COMPOUNDS AND METHODS FOR THE TREATMENT OF NON-ALCOHOLIC STEATOHEPATITIS

FIELD OF INVENTION

[0001] The invention is in the field of prevention, amelioration and medical treatment of various diseases and conditions that result in inflammation, including non-alcoholic steatohepatitis.

BACKGROUND

[0002] Non-alcoholic fatty liver disease (NAFLD) is a disorder affecting as many as 1 in 3-5 adults and 1 in 10 children in the United States, and refers to conditions where there is an accumulation of excess fat in the liver of people who drink little or no alcohol. The most common form of NAFLD is a non-serious condition called hepatic steatosis (fatty liver), in which fat accumulates in the liver cells. Although not a normal condition, steatosis alone is considered relatively benign to the liver itself and is also a reversible condition. NAFLD most often presents itself in individuals with a constellation of risk factors called the metabolic syndrome, which is characterized by elevated fasting plasma glucose (FPG) with or without intolerance to post-prandial glucose, being overweight or obese, high blood lipids such as cholesterol and triglycerides (TGs) and low high-density lipoprotein cholesterol (HDL-C) levels, and high blood pressure; but not all patients have all the manifestations of the metabolic syndrome. Obesity is thought to be the most common cause of NAFLD; and some experts estimate that about two-thirds of obese adults and one-half of obese children may have fatty liver. NAFLD comprises a spectrum of liver diseases ranging from benign hepatic steatosis to more advanced liver diseases such as cirrhosis and fibrosis, which eventually might result in liver failure and death.

[0003] The transition of NAFLD towards NASH represents a key step in the pathogenesis, as it sets the stage for further damage to the liver, such as fibrosis, cirrhosis and liver cancer. NASH causes the liver to swell and become damaged and tends to develop in people who are overweight or obese, or have diabetes, high cholesterol or high triglycerides or inflammatory conditions. NASH, a potentially serious form of the disease, is marked by hepatocyte ballooning and liver inflammation, which may progress to scarring and irreversible damage. This damage is similar to the damage caused by heavy alcohol use. Macro and microscopically, NASH is characterized by lobular and/or portal inflammation, varying degrees of fibrosis, hepatocyte death and pathological angiogenesis. At its most severe, NASH can progress to cirrhosis, hepatocellular carcinoma and liver failure.

[0004] NASH is a leading cause of end-stage liver disease, yet despite the consistent rise of NASH worldwide, the mechanisms that govern the inflammatory aspect of this disease remain unknown, thereby restricting treatment options. Consequently, there is no established therapy for patients suffering from NASH. Therapy is, therefore, focused mainly on risk factors, weight reduction, and pharmacological intervention. A few pharmacological treatments have been demonstrated including antioxidants, insulin sensitizers, hepatoprotectants and lipid- lowering agents.

BRIEF SUMMARY

[0005] Described herein are various inventive embodiments that are generally directed to compounds, compositions, and methods useful for treating diseases, conditions, and abnormalities that result from inflammation of various tissues. In some embodiments, such inflammation results in liver diseases and related conditions. In some embodiments, the disclosed compounds are found to be potent inhibitors of lysosomal enzyme cathepsin D, understood from the present studies to be involved in the inflammatory response in prevalent liver diseases such as non-alcohol steatohepatitis.

[0006] In various embodiments, the present disclosure provides compounds of Formula (I):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein

— Y— represents a moiety selected from the group consisting of:

wherein any two R ⁵ groups taken together with the atoms to which they are attached can form a C5-i ₄ -aryl, C5-i ₄ -heteroaryl, C3-i ₂ -cycloalkyl, or C3-i ₂ -heterocycloalkyl ring, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

T and T are each independently -C(=0)-, -X-C(=0)-, -S(=0)2-, or -C= N(R ⁴ )-;

U and U' are each independently -CH2-, -NR ⁴ -, -0-, or -S-;

W is -NR ⁴ - or -C(R ³ )(R ³ )-;

X is each independently NR ⁴ , O, or S;

Y is NR ⁴ , O, S(=0)rf;

Z is O or S;

n, n', n", and n'" are each independently 0, 1, or 2;

o, o', o", and o'" are each independently 0 or 1 ;

p is 0, 1, 2, 3, or 4;

r is 0, 1, 2, or 3;

q is 0, 1, 2, 3, 4, or 5;

R ¹ and R ² are each independently -(CFh)n _" -C5-i ₄ -aryl, -(CFhV-Cs- 14-heteroaryl, - (CH2V-C3- 12-cycloalkyl, -(CH2)n"-C3-i4-heterocycloalkyl, -(X)-(CH2)n"-C5-i4-aryl, -(X)-C5-i4- aryl, -(X)-C5-i ₄ -heteroaryl, -(X)-C3-i ₂ -cycloalkyl, -(X)-C3-i ₄ -heterocycloalkyl, -C _2-4 -alkenyl- Cs-M-aryl, -C _2-4 -alkenyl-C5-i ₄ -heteroaryl, -C _2-4 -alkenyl-C3-i ₂ -cycloalkyl, -C _2-4 -alkenyl-C3-i ₂ - heterocycloalkyl, -Ci-5-alkyl, -C ₂ -5-alkenyl, or -C ₂ -5-alkynyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein any two R ⁵ groups taken together with the atoms to which they are attached can form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring;

R ³ and R ³ are each independently H, F, -Ci-5-alkyl, -C ₂ -5-alkenyl, -C ₂ -5-alkynyl, -C3- 12-cycloalkyl, -C3- 12-cycloalkenyl, -(CFh)p-aryl, -(CFh)p-heteroaryl, -(CH ₂ )p-C3- 12- cycloalkyl, -(CFh)p-C3 -12-cycloalkenyl, -(CH2)p-C3-i2-heterocycloalkyl, -(CFh)p-C5-i4- heteroaryl, -OH, -OCi-5-alkyl, -0C(=0)R ⁶ , or -NR ⁴ R ⁴ , each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein two geminal R ³ or two geminal R ^3' taken together with the carbon atom to which they are attached can form a -C3-12- cycloalkyl or -C3-i ₂ -heterocycloalkyl ring;

R ⁴ , R ^4' , and R ^4" are each independently H, -Ci-5-alkyl, -C ₂ -5-alkenyl, -C ₂ -5-alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ⁶ , -C(=0)0R ⁶ , -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -0C(=0)0R ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -C5- 12-aryl, -C5-12- heteroaryl, -C3-i ₂ -cycloalkyl, or -C3-i ₂ -heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein two of R ⁴ , R ⁴ ’, and R ⁴ ’ from group— V— taken together with the atoms to which they are attached can form a -C5-i ₄ -heteroaryl or -C3-i ₂ -heterocycloalkyl ring, or alternatively, wherein one of R ⁴ , R ⁴ ’, and R ⁴ ’ from group— V— and one R ³ when W is -C(R ³ )(R ³ )- taken together with the atoms to which they are attached can form a -C5- ₁₄ -heteroaryl or -C3-i ₂ -heterocycloalkyl ring;

R ⁵ is halogen, -Ci-5-alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ⁶ , -0C(=0)0R ⁶ , -SR ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ R ⁶ , -NO2, -NH ₂ , -N(H)S0 ₂ R ⁶ ,

O

N Ci-5-acyl; -COOH, -COOR ⁶ , -CONR ⁶ R ^6' , V*v _n - ^r4

-N(S0 ₂ R ⁶ )2, -NR ⁴ R ^4' , -NR ⁴ - AA

-(CH2)n-C5- 14-aryl, -(CH2)n-C5-i4-heteroaryl, -(CH2)n-C3 -12-cycloalkyl, or -(CH2)n-C3-14- heterocycloalkyl, wherein when R ⁵ is -S0 ₂ NR ⁶ NR ⁶ , R ⁶ and R ⁶ ’ taken together with the N to which they are attached can form an optionally substituted -C5-i4-heteroaryl, or -C3-12- heterocycloalkyl ring; and

R ⁶ and R ⁶ ’ are each independently H, -CF3, -CHF ₂ , -CH ₂ F, -Ci-5-alkyl, -C ₂ -5 -alkenyl, - C2-5-alkynyl, -Ci-5-acyl, -Cs-M-aryl, -Cs-M-heteroaryl, -C3-i2-cycloalkyl, or -C3- ₁₂ - heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

with the proviso that the compound is not BMCL-38 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0007] In various embodiments, the compound of Formula (I) is a compound of Formula (!'):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

V, T, T, U, U', R ¹ , R ² , R ³ , o, and o' are as defined above for Formula (I);

with the proviso that the compound is not BMCL-38 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0008] In various embodiments, the compound of Formula (I) or Formula (II) is a compound of Formula (I -A):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

T, T', U, U', R ¹ , R ² , R ³ , R ⁵ , n, o, o', o", o'", and r are as defined above for Formula (I); and

Z ¹ , Z ² , Z ³ , and Z ⁴ are each independently N or CR ⁵ , wherein at least one of Z ¹ , Z ² , Z ³ , and Z ⁴ is N, and wherein no more than two N atoms are adjacent. [0009] In various embodiments, the compound of Formula (I) or Formula (II) is a compound of Formula (I-B):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

R ¹ , R ³ , R ⁴ , R ^4' , R ⁶ , R ^6' , n, q, and r are as defined above for Formula (I);

Z ¹ , Z ² , Z ³ , and Z ⁴ are as defined above for Formula (I-A); and

R ⁵ and R ^5' are each independently selected from halogen, -Ci-5-alkyl, -CF3, -CHF2, - CH2F, -CN, -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -0C(=0)0R ⁶ , -SR ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -

R ⁴ ,-(CH2)n-C5-i4-aryl, -(CFb)n-C5- 14-heteroaryl, -(CH2)n-C3-i2-cycloalkyl, or -(CH2)n- C3-i ₄ -heterocycloalkyl, wherein when R ⁵ is -S0 ₂ NR ⁶ NR ⁶ , R ⁶ and R ⁶ ’ taken together with the N to which they are attached can form an optionally substituted -Cs-M-heteroaryl, or -C3-12- heterocycloalkyl ring.

[0010] In various embodiments, the compound of Formula (I) or Formula (II) is a compound of Formula (I-C):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein

represents an optional bond between respective atoms;

T, T, U, U', W, Y, R ¹ , R ² , R ³ , R ³ , R ⁵ , n, o, o', o", o'", and r are as defined above for

Formula (I).

[0011] In various embodiments, the compound of Formula (I) or Formula (II) is a compound of Formula (I-D):

I-D

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

- represents an optional bond between respective atoms;

T, T, Y, n', n", o, r, R ³ , R ⁴ , R ^{4 '} , R ⁶ , and R ^6' are as defined above for Formula (I);

q and q' are each independently 0, 1, 2, 3, 4, or 5; and

R ⁵ , R ^5' , and R ^5" are each independently halogen, -Ci-5-alkyl, -CF3, -CHF2, -CFhF, -CN, -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ⁶ , -0C(=0)0R ⁶ , -SR ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ R ⁶ , -

NOI, -NH ₂ , -NR ⁴ R ^4' , -NR ⁴ -Ci-5-acyl;

(CH ₂ ) _n -C5- 14-aryl, -(CH ₂ ) _n -C5- 14-heteroaryl, -(CH ₂ ) _n -C3 -i ₂ -cycloalkyl, or -(CH ₂ ) _n -C3-i4- heterocycloalkyl, wherein when R ⁵ is -S0 ₂ NR ⁶ NR ⁶ , R ⁶ and R ⁶ ’ taken together with the N to which they are attached can form an optionally substituted -C5-i4-heteroaryl, or -C3-i ₂ - heterocycloalkyl ring.

[0012] In some embodiments, the compound of Formula (I) or Formula (II) is a compound of Formula (I-E):

I-E

wherein

- represents an optional bond between respective atoms;

T, T, R ³ , R ⁴ , R ⁴ , R ^{4 '} , R ⁵ , R ⁵ , and o are as defined above for Formula (I), and q and q' are as defined above for Formula (I-D).

[0013] In various embodiments, the compound of Formula (I) is a compound of Formula (I-F):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

T, T', U, U', R ¹ , R ² , R ³ , n', o, o', o", and o'" are as defined above for Formula (I);

X and X' are each independently NR ⁴ , O, or S, wherein when X' is NR ⁴ , R ⁴ and R ³ taken together with the atoms to which they are attached can form a Cs-w-heteroaryl or C3-12- heterocycloalkyl ring, wherein when X and X' are each NR ⁴ , the two R ⁴ taken together with the atoms to which they are attached can form a -Cs-M-heteroaryl or -C3-i ₂ -heterocycloalkyl ring, and wherein when X' and U are NR ^4' , the two R ⁴ taken together with the atoms to which they are attached can form a -C3-i ₂ -heterocycloalkyl ring; and

m is 0 or 1;

with the proviso that the compound is not BMCF-38 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0014] In various embodiments, the compound of Formula (I) is a compound of Formula (I-G):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

T, R ¹ , R ² , R ³ , R ³ , R ⁴ , R ⁴ , and R ^4" are as defined above for Formula (I); and

X is -NR ⁴ - or-O-.

[0015] In various embodiments, the compound of Formula (I) is a compound of Formula (I-H):

I-H

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

X, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , and R ⁶ ’ are as defined above for Formula (I);

m is 0 or 1;

R ⁴ , R ⁴ ’, R ^4" , R ^{4 "} , and R ^4"" are each independently H, -Ci-5-alkyl, -C ₂ -5-alkenyl, -C2-5- alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ^6' , -C(=0)OR ⁶ , -OH, -OR ⁶ , -OC(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -OC(=0)OR ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -C5- 12-aryl, -C5-12- heteroaryl, -C3-i ₂ -cycloalkyl, or -C3-i ₂ -heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein R ⁴ ’ and R ^{4 "} taken together with the atoms to which they are attached can form a C5- 14-heteroaryl or C3-12- heterocycloalkyl ring optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, or alternatively, wherein R ^{4 "} and R ³ taken together with the atoms to which they are attached can form a C\ _{> 14} -heteroaryl or C3-i2-heterocycloalkyl ring optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

with the proviso that the compound is not BMCL-38 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0016] In some embodiments, the compound of Formula (I-H) is a compound of Formula (I -H _a ) having the following structure:

I-Ha

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

X, R ¹ , R ² , R ³ , R ^4" , and R ^4"" are as defined above for Formula (I) and Formula (I-H); and

s is 1, 2, 3, or 4.

[0017] In some embodiments, the compound of Formula (I-H) is a compound of Formula (I-Hb) having the following structure:

I-Hb

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

- represents an optional bond between respective atoms;

X, R ¹ , R ² , R ⁴ , R ^4" , and R ^4"" , and q are as defined above for Formula (I) and Formula

(I-H);

M, M' and M" are each independently CFh, C=0, NR ⁴ , O, or S; or alternatively, when — is present, M, M' and M" are each independently CH or N;

R ^4' , R ^4" , and R ^4"" are each independently H, -Ci-5-alkyl, -C ₂ -5-alkenyl, -C ₂ -5-alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ⁶ , -C(=0)0R ⁶ , -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -0C(=0)0R ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -Cs-12-aiyl, -C5-12- heteroaryl, -C3-i ₂ -cycloalkyl, or -C3-i ₂ -heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein R ⁴ ’ and R ^4" taken together with the atoms to which they are attached can form a C5- 14-heteroaryl or C3-12- heterocycloalkyl ring optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

R ⁵ is halogen, -Ci-s-alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ⁶ , -0C(=0)0R ⁶ , -SR ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ R ⁶ , -NO2, -NH ₂ , -N(H)S0 ₂ R ⁶ ,

-N(S0 ₂ R ⁶ )2, -NR ⁴ R ⁴ ', -NR ⁴ -C 1-5-acyl;

(CH2)n-C5- 14-aryl, -(CH2)n-C5- 14-heteroaryl, -(CH2)n-C3 -12-cycloalkyl, or -(CH2)n-C3-i4- heterocycloalkyl, wherein any two R ⁵ groups taken together with the atoms to which they are attached can form a C5-i ₄ -aryl, C5-i ₄ -heteroaryl, C3- 12-cycloalkyl, or C3-i ₂ -heterocycloalkyl ring, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN; and

r and r ¹ are each independently 0, 1, 2, or 3. [0018] In some embodiments, the compound of Formula (I) is a compound of Formula (I-I) having the following structure:

I-I

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

X, R ¹ , R ³ , R ⁵ , R ⁶ , R ⁶ ’, and q are as defined above for Formula (I);

m is 0 or 1; and

R ⁴ , R ⁴ ’, R ^4" , R ^{4 "} , and R ^4"" are each independently H, -Ci-5-alkyl, -C2-5-alkenyl, -C2-5- alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ^6' , -C(=0)OR ⁶ , -OH, -OR ⁶ , -OC(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -OC(=0)OR ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -C5- 12-aryl, -C5-12- heteroaryl, -C3-i2-cycloalkyl, or -C3-i2-heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein R ⁴ ’ and R ^{4 "} taken together with the atoms to which they are attached can form a C5- 14-heteroaryl or C3-12- heterocycloalkyl ring optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, or alternatively, wherein R ^{4 "} and R ³ taken together with the atoms to which they are attached can form a C5- 14-heteroaryl or C3-i ₂ -heterocycloalkyl ring optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

with the proviso that the compound is not BMCL-38 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0019] In other embodiments, the compound of Formula (I) is a compound of Formula (I-J) having the following structure:

I-J

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

X, R ¹ , R ³ , R ⁵ , R ⁶ , R ^6’ , and p are as defined above for Formula (I);

m is 0 or 1; and

R ⁴ , R ^4’ , R ⁴ ", R ⁴ ", and R ⁴ "" are each independently H, -C 1-5-alkyl, -C ₂ -5-alkenyl, -C2-5- alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ⁶ ', -C(=0)0R ⁶ , -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ⁶ ', -0C(=0)0R ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -Cs-12-aiyl, -C5-12- heteroaryl, -C3-i ₂ -cycloalkyl, or -C3-i ₂ -heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein R ^4’ and R ^{4 "} taken together with the atoms to which they are attached can form a C5- 14-heteroaryl or C3-12- heterocycloalkyl ring optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, or alternatively, wherein R ⁴ " and R ³ taken together with the atoms to which they are attached can form a C5-i ₄ -heteroaryl or C ₃ -i ₂ -heterocycloalkyl ring optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

with the proviso that the compound is not BMCL-38 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0020] In various embodiments, the compound of Formula (I) is a compound of Formula

(I-K):

I-K

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein,

T, R ¹ , R ² , R ³ , R ^4' , R ^4" , and n are as defined above for Formula (I).

[0021] In various embodiments, the compound of Formula (I) is a compound of Formula (I-L):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein,

T, R ¹ , R ³ , R ^4' , R ^4" , n and q are as defined above for Formula (I).

[0022] In various embodiments, the compound of Formula (I) is a compound of Formula (I-M):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein, X, R ¹ , R ³ , R ⁴ ’, R ^{4 "} , n, and q are as defined above for Formula (I).

