NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a,

-S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly

attached form heteroaryl or heterocyclyl;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a,

-OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C_3-10 cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

19. A method for reducing or preventing the formation of amyloid plaques in a subject, comprising administering to the subject a compound of Formula I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

i. R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_i₀

cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c,

-OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a,

-S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C₆-i4 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly

attached form heteroaryl or heterocyclyl;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a,

-OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C₃_i₀ cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c, -OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c, -NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

20. A method for treating, preventing, or ameliorating one or more symptoms of cancer in a subject, comprising administering to the subject a compound of Formula I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R¹ and R² are:

i. R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_6 alkenyl, C₂_₆ alkynyl, C₃_i₀

cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a,

-OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a,

-S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly

attached form heteroaryl or heterocyclyl;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a,

-OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C₃_i₀ cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

21. The method of claim 20, wherein the cancer is breast cancer.

22. A method for treating, preventing, or ameliorating one or more symptoms of obesity in a subject, comprising administering to the subject a compound of Formula I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

1. R is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10

cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c,

-NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly attached form heteroaryl or heterocyclyl;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d, -NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C_3-10 cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

23. A method for promoting thermogenesis in a subject, comprising administering to the subject a compound of Formula I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

i. R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_i₀

cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c,

-NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a,

-S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly attached form heteroaryl or heterocyclyl;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a,

-OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C3-10 cycloalkylene, C₆-i4 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C₆_i4 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C₆-i4 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C₆-i4 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C₆-i4 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

24. The method of any one of claims 1 to 23, wherein the method comprises administering to the subject a second therapeutic agent, in combination or alternation.

25. The method of any one of claims 1 to 24, wherein the subject is a human.

26. The method of any one of claims 1 to 25, wherein the compound is a compound of Formula I, or an enantiomer, a mixture of enantiomers, a mixture of two or more

diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

27. The method of claim 26, wherein R³ is (i) hydrogen; (ii) C₁_₆ alkyl or heteroaryl, each optionally substituted with one or more substituents Q; or (iii) -C(O)OR^1a or

-S(O)NR^1bR^1c.

28. The method of claim 27, wherein R³ is (i) hydrogen; (ii) Ci_₃ alkyl or 5-membered heteroaryl, each optionally substituted with one or more substituents Q; or (iii) -C(O)OR^1a.

29. The method of claim 27, wherein R³ is (i) hydrogen; (ii) methyl or pyrazolyl, each optionally substituted with one or more substituents Q; or -C(O)OH.

30. The method of claim 26, wherein the compound has the structure of Formula VI:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

31. The method of claim 26, wherein the compound has the structure of Formula VII:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R^3a, R^3b, and R^3c are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C₆_i4 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (c) -C(O)R^1a,

-C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a,

-OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c,

-OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c,

-NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d, -NR^1aS(O)NR^1bR^1c,

-NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c.

32. The method of claim 31 , wherein R^3a, R^3b, and R^3c are each independently hydrogen or C₁_₆ alkyl optionally substituted with one or more substituents Q.

33. The method of claim 32, wherein R ^a, R , and R ^c are each independently hydrogen or methyl.

34. The method of any one of claims 26 to 33, wherein R² is C₁_₆ alkyl, C_6-14 aryl, C₇_ 15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q.

35. The method of claim 34, wherein R² is C_6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q.

36. The method of claim 34, wherein R² is phenyl, thienyl, or benzothienyl, each optionally substituted with one or more substituents Q.

37. The method of any one of claims 26 to 36, wherein the compound has the structure of Formula V:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein each R⁹ is independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c,

-OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c,

-NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d, -NR^1aS(O)NR^1bR^1c,

-NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c.

38. The method of claim 37, wherein each R⁹ is independently (a) halo, cyano, or nitro; (b) C₁_₆ alkyl, optionally substituted with one or more substituents Q; or (c) -C(O)OR^1a, -OR^1a, or -NR^1bR^1c, wherein each R^1a is independently hydrogen or C₁_₆ alkyl, optionally substituted with one or more substituents Q.

39. The method of claim 37, wherein each R⁹ is independently (a) fluoro, chloro, bromo, cyano, nitro, or hydroxyl; (b) C₁_₆ alkyl, optionally substituted with one or more substituents Q; (c) C₁_₆ alkoxy or -NH-C₁_₆ alkyl, each optionally substituted with one or more substituents Q; or (d) carboxy.

40. The method of claim 37, wherein each R⁹ is independently fluoro, chloro, bromo, cyano, nitro, methyl, butyl, hydroxyl, methoxy, ethoxy, propoxy, ethylamino, or carboxy; and wherein each methyl, butyl, methoxy, ethoxy, propoxy, and ethylamino is optionally substituted with one or more substituents Q.

41. The method of any one of claims 37 to 40, wherein n is an integer of 0, 1 , 2, or 3.

42. The method of claim 41 , wherein n is an integer of 1.

43. The method of any one of claims 26 to 42, wherein R¹ is hydrogen.

44. The method of any one of claims 26 to 43, wherein R⁴ is hydrogen or methoxy.

45. The method of any one of claims 26 to 44, wherein R⁵ is hydrogen or methoxy.

46. The method of any one of claims 26 to 45, wherein R⁶ is hydrogen or methoxy.

47. The method of any one of claims 26 to 46, wherein R⁷ is hydrogen, methoxy, or chloro.

48. The method of any one of claims 26 to 47, wherein R⁸ is hydrogen or methoxy.

49. The method of claim 26, wherein the compound has the structure of Formula

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R^3a, R^3b, and R^3c are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C₆-i4 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a,

-OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c,

-OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c,

-NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d, -NR^1aS(O)NR^1bR^1c,

-NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c.

50. The method of claim 49, wherein R¹ is hydrogen.

51. The method of claim 49 or 50, wherein R³ is hydrogen or C₁_₆ alkyl, optionally substituted with one or more substituents Q.

52. The method of any of claims 49 to 51 , wherein R³ is hydrogen or methyl.

53. The method of any of claims 49 to 52, wherein R⁴, R⁵, R⁶, R⁷, and R⁸ are each hydrogen.

54. The method of claim 26, wherein the compound is selected from the group consisting of: 42

42

and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.

55. The method of any one of claims 1 to 25, wherein the compound has the structure of Formula IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

56. The method of claim 55, wherein the compound has the structure of Formula IIB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

57. The method of claim 55, wherein the compound has the structure of Formula

IVB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein r is an integer of 0, 1, 2, 3, 4, 5, or 6.

58. The method of claim 55, wherein the compound is selected from the group consisting of:

D7

and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.

59. A pharmaceutical composition comprising a compound selected from the group consisting of:

and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof; and one or more pharmaceutically acceptable excipients.

60. A pharmaceutical comprising a compound of Formula VI, VII, or VIII:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient; wherein:

each R¹ and R² is independently hydrogen, C₁_₆ alkyl, C₂_6 alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C₆-i4 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl;

R^3a, R^3b, and R^3c are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a,

-OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d,

-NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d, -NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a,

-OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d - NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or

-S(O)₂NR^1bR^1c; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C₆-i4 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

61. A pharmaceutical composition comprising a compound selected from the group consisting of:

and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof; and one or more pharmaceutically acceptable excipients.

62. The pharmaceutical composition of any one of claims 59 to 61, wherein the pharmaceutical composition is formulated for single dose administration.

63. The pharmaceutical composition of any one of claims 59 to 62, wherein the pharmaceutical composition is formulated as an oral, parenteral, or intravenous dosage form.

64. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition is formulated as an oral dosage form.

65. The pharmaceutical composition of claim 64, wherein the pharmaceutical composition is formulated as a tablet or capsule.