[0023] In various embodiments, the present disclosure also provides compounds of Formula (II):

II

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

Het is a 5-14 membered heteroaryl, optionally substituted by one of more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

T and T are each independently -C(=0)-, -X-C(=0)-, -S(=0)2-, or -C=NR ⁴ - ;

U and U' are each independently -CH2-, -NR ⁴ -, -0-, or -S-;

W is -NR ⁴ - or -C(R ³ )(R ³ )-;

X is NR ⁴ , O, or S;

n, n', and n" are each independently 0, 1, or 2;

o, o', o", and o'" are each independently 0 or 1 ;

p is 0, 1, 2, 3, or 4;

R ¹ and R ² are each independently -(CFb)n"-C5-i4-aryl, -(CH2V-C5- 14-heteroaryl, - (CH2V-C3- 12-cycloalkyl, -(CH2)n"-C3-i4-heterocycloalkyl, -(X)-(CH2)n"-C5-i4-aryl, -(X)-C5-i4- aryl, -(X)-C5-i ₄ -heteroaryl, -(X)-C3-i ₂ -cycloalkyl, -(X)-C3-i ₄ -heterocycloalkyl, -C _2-4 -alkenyl- Cs-M-aryl, -C _2-4 -alkenyl-C5-i ₄ -heteroaryl, -C _2-4 -alkenyl-C3-i ₂ -cycloalkyl, -C _2-4 -alkenyl-C3-i ₂ - heterocycloalkyl, -Ci-5-alkyl, -C2-5-alkenyl, or -C2-5-alkynyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein any two R ⁵ groups taken together with the atoms to which they are attached can form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring;

R ³ and R ³ ’ are each independently H, F, -Ci-5-alkyl, -C ₂ -5-alkenyl, -C ₂ -5-alkynyl, -C3- 12-cycloalkyl, -C3- 12-cycloalkenyl, -(CFh)p-aryl, -(CFh)p-heteroaryl, -(CFh)p-C3- 12- cycloalkyl, -(CFh)p-C3 -12-cycloalkenyl, -(CFb)p-C3-i2-heterocycloalkyl, -(CH2)p-C5-i4- heteroaryl, -OH, -OCi-5-alkyl, -0C(=0)R ⁶ , or -NR ⁴ R ⁴ , each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein two geminal R ³ or two geminal R ^3' taken together with the carbon atom to which they are attached can form a -C3-12- cycloalkyl or -C3-i ₂ -heterocycloalkyl ring;

R ⁴ and R ^4' are each independently H, -Ci-5-alkyl, -C2-5-alkenyl, -C2-5-alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ⁶ , -C(=0)OR ⁶ , -OH, -OR ⁶ , -OC(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -OC(=0)OR ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -C5- 12-aryl, -C5-12- heteroaryl, -C3-i2-cycloalkyl, or -C3-i2-heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

R ⁵ is halogen, -Ci-5-alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -OR ⁶ , -OC(=0)R ⁶ , -0C(=0)NR ⁶ R ⁶ , -OC(=0)OR ⁶ , -SR ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ R ⁶ , -NO2, -NH ₂ , -N(H)S0 ₂ R ⁶ ,

-N(S0 ₂ R ⁶ ) ₂ , -NR ⁴ R ⁴ ’, -NR ⁴ -C 1-5-acyl;

(CH2)n-C5- 14-aryl, -(CH2)n-C5- 14-heteroaryl, -(CH2)n-C3 -12-cycloalkyl, or -(CH2)n-C3-14- heterocycloalkyl, wherein when R ⁵ is -S0 ₂ NR ⁶ NR ⁶ , R ⁶ and R ⁶ ’ taken together with the N to which they are attached can form an optionally substituted -C5-i4-heteroaryl, or -C3-12- heterocycloalkyl ring; and

R ⁶ and R ⁶ ’ are each independently H, -CF3, -CHF ₂ , -CH ₂ F, -Ci-5-alkyl, -C ₂ -5 -alkenyl, - C2-5-alkynyl, -Ci-5-acyl, -Cs-M-aryl, -Cs-M-heteroaryl, -C3-i2-cycloalkyl, or -C3- ₁₂ - heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN.

[0024] The present disclosure also provides a method for treating or preventing a liver disease or an abnormal liver condition, including by not limited to, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-H _a ), Formula (I-Hb), Formula (I-I), Formula (I-J), Formula (I-K), Formula (I-L), Formula (I-M), Formula (I-N), or Formula (II), a pharmaceutically acceptable salt thereof, or a composition thereof.

[0025] The present disclosure provides a method of treating liver disease or an abnormal liver condition such as non-alcoholic steatohepatitis in a subject in need thereof, wherein the method comprises proteolytic inhibition of cathepsin D (CTSD) by an effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-H _a ), Formula (I-Hb), Formula (I-I), Formula (I-J), Formula (I-K), Formula (I-L), Formula (I-M), or Formula (II), a pharmaceutically acceptable salt thereof, or a composition thereof.

[0026] The present disclosure provides a method of reducing systemic and hepatic inflammation in a patient suffering from NASH comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (G), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-H _a ), Formula (I-Hb), Formula (I-I), Formula (I-J), Formula (I-K), Formula (I-L), Formula (I-M), or Formula (II), a pharmaceutically acceptable salt thereof, or a composition thereof to a subject in need.

[0027] The present disclosure provides a method of regulating cholesterol homeostasis in a subject with NASH or NAFLD comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (G), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-H _a ), Formula (I-Hb), Formula (I-I), Formula (I-J), Formula (I-K), Formula (I-L), Formula (I-M), or Formula (II), a pharmaceutically acceptable salt thereof, or a composition thereof to a subject in need.

[0028] The present disclosure provides a method of reducing the accumulation of liver fat in a subject comprising the administration of a therapeutically effective amount of a compound of Formula (I), Formula (G), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-H _a ), Formula (I-Hb), Formula (I-I), Formula (I-J), Formula (I-K), Formula (I-L), Formula (I-M), or Formula (II), a pharmaceutically acceptable salt thereof, or a composition thereof.

[0029] The present disclosure provides a method of improving aberrant lysosomal function in a patient suffering from NASH comprising administering a therapeutically effective amount of ta compound of Formula (I), Formula (G), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-H _a ), Formula (I-Hb), Formula (I-I), Formula (I-J), Formula (I-K), Formula (I-L), Formula (I-M), or Formula (II), a pharmaceutically acceptable salt thereof, or a composition thereof to a subject in need.

[0030] The present disclosure provides a method for reducing in a subject’s blood plasma or blood serum the subject's total cholesterol level, low-density lipoprotein cholesterol concentration, low-density lipoprotein concentration, very low-density lipoprotein cholesterol concentration, very low-density lipoprotein concentration, non-HDL cholesterol concentration, non-HDL concentration, apolipoprotein B level, triglyceride concentration, apolipoprotein C- III level, C-reactive protein level, fibrinogen level, or lipoprotein level, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I), Formula (G), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-H _a ), Formula (I-Hb), Formula (I-I), Formula (I-J), Formula (I-K), Formula (I-L), Formula (I-M), or Formula (II), a pharmaceutically acceptable salt thereof, or a composition thereof to a subject in need.

[0031] The present disclosure provides a method of stabilizing, reducing, or slowing the upward progression of the NAFDL activity score (NAS) in a subject, comprising administration of a therapeutically effective amount of a compound of Formula (I), Formula (G), Formula (I- A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-H _a ), Formula (I-Hb), Formula (I-I), Formula (I-J), Formula (I-K), Formula (I-L), Formula (I-M), or Formula (II), a pharmaceutically acceptable salt thereof, or a composition thereof.

[0032] The present disclosure provides a method for treating or preventing a cardiovascular disorder or a related vascular disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (G), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-H _a ), Formula (I-Hb), Formula (I-I), Formula (I-J), Formula (I-K), Formula (I-L), Formula (I-M), or Formula (II), a pharmaceutically acceptable salt thereof, or a composition thereof.

[0033] The present disclosure provides a method for treating or preventing a disorder of glucose metabolism, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (G), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-H _a ), Formula (I-Hb), Formula (I-I), Formula (I-J), Formula (I-K), Formula (I-L), Formula (I-M), or Formula (II), a pharmaceutically acceptable salt thereof, or a composition thereof. BRIEF DESCRIPTION OF THE FIGURES

[0034] The skilled artisan will understand that the drawings primarily are for illustrative purposes and are not intended to limit the scope of the inventive subject matter described herein.

[0035] FIG. 1 shows a schematic representation of how therapeutic intervention can be used to exploit the cathepsin D (CTSD)-inflammation correlation in order to treat certain disease states related to disturbed lipid metabolism.

[0036] FIG. 2 describes the TNFa cytokine level of oxLDL-loaded bone marrow-derived macrophages (BMDM) treated with D-002. TNFa cytokine secretion is measured in supernatant of wild type mouse BMDM exposed to oxLDL for 24 h and subsequently treated with D-002 (4 h) and LPS (4 h).

[0037] FIG. 3 shows the gene expression levels in oxLDL-loaded bone marrow-derived macrophages of (A) the pro-inflammatory marker TNFa after incubation with D-002 (100 uM) and LDS, (B) the pro-inflammatory marker Ccl2 after incubation with D-002 (100 uM) and LDS, (C) the pro-inflammatory marker caspase /after incubation with D-002 (100 uM) and LDS, and (D) Cyp 27, the gene responsible for encoding the enzyme responsible for the breakdown of cholesterol after incubation with D-002 (100 uM) and LDS.

DETAILED DESCRIPTION

[0038] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention can be practiced without these details. In other instances, well- known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.

[0039] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms. Use of flow diagrams is not meant to be limiting with respect to the order of operations performed for all embodiments. The indefinite articles“a” and“an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean“at least one.”

[0040] Reference throughout this specification to“one embodiment” or“an embodiment,” etc. means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases“in one embodiment” or“in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics can be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,”“an,” and“the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term“or” is generally employed in its sense including“and/or” unless the content clearly dictates otherwise.

[0041] As used herein in the specification and in the claims, the phrase“at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase“at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example,“at least one of A and B” (or, equivalently,“at least one of A or B,” or, equivalently“at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0042] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases“consisting of’ and“consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0043] “Alkyl” or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a C1-C6 alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C ₃ alkyls, C2 alkyls and Ci alkyl (i.e., methyl). A C1-C ₆ alkyl includes all moieties described above for C1-C5 alkyls but also includes C6 alkyls. A C1-C1 ₀ alkyl includes all moieties described above for C1-C5 alkyls and C1-C ₆ alkyls, but also includes C7, Cs, C ₉ and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, «-propyl, /-propyl, sec-propyl, «-butyl, /-butyl, sec-butyl, /-butyl, «-pentyl, /-amyl, «-hexyl, «-heptyl, «-octyl, «-nonyl, «-decyl, «-undecyl, and «- dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0044] “Alkylene” or“alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical. Alkylenes comprising any number of carbon atoms from 1 to 12 are included. Non-limiting examples of C1-C12 alkylene include methylene, ethylene, propylene, «-butylene, ethenylene, propenylene, «-butenylene, propynylene, «-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[0045] “Alkenyl” or“alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C ₂ -C ₁₂ alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C1 ₀ alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C ₆ alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes Cs alkenyls, C4 alkenyls, C ₃ alkenyls, and C2 alkenyls. A C2-C ₆ alkenyl includes all moieties described above for C2-C5 alkenyls but also includes C6 alkenyls. A C2-C1 ₀ alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C ₆ alkenyls, but also includes C ₇ , Cs, C ₉ and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes C11 and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), l-propenyl, 2-propenyl (allyl), iso-propenyl, 2 -methyl- l-propenyl, l-butenyl, 2-butenyl, 3- butenyl, l-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, l-hexenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, l-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1- octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, l-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, l-decenyl, 2-decenyl, 3- decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, l-undecenyl, 2- undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9- undecenyl, lO-undecenyl, l-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, lO-dodecenyl, and 1 l-dodecenyl. Examples of C1-C3 alkyl includes methyl, ethyl, «-propyl, and /-propyl. Examples of C1-C4 alkyl includes methyl, ethyl, «-propyl, /-propyl, «-butyl, /-butyl, and .suc-butyl . Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0046] “Alkenylene” or“alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C2-C12 alkenylene include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.

[0047] “Alkynyl” or“alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl groups comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C ₂ -C ₁₂ alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C1 ₀ alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C2-C ₆ alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. A C2-C ₆ alkynyl includes all moieties described above for C2-C5 alkynyls but also includes G alkynyls. A C2-C1 ₀ alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C ₆ alkynyls, but also includes C ₇ , G. C ₉ and C10 alkynyls. Similarly, a C2-C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls. Non-limiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0048] “Alkynylene” or“alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non-limiting examples of C2-C12 alkynylene include ethynylene, propargylene and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.

[0049] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[0050] “Alkylamino” refers to a radical of the formula -NHRa or -NRaRa where each Ra is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.

[0051] “Alkylcarbonyl” refers to the -C(=0)Ra moiety, wherein Ra is an alkyl, alkenyl or alkynyl radical as defined above. A non-limiting example of an alkyl carbonyl is the methyl carbonyl (“acetal”) moiety. Alkylcarbonyl groups can also be referred to as“Cw-Cz acyl” where w and z depicts the range of the number of carbon in Ra, as defined above. For example, “CI-C10 acyl” refers to alkylcarbonyl group as defined above, where Ra is C1-C10 alkyl, C1-C10 alkenyl, or C1-C10 alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkyl carbonyl group can be optionally substituted.

[0052] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 5 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, av-indaccnc. v-indaccnc. indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term“aryl” is meant to include aryl radicals that are optionally substituted.

[0053] “Aralkyl” refers to a radical of the formula -Rb-Rc where Rb is an alkylene, alkenylene or alkynylene group as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted. [0054] “Carbocyclyl,” “carbocyclic ring” or“carbocycle” refers to a rings structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.

[0055] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbomyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0056] “Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2. l]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.

[0057] “Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.

[0058] “Cycloalkylalkyl” refers to a radical of the formula -Rb-Rd where Rb is an alkylene, alkenylene, or alkynylene group as defined above and Rd is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted.

[0059] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g. , trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l,2-difluoroethyl, 3-bromo-2-fluoropropyl, l,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0060] “Haloalkenyl” refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., l-fluoropropenyl, l, l-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.

[0061] “Haloalkynyl” refers to an alkynyl radical, as defined above that is substituted by one or more halo radicals, as defined above, e.g., l-fluoropropynyl, l-fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.

[0062] “Heterocyclyl,” “heterocyclic ring” or “heterocycle” refers to a stable 3- to 20-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclyl or heterocyclic rings include heteroaryls as defined below. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, l-oxo-thiomorpholinyl, and l,l-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted. [0063] L'-hctcrocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a A'-heterocyclyl group can be optionally substituted.

[0064] “Heterocyclylalkyl” refers to a radical of the formula -Rb-Re where Rb is an alkylene, alkenylene, or alkynylene chain as defined above and Re is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl can be attached to the alkyl, alkenyl, alkynyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group can be optionally substituted.

[0065] “Heteroaryl” refers to a 5- to 20-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[6][l,4]dioxepinyl, l,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, l-oxidopyridinyl, l-oxidopyrimidinyl, l-oxidopyrazinyl, 1- oxidopyridazinyl, 1 -phenyl- l//-pyrrolyl. phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in this disclosure, a heteroaryl group can be optionally substituted.

[0066] A'-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an A'-heteroaryl group can be optionally substituted.

[0067] “Heteroarylalkyl” refers to a radical of the formula -Rb-Rf where Rb is an alkylene, alkenylene, or alkynylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can be optionally substituted.

[0068] “Thioalkyl” refers to a radical of the formula -SRa where Ra is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.

[0069] The term“substituted” used herein means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, /V-heterocyclyl. heterocyclylalkyl, heteroaryl, A'-heteroaryl and/or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups.“Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgC(=0)ORh, -NRgSOiRh, -OC(=0)NR _g Rh, -OR _g , -SRg, -SOR _g , -SOiRg, -OSOiRg, -S OiOR _g . =NSC R _g , and -SChNRyRh.“Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=0)R _g , -C(=0)OR _g , -C(=0)NR _g R _h , -CHiSOiRg, -CHiSOiNRgRh. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, /V-heterocyclyl, heterocyclylalkyl, heteroaryl, A'-heteroaryl and/or heteroarylalkyl.“Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, /V-heterocyclyl. heterocyclylalkyl, heteroaryl, A'-hctcroaryl and/or heteroarylalkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[0070] As used herein, the symbol (hereinafter can be referred to as“a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of

XY-j- which is not depicted as being attached to the point of attachment bond. For example,“

” indicates that the chemical entity“XY” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound CFF-R ³ , wherein R ³ is H or“

XY-j-

” infers that when R ³ is“XY”, the point of attachment bond is the same bond as the bond by which R ³ is depicted as being bonded to CFF.

[0071] ‘Fused” refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring can be replaced with a nitrogen atom.

[0072] ‘Geminal” refers to any two substituents (e.g., those described herein such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.) that are attached to the same atom. In some embodiments, geminal substitution refers to substitution on the same

carbon atom. The structure exemplifies geminal methyl substitution on cyclohexane.

[0073] “Optional” or “optionally” means that the subsequently described event of circumstances can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example,“optionally substituted aryl” means that the aryl radical can or cannot be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution. [0074] The compounds of the invention, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as ( R )- or (5)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms whether or not they are specifically depicted herein. Optically active (+) and (-), ( R )- and (5)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0075] A‘‘stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.

[0076] A“tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any said compounds.

[0077] “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0078] “Pharmaceutically acceptable salt” includes both acid and base addition salts.

[0079] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor- lO-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- l,2-disulfonic acid, ethane sulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, 1 -hydroxy-2 -naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid. /Molucncsulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0080] “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, A'-cthylpipcridinc. polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0081] Crystallization is a method commonly used to isolate a reaction product, for example one of the compounds disclosed herein, in purified form. Often, crystallization produces a solvate of the compound of the invention. As used herein, the term“solvate” refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent, typically in co-crystallized form. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present invention can exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compound of the invention can be true solvates, while in other cases, the compound of the invention can merely retain adventitious water or be a mixture of water plus some adventitious solvent.

[0082] The chemical naming protocol and structure diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, using the ACD/Name Version 9.07 software program, ChemDraw Ultra Version 11.0.1 and/or ChemDraw Ultra Version 14.0 and/or ChemDraw Professional 16.0.0.82 software naming program (CambridgeSoft), or the like. For complex chemical names employed herein, a substituent group is named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.

[0083] The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products can result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

[0084] ‘Stable compound” and“stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0085] As used herein, a“subject” can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, insect and the like. The subject can be suspected of having or at risk for having a cancer, such as a blood cancer, or another disease or condition. Diagnostic methods for various cancers, and the clinical delineation of cancer, are known to those of ordinary skill in the art. The subject can also be suspected of having an infection or abnormal cardiovascular function.

[0086] ‘Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non domestic animals such as wildlife and the like.

[0087] A“pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.

[0088] “An “effective amount” refers to a therapeutically effective amount or a prophylactically effective amount. A“therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduced tumor size, increased life span or increased life expectancy. A therapeutically effective amount of a compound can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as smaller tumors, increased life span, increased life expectancy or prevention of the progression of prostate cancer to a castration-resistant form. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount can be less than a therapeutically effective amount.

[0089] “Treating” or“treatment” as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes (but is not limited to):

1. preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it;

2. inhibiting the disease or condition, i.e., arresting its development; 3. relieving the disease or condition, i.e., causing regression ofthe disease or condition (ranging from reducing the severity of the disease or condition to curing the disease of condition); or

4. relieving the symptoms resulting from the disease or condition, i.e., relieving pain without addressing the underlying disease or condition. As used herein, the terms “disease” and“condition” can be used interchangeably or can be different in that the particular malady or condition cannot have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.

[0090] Throughout the present specification, the terms“about” and/or“approximately” can be used in conjunction with numerical values and/or ranges. The term“about” is understood to mean those values near to a recited value. For example,“about 40 [units]” can mean within ± 25% of 40 (e.g., from 30 to 50), within ± 20%, ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, less than ± 1%, or any other value or range of values herein. Furthermore, the phrases“less than about [a value]” or“greater than about [a value]” should be understood in view of the definition of the term“about” provided herein. The terms“about” and“approximately” can be used interchangeably.

[0091] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range“from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range can be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc ).