66. The pharmaceutical composition of any one of claims 59 to 65, further comprising a second therapeutic agent.

67. A method for reducing stress in an ER, comprising contacting the ER with a compound of Formula I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

i. R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂-6 alkynyl, C_3-10

cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a,

-S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly attached form heteroaryl or heterocyclyl;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a,

-OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C_3-10 cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl; wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

68. The method of claim 67, wherein the stress is resulted from the perturbation of the homeostasis of the ER.

69. A method for restoring or maintaining homeostasis in an ER, comprising contacting the ER with a compound of Formula I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

i. R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10

cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c,

-NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly attached form heteroaryl or heterocyclyl;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C_3-10 cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

70. A method for increasing the Ca²⁺ concentration of an ER, comprising contacting the ER with a compound of Formula I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

i. R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀

cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c,

-NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a,

-S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly attached form heteroaryl or heterocyclyl; each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a,

-OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C₃_₁₀ cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C₆-i4 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

71. A method for modulating the activity of a SERCA, comprising contacting the SERCA with a compound of Formula I or IB:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are:

i. R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_i₀

cycloalkyl, C₆-i4 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d, -NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a,

-S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R² is independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or ii. R¹ and R² together with the C and N atoms to which they are directly

attached form heteroaryl or heterocyclyl;

each R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a,

-OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c;

X is a bond, -0-, -NR^1a-, C₁_₆ alkylene, C₂_₆ alkenylene, C₂_₆ alkynylene, C_3-10 cycloalkylene, C_6-14 arylene, heteroarylene, or heterocyclylene; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

72. The method of claim 71 , wherein the SERC A is SERC A 1.

73. The method of claim 71 , wherein the SERC A is SERC A 1 a or SERCAlb.

74. The method of claim 71 , wherein the SERC A is SERC A2.

75. The method of claim 71 , wherein the SERC A is SERCA2a or SERCA2b.

76. The method of claim 71 , wherein the SERC A is SERCA2b.

77. The method of claim 71 , wherein the SERC A is SERC A3.

78. The method of claim 71, wherein the SERCA is SERC A3 a, SERCA3b, or SERCA3C.

79. A compound of Formula VI:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are each independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl;

R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently (a) hydrogen, cyano, halo, or nitro; (b) Ci_6 alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a,

-OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d,

-NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

with the proviso that R⁵ is neither -OH nor -0-C_1-6 alkyl and that the compound is neither 8-benzamidoquinoline-2-carboxylic acid nor 8-(quinoline-2-carboxamido)quinoline-2- carboxylic acid;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

80. A compound of Formula VII:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ and R² are each independently hydrogen, C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C3-10 cycloalkyl, C₆-i4 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl;

R^3a, R^3b, R^3c, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a,

-OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d, -NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d,

-NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and

each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

with the proviso that the compound is not N-(2-(3,5-dimethyl-lH-pyrazol-l- yl)quinolin-8-yl)-3-isopropoxybenzamide;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

81. The compound of claim 80, wherein R^3a, R^3b, and R^3c are each independently hydrogen or C₁_₆ alkyl optionally substituted with one or more substituents Q.

82. The compound of claim 80, wherein R^3a, R^3b, and R^3c are each independently hydrogen or methyl.

83. The compound of any one of claims 79 to 82, wherein R² is C₁_₆ alkyl, C_6-14 aryl, C_7-15 aralkyl, or heteroaryl, each optionally substituted with one or more substituents Q.

84. The compound of claim 83, wherein R² is C_6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q.

85. The compound of claim 83, wherein R² is phenyl, thienyl, or benzothienyl, each optionally substituted with one or more substituents Q.

86. The compound of any one of claims 79 to 85, wherein R¹ is hydrogen.

87. The compound of any one of claims 79 to 86, wherein R⁴ is hydrogen or methoxy.

88. The compound of any one of claims 79 to 87, wherein R⁵ is hydrogen or methoxy.

89. The compound of any one of claims 79 to 88, wherein R⁶ is hydrogen or methoxy.

90. The compound of any one of claims 79 to 89, wherein R⁷ is hydrogen, methoxy, or chloro.

91. The compound of any one of claims 79 to 90, wherein R⁸ is hydrogen or methoxy.

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is (a) hydrogen; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c, -C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d,

-NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d, -NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or