[0092] Following below are more detailed descriptions of various concepts related to, and embodiments of inventive compounds and methods for the treatment of liver diseases and abnormal conditions of the liver. It should be appreciated that various concepts introduced above and discussed in greater detail below may be implemented in any of numerous ways, as the disclosed concepts are not limited to any particular manner of implementation. Examples of specific implementations and applications are provided primarily for illustrative purposes. Compounds and Compositions

[0093] In various embodiments, the present disclosure provides compounds of Formula (I):

I

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein

— Y— represents a moiety selected from the group consisting of:

wherein any two R ⁵ groups taken together with the atoms to which they are attached can form a C5-i ₄ -aryl, C5-i ₄ -heteroaryl, C3-i ₂ -cycloalkyl, or C3-i ₂ -heterocycloalkyl ring, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

T and T are each independently -C(=0)-, -X-C(=0)-, -S(=0)2-, or -C= N(R ⁴ )-; U and U' are each independently -CFF-, -NR ⁴ -, -0-, or -S-;

W is -NR ⁴ - or -C(R ³ )(R ³ )-;

X is each independently NR ⁴ , O, or S;

Y is NR ⁴ , O, S(=0)rf;

Z is O or S;

n, n', n", and n'" are each independently 0, 1, or 2; o, o', o", and o'" are each independently 0 or 1 ;

p is 0, 1, 2, 3, or 4;

r is 0, 1, 2, or 3;

q is 0, 1, 2, 3, 4, or 5;

R ¹ and R ² are each independently -(QrhV _' -Cs-M-aryl, -(CH ₂ )n _" -C5-i ₄ -heteroaryl, - (CH2V-C3- 12-cycloalkyl, -(CH2)n"-C3-i4-heterocycloalkyl, -(X)-(CH2)n"-C5-i4-aryl, -(X)-C5-i4- aryl, -(X)-C5-i ₄ -heteroaryl, -(X)-C3-i ₂ -cycloalkyl, -(X)-C3-i ₄ -heterocycloalkyl, -C _2-4 -alkenyl- Cs-M-aryl, -C2-4-alkenyl-C5-i4-heteroaryl, -C2-4-alkenyl-C3-i2-cycloalkyl, -C2-4-alkenyl-C3-i2- heterocycloalkyl, -Ci-5-alkyl, -C ₂ -5-alkenyl, or -C ₂ -5-alkynyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein any two R ⁵ groups taken together with the atoms to which they are attached can form Cs-M-aryl, C5-14- heteroaryl, C3-i ₂ -cycloalkyl, or C3-i ₂ -heterocycloalkyl ring;

R ³ and R ³ ’ are each independently H, F, -Ci-5-alkyl, -C2-5-alkenyl, -C2-5-alkynyl, -C ₃ - ₁₂ -cycloalkyl, -C ₃ - ₁₂ -cycloalkenyl, -(CH ₂ )p-aryl, -(CH ₂ )p-heteroaryl, -(CFh)p-C3- ₁₂ - cycloalkyl, -(CH2)p-C3 -12-cycloalkenyl, -(CFb)p-C3-i2-heterocycloalkyl, -(CH2)p-C5-i4- heteroaryl, -OH, -OCi-5-alkyl, -OC(=0)R ⁶ , or-NR ⁴ R ⁴ , each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein two geminal R ³ or two geminal R ³ ’ taken together with the carbon atom to which they are attached can form a -C3-12- cycloalkyl or -C3-i2-heterocycloalkyl ring;

R ⁴ , R ⁴ ’, and R ^4" are each independently H, -Ci-5-alkyl, -C ₂ -5-alkenyl, -C ₂ -5-alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ⁶ , -C(=0)OR ⁶ , -OH, -OR ⁶ , -OC(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -OC(=0)OR ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -C5- 12-aryl, -C5-12- heteroaryl, -C3-i ₂ -cycloalkyl, or -C3-i ₂ -heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein two of R ⁴ , R ⁴ ’, and R ⁴ ’ from group— V— taken together with the atoms to which they are attached can form a -C5-i ₄ -heteroaryl or -C3-i ₂ -heterocycloalkyl ring, or alternatively, wherein one of R ⁴ , R ⁴ ’, and R ⁴ ’ from group— V— and one R ³ when W is -C(R ³ )(R ³ )- taken together with the atoms to which they are attached can form a -Cs-M-heteroaryl or -C3-i ₂ -heterocycloalkyl ring;

R ⁵ is halogen, -Ci-s-alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ⁶ , -0C(=0)0R ⁶ , -SR ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ R ⁶ , -NO2, -NH ₂ , -N(H)S0 ₂ R ⁶ ,

N(S0 ₂ R ⁶ )2, -NR ⁴ R ^4' , -NR ⁴ -C 1-5-acyl; (CH2)n-C5- 14-aryl, -(CH2)n-C5-i4-heteroaryl, -(CH2)n-C3 -12-cycloalkyl, or -(CFh)n-C3-i4- heterocycloalkyl, wherein when R ⁵ is -S0 ₂ NR ⁶ NR ⁶ , R ⁶ and R ⁶ ' taken together with the N to which they are attached can form an optionally substituted -C5-i4-heteroaryl, or -C3-12- heterocycloalkyl ring; and

R ⁶ and R ^6' are each independently H, -CF3, -CHF2, -CFhF, -Ci-5-alkyl, -C2-5 -alkenyl, -

C ₂ -5-alkynyl, -Ci-5-acyl, -Cs-M-aryl, -Cs-M-heteroaryl, -C3-i ₂ -cycloalkyl, or -C3- ₁₂ - heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN.

[0094] In various embodiments, the present disclosure provides compounds of Formula (I):

I

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein

— Y— represents a moiety selected from the group consisting of:

wherein any two R ⁵ groups taken together with the atoms to which they are attached can form a C5-i ₄ -aryl, C5-i ₄ -heteroaryl, C ₃ -i ₂ -cycloalkyl, or C ₃ -i ₂ -heterocycloalkyl ring, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN; T and T' are each independently -C(=0)-, -X-C(=0)-, -S(=0)2-, or -C= N(R ⁴ )-;

U and U' are each independently -CH2-, -NR ⁴ -, -0-, or -S-;

W is -NR ⁴ - or -C(R ³ )(R ³ )-;

X is each independently NR ⁴ , O, or S;

Y is NR ⁴ , O, S(=0)rf;

Z is O or S;

n, n', n", and n'" are each independently 0, 1, or 2;

o, o', o", and o'" are each independently 0 or 1 ;

p is 0, 1, 2, 3, or 4;

r is 0, 1, 2, or 3;

q is 0, 1, 2, 3, 4, or 5;

R ¹ and R ² are each independently -(QrhV _' -Cs-w-aryl, -(CH2V-C5- 14-heteroaryl, - (CH2)n"-C3- 12-cycloalkyl, -(CH2)n"-C3-i4-heterocycloalkyl, -(X)-(CH2)n"-C5-i4-aryl, -(X)-C5-i4- aryl, -(X)-C5-i ₄ -heteroaryl, -(X)-C3-i ₂ -cycloalkyl, -(X)-C3-i ₄ -heterocycloalkyl, -C _2-4 -alkenyl- Cs-M-aryl, -C _2-4 -alkenyl-C5-i ₄ -heteroaryl, -C _2-4 -alkenyl-C3-i ₂ -cycloalkyl, -C _2-4 -alkenyl-C3-i ₂ - heterocycloalkyl, -Ci-5-alkyl, -C ₂ -5-alkenyl, or -C ₂ -5-alkynyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein any two R ⁵ groups taken together with the atoms to which they are attached can form a C5-i4-aryl, C5-14- heteroaryl, C3-i ₂ -cycloalkyl, or C3-i ₂ -heterocycloalkyl ring;

R ³ and R ³ are each independently H, F, -Ci-5-alkyl, -C ₂ -5-alkenyl, -C ₂ -5-alkynyl, -C3- 12-cycloalkyl, -C3- 12-cycloalkenyl, -(CFh)p-aryl, -(CH2)p-heteroaryl, -(CH ₂ )p-C3- 12- cycloalkyl, -(CFk)p-C3 -12-cycloalkenyl, -(CH2)p-C3-i2-heterocycloalkyl, -(CH2)p-C5-i4- heteroaryl, -OH, -OCi-5-alkyl, -OC(=0)R ⁶ , or -NR ⁴ R ⁴ , each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein two geminal R ³ or two geminal R ³ ’ taken together with the carbon atom to which they are attached can form a -C3-12- cycloalkyl or -C3-i ₂ -heterocycloalkyl ring;

R ⁴ , R ⁴ ’, and R ^4" are each independently H, -Ci-5-alkyl, -C ₂ -5-alkenyl, -C ₂ -5-alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ⁶ , -C(=0)OR ⁶ , -OH, -OR ⁶ , -OC(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -OC(=0)OR ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -C5- 12-aryl, -C5-12- heteroaryl, -C3-i2-cycloalkyl, or -C3-i2-heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein two of R ⁴ , R ⁴ ’, and R ⁴ ’ from group— V— taken together with the atoms to which they are attached can form a -C5-i ₄ -heteroaryl or -C3-i ₂ -heterocycloalkyl ring, or alternatively, wherein one of R ⁴ , R ⁴ ’, and R ^4' from group— V— and one R ³ when W is -C(R ³ )(R ³ )- taken together with the atoms to which they are attached can form a -Cs-w-heteroaryl or -C3-i ₂ -heterocycloalkyl ring;

R ⁵ is halogen, -Ci-s-alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ⁶ , -0C(=0)0R ⁶ , -SR ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ R ⁶ , -NOi, -NIL·, -N(H)S0 ₂ R ⁶ ,

-N(S0 ₂ R ⁶ ) ₂ , -NR ⁴ R ⁴ , -NR ⁴ -C ₁ -5-acyl;

(CH ₂ ) _n -C5- 14-aryl, -(CH ₂ ) _n -C5-i4-heteroaryl, -(CH ₂ ) _n -C3 -12-cycloalkyl, or -(CH ₂ )n-C3-i4- heterocycloalkyl, wherein when R ⁵ is -S0 ₂ NR ⁶ NR ⁶ , R ⁶ and R ^6' taken together with the N to which they are attached can form an optionally substituted -C5-i4-heteroaryl, or -C3-12- heterocycloalkyl ring; and

R ⁶ and R ^6' are each independently H, -CF3, -CHF ₂ , -CH ₂ F, -Ci-5-alkyl, -C ₂ -5 -alkenyl, - C ₂ -5-alkynyl, -Ci-5-acyl, -Cs-M-aryl, -Cs-M-heteroaryl, -C3-i ₂ -cycloalkyl, or -C3- ₁₂ - heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

with the proviso that the compound is not BMCL-38 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0095] In various embodiments, the compound of Formula (I) is a compound of Formula (!'):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

V, T, T, U, U', R ¹ , R ² , R ³ , o, and o' are as defined above for Formula (I);

with the proviso that the compound is not BMCL-38 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0096] In some embodiments, the present disclosure provides compounds of Formula (I), wherein— V— is:

[0098] In specific embodiments, In other specific

O

embodiments, — V— is . In still other specific embodiments, — V— is ,

a specific embodiment,— V— is— N(R ⁴ )— . In another specific embodiment,— V— is -

I

j4-

^R " p R4 . In still another specific embodiment,— V— is ^R . In yet another specific

embodiment, , . In other certain embodiments of Formula (I),— V— is a bond. In another embodiment,— V— is

NR ⁴ '

N

[0099] In various embodiments of Formula (I), T and T are each independently -C(=0)-, -X-C(=0)— , or— S(=0)2-. In some embodiments, T and T ¹ are each independently -C(=0)-, -X-C(=0)— , or -C=N(R ⁴ )-. In some embodiments, T and T ¹ are each independently -C(=0)- ,— S(=0)2— , or -C=N(R ⁴ )-. In some embodiments, T and T ¹ are each independently -S(=0)2-

, -X-C(=0)— , or-C=N(R ⁴ )-. In some embodiments, T and T ¹ are each independently -C(=0)- or -S(=0)2-. In some embodiments, T and T ¹ are each independently -X-C(=0)-. In some embodiments, T and T ¹ are each independently -C(=0)-. In some embodiments, T and T ¹ are each independently -S(=0)2- In some embodiments, T and T ¹ are each independently - C=N(R ⁴ )-.

[00100] In some embodiments of Formula (I), T is -C(=0)-, -X-C(=0)-, -C=N(R ⁴ )-, or - S(=0)2- and T ¹ is -C(=0)-. In other embodiments, T is -C(=0)-, -X-C(=0)-, -C=N(R ⁴ )-, or -S(=0)2- and T ¹ is -S(=0)2-. In still other embodiments, T is -C(=0)-, -X-C(=0)-, - C=N(R ⁴ )-, or -S(=0)2- and T ¹ is -C=N(R ⁴ )-. In certain embodiments, T is -C(=0)- and T ¹ is — C(=0)— , -X-C(=0)— , -C=N(R ⁴ )-, or -S(=0)2-. In certain other embodiments, T is -S(=0)2- and T ¹ is -C(=0)-, -C=N(R ⁴ )-, -X-C(=0)-, or -S(=0)2-. In various other embodiments, T is -C=N(R ⁴ )- and T ¹ is -C(=0)-, -C=N(R ⁴ )-, -X-C(=0)-, or -S(=0)2-. In various other embodiments, T is -X-C(=0)- and T is -C(=0)-, -C=N(R ⁴ )-, -X-C(=0)-, or -S(=0)2-. In some embodiments, T is -C(=0)-, -C=N(R ⁴ )-, or -S(=0)2- and T' is -C(=0)-. In other embodiments, T is -C(=0)-, -C=N(R ⁴ )-, or -S(=0) ₂ - and T' is -S(=0) ₂ -. In still other embodiments, T is -C(=0)-, -C=N(R ⁴ )-, or -S(=0)2- and T' is -C=N(R ⁴ )-. In certain embodiments, T is -C(=0)- and T' is -C(=0)-, -C=N(R ⁴ )-, or -S(=0)2-. In certain other embodiments, T is -S(=0)2- and T' is -C(=0)-, -C=N(R ⁴ )-, or -S(=0)2-. In various other embodiments, T is -C=N(R ⁴ )- and T' is -C(=0)-, -C=N(R ⁴ )-, or -S(=0)2-. In still other embodiments, T is -C(=0)- or -S(=0)2- and T' -C(=0)-. In yet other embodiments, T is -C(=0)— or— S(=0)2- and T' -S(=0)2-. In various other embodiments, T and T' are the same. In some embodiments, T is -C(=0)- and T' is -C(=0)-. In some other embodiments, T is - C=N(R ⁴ )- and T' is -C=N(R ⁴ )-. In still other embodiments, T is -S(=0)2- and T' is -S(=0)2-.

[00101] In various embodiments, the present disclosure further provides compounds of Formula (I), wherein U and U' are each independently -NR ⁴ -, -CFh-, or -0-. In some embodiments, U and U' are each independently -NR ⁴ - or -0-. In some embodiments, U and U' are each independently -NR ⁴ - or -CFh-. In some embodiments, U and U' are each independently -NR ⁴ -. In certain embodiments, U is -NR ⁴ -. In other certain embodiments, U is -0-. In still other certain embodiments, U is -CFh- In yet other certain embodiments, U is— S— . In specific embodiments, U' is -NR ⁴ -. In other specific embodiments, U' is -0-. In still other specific embodiments, U' is -CFb-. In yet other specific embodiments, U' is -S-.

[00102] In some embodiments, U is -NR ⁴ -, -0-, or -S- and U' is -NR ⁴ -, -0-, or -S-. In various other embodiments, U is -NR ⁴ - or -O-and U' is NR ⁴ or -0-. In some embodiments, U is -NR ⁴ - and U' is -CFb-, -NR ⁴ -, -0-, or -S-. In other embodiments, U is -O- and U' is -CFb-, -NR ⁴ -, -O-, or -S-. In another embodiment, U is -S- and U' is -CFb-, -NR ⁴ -, - O-, or— S— . In some other embodiments, U is -CFb-, -NR ⁴ -, -0-, or -S- and U' is -NR ⁴ -. In various other embodiments, U is -CFb-, -NR ⁴ -, -0-, or -S- and U' is -0-. In yet another embodiment, U is -CFb-, -NR ⁴ -, -0-, or -S- and U' is -S-. In some embodiments, U and U' are each -NR ⁴ -. In still other embodiments, U is -O- and U' is -NR ⁴ -. In still other embodiments, U is -S- and U' is -NR ⁴ -. In some embodiments, U and U' are each -0-. In still other embodiments, U is -NR ⁴ - and U' is -0-. In various embodiments, U is -S- and U' is -0-. In another embodiment, U and U' are each -S-. In still other embodiments, U is - NR ⁴ - and U' is -S-. In yet another embodiment, U is -O- and U' is -S-. In certain other embodiments, U is -NR ⁴ - and U' is -CFb-. [00103] In certain embodiments of Formula (I), U is -NR ⁴ - and T is -C(=0)-. In some embodiments, U is -NR ⁴ - and T is -S(=0)2-. In other embodiments, U is -NR ⁴ - and T is absent (e.g., o'" is 0).

[00104] In some embodiments of Formula (I), W is -N(R ⁴ )-. In other embodiments, W is -C(R ³ )(R ³ )-.

[00105] In some embodiments, n is 1, and o, o', o", and o'" are each 1. In other embodiments, n is l, o and o' are each 0, and o", and o'" are each 1. In yet other embodiments, n is 1, o is 1, o' is 0, and o", and o'" are each 1. In certain embodiments, n is 1, o is 0, o' is 1, and o", and o'" are each 1. In some embodiments, n is 0, and o, o', o", and o'" are each 1. In other embodiments, n is 0, o and o' are each 0, and o", and o'" are each 1. In yet other embodiments, n is 0, o is 1, o' is 0, and o", and o'" are each 1. In certain embodiments, n is 0, o is 0, o' is 1, and o", and o'" are each 1.

[00106] In some embodiments,

, wherein q is 0, 1, 2, 3, 4, or 5.

[00107] In some embodiments,

and U is -NR ⁴ ’.

[00109] In some embodiments,

W is -C(R ³ )(R ³ )-, and U and U ¹ are each independently -NR ⁴ ’. [00110] In some embodiments,

W is -C(R ³ )(R ³ )-, U and U ¹ are each independently -NR ⁴ ’, and T is -C(=0)-, -S(=0)2 -

C=N(R ⁴ )-, or -X-C(=0)-, wherein X ¹ is NR ⁴ . In other embodiments, T is -C(=0)-. In still other embodiments, T is -S(=0)2 In yet other embodiments, T is -C=N(R ⁴ )-. In certain embodiments, T is -X -C(=0)-. In some embodiments, each R ⁴ is independently H or Me. In other embodiments, each R ⁴ is H. In some embodiments, each R ⁴ ’ is independently H, Me, or NH ₂ . In certain embodiments, each R ⁴ ’ is H. In some embodiments, each R ^4" is independently H or Me In certain embodiments, each R ^4" is H.

[00111] In some embodiments,

W is -C(R ³ )(R ³ )-, U and U ¹ are each independently -NR ⁴ ’, T is -C(=0)-, and T ¹ is -C(=0)-, — S(=0) ₂ -, -C=N(R ⁴ )-, or -X -C(=0)-, wherein X ¹ is NR ⁴ . In other embodiments, T ¹ is - C(=0)-. In still other embodiments, T ¹ is -S(=0) ₂ -. In yet other embodiments, T ¹ is - C=N(R ⁴ )-. In certain embodiments, T ¹ is -X -C(=0)-. In other embodiments, each R ⁴ is H. In some embodiments, each R ⁴ ’ is independently H, Me, or NH ₂ . In certain embodiments, each R ^4' is H. In some embodiments, each R ^4" is independently H or Me In certain embodiments, each R ^4" is H.

[00112] In some embodiments,

W is -C(R ³ )(R ³ )-, U and U ¹ are each independently -NR ⁴ ’, T is -S(=0)2-, and T ¹ is -C(=0)-, — S(=0) ₂ -, -C=N(R ⁴ )-, or -X -C(=0)-, wherein X ¹ is NR ⁴ . In other embodiments, T ¹ is - C(=0)-. In still other embodiments, T ¹ is -S(=0) ₂ -. In yet other embodiments, T ¹ is - C=N(R ⁴ )-. In certain embodiments, T ¹ is -X -C(=0)-. In other embodiments, each R ⁴ is H. In some embodiments, each R ⁴ ’ is independently H, Me, or NH ₂ . In certain embodiments, each R ^4' is H. In some embodiments, each R ^4" is independently H or Me In certain embodiments, each R ^4" is H. [00113] In some embodiments,

W is -C(R ³ )(R ³ )-, U and U ¹ are each independently -NR ⁴ ’, T is -C=N(R ⁴ )-, and T is -C(=0)-, -S(=0)2 -C=N(R ⁴ )-, or -X -C(=0)-, wherein X ¹ is NR ⁴ . In other embodiments, T ¹ is -

C(=0)-. In still other embodiments, T ¹ is -S(=0)2 In yet other embodiments, T ¹ is - C=N(R ⁴ )-. In certain embodiments, T ¹ is -X -C(=0)-, wherein X ¹ is NR ⁴ . In other embodiments, each R ⁴ is H. In some embodiments, each R ⁴ ’ is independently H, Me, or NH2. In certain embodiments, each R ⁴ ’ is H. In some embodiments, each R ^4" is independently H or Me In certain embodiments, each R ^4" is H.

[00114] In some embodiments,

W is -C(R ³ )(R ³ )-, U and U ¹ are each independently -NR ⁴ ’, T is -X -C(=0)-, wherein X ¹ is NR ⁴ , and T ¹ is -C(=0)-, -S(=0)2 -, -C=N(R ⁴ )-, or -X -C(=0)-, wherein X ¹ is NR ⁴ . In other embodiments, T ¹ is -C(=0)-. In still other embodiments, T is -S(=0)2 -. In yet other embodiments, T ¹ is -C=N(R ⁴ )-. In certain embodiments, T ¹ is -X -C(=0)-, wherein X ¹ is NR ⁴ . In other embodiments, each R ⁴ is H. In some embodiments, each R ⁴ ’ is independently H, Me, or NH2. In certain embodiments, each R ⁴ ’ is H. In some embodiments, each R ^4" is independently H or Me In certain embodiments, each R ^4" is H.

[00115] In some embodiments of Formula (I), X is NR ⁴ or O. In other embodiments, X is O. In still other embodiments, X is NR ⁴ . In certain embodiments, X is S. In some embodiments, X is N-Cs-n-aryl, N-Cs-n-heteroaryl, N-C3-i2-cycloalkyl, or N-C3-12- heterocycloalkyl. In certain embodiments, the N-Ci-5-alkyl is N-Me, N-Et, N-Pr, or N-/Pr. In certain embodiments, the N-C3-i ₂ -cycloalkyl is N-cPr, N-cBu, N-cCsFE, or N-c ,H 1 1. In certain embodiments, the N-Cs-n-aryl is N-Ph. N-CFh-cCeHn, N-CFhPh, and. In specific embodiments, X is N-H. In other specific embodiments, X is N-Me.

[00116] The present disclosure also provides compounds of Formula (I), wherein Y is O. In some embodiments, Y is NR ⁴ . In certain embodiments, the NR ⁴ is selected from the group consisting of N-H, N-Me, N-Et, N-Pr, N-/Pr, N-CFhPh, and N-Ph. In specific embodiments, Y is N-H. In other specific embodiments, Y is N-Me. In yet other specific embodiments, Y is SOi.

[00117] In some embodiments of Formula (I), Z is O. In other embodiments, Z is S.

[00118] The present disclosure further provides compounds of Formula (I), wherein n, n', n", and n'" are each independently 0 or 1. In some embodiments, n, n', n", and n'" are each independently 0. In other embodiments, n, n', n", and n'" are each independently 1. In various n is 0 or 1. In certain embodiments of the present disclosure, n is 0. In other embodiments, n is 1. In various other embodiments, n is 2. In various embodiments, the present disclosure provides compounds wherein n' is 0 or 1. In certain embodiments of the present disclosure, n' is 0. In other embodiments, n' is 1. In various other embodiments, n' is 2. In various embodiments, the present disclosure provides compounds wherein n" is 0 or 1. In certain embodiments of the present disclosure, n" is 0. In other embodiments, n" is 1. In various other embodiments, n" is 2. In certain embodiments of the present disclosure, n'" is 0. In other embodiments, n'" is 1. In various other embodiments, n'" is 2. In some embodiments, n, n', n", and n'" are the same. In some embodiments, n, n', n", and n'" are each different.

[00119] In some embodiments of Formula (I), o, o', o", and o'" are each independently 0. In some embodiments, o, o', o", and o'" are each independently 1. In some embodiments, o is 0. In other embodiments, o is 1. In still other embodiments, o' is 0. In yet other embodiments, o' is 1. In certain embodiments, o" is 0. In other certain embodiments, o" is 1. In specific embodiments, o'" is 0. In other specific embodiments, o'" is 1. In some embodiments, o is 1 and o' is 0. In other embodiments, o is 0 and o' is 1. In some embodiments, o and o' are both 0. In other embodiments, o and o' are both 1. In some embodiments, o" is 1 and o'" is 0. In other embodiments, o" is 0 and o'" is 1. In some embodiments, o" and o'" are both 0. In some embodiments, o" and o'" are both 1.

[00120] In some embodiments of Formula (I), p is 0, 1, 2, or 3. In other embodiments, p is 0, 1, or 2. In various other embodiments, p is 0 or 1. In specific embodiments, p is 0. In other specific embodiments, p is 1. In certain embodiments, p is 2. In certain other embodiments, p is 3. In certain specific embodiments, p is 4.

[00121] In some embodiments of Formula (I), q is 0, 1, 2, 3, or 4. In other embodiments, q is 0, 1, 2, or 3. In still other embodiments, q is 0, 1, or 2. In various other embodiments, q is 0 or 1. In specific embodiments, q is 0. In other specific embodiments, q is 1. In certain embodiments, q is 2. In certain other embodiments, q is 3. In certain specific embodiments, q is 4. In another embodiment, q is 5.

[00122] In some embodiments of Formula (I), r is 0, 1, or 2. In yet other embodiments, r is 1 or 2. In certain embodiments, r is 0. In specific embodiments, r is 1. In other specific embodiments, r is 2. In another embodiment, r is 3.

[00123] In various of Formula (I), R ¹ is selected from the group consisting of -Ci-5-alkyl, -Ci -5-alkenyl, or -Ci-5-alkynyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , =NCN.

[00124] In some embodiments, R ¹ is -(CFhV-Cs-w-aryl, -(CFhV _' -Cs-M-heteroaryl, - (CH2V-C3 -12-cycloalkyl, or -(CH ₂ )n _" -C3-i ₄ -heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein any two R ⁵ groups taken together with the atoms to which they are attached can form a -Cs-n-aryl, -C5-12- heteroaryl, -C ₃ -i ₂ -cycloalkyl, or -C ₃ -i ₂ -heterocycloalkyl ring.

[00125] In some embodiments, R ¹ is -(CH2)n"-C5-i4-aryl, optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In some embodiments, the -(CFhV-Cs-w-aryl

[00126] In some embodiments, R ¹ is -(CH2)n"-C5-i4-heteroaryl, optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In some embodiments, the -(CtRh'-Cs-

i ₄ -heteroaryl is

[00127] In some embodiments, R ¹ is -(CH2)n"-C3-i2-cycloalkyl, optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In some embodiments, the -(CH2)n"-C3-

12-cycloalkyl

[00128] In some embodiments, R ¹ is -(CH2)n"-C3-i4-heterocycloalkyl, optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In some embodiments, the -(CFhV-

[00129] In some embodiments, R ¹ is -(X)-(CH2)n"-C5-i4-aryl, optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein X is as defined in Formula (I), and wherein any two R ⁵ groups taken together with the atoms to which they are attached can form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring. In some embodiments, the -(X)-

(CH ₂ )n _" -C5-i ₄ -aryl certain embodiments, R ⁴ is H.

[00130] In some embodiments, R ¹ is -(X)-C5-i4-aryl, -(X)-C5-i4-heteroaryl, -(X)-C3-i2- cycloalkyl, or -(X)-C3-i ₄ -heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein X is as defined in Formula (I), and wherein any two R ⁵ groups taken together with the atoms to which they are attached can form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring. In some embodiments, the -(X)-Cs-

1 ₄ -aryl , wherein X is as defined in Formula (I). In some embodiments,

the -(X)-C5-i ₄ -heteroaryl is

wherein X is as defined in Formula (I).

[00131] In various embodiments of R ¹ , X, Y, R ⁴ , R ⁵ ,R ⁶ , n, n", p, q, and r are as defined in Formula (I).

[00132] In some embodiments, R ¹ is selected from the group consisting of:

'Od

wherein any two R ⁵ groups taken together with the atoms to which they are attached can form a -C5-8-aryl, -Cs-s-heteroaryl, -C3 -8-cycloalkyl, or -C3-8-heterocycloalkyl ring, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, and wherein X, Y, R ⁴ , R ⁵ , R ⁶ , n, p, q, and r are as defined in Formula (I).

[00133] In some embodiments, R ¹ is selected from the group consisting of:

, y g p g y attached can form a -C5-i4-aryl, -C5-i4-heteroaryl, -C3-i2-cycloalkyl, or -C3-12- heterocycloalkyl ring, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, and wherein X, Y, R ⁴ , R ⁵ , R ⁶ , n, p, q, and r are as defined in Formula

(I)·

[00134] In other embodiments, R ¹ is selected from the group consisting of -C ₁ -5-alkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

. p, q, and r are as defined in Formula (I).

[00135] In some embodiments, the one or more R ⁵ attached to R ¹ is selected from the group consisting of Me, Et, cPr, /Pr, OH, OMe, OEt, OPr, O/Pr, OBu, S0 ₂ Me, CN, CF3, F, Cl, Br, OCF3, and OCF2. In other embodiments, R ⁵ is selected from the group consisting of OMe, OEt, OPr, O/Pr, OBu, SOrMe, CN, CF ₃ , F, Cl, Br, and OCF3. [00136] In certain embodiments, R ¹ is selected from the group consisting of:

[00137] In certain embodiments, R ¹ is selected from the group consisting of:

[00138] In specific embodiments, R ¹ is In other specific embodiments,

. In various specific embodiments, R ¹ is . In still other specific embodiments, R ¹ is In certain specific embodiments, another specific embodiment, yet another specific embodiment,

In certain other specific embodiments, yet another specific embodiment, R ¹ , In other embodiments, R ¹ is . In other specific embodiments, other various embodiments, yet other various embodiments, In still other various embodiments, In yet other various embodiments, In certain embodiments, another embodiment, yet

other specific embodiments, R ¹ is 5 O . In specific embodiments, R i ¹ i iss . In various

specific embodiments, other some specific embodiments, R ¹ is _ _

/ Y

Ό In yet another specific embodiment, R ¹ is In still other

/ ^H specific embodiments, R •H ¹ ies N— ^ . In certain embodiments, certain

other embodiments, R ¹ is In various specific embodiments, R ¹ is

, In various other specific

embodiments, other specific embodiments,

[00139] In various of Formula (I), R ² is selected from the group consisting of -Ci-5-alkyl, -Ci -5-alkenyl, or -Ci-5-alkynyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , =NCN. In certain embodiments, R ² is -Ci-5-alkyl. In specific

embodiments, the

[00140] In some embodiments, R ² is -(CH2)n"-C5-i4-aryl, -(CH2)n"-C5-i4-heteroaryl, - (CH ₂ )n _" -C ₃ -12-cycloalkyl, or -(CH ₂ )n _" -C3-i ₄ -heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein any two R ⁵ groups taken together with the atoms to which they are attached can form a -Cs-M-aryl, -C5-14- heteroaryl, -C3-i ₂ -cycloalkyl, or -C3-i ₂ -heterocycloalkyl ring.

[00141] In some embodiments, R ² is -(ChkV'-Cs-M-aryl, optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In some embodiments, the -(ChkV-Cs-M-aryl

In other

embodiments, the -(CH ₂ )n _" -C5-i ₄ -aryl In certain embodiments,

[00142] In some embodiments, R ² is -(CH2)n"-C5-i4-heteroaryl, optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In some embodiments, the -(Chk -Cs-

certain embodiments, the (CH ₂ )n _" -C5-i ₄ -heteroaryl is

[00143] In some embodiments, R ² is -(CH2)n"-C3-i2-cycloalkyl, optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In some embodiments, the -(CH2)n'-C3-

12-cycloalkyl

[00144] In some embodiments, R ² is -(CH2)n"-C3-i4-heterocycloalkyl, optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In some embodiments, the -(Cfh - C ₃ -i ₄ -heterocycloalkyl is ifi 'Od . In certain embodiments, the

(CH ₂ )n _" -C ₃ -i ₄ -heterocycloalkyl

[00145] In some embodiments, R ² is -(X)-C5-i4-aryl, -(X)-C5-i4-heteroaryl, -(X)-C ₃ -i2- cycloalkyl, or -(X)-C3-i ₄ -heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein X is as defined in Formula (I), wherein any two R ⁵ groups taken together with the atoms to which they are attached can form a -C5-14- aryl, -C5-i4-heteroaryl, -C3-i2-cycloalkyl, or -C3-i2-heterocycloalkyl ring. In some

embodiments, the -(X)-Cs- 14-aryl In some embodiments, the -(X)-Cs-i4-

heteroaryl

[00146] In various embodiments of R ² , X, Y, R ⁴ , R ⁵ ,R ⁶ , n, n", p, q, and r are as defined in Formula (I).

[00147] In some embodiments of Formula (I), R ² is selected from the group consisting of:

wherein any two R ⁵ groups taken together with the atoms to which they are attached can form a -Cs-w-aryl, -Cs-w-heteroaryl, -C ₃ -i ₂ -cycloalkyl, or -C3 -12-heterocycloalkyl ring, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, and wherein X, R ⁵ , R ⁶ , n, p, q, and r are as defined in Formula (I).

[00148] In other embodiments, R ² is selected from the group consisting of:

groups taken together with the atoms to which they are attached can form a -Cs-w-aryl, -Cs-w- heteroaryl, -C3- 12-cycloalkyl, or -C3-i ₂ -heterocycloalkyl ring, Y, R ⁴ , R ⁵ , n, p, q, and r are as defined in Formula (I).

[00149] In other embodiments, R ² is selected from the group consisting of:

, wherein any two R ⁵ groups taken together with the atoms to which they are attached can form a -Cs-w-aryl, -Cs-w-heteroaryl, -C3-i ₂ -cycloalkyl, or -C3-12- heterocycloalkyl ring, R ⁵ , p, q, and r are as defined in Formula (I).

[00150] In some embodiments of Formula (I), the one or more R ⁵ attached to R ² is Ci-5-alkyl , halogen, -OR ⁶ , -S0 ₂ N(H)(Ci-5-alkyl), -S0 ₂ N(H)(C5-8-aryl), -S0 ₂ N(H)(C5-8-heteroaryl), -S0 ₂ N(H)(C3-8-cycloalkyl), -S0 ₂ N(H)(C3-8-heterocycloalkyl), -S0 ₂ N(Ci-5-alkyl) ₂ , -S02N(C5-8-aryl)2, -S02N(C5-8-heteroaryl)2, -S02N(C3-8-cycloalkyl)2, -SChN(C3-8- heterocycloalkyl)2, -N(H)S0 ₂ (Ci-5-alkyl), -N(H)S0 ₂ (C5-8-aryl), -N(H)S0 ₂ (C5-8-heteroaryl), -N(H)S02(C3-8-cycloalkyl), -N(H)S02(C3-8-heterocycloalkyl), -N(S02-Ci-5-alkyl)2, -N(S02- C5-8-aryl)2, -N(S02-C5-8-heteroaryl)2, -N(S02-C3-8-cycloalkyl)2, or -N(S02-C3-8- heterocycloalkyl)2. In other embodiments, R ⁵ is -S02N(H)(Ci-5-alkyl), -S02N(H)(C3-8- cycloalkyl), -S02N(H)(C3-8-heterocycloalkyl), -S02N(Ci-5-alkyl)2, -S02N(C3-8-cycloalkyl)2, -S02N(C3-8-heterocycloalkyl)2, -N(H)S02(Ci-5-alkyl), -N(H)S02(C3-8-cycloalkyl),

-N(H)S02(C3-8-heterocycloalkyl), -N(S02-Ci-5-alkyl)2, -N(S02-C3-8-cycloalkyl)2, or -N(S02-C3-8-heterocycloalkyl)2. In certain embodiments, R ⁵ is -N(H)S02Me, -N(S02Me)2, -SO2NH2, -SChNHMe, -SChNHEt, -SChNHPr, -SChNH/Pr, -SO2NMC2. -S0 ₂ NEt ₂ , wherein X is X is O, S, or NR ⁴ . In specific embodiments, R ⁵ is -SChNHMe. In other specific embodiments, R ⁵ is -SChNMei. In still other specific embodiments, R ⁵ is -SChNH/Pr. In yet other specific embodiments, R ⁵ is S02N(/Pr)2. In certain embodiments, R ⁵ is -SChNEt2. In other certain embodiments, R ⁵ is -SChNHcCeHn. In still other certain embodiments, R ⁵ is -SO2NH2. In yet other certain SO ₂ NH <] embodiments, R ⁵ is In some embodiments, R ⁵ is . In other

— S0 ₂ N NMe

embodiments, R ⁵ is \— f . In yet other embodiments, R ⁵ is . In still other embodiments, R ⁵ is -N(S02Me)2.

In specific embodiments, In another specific embodiment, R ² is

In yet another specific embodiment, certain other

specific embodiments, In yet another specific embodiment, R ² is , _T ,

some embodiments, In other embodiments, R

T „ , , ,

In still other embodiments, yet another

embodiment, ,

yet other specific embodiments, specific embodiments, R ² is

various specific embodiments, other some yet another specific embodiment, R ² is

In still other specific embodiments, , wherein X

is CFk, N-Me, or O. In certain embodiments, wherein X is CFk, N-

Me, or O.

[00151] In various embodiments of the compounds of Formula (I), R ³ and R ^3’ are each independently selected from the group consisting of -Ci-5-alkyl, -C ₃ -i ₂ -cycloalkyl, -(CFk)p- aryl, -(CH2)p-heteroaryl, -(CH2)p-C3- 12-cycloalkyl, -(CH2)p-C3 -12-cycloalkenyl, -(CEb)p-C3- 12-heterocycloalkyl, or -(CH2)p-C5- 14-heteroaryl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In some embodiments, R ³ and R ³ ’ are each independently selected from the group consisting of -Ci-5-alkyl, -C3-i2-cycloalkyl, -(CH ₂ ) _P -Ph, -(CH ₂ )p-C ₃ -12-cycloalkyl, or -(CH ₂ )p-C5-i ₄ -heteroaryl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN.

[00152] In some embodiments, R ³ and R ³ ’ are each independently -Ci-5-alkyl, optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In certain embodiments, the -Ci-5-alkyl is Me, Et, Pr, /Pr, Bu, /Bu or CH2-CH(CH3)2, optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In further embodiments, the R ⁵ is -NR ⁴ R ⁴ , -OR ⁶ , or -SR ⁶ , wherein R ⁴ , R ⁴ ’, and R ⁶ are each independently Me, Et, Pr, /- Pr, or /-Bu. In other certain embodiments, the -Ci-5-alkyl is Me, Et, Pr, /Pr, Bu, /Bu or CH2-CH(CH3)2.

[00153] In some embodiments, R ³ and R ³ are each independently -(CH ₂ )p-C3-i ₂ -cycloalkyl, wherein p is 0 to 4. In certain embodiments, the -(CH ₂ )p-C3- 12-cycloalkyl is , optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In some embodiments, the -(CH ₂ )p-C3-i ₂ -cycloalkyl is . wherein p is 0. In some embodiments, the -(CH ₂ ) _p -C ₃ - 12-cycloalkyl is , _w herein p is 1. In some embodiments, the -(CH ₂ )p-C3-i ₂ -cycloalkyl is . wherein p is 2. In some embodiments, the -(CH ₂ )p-C3-i ₂ -cycloalkyl is . wherein p is 3. In some embodiments, the -(CH2)p-C3- 12-cycloalkyl . wherein p is 4.

[00154] In some embodiments, R ³ and R ^3' are each independently -C3- 12-cycloalkyl. In some embodiments, the -C3- 12-cycloalkyl is . wherein p is 0. In some embodiments, -C3-

12-cycloalkyl is , wherein p is 1. In some embodiments, -C3-i ₂ -cycloalkyl is , wherein r is 2. In some embodiments, -C3-i ₂ -cycloalkyl is ^/ o '"' ^r '. ^p _ wherein p is

3. In some embodiments, -C3-i ₂ -cycloalkyl i , wherein p is 4.

[00155] In some embodiments of Formula (I), R ³ and R ^3' are each independently

(CFk)p-aryl, wherein p is 0 to 4. In certain embodiments, the -(CFk)p-aryl

,

some embodiments,

[00156] In some embodiments of Formula (I), R ³ and R ^3' are each independently -(CFk)p- heteroaryl, wherein p is 0 to 4. In some embodiments, the -(CFh)p-heteroaryl is from the group

consisting , wherein X, R ⁵ , and q are as defined in Formula

(I) , and wherein two R ⁵ taken together with the carbon atoms to which they are attached can form a -Cs-M-aryl, -Cs-M-heteroaryl, -C3- 12-cycloalkyl, or -C3-i ₂ -heterocycloalkyl ring. In

certain embodiments, the -(CH2)p-heteroaryl [00157] In some embodiments, R ³ and R ^3' are each independently -(CH2)p-C3- 12- cycloalkenyl, wherein p is 0 to 4. In certain embodiments, the -(CH ₂ )p-C3-i ₂ -cycloalkenyl is

(R ⁵

[00158] In some embodiments, R ³ and R ³ are each independently . In other

embodiments, R ³ and R ³ are each independently . In some embodiments, R ³ and

R ³ are each independently In some embodiments, R ³ and R ³ are each

independently In some embodiments, R ³ and R ³ are each independently In some embodiments, R ³ and R ³ are each independently . In some embodiments, R ³ and R ^3' are each independently 'S ^v z . In some embodiments, R ³ and R ^3' are each independently

[00159] In some embodiments, two geminal R ³ groups or two geminal R ^3' groups taken together with the carbon atom to which they are attached form a cyclopropyl, a cyclobutyl, a cyclopentyl, or a cyclohexyl ring, optionally substituted.

[00160] In various embodiments of Formula (I), R ⁴ , R ^4' , and R ^4" are each independently selected from the group consisting of H, -NR ⁶ R ⁶ _{, -} Ci-5-alkyl, -C ₃ - ₁₂ -cycloalkyl, -C3- ₁₂ - heterocycloalkyl, -Ci-5-alkenyl, -Ci-5-alkynyl, -Ph, -C(=0)R ⁶ , and -S(=0)2R ⁶ , each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In some embodiments, R ⁴ , R ^4' , and R ^4" are each independently H. [00161] In some embodiments, R ⁴ , R ^4' , and R ^4" are each independently -Ci-5-alkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In related embodiments, the -Ci-5-alkyl is Me, Et, Pr, /Pr, Bu, /Bu. or CH2-CH(CH3)2. In specific embodiments, the -Ci-5-alkyl is Me. In other specific embodiments, the -Ci-5-alkyl is Et. In still other specific embodiments, the -Ci-5-alkyl is Pr. In yet other specific embodiments, the -Ci-5-alkyl is /Pr. In certain embodiments, the -Ci-5-alkyl is /Bu.

[00162] In some embodiments, R ⁴ , R ^4' , and R ^4" are each independently -C3-i ₂ -cycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or

=NCN. In certain embodiments, the -C3-i2-cycloalkyl is

In other specific embodiments, -C3-i ₂ -cycloalkyl is

[00163] In certain embodiments, R ⁴ , R ^4' , and R ^4" are each independently -C(=0)R ⁶ . In a specific embodiment, the -C(=0)R ⁶ is -C(=0)Me.

[00164] In some embodiments, R ⁴ , R ⁴ , and R ^4" are each independently -S(=0)2NR ⁶ R ⁶ . In certain embodiments, the -S(=0) ₂ NR ⁶ R ^6' is -S0 ₂ N(H)(Ci-5-alkyl), -S0 ₂ N(H)(C5-8-aryl), -S0 ₂ N(H)(C5-8-heteroaryl), -S0 ₂ N(H)(C3-8-cycloalkyl), -S0 ₂ N(H)(C3-8-heterocycloalkyl), -S02N(Ci-5-alkyl)2, -S02N(C5-8-aryl)2, -S02N(C5-8-heteroaryl)2, -S02N(C3-8-cycloalkyl)2, or -S02N(C3-8-heterocycloalkyl)2. In other certain embodiments, the -S02NR ⁶ NR ^6' is -SO2NH2, -SChNHMe, -SChNHEt, -SChNHPr, -SChNH/Pr, -SO2NMC2. -S0 ₂ NEt ₂ , -S0 ₂ NPr ₂ , or -S02N(/Pr) ₂ .

[00165] In some embodiments, R ⁴ , R ^4' , and R ^4" are each independently -S(=0)2R ⁶ . In certain embodiments, -S(=0)2R ⁶ is -S(=0)2Me, -S(=0)2Et, or -S(=0)2-cC6Hn.

[00166] In some embodiments, R ⁴ , R ^4' , and R ^4" are each independently -NR ⁶ R ⁶ . In certain embodiments, -NR ⁶ R ⁶ is -NEh, -NHMe, NMe2, -NHEt, or -NEhPr. In a specific embodiment, 2. In other specific embodiments, -NR ⁶ R ⁶ is -NHMe.

[00167] In various embodiments of the present disclosure, any of R ⁴ , R ^4' , R ^4" , R ^{4 "} , and R ^4"" described herein for Formula (I), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-H _a ), Formula (I-Hb), Formula (I-I), Formula (I-J), Formula (I-K), Formula (I-F), Formula (I-M), or Formula (II) can be used interchangeably to describe a compound disclosed herein. [00168] In various embodiments of Formula (I), R ⁵ is selected from the group consisting of H, halogen, -Ci-s-alkyl, -CF ₃ , -OR ⁶ , -S0 ₂ NR ⁶ NR ^6' , -N(H)S0 ₂ R ⁶ , -N(S0 ₂ R ⁶ ) ₂ , -NR ⁴ R ^4' , O ,,,R ⁴

N

A NL R ⁴

R ⁴ and ' ' H , wherein when R ⁵ is -S0 ₂ NR ⁶ NR ⁶ , R ⁶ and R ⁶ ’ taken together with the N to which they are attached can form an optionally substituted -C5-i4-heteroaryl, or -C ₃ - i ₂ -heterocycloalkyl ring. In specific embodiments, R ⁵ is CF ₃ .

[00169] In some embodiments of Formula (I), R ⁵ is halogen. In certain embodiments, the halogen is F, Cl, Br, or I. In more specific embodiments, the halogen is F or Cl.

[00170] In some embodiments, R ⁵ is -Ci-5-alkyl. In certain embodiments, the -Ci-5-alkyl is Me, Et, Pr, /Pr, Bu, or /Bu. 4

[00171] In some embodiments, R ⁵ is In other embodiments, R ⁵ is

. ..R ⁴

A NX

' H , wherein R ⁴ is H or Me. In still other embodiments, R ⁵ is R ⁴ wherein R ⁴ is

H or Me.

[00172] In some embodiments, R ⁵ is -NR ⁴ R ⁴ , -OR ⁶ , or -SR ⁶ . In certain embodiments, the -OR ⁶ is OH, OMe, OEt, OPr, O/Pr, 0/Bu. OCF ₃ , or OCF ₂ . In certain embodiments, the -SR ⁶ is SH, SMe, SEt, SPr, S/Pr, S/Bu. SCF ₃ , or SCF ₂ . In certain embodiments, the -NR ⁴ R ⁴ ’ is N(Ci- 5-alkyl) ₂ or NH(Ci-5-alkyl).

[00173] In some embodiments, R ⁵ is H. In other embodiments, R ⁵ is Cl. In still other embodiments, R ⁵ is F. In yet other embodiments, R ⁵ is Me. In another embodiment, R ⁵ is Et. In various other embodiments, R ⁵ is Pr. In certain other embodiments, R ⁵ is /Pr. In some other embodiments, R ⁵ is OH. In various embodiments, R ⁵ is OMe. In certain other embodiments, R ⁵ is OEt. In another embodiment, R ⁵ is OPr. In various embodiments, R ⁵ is O/Pr. In some embodiments, R ⁵ is NH ₂ . In related- embodiments, R ⁵ is NHMe. In still other embodiments,

R ⁵ is NIVIci. In various other embodiments, R ⁵ is H . In another embodiment, R ⁵ is

[00174] In some embodiments of Formula (I), R ⁵ is -S02NR ⁶ NR ⁶ . In various embodiments, the -S0 ₂ NR ⁶ NR ^6' is -S0 ₂ N(H)(Ci-5-alkyl), -S0 ₂ N(H)(C5-8-aryl), -S0 ₂ N(H)(C5-8-heteroaryl), -S0 ₂ N(H)(C3-8-cycloalkyl), -S0 ₂ N(H)(C3-8-heterocycloalkyl), -SC N(Ci-5-alkyl) ₂ ,

-S02N(C5-8-aryl)2, -S02N(C5-8-heteroaryl)2, -S02N(C3-8-cycloalkyl)2, or -SC N(C3-8- heterocycloalkyl)2. In other embodiments, the -S02NR ⁶ NR ^6' is -S02N(H)(Ci-5-alkyl), -S0 ₂ N(H)(C3-8-cycloalkyl), -S0 ₂ N(H)(C3-8-heterocycloalkyl), -S0 ₂ N(Ci-5-alkyl) ₂ ,

-S02N(C3-8-cycloalkyl)2, or -S02N(C3-8-heterocycloalkyl)2. In certain embodiments, the -S0 ₂ NR ⁶ NR ^6' is -SO2NH2, -SChNHMe, -SOrNHEt, -SOrNHPr, -SChNH/Pr, -SO2NMC2.

above. In specific embodiments, the -S02NR ⁶ NR ⁶ ’ is -SChNHMe. In other specific embodiments, the -S02NR ⁶ NR ⁶ ’ is -SChNMe2. In still other specific embodiments, the -S0 ₂ NR ⁶ NR ⁶ ’ is -SChNH/Pr. In yet other specific embodiments, the -S0 ₂ NR ⁶ NR ⁶ ’ is S02N(/Pr)2. In certain embodiments, the -S02NR ⁶ NR ⁶ ’ is -S02NEt2. In other certain embodiments, the -S0 ₂ NR ⁶ NR ⁶ ’ is -SChNHcCeElii. In still other certain embodiments, the -S02NR ⁶ NR ⁶ ’ is -SO2NH2. In yet other certain embodiments, the -S02NR ⁶ NR ⁶ ’ is

[00175] In some embodiments of Formula (I), R ⁵ is -N(H)S02R ⁶ . In certain embodiments, the -N(H)S0 ₂ R ⁶ is -N(H)S0 ₂ (Ci-5-alkyl), -N(H)S0 ₂ (C5-8-aryl), -N(H)S0 ₂ (C5-8-heteroaryl), -N(H)S0 ₂ (C3-8-cycloalkyl), or -N(H)S0 ₂ (C3-8-heterocycloalkyl). In other embodiments, the - N(H)S0 ₂ R ⁶ is -N(H)S0 ₂ (Ci-5-alkyl), -N(H)S0 ₂ (C3-8-cycloalkyl), or -N(H)S0 ₂ (C3-8- heterocycloalkyl). In specific embodiments, the -N(H)S02R ⁶ is -N(H)S02Me.

[00176] In some embodiments of Formula (I), R ⁵ is -N(S02R ⁶ )2. In certain embodiments, the -N(S0 ₂ R ⁶ )2 is -N(S02-Ci-5-alkyl)2, -N(S02-C5-8-aryl)2, -N(S02-C5-8-heteroaryl)2, -N(S02-C3-8-cycloalkyl)2, or -N(S02-C3-8-heterocycloalkyl)2. In other embodiments, the - N(S0 ₂ R ⁶ )2 is -N(S02-Ci-5-alkyl)2, -N(S02-C3-8-cycloalkyl)2, or -N(S02-C3-8- heterocycloalkyl)2. In specific embodiments, the -N(S02R ⁶ )2 is -N(S02Me)2.

[00177] In some embodiments of Formula (I), R ⁶ and R ^6' are each independently -C1-5- alkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In related embodiments, the -Ci-5-alkyl is Me, Et, Pr, /Pr, Bu, /Bu. or CFh- CH(CH ₃ )2. In specific embodiments, the -C 1-5-alkyl is Me. In other specific embodiments, the -Ci-5-alkyl is Et. In still other specific embodiments, the -C _1-5 -alkyl is Pr. In yet other specific embodiments, the -Ci-5-alkyl is /Pr. In certain embodiments, the -Ci-5-alkyl is /Bu.

[00178] In some embodiments, R ⁶ and R ^6' are each independently -C3- 12-cycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN. In certain embodiments, the -C3-i ₂ -cycloalkyl is . In other specific embodiments, -C3-i2-cycloalkyl is .

[00179] In some embodiments, R ⁶ and R ^6' are each independently CF3, CHF2, or CFbF. In specific embodiments, R ⁶ and R ^6' are each independently CF3.

[00180] In some embodiments of Formula are each independently -N(R ⁴ )-, T is -C(=0)-, T' is -S(=0)2-, R ^3' is -CH2-C3-i2-cycloalkyl or In some embodiments, R ^3' is -CFk-cCeHii. In other embodiments, R ^3' is -CFh-Ph. In some embodiments, R ⁴ is H. NR ^4'

A i--

[00181] In some embodiments of Formula (I), — V— is ^R , U and U' are each -N(R ⁴ )-, W is -C(R ³ )(R ³ )-, T and T' are each independently -C(=0)- or -S(=0)2-, n is 0, and o, o', o", o'" are each 1. In some embodiments, R ³ is -Chh-C3-i2-cycloalkyl or -CFh-aryl. In some embodiments, the -CFh-C3-i2-cycloalkyl is -CFh-cCeHn. In other embodiments, the -CFh-aryl is -CFh-Ph.

[00182] In some embodiments of Formula are each -N(R ⁴ )-, W is -C(R ³ )(R ³ )-, T and T are each independently -C(=0)- or -S(=0)2-, n is 0, and o, o', o", o'" are each 1. In some embodiments, R ⁴ is each independently H or Me. In specific embodiments, each R ⁴ is H. In some embodiments, R ^4' is H or Me. In specific embodiments, each R ^4' is H.

[00183] In some embodiments of Formula (I),— V— is— N(R ⁴ )— , U and U' are each -N(R ⁴ )-, W is -C(R ³ )(R ³ )-, T and T' are each independently -C(=0)- or -S(=0)2-, n is 0, and o, o', o", o'" are each 1. In some embodiments, R ³ is -CH2-C3-i2-cycloalkyl or -CFh-aryl. In some embodiments, the -CH2-C3-i2-cycloalkyl is -CFh-cCeHn. In other embodiments, the -CFh-aryl is -CFh-Ph.

[00184] In some embodiments of Formula (I),— V— is— N(R ⁴ )— , U and U' are each -N(R ⁴ )-, W is -C(R ³ )(R ³ )-, T and T' are each independently -C(=0)- or -S(=0)2-, n is 0, and o, o', o", o'" are each 1. In some embodiments, R ⁴ is each independently H or Me. In specific embodiments, each R ⁴ is H. In some embodiments, R ^4' is H or Me. In specific embodiments, each R ^4' is H.

[00185] In some embodiments of Formula (I),— V— is N , U is -N(R ⁴ )-, W is -N(R ⁴ )-, T is— C(=0)— or -S(=0)2-, n is 0, o and o' are each 0, and o" and o'" are each 1. In some embodiments, R ³ is -(Chh)p-C3-i ₂ -cycloalkyl or -(CH2)p-aryl.

[00186] In some embodiments of Formula (I),— V— is \ , U is -N(R ⁴ )-, W is -N(R ⁴ )-, T is— C(=0)— or -S(=0)2-, n is 0, o and o' are each 0, and o" and o'" are each 1. In some embodiments, each R ⁴ is independently H or Me. In certain embodiments, each R ⁴ is H.

[00187] In various embodiments, the compound of Formula (I) or Formula (II) is a compound of Formula (I -A):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

T, T ¹ , U, U ¹ , R ¹ , R ² , R ³ , R ⁵ , n, o, o', o", o'" and r are as defined above for Formula (I); and

Z ¹ , Z ² , Z ³ , and Z ⁴ are each independently N or CR ⁵ , wherein at least one of Z ¹ , Z ² , Z ³ , and Z ⁴ is N, and wherein no more than two N atoms are adjacent. [00188] In some embodiments, one of Z -Z ⁴ is N, U and U ¹ are each NR ⁴ , and T and T ¹ are each— C(=0)— or -S(=0)2- In certain embodiments, R ⁴ is H or Me and R ⁵ is H. In specific embodiments, R ⁴ is H.

[00189] In some embodiments, Z ¹ is N, Z ² -Z ⁴ are each CR ⁵ , U and U ¹ are each NR ⁴ , and T and T ¹ are each -C(=0)- or -S(=0) ₂ -. In certain embodiments, R ⁴ is H or Me and R ⁵ is H. In specific embodiments, R ⁴ is H.

[00190] In some embodiments, Z ¹ is N, Z ² -Z ⁴ are each CR ⁵ , U and U ¹ are each NR ⁴ , and T and T ¹ are each -C(=0)-. In certain embodiments, R ⁴ is H or Me and R ⁵ is H. In specific embodiments, R ⁴ is H. [00191] In some embodiments, Z ⁴ is N, Z'-Z ³ are each CR ⁵ , U and U' are each NR ⁴ , and T and T' are each -C(=0)- or -S(=0)2-. In certain embodiments, R ⁴ is H or Me and R ⁵ is H. In specific embodiments, R ⁴ is H.

[00192] In some embodiments, Z ⁴ is N, Z'-Z ³ are each CR ⁵ , U and U' are each NR ⁴ , and T and T' are each -C(=0)-. In certain embodiments, R ⁴ is H or Me and R ⁵ is H. In specific embodiments, R ⁴ is H.

[00193] In some embodiments, one of Z'-Z ⁴ are N, U and U' are each NR ⁴ , T and T' are each— C(=0)— or -S(=0)2-, and R ³ is -(CH ₂ )p-aryl or -(CH2)p-C3-i2-cycloalkyl. In certain embodiments, the -(CH2)p-aryl is -CFh-Ph. In other certain embodiments, the -(CFh)p-C3-i2- cycloalkyl is -CFh-cCeHn

[00194] In some embodiments of Formula (I-A), any two of Z ¹ . Z ² , Z ³ , and Z ⁴ are N and the remaining Z are CR ⁵ . In some embodiments, Z ¹ and Z ³ are N and the remaining Z are CR ⁵ . In other embodiments, Z ² and Z ⁴ are N and the remaining Z are CR ⁵ . In some embodiments, Z ¹ , Z ² , and Z ⁴ are N and Z ³ is CR ⁵ . In other embodiments, Z ¹ , Z ³ , and Z ⁴ are N and Z ² is CR ⁵ . In certain embodiments Z ¹ is N. In another embodiment Z ² is N. In yet another embodiment Z ³ is N. In still another embodiment Z ⁴ is N.

[00195] In some embodiments of Formula (I-A), Z ¹ and Z ² are both N. In various embodiments, Z ¹ and Z ³ are both N. In certain embodiments, Z ¹ and Z ⁴ are both N. In some embodiments, Z ² and Z ³ are both N. In various embodiments, Z ² and Z ⁴ are both N. In certain embodiments, Z ³ and Z ⁴ are both N.

[00196] In some embodiments of Formula (I-A), r is 0, 1, or 2. In various embodiments, r is 0 or 1. In various other embodiments, r is 0. In specific embodiments, r is 1. In other specific embodiments, r is 2.

[00197] In some embodiments of Formula (I-A), q is 0, 1, 2, 3, or 4. In other embodiments, q is 0, 1, 2, or 3. In still other embodiments, q is 0, 1, or 2. In yet other embodiments, q is 0 or 1. In certain embodiments, q is 0. In specific embodiments, q is 1. In other specific embodiments, q is 2. In another embodiment, q is 3. In yet another embodiment, q is 4. In still another embodiment, q is 5.

[00198] In some embodiments of Formula (I-A), p is 0, 1, 2, or 3. In other embodiments, p is 0, 1, or 2. In other embodiments, p is 0 or 1. In other embodiments, p is 1 or 2. In other embodiments, p is 0. In specific embodiments, p is 1. In other specific embodiments, p is 2. In another embodiment, p is 3. In yet another embodiment, p is 4.

[00199] In various embodiments, the compound of Formula (I) is a compound of Formula (I-B):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

R ¹ , R ³ , R ⁴ , R ⁴ , R ⁶ , R ⁶ , n, q, and r are as defined above for Formula (I);

Z ¹ , Z ² , Z ³ , and Z ⁴ are as defined above for Formula (I-A); and

R ⁵ and R ^5' are each independently selected from halogen, -Ci-5-alkyl, -CF3, -CHF2, - CH2F, -CN, -OH, -OR ⁶ , -OC(=0)R ⁶ , -0C(=0)NR ⁶ R ⁶ ', -OC(=0)OR ⁶ , -SR ⁶ , -S(=0) ₂ NR ⁶ R ⁶ ', - S(=0) ₂ R ⁶ , -NOI, -NHI, -NR ⁴ R ^4' , -NR ⁴ -Ci-5-acyl; -COOH, -COOR ⁶ , -CONR ⁶ R ^6' , -(CH ₂ ) _n -C ₅ - 14-aryl, -(CH ₂ ) _n -C5-i ₄ -heteroaryl, -(CH ₂ )n-C3-i ₂ -cycloalkyl,-(CH ₂ ) _n -C3-i ₄ -heterocycloalkyl, or

[00200] In various embodiments of Formula (I-B), R ⁵ is selected from the group consisting

O A

AA

of H, halogen, -Ci-5-alkyl, CF3, -OR ⁶ , -NR ⁴ R ⁴ , R , and In another embodiment, R ⁵ is selected from the group consisting of H, Cl, F, Me, Et, Pr, i Pr NH ₂ , OH, some embodiments, R ⁵ is H. In other embodiments, R ⁵ is Cl. In still other embodiments, R ⁵ is F. In yet other embodiments, R ⁵ is Me. In another embodiment, R ⁵ is Et. In various other embodiments, R ⁵ is. In certain other embodiments, R ⁵ is /Pr. In some other embodiments, R ⁵ is OH. In various embodiments, R ⁵ is OMe. In certain other embodiments, R ⁵ is OEt. In another embodiment, R ⁵ is OPr. In various embodiments, R ⁵ is O/Pr. In some embodiments, R ⁵ is NH2. In other embodiments, R ⁵ is NHMe. In still other embodiments, R ⁵ is NIVIci. In various other

embodiments, R ⁵ another embodiment, R ⁵ is

[00201] In some embodiments of Formula (I-B), R ^5' is -S02NR ⁶ NR ^6' . In various embodiments, the -SChNRNlR ^6' is -S0 ₂ N(H)(Ci-5-alkyl), -S0 ₂ N(H)(C5-8-aryl),

-S0 ₂ N(H)(C5-8-heteroaryl), -S0 ₂ N(H)(C3-8-cycloalkyl), -S0 ₂ N(H)(C3-8-heterocycloalkyl), -S02N(Ci-5-alkyl)2, -S02N(C5-8-aryl)2, -S02N(C5-8-heteroaryl)2, -S02N(C3-8-cycloalkyl)2, or -S02N(C3-8-heterocycloalkyl)2. In other embodiments, the -SChNRNlR ^6' is -S02N(H)(CI-5- alkyl), -S0 ₂ N(H)(C3-8-cycloalkyl), -S0 ₂ N(H)(C3-8-heterocycloalkyl), -S0 ₂ N(Ci-5-alkyl) ₂ , -S02N(C3-8-cycloalkyl)2, or -S02N(C3-8-heterocycloalkyl)2. In certain embodiments, the -S0 ₂ NR ⁶ NR ^6' is -SO2NH2, -SOrNHMc. -SOrNHEt, -SOrNHPr, -SOrNH/Pr, -SO2NMC2.

.

In specific embodiments, the -S02NR ⁶ NR ^6' is -S02NHMe. In other specific embodiments, the -S02NR ⁶ NR ^6' is -S02NMe2. In still other specific embodiments, the -S02NR ⁶ NR ^6' is -S02NH/Pr. In yet other specific embodiments, the -S02NR ⁶ NR ^6' is S02N(/Pr)2. In certain embodiments, the -SChNR ⁶ NR ⁶ is -S02NEt2. In other certain embodiments, the -S0 ₂ NR ⁶ NR ^6' is -SChNHcCeHn. In still other certain embodiments, the -SChNRNlR ⁶ is

-SO2NH2. In yet other certain embodiments, the -SChNRNlR ⁶ is . In some embodiments _, the the -S0 ₂ NR ⁶ NR ⁶ '

H0 ₂ C

— S0 ₂ N NMe — S0 ₂ N

is ^— / . In yet other embodiments, the -S02NR ⁶ NR ^6' is

[00202] In some embodiments of Formula (I-B), R ⁵ ’ is -N(H)S02R ⁶ . In certain embodiments, the -N(H)SChR ⁶ is -N(H)SCh(Ci-5-alkyl), -N(H)S02(C5-8-aryl), -N(H)S02(C5- 8-heteroaryl), -N(H)S0 ₂ (C3-8-cycloalkyl), or -N(H)S0 ₂ (C3-8-heterocycloalkyl). In other embodiments, the -N(H)SOiR ⁶ is -N(H)S02(Ci-5-alkyl), -N(H)S02(C3-8-cycloalkyl), or -N(H)S02(C3-8-heterocycloalkyl). In specific embodiments, the -N(H)S02R ⁶ is -N(H)S02Me.

[00203] In some embodiments of Formula (I-B), R ^5' is -N(S02R ⁶ )2. In certain embodiments, the -N(S0 ₂ R ⁶ )2 is -N(S02-Ci-5-alkyl)2, -N(S02-C5-8-aryl)2, -N(S02-C5-8-heteroaryl)2, -N(S02-C3-8-cycloalkyl)2, or -N(S02-C3-8-heterocycloalkyl)2. In other embodiments, the - N(SC R ⁶ )2 is -N(S02-Ci-5-alkyl)2, -N(S02-C3-8-cycloalkyl)2, or -N(S02-C3-8- heterocycloalkyl)2. In specific embodiments, the -N(SChR )2 is -N(S02Me)2.

[00204] In various embodiments, the compound of Formula (I) or Formula (II) is a compound of Formula (I-C):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

- represents an optional bond between respective atoms;

T, T, U, U', W, Y, R ¹ , R ² , R ³ , R ^3' , R ⁵ , n, o, o', o", o'", and r are as defined above for Formula (I).

[00205] In some embodiments of Formula (I-C), Y is NR ⁴ or O. In other embodiments Y is O. In still other embodiments, Y is NR ⁴ .

[00206] In some embodiments of Formula (I-C), U is -NR ⁴ -, T is -S(=0)2-, n is 0, o" is 1, and o'" is 1.

[00207] In some embodiments, of Formula (I-C), R ³ is -(CFh)p-Ph, -(CFh)p-pyridinyl, or -(CH ₂ ) _P -C3 -12-cycloalkyl. In various embodiments, p is 1. In other embodiments, -(CFh)p-C3-

12-cycloalkyl is -CFh-cCeFlii. some embodiments, of Formula (I-C), R ¹ and R ² are each independently

certain embodiments, n is 0. In certain other embodiments, n is 1.

[00209] In some embodiments of Formula (I-C), W is -NR ⁴ -, o is 0, and o' is 0.

[00210] In some embodiments of Formula (I-C), U is -NR ⁴ -, T is -S(=0)2-, W is -NR ⁴ -, n is 0, o is 0, o' is 0, o" is 1, and o'" is 1. In certain embodiments, each R ⁴ is H or Me. In specific embodiments, R ⁴ is H.

[00211] In some embodiments of Formula (I-C), R ⁵ is In certain embodiments, each R ⁴ is H.

[00212] In various embodiments, the compound of Formula (I) or Formula (II) is a compound of Formula (I-D):

I-D

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

- represents an optional bond between respective atoms;

T, T', Y, n', n", o, r, R ³ , R ⁴ , R ^4' , R ^{4 "} , R ⁵ , R ^5' , R ⁶ , and R ^6' are as defined above for Formula (I), Formula (I-B), and Formula (I-C);

q and q' are each independently 0, 1, 2, 3, 4, or 5; and

R ^5" is each independently halogen, -Ci-5-alkyl, -CF3, -CHF2, -CFhF, -CN, -OH, -OR ⁶ , -OC(=0)R ⁶ , -0C(=0)NR ⁶ R ⁶ , -OC(=0)OR ⁶ , -SR ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ R ⁶ , -NO2, -NH ₂ ,

-NR ⁴ R ⁴ , -NR ⁴ -Ci-5-acyl; 4-aryl, -

(CH ₂ )n-C5- 14-heteroaryl, -(CH ₂ )n-C3 -12-cycloalkyl, or -(CH ₂ )n-C3-i ₄ -heterocycloalkyl. [00213] In some embodiments of Formula (I-D), T is -S(=0)2-, and T' is -C(=0)-. In other embodiments, Y is O, T is -S(=0)2-, and T' is -C(=0)-.

[00214] In some embodiments, the compound of Formula (I) or Formula (II) is a compound of Formula (I-E):

I-E

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

- represents an optional bond between respective atoms;

T, T', R ³ , R ⁴ , R ⁴ , R ^4" , R ⁵ , R ⁵ , o, q, and q' are as defined above for Formula (I) and

Formula (I-D).

[00215] In some embodiments of Formula (I-E), T is T is -S(0) _2- or -C(O)-.

[00216] In various embodiments, the compound of Formula (I) is a compound of Formula

(I-F):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

T, T', U, U', R ¹ , R ² , R ³ , n', o, o', o", and o'" are as defined above for Formula (I);

X and X' are each independently NR ⁴ , O, or S, wherein when X' is NR ⁴ , R ⁴ and R ³ taken together with the atoms to which they are attached can form a C5-i4-heteroaryl or C3-12- heterocycloalkyl ring, wherein when X and X' are each NR ⁴ , the two R ⁴ taken together with the atoms to which they are attached can form a -Cs- 14-heteroaryl or -C ₃ -i2-heterocycloalkyl ring, and wherein when X' and U are NR ^4' , the two R ⁴ taken together with the atoms to which they are attached can form a -C3-i ₂ -heterocycloalkyl ring; and

m is 0 or 1.

[00217] In various embodiments, the present disclosure provides compounds of Formula (I-F), wherein, X and X' are each independently NR ⁴ or O. In other embodiments, X and X' are each independently O. In still other embodiments, X and X' are each independently NR ⁴ . In certain embodiments, X and X' are each independently S. In some embodiments, X and X' are each independently N-Cs-n-aryl, N-Cri-ii-heteroaryl. N-C3-i ₂ -cycloalkyl, or N-C3-12- heterocycloalkyl. In other embodiments, X and X' are each independently is N-Ci-5-alkyl. In other certain embodiments, X and X' are each independently is selected from the group consisting of N-H, N-Me, N-Et, N-Pr, N-/Pr, N-cCeHn, N-CFh-cG.Hi 1. N-CFhPh. and N-Ph. In specific embodiments, X and X' are each independently is N-H. In other specific embodiments, X and X' are each independently is N-Me.

[00218] In various embodiments, the present disclosure provides compounds of Formula (I-F), wherein U and U' are each independently selected from -NR ⁴ -, -O-, and-S-. In various other embodiments, U and U' are each independently selected from NR ⁴ and-O-. In some embodiments, U and U' are -NR ⁴ - and X and X' are each independently -NR ⁴ -, -O-, or -S-. In other embodiments, U and U' are -O- and X and X' are each independently -NR ⁴ -, -O-, or — S— . In another embodiment, U and U' are -S- and X and X' are each independently -NR ⁴ -, - O-, or— S— . In some other embodiments, U and U' are -CH2-, -NR ⁴ -, -0-, or -S- and X and X' are each independently -NR ⁴ -. In various other embodiments, U and U' are -CH2-, -NR ⁴ - , -0-, or -S- and X and X' are each independently -0-. In yet another embodiment, U and U' are -CH2-, -NR ⁴ -, -0-, or -S- and X and X' are each independently -S-. In some embodiments, U, U', X, and X' are each independently -NR ⁴ -. In still other embodiments, U is -O- and U', X and X' are each independently -NR ⁴ -. In still other embodiments, U and U' are -S- and X and X' are each independently -NR ⁴ -. In some embodiments, U, U', X and X' are each independently -0-. In still other embodiments, U and U' are -NR ⁴ - and X and X' are each independently -O- or -NR ⁴ -. In various embodiments, U is -S- and U', X, and X' are each independently -O- and -NR ⁴ -. In specific embodiments, U is -NR ⁴ -, X and X' are each independently -NR ⁴ -. In other specific embodiments, U is -O- and X and X' are each independently -NR ⁴ -. In still other specific embodiments, U is -CH2- and X and X' are each independently -NR ⁴ -. In yet another specific embodiment, U is -S- and X and X' are each independently -NR ⁴ -. In another embodiment, U' is -NR ⁴ - and X and X' are each independently -NR ⁴ -. In yet another embodiment, U' is -O- and X and X' are each independently -NR ⁴ -. In still other specific embodiments, U' is -CFh- and X and X' are each independently -NR ⁴ -. In yet another specific embodiment, U' is -S- and X and X' are each independently -NR ⁴ -. In specific embodiments, X and X' are each independently -NR ⁴ — NR ⁴ -.

[00219] In some embodiments, m is 0. In other embodiments, m is 1.

[00220] In various embodiments, the compound of Formula (I) is a compound of Formula (I-F):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

T, T, U, U', R ¹ , R ² , R ³ , ri, o, o', o", and o'" are as defined above for Formula (I);

X and X' are each independently NR ⁴ , O, or S, wherein when X' is NR ⁴ , R ⁴ and R ³ taken together with the atoms to which they are attached can form a Cs-w-heteroaryl or C3-12- heterocycloalkyl ring, wherein when X and X' are each NR ⁴ , the two R ⁴ taken together with the atoms to which they are attached can form a -Cs-M-heteroaryl or -C3-i ₂ -heterocycloalkyl ring, and wherein when X' and U are NR ^4' , the two R ⁴ taken together with the atoms to which they are attached can form a -C3-i ₂ -heterocycloalkyl ring; and

m is 0 or 1;

with the proviso that the compound is not BMCL-38 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[00221] In various embodiments, the present disclosure provides compounds of Formula (I-F), wherein, X and X' are each independently NR ⁴ or O. In other embodiments, X and X' are each independently O. In still other embodiments, X and X' are each independently NR ⁴ . In certain embodiments, X and X' are each independently S. In some embodiments, X and X' are each independently N-Cs-n-aryl, N-Cs-n-heteroaryl, N-C ₃ -i2-cycloalkyl, or N-C3-12- heterocycloalkyl. In other embodiments, X and X' are each independently is N-Ci-5-alkyl. In other certain embodiments, X and X' are each independently is selected from the group consisting of N-H, N-Me, N-Et, N-Pr, N-/Pr, N-cCeHn, N-CTF-cCeHn, N-CH2PI1, and N-Ph. In specific embodiments, X and X' are each independently is N-H. In other specific embodiments, X and X' are each independently is N-Me.

[00222] In various embodiments, the present disclosure provides compounds of Formula (I-F), wherein U and U' are each independently selected from -NR ⁴ -, -0-, and-S-. In various other embodiments, U and U' are each independently selected from NR ⁴ and-O-

[00223] In some embodiments, U and U' are -NR ⁴ - and X and X' are each independently -NR ⁴ -, -0-, or -S-. In other embodiments, U and U' are -O- and X and X' are each independently -NR ⁴ -, -O-, or -S-. In another embodiment, U and U' are -S- and X and X' are each independently -NR ⁴ -, -O-, or -S-. In some other embodiments, U and U' are -CH2- , -NR ⁴ -, -0-, or -S- and X and X' are each independently -NR ⁴ -. In various other embodiments, U and U' are -CH2-, -NR ⁴ -, -0-, or -S- and X and X' are each independently -0-. In yet another embodiment, U and U' are -CH2-, -NR ⁴ -, -0-, or -S- and X and X' are each independently -S-. In some embodiments, U, U', X, and X' are each independently - NR ⁴ -. In still other embodiments, U is -O- and U', X and X' are each independently -NR ⁴ -. In still other embodiments, U and U' are -S- and X and X' are each independently -NR ⁴ -. In some embodiments, U, U', X and X' are each independently -0-. In still other embodiments, U and U' are -NR ⁴ - and X and X' are each independently -O- or -NR ⁴ -. In various embodiments, U is -S- and U', X, and X' are each independently -O- and -NR ⁴ -. In specific embodiments, U is -NR ⁴ -, X and X' are each independently -NR ⁴ -. In other specific embodiments, U is -O- and X and X' are each independently -NR ⁴ -. In still other specific embodiments, U is -CH2- and X and X' are each independently -NR ⁴ -. In yet another specific embodiment, U is -S- and X and X' are each independently -NR ⁴ -. In another embodiment, U' is -NR ⁴ - and X and X' are each independently -NR ⁴ -. In yet another embodiment, U' is - O- and X and X' are each independently -NR ⁴ -. In still other specific embodiments, U' is - CH2- and X and X' are each independently -NR ⁴ -. In yet another specific embodiment, U' is -S- and X and X' are each independently -NR ⁴ -. In specific embodiments, X and X' are each independently -NR ⁴ — NR ⁴ -. [00224] In some embodiments, m is 0. In other embodiments, m is 1.

[00225] In some embodiments, m is 0 and n' is 0. In some embodiments, m is 0 and n' is 1. In some embodiments, m is 1 and n' is 0. In some embodiments, m is 1 and n' is 1.

[00226] In some embodiments, m is 1, n' is 1, o is 1 and o' is 1. In other embodiments, m is 0, n' is 1, o is 1 and o' is 1. In still other embodiments, m is 1, n' is 1, o is 0 and o' is 1. In yet other embodiments, m is 1, n' is 1, o is 1 and o' is 0.

[00227] In some embodiments, m is 1, n' is 1, and o, o', o", and o'" are each 1. In other embodiments, m is 0, n' is 1, and o, o', o", and o'" are each 1. In still other embodiments, m is 1, n' is l, o and o' are each 0, and o", and o'" are each 1. In yet other embodiments, m is 1, n' is 1, o is 1, o' is 0, and o", and o'" are each 1. In certain embodiments, m is 1, n' is 1, o is 0, o' is 1, and o", and o'" are each 1. In other certain embodiments, m is 1, n' is 0, o and o' are each 0, and o", and o'" are each 1. In yet other certain embodiments, m is 1, n' is 0, o is 1, o' is 0, and o", and o'" are each 1. In still other certain embodiments, m is 1, n' is 0, o is 0, o' is 1, and o", and o'" are each 1.

[00228] In some embodiments, X is NR ⁴ and X' is NR ⁴ or O.

[00229] In some embodiments, X is NR ⁴ , X' is NR ⁴ or O, and U is -NR ^4' .

[00230] In some embodiments, X is NR ⁴ , X' is NR ⁴ , and U is -NR ^4' .

[00231] In some embodiments, X is NR ⁴ , X' is NR ⁴ or O, and U and U' are each independently -NR ^4' .

[00232] In some embodiments, X is NR ⁴ , X' is NR ⁴ or O, U and U' are each independently -NR ^4' , and T is -C(=0)-, -S(=0)2-, -C=N(R ^4' )-, or -X ^' -C(=0)-, wherein X' is NR ⁴ . In other embodiments, T is -C(=0)-. In still other embodiments, T is -S(=0)2 -. In yet other embodiments, T is -C=N(R ^4' )-. In certain embodiments, T is -X ^' -C(=0)-. In some embodiments, each R ⁴ is independently H or Me. In other embodiments, each R ⁴ is H. In some embodiments, each R ^4' is independently H, Me, or NH ₂ . In certain embodiments, each R ^4' is H.

[00233] In some embodiments, X is NR ⁴ , X' is NR ⁴ or O, U and U' are each independently -NR ^4' , T is -C(=0)-, and T is -C(=0)-, -S(=0) ₂ -, -C=N(R ^4' )-, or -X ^' -C(=0)-, wherein X' is NR ⁴ . In other embodiments, T ¹ is -C(=0)-. In still other embodiments, T ¹ is -S(=0)2 -. In yet other embodiments, T ¹ is -C=N(R ⁴ )-. In certain embodiments, T ¹ is -X-C(=0)-. In other embodiments, each R ⁴ is H. In some embodiments, each R ⁴ ’ is independently H, Me, or Nth. In certain embodiments, each R ⁴ ’ is H. [00234] In some embodiments, X is NR ⁴ , X ¹ is NR ⁴ or O, U and U ¹ are each independently

-NR ^4' , T is -S(=0) ₂ and T is -C(=0)-, -S(=0) ₂ -C=N(R ^4' )-, or -X ^' -C(=0)-, wherein X' is NR ⁴ . In other embodiments, T ¹ is -C(=0)-. In still other embodiments, T ¹ is -S(=0)2 -. In yet other embodiments, T ¹ is -C=N(R ⁴ )-. In certain embodiments, T ¹ is -X-C(=0)-. In other embodiments, each R ⁴ is H. In some embodiments, each R ⁴ ’ is independently H, Me, or NFh. In certain embodiments, each R ⁴ ’ is H.

[00235] In some embodiments, X is NR ⁴ , X ¹ is NR ⁴ or O, U and U ¹ are each independently -NR ^4' , T is -C=N(R ⁴ )-, and T is -C(=0)-, -S(=0) ₂ -, -C=N(R ^4' )-, or -X ^' -C(=0)-, wherein X ¹ is NR ⁴ . In other embodiments, T ¹ is -C(=0)-. In still other embodiments, T ¹ is -S(=0)2 -. In yet other embodiments, T ¹ is -C=N(R ⁴ )-. In certain embodiments, T ¹ is -X -C(=0)-, wherein X ¹ is NR ⁴ . In other embodiments, each R ⁴ is H. In some embodiments, each R ⁴ ’ is independently H, Me, or NFh. In certain embodiments, each R ⁴ ’ is H.

[00236] In some embodiments, X is NR ⁴ , X ¹ is NR ⁴ or O, U and U ¹ are each independently

-NR ^4' , T is -X ^' -C(=0)-, wherein X' is NR ⁴ , and T is -C(=0)-, -S(=0) ₂ -, -C=N(R ^4' )-, or

— X -C(=0)— , wherein X ¹ is NR ⁴ . In other embodiments, T ¹ is -C(=0)-. In still other embodiments, T ¹ is -S(=0)2 -. In yet other embodiments, T ¹ is -C=N(R ⁴ )-. In certain embodiments, T ¹ is -X -C(=0)-, wherein X ¹ is NR ⁴ . In other embodiments, each R ⁴ is H. In some embodiments, each R ⁴ ’ is independently H, Me, or NFh. In certain embodiments, each R ^4' is H.

[00237] In various embodiments, the compound of Formula (I) is a compound of Formula

(I-G):

I-G

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

T, R ¹ , R ² , R ³ , R ³ , R ⁴ , R ⁴ , and R ⁴ are as defined above for Formula (I); and

X is -NR ⁴ - or-O-.

[00238] In various embodiments, the present disclosure provides Formula (I-G) compounds wherein X is -NR ⁴ -. In some embodiments, X is -O-. [00239] In various embodiments, the compound of Formula (I) is a compound of Formula

(I-H):

I-H

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

X, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , and R ^6' are as defined above for Formula (I);

m is 0 or 1;

R ⁴ , R ^4' , R ^4" , R ^{4 "} , and R ^4"" are each independently H, -Ci-5-alkyl, -C ₂ -5-alkenyl, -C2-5- alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ^6' , -C(=0)0R ⁶ , -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -0C(=0)0R ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -C5- 12-aryl, -C5-12- heteroaryl, -C3-i ₂ -cycloalkyl, or -C3-i ₂ -heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein R ⁴ ’ and R ^{4 "} taken together with the atoms to which they are attached can form a C5- 14-heteroaryl or C3-12- heterocycloalkyl ring optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, or alternatively, wherein R ^{4 "} and R ³ taken together with the atoms to which they are attached can form a Cs- 14-heteroaryl or C3-i2-heterocycloalkyl ring optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN.

[00240] In some embodiments, m is 0. In other embodiments, m is 1.

[00241] In some embodiments, X is each independently NH, NMe, or N-NH2. In other embodiments, X is each independently O.

[00242] In various embodiments, the compound of Formula (I) is a compound of Formula

(I-H):

I-H or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein

X, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , and R ⁶ ’ are as defined above for Formula (I);

m is 0 or 1;

R ⁴ , R ⁴ ’, R ^4" , R ^{4 "} , and R ^4"" are each independently H, -Ci-5-alkyl, -C2-5-alkenyl, -C2-5- alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ^6' , -C(=0)0R ⁶ , -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -0C(=0)0R ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -C5- 12-aryl, -C5-12- heteroaryl, -C3-i2-cycloalkyl, or -C3-i2-heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein R ⁴ ’ and R ^{4 "} taken together with the atoms to which they are attached can form a C5- 14-heteroaryl or C3-12- heterocycloalkyl ring optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, or alternatively, wherein R ^{4 "} and R ³ taken together with the atoms to which they are attached can form a C5- 14-heteroaryl or C3-i ₂ -heterocycloalkyl ring optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

with the proviso that the compound is not BMCL-38 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[00243] In some embodiments, m is 0. In other embodiments, m is 1.

[00244] In some embodiments, X is each independently NH, NMe, or N-NH2. In other embodiments, X is each independently O.

[00245] In some embodiments, the compound of Formula (I-H) is a compound of Formula (I -Ha) having the following structure:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein

X, R ¹ , R ² , R ³ , R ^4" , R ^4"" , R ⁵ , R ⁶ , and R ^6' are as defined above for Formula (I) and Formula (I-H); and

s is 1, 2, 3, or 4.

[00246] In some embodiments, s is 1. In other embodiments, s is 2. In still other embodiments, s is 3. In yet other embodiments, s is 4.

[00247] In some embodiments, the compound of Formula (I-H) is a compound of Formula (I-Hb) having the following structure:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

- represents an optional bond between respective atoms;

X, R ¹ , R ² , R ^4' , R ^4" , and q are as defined above for Formula (I);

M, M' and M" are each independently CH2, C=0, NR ⁴ , O, or S; or alternatively, when — is present, M, M' and M" is each independently CH or N;

R ^4' , R ^4" , and R ^4"" are each independently H, -Ci-5-alkyl, -C ₂ -5-alkenyl, -C ₂ -5-alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ⁶ , -C(=0)OR ⁶ , -OH, -OR ⁶ , -OC(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -OC(=0)OR ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -Cs-12-aiyl, -C5-12- heteroaryl, -C3-i2-cycloalkyl, or -C3-i2-heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein R ⁴ ’ and R ^4" taken together with the atoms to which they are attached can form a C5- 14-heteroaryl or C3-12- heterocycloalkyl ring optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

R ⁵ is halogen, -Ci-s-alkyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CN, -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ⁶ , -0C(=0)0R ⁶ , -SR ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ R ⁶ , -NO2, -NH ₂ , -NR ⁴ R ^4' , - NR ⁴ -Ci-5-acyl; 4-aryl, -(CH2)n-C5-14- heteroaryl, -(CH ₂ )n-C3-i ₂ -cycloalkyl, or -(CH ₂ )n-C3-i ₄ -heterocycloalkyl, wherein any two R ⁵ groups taken together with the atoms to which they are attached can form a C5- 14-aryl. C5-14- heteroaryl, C3-i ₂ -cycloalkyl, or C3-i ₂ -heterocycloalkyl ring, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN; and

r and r' are each independently 0, 1, 2, or 3.

[00248] In some embodiments, M, M' and M" are each independently CH2, C=0, NR ⁴ , O, or S. In other embodiments, M, M' and M" are each independently C=0, NR ⁴ , O, or S. In still other embodiments, M, M' and M" are each independently NR ⁴ , O, or S. In yet other embodiments, M, M' and M" are each independently NR ⁴ or O. In some embodiments, M, M' and M" are each CH2. In some embodiments, M is NR ⁴ and M' and M" are CH2.

[00249] In some embodiments, when— is present, M, M' and M" is each independently CH. In other embodiments, when— is present, M and M" are each CH and M' is N. In still other embodiments, when— is present, M and M" are each CH and M' is N. In still other embodiments, M' and M" are each CH and M is N.

[00250] In some embodiments, r and r' are 1. In some embodiments, r and r' are 2. In some embodiments, r and r' are 3. In some embodiments, r is 0 and r' is 1. In some embodiments, r is 0 and r' is 2. In some embodiments, r is 0 and r' is 3. In some embodiments, r is 1 and r' is 0. In some embodiments, r is 2 and r' is 0. In some embodiments, r is 3 and r' is 0. In some embodiments r is 1 and r' is 2. In some embodiments, r is 1 and r' is 3. In some embodiments, r is 3 and r' is 1. In some embodiments, r is 3 and r' is 2.

[00251] In some embodiments, the compound of Formula (I) is a compound of Formula (I-I) having the following structure:

I-I

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein X, R ¹ , R ³ , R ⁵ , R ⁶ , and R ⁶ ’ are as defined above for Formula (I);

m is 0 or 1;

q is 0, 1, 2, 3, 4, or 5; and

R ⁴ , R ⁴ ’, R ^4" , R ^{4 "} , and R ^4"" are each independently H, -C 1-5-alkyl, -C2-5-alkenyl, -C2-5- alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ^6' , -C(=0)OR ⁶ , -OH, -OR ⁶ , -OC(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -OC(=0)OR ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -C ₅ -i2-aryl, -C5-12- heteroaryl, -C3-i ₂ -cycloalkyl, or -C3-i ₂ -heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein R ⁴ ’ and R ^{4 "} taken together with the atoms to which they are attached can form a C5- 14-heteroaryl or C3-12- heterocycloalkyl ring, or alternatively, wherein R ^{4 "} and R ³ taken together with the atoms to which they are attached can form a C5- 14-heteroaryl or C3-i ₂ -heterocycloalkyl ring;

with the proviso that the compound is not BMCL-38 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[00252] In other embodiments, the compound of Formula (I) is a compound of Formula (I-J) having the following structure:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

X, R ¹ , R ³ , R ⁵ , R ⁶ , R ⁶ , and p are as defined above for Formula (I);

m is 0 or 1; and

R ⁴ , R ^4' , R ^4" , R ^{4 "} , and R ^4"" are each independently H, -C 1-5-alkyl, -C ₂ -5-alkenyl, -C2-5- alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ^6' , -C(=0)0R ⁶ , -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -0C(=0)0R ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -Cs-12-aiyl, -C5-12- heteroaryl, -C3-i ₂ -cycloalkyl, or -C3-i ₂ -heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein R ^4' and R ^{4 "} taken together with the atoms to which they are attached can form a CNu-heteroaryl or C3-12- heterocycloalkyl ring, or alternatively, wherein R ^{4 "} and R ³ taken together with the atoms to which they are attached can form a C5- 14-heteroaryl or C3-i ₂ -heterocycloalkyl ring;

with the proviso that the compound is not BMCL-38 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[00253] In various embodiments, the compound of Formula (I) is a compound of Formula (I-K):

I-K

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein,

T, R ¹ , R ² , R ³ , R ^4' , R ^{4 "} , and n are as defined above for Formula (I).

[00254] In various embodiments, the compound of Formula (I) is a compound of Formula (I-L):

I-L

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein,

T, R ¹ , R ³ , R ^4' , R ^{4 "} , and n are as defined above for Formula (I); and

q is 0, 1, 2, 3, 4, or 5.

[00255] In various embodiments, the compound of Formula (I) is a compound of Formula (I-M):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein,

X, R ¹ , R ³ , R ^4' , R ^4" , and n are as defined above for Formula (I); and

q is 0, 1, 2, 3, 4, or 5.

[00256] In various embodiments, the present disclosure also provides compounds of Formula (II):

II

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein

Het is a 5-14 membered heteroaryl, optionally substituted by one of more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

T and T are each independently -C(=0)-, -X-C(=0)-, -S(=0)2-, or -C=NR ⁴ - ;

U and U ¹ are each independently -CFh-, -NR ⁴ -, -0-, or -S-;

W is -NR ⁴ - or -C(R ³ )(R ³ )-;

X is NR ⁴ , O, or S;

n, ri, and n" are each independently 0, 1, or 2;

o, o', o", and o'" are each independently 0 or 1 ; p is 0, 1, 2, 3, or 4;

R ¹ and R ² are each independently -(QrhV _' -Cs-w-aryl, -(CH ₂ V-C5- ₁₄ -heteroaryl, - (CH ₂ V-C3- ₁₂ -cycloalkyl, -(CH2)n _" -C3-i4-heterocycloalkyl, -(X)-(CH2)n _" -C5-i4-aryl, -(X)-C5-i4- aryl, -(X)-C5-i4-heteroaryl, -(X)-C3-i2-cycloalkyl, -(X)-C3-i4-heterocycloalkyl, -C2-4-alkenyl-

C5-i ₄ -aryl, -C _2-4 -alkenyl-C5-i ₄ -heteroaryl, -C _2-4 -alkenyl-C3-i ₂ -cycloalkyl, -C _2-4 -alkenyl-C3-i ₂ - heterocycloalkyl, -Ci-5-alkyl, -C ₂ -5-alkenyl, or -C ₂ -5-alkynyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein any two R ⁵ groups taken together with the atoms to which they are attached can form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring;

R ³ and R ^3' are each independently H, F, -Ci-5-alkyl, -C ₂ -5-alkenyl, -C ₂ -5-alkynyl, -C3- 12-cycloalkyl, -C3- 12-cycloalkenyl, -(CFk)p-aryl, -(CFk)p-heteroaryl, -(CFk)p-C3- 12- cycloalkyl, -(CH2)p-C3 -12-cycloalkenyl, -(CFb)p-C3-i2-heterocycloalkyl, -(CH2)p-C5-i4- heteroaryl, -OH, -OCi-5-alkyl, -0C(=0)R ⁶ , or -NR ⁴ R ⁴ , each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN, wherein two geminal R ³ or two geminal R ^3' taken together with the carbon atom to which they are attached can form a -C3-12- cycloalkyl or -C3-i ₂ -heterocycloalkyl ring;

R ⁴ and R ^4' are each independently H, -Ci-5-alkyl, -C2-5-alkenyl, -C2-5-alkynyl, -C(=0)R ⁶ , -C(=0)NR ⁶ R ⁶ , -C(=0)0R ⁶ , -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ^6' , -0C(=0)0R ⁶ , -S(=0) ₂ R ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ 0R ⁶ , -NR ⁶ R ⁶ , -C5- 12-aryl, -C5-12- heteroaryl, -C3-i2-cycloalkyl, or -C3-i2-heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN;

R ⁵ is halogen, -Ci-5-alkyl, -CF3, -CHF2, -CH2F, -CN, -OH, -OR ⁶ , -0C(=0)R ⁶ , -0C(=0)NR ⁶ R ⁶ , -0C(=0)0R ⁶ , -SR ⁶ , -S(=0) ₂ NR ⁶ R ^6' , -S(=0) ₂ R ⁶ , -NO2, -NH ₂ , -N(H)S0 ₂ R ⁶ ,

-N(S0 ₂ R ⁶ ) ₂ , -NR ⁴ R ⁴ ’, -NR ⁴ -C ₁ -5-acyl;

(CH2)n-C5- 14-aryl, -(CH2)n-C5- 14-heteroaryl, -(CH2)n-C3 -12-Cycloalkyl, OG -(CH2)n-C3-14- heterocycloalkyl, wherein when R ⁵ is -S0 ₂ NR ⁶ NR ⁶ , R ⁶ and R ⁶ ’ taken together with the N to which they are attached can form an optionally substituted -C5-i4-heteroaryl, or -C3-12- heterocycloalkyl ring; and

R ⁶ and R ⁶ ’ are each independently H, -CF3, -CHF ₂ , -CH ₂ F, -Ci-5-alkyl, -C ₂ -5 -alkenyl, - C2-5-alkynyl, -Ci-5-acyl, -C5-i4-aryl, -C5-i4-heteroaryl, -C3-i2-cycloalkyl, or -C3-12- heterocycloalkyl, each of which is optionally substituted with one or more R ⁵ groups, =0, =NR ⁴ , =NOR ⁴ , or =NCN.

[00257] In various embodiments, the present disclosure provides compounds of Formula

[00258] In various embodiments, the present disclosure provides compounds of Formula (I), wherein the compounds of Formula (I) are the compounds of Table 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[00259] In various embodiments, the compounds of the present disclosure are the compounds of Table 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[00260] In some embodiments, the present disclosure provides compounds of Formula (I), wherein the compounds of Formula (I) are the compounds of Table 4, a stereoisomer thereof, a different pharmaceutically acceptable salt thereof, or a freebase (i.e., salt-free form) thereof.

[00261] In some embodiments, the compounds of the present disclosure are the compounds of Table 4, a stereoisomer thereof, a different pharmaceutically acceptable salt thereof, or a freebase (i.e., salt-free form) thereof.

[00262] In some embodiments, the present disclosure provides compounds of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof having the structure:

[00263] In some embodiments, the present disclosure provides compounds of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof having the structure: [00264] In some embodiments, the present disclosure further provides compounds of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof having the structure:

[00265] In some embodiments, the present disclosure further provides compounds of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof having the structure:

[00266] In some embodiments, the present disclosure further provides compounds of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof having the structure:

[00267] In some embodiments, the present disclosure further provides compounds of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof having the structure:

[00268] In some embodiments, the present disclosure further provides compounds of Formula (I) or a pharmaceutically acceptable salt thereof having the structure:

[00269] In some embodiments, the present disclosure further provides compounds having the structure:

or a pharmaceutically acceptable salt thereof.

[00270] In some embodiments, the present disclosure further provides compounds of Formula (I-Hb), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof having the structure:

[00271] In some embodiments, the present disclosure further provides compounds having the structure:

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[00272] In addition, the compounds described herein are meant to include all racemic mixtures, all individual enantiomers or combinations thereof, as well as all diastereomers or combinations thereof when two or more stereocenters are present, regardless of whether or not they are specifically depicted herein. Representative examples are shown below in the following Tables 1-4.

Methods of Treatment

[00273] Herein, it is demonstrated that circulating cathepsin D (CTSD) plays a key role in the development of steatohepatitis. In particular, it has been established that inhibition of circulating CTSD results in an elevation of hepatic cholesterol degradation and dramatically reduced hepatic and plasma lipid levels. Consistently, inhibition of extracellular CTSD in bone-marrow derived macrophages revealed a similar effect on inflammation and lipid metabolism. As inhibition of circulating CTSD decreased hepatic inflammation in hyperlipidemic mice, the present disclosure shows that inhibiting circulating CTSD is useful for treating, ameliorating, and/or prevent non alcoholic steatohepatitis (NASH) and other diseases (see for example, Fig. 1).

[00274] To this end, the present disclosure provides methods of treatment. In some embodiments, the present disclosure provides a method for treating or preventing a liver disease or an abnormal liver condition, comprising administering to a subject in need thereof an effective amount of any of the compounds described herein, a pharmaceutically acceptable salt thereof, or a composition thereof.

[00275] In various embodiments, the liver disease or abnormal liver condition includes, non alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, cirrhosis, inflammation, hepatic fibrosis, partial fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, liver failure, hepatocellular carcinoma, liver cancer, hepatic steatosis, hepatocyte ballooning, hepatic lobular inflammation, and hepatic triglyceride accumulation. In another embodiment of the present disclosure, the liver disease or abnormal liver condition is non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. In a specific embodiment, the liver disease or abnormal liver condition is non-alcoholic steatohepatitis.

[00276] Nonalcoholic fatty liver disease (NAFLD) is a condition in which fat builds up in the liver. This buildup of fat is not caused by heavy alcohol use. When heavy alcohol use causes fat to build up in the liver, this condition is called alcoholic liver disease. Two types of NAFLD are simple fatty liver and nonalcoholic steatohepatitis (NASH). Simple fatty liver and NASH are two separate conditions. People typically develop one type of NAFLD or the other, although sometimes people with one form are later diagnosed with the other form of NAFLD. Simple fatty liver, also called non-alcoholic fatty liver (NAFL), is a form of NAFLD in which you have fat in your liver but little or no inflammation or liver cell damage. Simple fatty liver typically does not progress to cause liver damage or complications. [00277] On the other hand, NASH is a form of NAFLD in which you have inflammation and liver cell damage, in addition to fat in your liver. Inflammation and liver cell damage can cause fibrosis, or scarring of the liver. NASH may lead to cirrhosis or liver cancer.

[00278] The present disclosure demonstrates the viability of cathepsin D inhibition as a pathway for the treatment of liver diseases and abnormal liver conditions such as those mentioned above. In various embodiments, the liver disease is NASH. In some embodiments, treatment of liver diseases and abnormal liver conditions comprises proteolytic inhibition of cathepsin D (CTSD). In some embodiments, the cathepsin D being inhibited is intracellular or circulating CTSD. In other embodiments, the cathepsin D being inhibited is circulating CTSD.

[00279] Cathepsin D is a protein that in humans is encoded by the CTSD gene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. This proteinase, which is a member of the peptidase A 1 family, has a specificity similar to but narrower than that of pepsin A. Transcription of this gene is initiated from several sites, including one that is a start site for an estrogen-regulated transcript. Mutations in this gene are involved in the pathogenesis of several diseases, including breast cancer and possibly Alzheimer disease. It has been used as a breast cancer tumor marker. Cathepsin D is an aspartic protease that depends critically on protonation of its active site Asp residue and gets activated at pH 5 in the endosomes of hepatocytes, where it degrades insulin. Along with Asp-protonation, lower pH also leads to conformational switch in cathepsin-D: the N terminal segment of the protease moves out of the active site as pH drops. Ceramide binds-to and activates cathepsin D. Cathepsin D is synthesized in the rough endoplasmic reticulum (RER) in a form of preprocathepsin D, built up of 412 amino acid residues. The RER is the site of glycosylation and formation of disulphide bridges in preprocathepsin D. Splitting off of the N-terminal 20 aminoacid prepeptide by signalase causes release of procathepsin D and its passage to the Golgi apparatus and primary lysosomes. In an acid environment of the primary lysosomes, intramolecular autocatalytic splitting off of the 44 amino acid propeptide and the formation of active enzyme occur.

[00280] The present disclosure further provides a method of regulating cholesterol homeostasis in a subject with NASH or NAFLD comprising administering a therapeutically effective amount of any of the compounds described herein, a pharmaceutically acceptable salt thereof, or a composition thereof to a subject in need. In various embodiments, regulating cholesterol homeostasis is indicated by reduced gene expression levels of Cluster of differentiation 36 ( Cd36 ), Niemann-Pick C2 ( Npc2 '), Liver X receptor alpha ( Lxra ), and peroxisome proliferator-activator receptor gamma iff par†).

[00281] In some embodiments, the present disclosure provides a method for regulating cholesterol homeostasis that occurs by increasing lipid and lipoprotein metabolism. In various embodiments, the increase in lipid and lipoprotein metabolism are determined by measuring one or more of plasma cholesterol, plasma triglycerides, hepatic total cholesterol, and hepatic total triglycerides.

[00282] In some embodiments, plasma cholesterol is reduced by at least about 1% to at least about 95%. In various other embodiments, plasma cholesterol is reduced by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, plasma cholesterol is reduced by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, plasma cholesterol is reduced by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, plasma cholesterol is reduced by at least about 15%.

[00283] In some embodiments, hepatic total cholesterol is reduced by at least about 1% to at least about 95%. In various other embodiments, hepatic total cholesterol is reduced by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, hepatic total cholesterol is reduced by at least about 5% to at least about 35%, at least about 10% to at least about 35%, at least about 15% to at least about 35%, at least about 20% to at least about 35%, at least about 25% to at least about 35%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, hepatic total cholesterol is reduced by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, hepatic total cholesterol is reduced by at least about 35%.

[00284] In some embodiments, plasma triglycerides are reduced by at least about 1% to at least about 95%. In various other embodiments, plasma triglycerides are reduced by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, plasma triglycerides are reduced by at least about 30% to at least about 50%, at least about 30% to at least about 55%, at least about 30% to at least about 60%, at least about 30% to at least about 65%, at least about 25% to at least about 65%, at least about 30% to at least about 70%, at least about 35% to at least about 75%, at least about 40% to at least about 75%, at least about 45% to at least about 75%, at least about 50% to at least about 75%, at least about 60% to at least about 75%, at least about 65% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 75% to at least about 95%. In still other embodiments, plasma triglycerides are reduced by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, plasma triglycerides are reduced by at least about 62%.

[00285] In some embodiments, hepatic total triglycerides are reduced by at least about 1% to at least about 95%. In various other embodiments, hepatic total triglycerides are reduced by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, hepatic total triglycerides are reduced by at least about 30% to at least about 50%, at least about 30% to at least about 55%, at least about 30% to at least about 60%, at least about 30% to at least about 65%, at least about 25% to at least about 65%, at least about 30% to at least about 70%, at least about 35% to at least about 75%, at least about 40% to at least about 75%, at least about 45% to at least about 75%, at least about 50% to at least about 75%, at least about 60% to at least about 75%, at least about 65% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 75% to at least about 95%. In still other embodiments, hepatic total triglycerides are reduced by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, hepatic total triglycerides are reduced by at least about 60%. [00286] The present disclosure also provides a method, wherein the increase in lipoprotein metabolism is effective in treating a lipoprotein disorder. In various embodiments of the present disclosure, the lipoprotein disorder is dyslipidemia, dyslipoproteinemia, mixed dyslipidemia, atherosclerotic cardiovascular disease (ASCVD), familial chylomicronemia syndrome, hypertriglycerdemia, dysbetalipoproteinemia, type lib hyperlipidemia, familial combined hyperlipidemia, familial hypercholesterolemia, metabolic syndrome, lipoprotein overproduction, lipoprotein deficiency, non-insulin dependent diabetes, abnormal lipid elimination in bile, a metabolic disorder, abnormal phospholipid elimination in bile, an abnormal oxysterol elimination in bile, an abnormal bile production, a peroxisome proliferator activated receptor-associated disorder, hypercholesterolemia, hyperlipidemia or visceral obesity.

[00287] Lipoprotein disorders result from abnormal synthesis, processing, or catabolism of plasma lipoprotein particles. These particles consist of a core of cholesterol ester and triglyceride enclosed in a coat of phospholipids and apolipoproteins. Four types of lipoprotein abnormalities are observed: elevated LDL cholesterol; reduced HDL cholesterol, usually with increased triglycerides and very-low-density lipoprotein (VLDL) cholesterol; elevated levels of chylomicron remnants and intermediate-density lipoproteins (IDL); and elevated levels of lipoprotein (a) [Lp(a)] particles. Lipoprotein transport genes have been implicated in each of these abnormal lipoprotein phenotypes. The clinical importance of lipoprotein disorders derives chiefly from the role of lipoproteins in atherogenesis and its associated risk of coronary and peripheral vascular disease. The greatly increased risk of acute pancreatitis associated with severe hypertriglyceridemia is an additional indication for intervention. Disordered lipid metabolism is also a critical element in nonalcoholic fatty liver disease. Characterization of dyslipidemia is important for selection of appropriate treatment and may provide clues to underlying primary clinical disorders.

[00288] Regulating cholesterol homeostasis can be accomplished in other ways as well. For instance, in various embodiments of the present disclosure, regulating cholesterol homeostasis occurs by increasing cholesterol degradation.

[00289] In some embodiments, the increase in cholesterol degradation corresponds with at least about a 10% to at least about a 110% increase in gene expression levels of cytochrome P450 7A1 ( Cyp7al ). In various other embodiments, the increase in cholesterol degradation corresponds with about a at least about a 15% to at least about a 110%, at least about a 20% to at least about a 110%, at least about a 25% to at least about a 110%, at least about a 30% to at least about a 110%, at least about a 35% to at least about a 110%, at least about a 40% to at least about a 110%, at least about a 45% to at least about a 110%, at least about a 50% to at least about a 110%, at least about a 55% to at least about a 110%, at least about a 60% to at least about a 110%, at least about a 65% to at least about a 110%, at least about a 70% to at least about a 110%, at least about a 75% to at least about a 110%, at least about an 80% to at least about a 110%, at least about an 85% to at least about a 110%, at least about a 90% to at least about a 110%, at least about a 95% to at least about a 110%, or at least about a 100% to at least about a 110% increase in gene expression levels of cytochrome P450 7A1. In certain embodiments, the increase in cholesterol degradation corresponds with at least about an 80% to at least about a 120%, at least about a 90% to at least about a 120%, at least about a 100% to at least about a 120%, at least about a 110% to at least about a 120%, at least about a 50% to at least about a 150%, at least about a 75% to at least about a 150%, at least about a 100% to at least about a 150%, at least about a 125% to at least about a 150%, at least about a 100% to at least about a 200%, at least about a 125% to at least about a 200%, at least about a 150% to at least about a 200%, at least about a 175% to at least about a 200%, at least about a 175% to at least about a 225%, at least about a 200% to at least about a 250%, at least about a 225% to at least about a 250%, at least about a 250% to at least about a 275%, or at least about a 275% to at least about a 300% increase in gene expression levels of cytochrome P450 7A1. In still other embodiments, the increase in cholesterol degradation corresponds with about a at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, at least about a 30%, at least about a 35%, at least about a 40%, at least about a 45%, at least about a 50%, at least about a 55%, at least about a 60%, at least about a 65%, at least about a 70%, at least about a 75%, at least about an 80%, at least about an 85%, at least about a 90%, at least about a 95%, at least about a 100%, at least about a 110%, at least about a 120%, at least about a 130%, at least about a 140%, at least about a 150%, at least about a 160%, at least about a 170%, at least about a 180%, at least about a 190%, at least about a 200%, at least about a 210%, at least about a 220%, at least about a 230%, at least about a 240%, at least about a 250%, at least about a 260%, at least about a 270%, at least about a 280%, at least about a 290%, or at least about a 300% increase in gene expression levels of cytochrome P450 7A1. In specific embodiments, the increase in cholesterol degradation corresponds with at least about a 110% increase in gene expression levels of cytochrome P450 7A1 ( Cyp7al ).

[00290] In other embodiments, the increased cholesterol degradation is indicated by an increase in the metabolic products 27-hydroxycholesterol (27HC) and 7-alpha- hydroxycholesterol (7aHC). In some embodiments, the increase in metabolic products means that 27HC is increased by at least about 1% to at least about 95%. In various other embodiments, the increase in metabolic products means that 27HC is increased by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the increase in metabolic products means that 27HC is increased by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the increase in metabolic products means that 27HC is increased by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, the increase in metabolic products means that 27HC is increased by at least about 25%.

[00291] In some embodiments, the increase in metabolic products means that 7aHC is increased by at least about 10% to at least about 110%. In various other embodiments, the increase in metabolic products means that 7aHC is increased by at least about 15% to at least about 110%, at least about 20% to at least about 110%, at least about 25% to at least about 110%, at least about 30% to at least about 110%, at least about 35% to at least about 110%, at least about 40% to at least about 110%, at least about 45% to at least about 110%, at least about 50% to at least about 110%, at least about 55% to at least about 110%, at least about 60% to at least about 110%, at least about 65% to at least about 110%, at least about 70% to at least about 110%, at least about 75% to at least about 110%, at least about 80% to at least about 110%, at least about 85% to at least about 110%, at least about 90% to at least about 110%, at least about 95% to at least about 110%, or at least about 100% to at least about 110%. In certain embodiments, the increase in metabolic products means that 7aHC is increased by at least about 80% to at least about 120%, at least about 90% to at least about 120%, at least about 100% to at least about 120%, at least about 110% to at least about 120%, at least about 50% to at least about 150%, at least about 75% to at least about 150%, at least about 100% to at least about 150%, at least about 125% to at least about 150%, at least about 100% to at least about 200%, at least about 125% to at least about 200%, at least about 150% to at least about 200%, at least about 175% to at least about 200%, at least about 175% to at least about 225%, at least about 200% to at least about 250%, at least about 225% to at least about 250%, at least about 250% to at least about 275%, or at least about 275% to at least about 300%. In still other embodiments, the increase in metabolic products means that 7aHC is increased by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 110%, at least about 120%, at least about 130%, at least about 140%, at least about 150%, at least about 160%, at least about 170%, at least about 180%, at least about 190%, at least about 200%, at least about 210%, at least about 220%, at least about 230%, at least about 240%, at least about 250%, at least about 260%, at least about 270%, at least about 280%, at least about 290%, or at least about 300%. In specific embodiments, the increase in metabolic products means that 7aHC is increased by at least about 100%.

[00292] The present disclosure provides another method for regulating cholesterol homeostasis, wherein the regulation occurs by a decrease in hepatic cholesterol synthesis. In certain embodiments, the decrease in hepatic cholesterol synthesis is measured from hepatic desmosterol levels.

[00293] In some embodiments, the hepatic desmosterol level is reduced by at least about 1% to at least about 95%. In various other embodiments, the hepatic desmosterol level is reduced by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the hepatic desmosterol level is reduced by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the hepatic desmosterol level is reduced by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. More specifically, in certain embodiments, the hepatic desmosterol level is reduced by at least about 31%.

[00294] In some embodiments, the reduced hepatic desmosterol level correlates with at least about a 1% to at least about a 95% reduction in the gene expression levels of 3-hydroxy-3- methyl-glutaryl-Coenzyme A reductase ( HmG-CoAR ). In various other embodiments, the reduced hepatic desmosterol level correlates with at least about a 5% to at least about a 95%, at least about a 10% to at least about a 95%, at least about a 15% to at least about a 95%, at least about a 20% to at least about a 95%, at least about a 25% to at least about a 95%, at least about a 30% to at least about a 95%, at least about a 35% to at least about a 95%, at least about a 40% to at least about a 95%, at least about a 45% to at least about a 95%, at least about a 50% to at least about a 95%, at least about a 55% to at least about a 95%, at least about a 60% to at least about a 95%, at least about a 65% to at least about a 95%, at least about a 70% to at least about a 95%, at least about a 75% to at least about a 95%, at least about an 80% to at least about a 95%, at least about a 85% to at least about a 95%, or at least about a 90% to at least about a 95% reduction in the gene expression levels of 3-hydroxy-3-methyl-glutaryl-Coenzyme A reductase. In certain embodiments, the reduced hepatic desmosterol level correlates with at least about a 5% to at least about a 15%, at least about a 10% to at least about a 20%, at least about a 15% to at least about a 25%, at least about a 20% to at least about a 35%, at least about a 25% to at least about a 40%, at least about a 30% to at least about a 45%, at least about a 35% to at least about a 50%, at least about a 40% to at least about a 55%, at least about a 45% to at least about a 60%, at least about a 50% to at least about a 65%, at least about a 55% to at least about a 70%, at least about a 60% to at least about a 75%, at least about a 65% to at least about an 80%, at least about a 70% to at least about an 85%, at least about a 75% to at least about a 90%, or at least about an 80% to at least about an 85% reduction in the gene expression levels of 3-hydroxy-3-methyl-glutaryl-Coenzyme A reductase. In still other embodiments, the reduced hepatic desmosterol level correlates with at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 11%, at least about a 12%, at least about a 13%, at least about a 14%, at least about a 15%, at least about a 16%, at least about a 17%, at least about an 18%, at least about a 19%, at least about a 20%, at least about a 21%, at least about a 22%, at least about a 23%, at least about a 24%, at least about a 25%, at least about a 26%, at least about a 27%, at least about a 28%, at least about a 29%, at least about a 30%, at least about a 31%, at least about a 32%, at least about a 33%, at least about a 34%, at least about a 35%, at least about a 36%, at least about a 37%, at least about a 38%, at least about a 39%, at least about a 40%, at least about a 41 %, at least about a 42%, at least about a 43%, at least about a 44%, at least about a 45%, at least about a 46%, at least about a 47%, at least about a 48%, at least about a 49%, at least about a 50%, at least about a 51%, at least about a 52%, at least about a 53%, at least about a 54%, at least about a 55%, at least about a 56%, at least about a 57%, at least about a 58%, at least about a 59%, at least about a 60%, at least about a 61%, at least about a 62%, at least about a 63%, at least about a 64%, at least about a 65%, at least about a 66%, at least about a 67%, at least about a 68%, at least about a 69%, at least about a 70%, at least about a 71%, at least about a 72%, at least about a 73%, at least about a 74%, at least about a 75%, at least about a 76%, at least about a 77%, at least about a 78%, at least about a 79%, at least about an 80%, at least about an 81%, at least about an 82%, at least about an 83%, at least about an 84%, at least about an 85%, at least about an 86%, at least about an 87%, at least about an 88%, at least about an 89%, at least about a 90%, at least about a 91%, at least about a 92%, at least about a 93%, at least about a 94%, or at least about a 95%reduction in the gene expression levels of 3-hydroxy-3-methyl-glutaryl-Coenzyme A reductase. In specific embodiments, the reduced hepatic desmosterol level correlates with at least about a 38% reduction in the gene expression levels of 3-hydroxy-3-methyl-glutaryl-Coenzyme A reductase ( HmG-CoAR ). [00295] In yet another embodiment of the present disclosure, cholesterol homeostasis is regulated by increasing total fecal bile acid and fecal cholesterol levels. In some embodiments, fecal bile acid is increased by at least about 100% to at least about 1000%. In various other embodiments, fecal bile acid is increased by at least about 150% to at least about 1000%, at least about 200% to at least about 1000%, at least about 250% to at least about 1000%, at least about 300% to at least about 1000%, at least about 350% to at least about 1000%, at least about 400% to at least about 1000%, at least about 450% to at least about 1000%, or at least about 500% to at least about 1000%. at least about 550% to at least about 1000%, at least about 600% to at least about 1000%, at least about 650% to at least about 1000%, at least about 700% to at least about 1000%, at least about 750% to at least about 1000%, at least about 800% to at least about 1000%, at least about 850% to at least about 1000%, at least about 900% to at least about 1000%, or at least about 950% to at least about 1000%. In certain embodiments, fecal bile acid is increased by at least about 50% to at least about 100%, at least about 100% to at least about 150%, at least about 150% to at least about 200%, at least about 250% to at least about 300%, at least about 350% to at least about 400%, at least about 400% to at least about 450%, at least about 500% to at least about 550%, at least about 550% to at least about 600%, at least about 600% to at least about 650%, at least about 650% to at least about 700%, at least about 750% to at least about 800%, at least about 800% to at least about 850%, at least about 850% to at least about 900%, at least about 950% to at least about 1000%, at least about 1000% to at least about 1050%, at least about 1050% to at least about 1100%, or at least about 1150% to at least about 1200%. In still other embodiments, fecal bile acid is increased by at least about 20%, at least about 40%, at least about 60%, at least about 80%, at least about 100%, at least about 120%, at least about 140%, at least about 160%, at least about 180%, at least about 200%, at least about 220%, at least about 240%, at least about 260%, at least about 280%, at least about 300%, at least about 320%, at least about 340%, at least about 360%, at least about 380%, at least about 400%, at least about 420%, at least about 440%, at least about 460%, at least about 480%, at least about 500%, at least about 520%, at least about 540%, at least about 560%, at least about 580%, at least about 6000%, at least about 620%, at least about 640%, at least about 660%, at least about 680%, at least about 700%, at least about 720%, at least about 740%, at least about 760%, at least about 780%, at least about 800%, at least about 820%, at least about 840%, at least about 860%, at least about 880%, at least about 900%, at least about 920%, at least about 940%, at least about 960%, at least about 980%, or at least about 1000%. In specific embodiments, fecal bile acid is increased by at least about 700%. [00296] In some embodiments, fecal cholesterol is increased by at least about 10% to at least about 110%. In various other embodiments, fecal cholesterol is increased by at least about 15% to at least about 100%, at least about 20% to at least about 100%, at least about 25% to at least about 100%, at least about 30% to at least about 100%, at least about 35% to at least about 100%, at least about 40% to at least about 100%, at least about 45% to at least about 100%, at least about 50% to at least about 100%, at least about 55% to at least about 100%, at least about 60% to at least about 100%, at least about 65% to at least about 100%, at least about 70% to at least about 100%, at least about 75% to at least about 100%, at least about 80% to at least about 100%, at least about 85% to at least about 100%, at least about 90% to at least about 100%, at least about 95 % to at least about 110%, or at least about 100% to at least about 110%. In certain embodiments, fecal cholesterol is increased by at least about 80% to at least about 120%, at least about 90% to at least about 120%, at least about 100% to at least about 120%, at least about 110% to at least about 120%, at least about 50% to at least about 150%, at least about 75% to at least about 150%, at least about 100% to at least about 150%, at least about 125% to at least about 150%, at least about 100% to at least about 200%, at least about 125% to at least about 200%, at least about 150% to at least about 200%, at least about 175% to at least about 200%, at least about 175% to at least about 225%, at least about 200% to at least about 250%, at least about 225% to at least about 250%, at least about 250% to at least about 275%, or at least about 275% to at least about 300%. In still other embodiments, fecal cholesterol is increased by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 110%, at least about 120%, at least about 130%, at least about 140%, at least about 150%, at least about 155%, at least about 160%, at least about 170%, at least about 180%, at least about 185%, at least about 190%, at least about 195%, at least about 200%, at least about 210%, at least about 220%, at least about 230%, at least about 240%, or at least about 250%. In specific embodiments, fecal cholesterol is increased by at least about 88%.

[00297] As already described, non-alcoholic fatty liver disease (NAFLD) is a condition in which fat builds up in the liver. Non-alcoholic steatohepatitis (NASH) is a type of NAFLD that has as a hallmark systemic and hepatic inflammation that ultimately leads to severe liver damage. Treatment is therefore required. [00298] Thus, the present disclosure provides methods of reducing systemic and hepatic inflammation in a patient suffering from NASH comprising administering a therapeutically effective amount of the compounds described herein, a pharmaceutically acceptable salt thereof, or a composition thereof to a subject in need. In various embodiments, the reduction of hepatic inflammation is from at least about 1% to at least about 95% relative to a subject with NASH not undergoing treatment. In other embodiments, the reduction of hepatic inflammation is from at least about at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In some embodiments, the reduction of hepatic inflammation is from at least about 10% to at least about 65%, at least about 15% to at least about 65%, at least about 20% to at least about 65%, at least about 25% to at least about 65%, at least about 30% to at least about 65%, at least about 35% to at least about 65%, at least about 40% to at least about 65%, at least about 45% to at least about 65%, at least about 50% to at least about 65%, or at least about 55% to at least about 65%, relative to a subject with NASH not undergoing treatment. In one embodiment, the reduction of hepatic inflammation is from at least about 20% to at least about 60% relative to a subject with NASH not undergoing treatment. In other embodiments the reduction is at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 1 1%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%.

[00299] Hepatic gene expression analysis of inflammatory markers can be used to establish at an early stage that a liver disease or abnormality such as NASH is present. In related embodiments, the reduction of hepatic inflammation correlates with a reduction in hepatic gene expression levels of tumor necrosis factor alpha, chemokine ligand-2, Caspasel, cluster of differentiation 68, interleukin-12, vascular cell adhesion protein, cluster of differentiation 206, Early growth response protein 2, and inducible nitric oxide/arginase 1.

[00300] In some embodiments, the reduction in hepatic gene expression level of tumor necrosis factor alpha ( TNFa ) is by at least about 1% to at least about 95%. In various other embodiments, the reduction in hepatic gene expression level of tumor necrosis factor alpha is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the reduction in hepatic gene expression level of tumor necrosis factor alpha is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the reduction in hepatic gene expression level of tumor necrosis factor alpha is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%.More specifically, in certain embodiments, the reduction in hepatic gene expression level of tumor necrosis factor alpha ( TNFa ) is by at least about 1% to at least about 45%.

[00301] In some embodiments, the reduction in hepatic gene expression level of tumor chemokine ligand-2 ( Ccl2 ) is by at least about 1% to at least about 95%. In various other embodiments, the reduction in hepatic gene expression level of tumor chemokine ligand-2 is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the reduction in hepatic gene expression level of tumor chemokine ligand-2 is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the reduction in hepatic gene expression level of tumor chemokine ligand-2 is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, the reduction in hepatic gene expression level of tumor chemokine ligand-2 ( Ccl2 ) is by at least about 50%. [00302] In some embodiments, the reduction in hepatic gene expression level of Caspasel is by at least about 1% to at least about 95%. In various other embodiments, the reduction in hepatic gene expression level of Caspasel is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the reduction in hepatic gene expression level of Caspasel is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the reduction in hepatic gene expression level of Caspasel is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, the reduction in hepatic gene expression level of Caspasel is by at least about 31%.