-S(O)₂NR^1bR^1c;

R³, R^3a, R^3b, R^3c, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently (a) hydrogen, cyano, halo, or nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C_3-10 cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R^1a, -C(O)OR^1a, -C(O)NR^1bR^1c,

-C(NR^1a)NR^1bR^1c, -OR^1a, -OC(O)R^1a, -OC(O)OR^1a, -OC(O)NR^1bR^1c, -OC(=NR^1a)NR^1bR^1c, -OS(O)R^1a, -OS(O)₂R^1a, -OS(O)NR^1bR^1c, -OS(O)₂NR^1bR^1c, -NR^1bR^1c, -NR^1aC(O)R^1d,

-NR^1aC(O)OR^1d, -NR^1aC(O)NR^1bR^1c, -NR^1aC(=NR^1d)NR^1bR^1c, -NR^1aS(O)R^1d, -NR^1aS(O)₂R^1d, -NR^1aS(O)NR^1bR^1c, -NR^1aS(O)₂NR^1bR^1c, -SR^1a, -S(O)R^1a, -S(O)₂R^1a, -S(O)NR^1bR^1c, or -S(O)₂NR^1bR^1c; and each R^1a, R^1b, R^1c, and R^1d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^1b and R^1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; and (c) -C(O)R^a, -C(O)OR^a,

-C(O)NR^bR^c, -C(NR^a)NR^bR^c, -OR^a, -OC(O)R^a, -OC(O)OR^a, -OC(O)NR^bR^c,

-OC(=NR^a)NR^bR^c, -OS(O)R^a, -OS(O)₂R^a, -OS(O)NR^bR^c, -OS(O)₂NR^bR^c, -NR^bR^c,

-NR^aC(O)R^d, -NR^aC(O)OR^d, -NR^aC(O)NR^bR^c, -NR^aC(=NR^d)NR^bR^c, -NR^aS(O)R^d,

-NR^aS(O)₂R^d, -NR^aS(O)NR^bR^c, -NR^aS(O)₂NR^bR^c, -SR^a, -S(O)R^a, -S(O)₂R^a, -S(O)NR^bR^c, and -S(O)₂NR^bR^c, wherein each R^a, R^b, R^c, and R^d is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a; or (iii) R^b and R^c together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^a;

wherein each Q^a is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C₇_₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R^e, -C(O)OR^e, -C(O)NR^fR^g, -C(NR^e)NR^fR^g, -OR^e, -OC(O)R^e, -OC(O)OR^e, -OC(O)NR^fR^g, -OC(=NR^e)NR^fR^g, -OS(O)R^e, -OS(O)₂R^e, -OS(O)NR^fR^g, -OS(O)₂NR^fR^g, -NR^fR^g, -NR^eC(O)R^h, -NR^eC(O)OR^h, -NR^eC(O)NR^fR^g, -NR^eC(=NR^h)NR^fR^g, -NR^eS(O)R^h, -NR^eS(O)₂R^h, -NR^eS(O)NR^fR^g, -NR^eS(O)₂NR^fR^g, -SR^e, -S(O)R^e, -S(O)₂R^e, -S(O)NR^fR^g, and -S(O)₂NR^fR^g; wherein each R^e, R^f, R^g, and R^h is independently (i) hydrogen; (ii) C₁_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ cycloalkyl, C_6-14 aryl, C_7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R^f and R^g together with the N atom to which they are attached form heterocyclyl.

93. The compound of claim 92, wherein R¹ is hydrogen.

94. The compound of claim 92 or 93, wherein R³ is hydrogen or C₁_₆ alkyl, optionally substituted with one or more substituents Q.

95. The compound of any of claims 92 to 94, wherein R³ is hydrogen or methyl.

96. The compound of any of claims 92 to 95, wherein R⁴, R⁵, R⁶, R⁷, and R⁸ are each hydrogen.

97. The compound of claim 74, selected from the group consisting of:

and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.

98. The compound of claim 75, selected from the group consisting of:

and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.

99. The compound of claim 92, selected from the group consisting of: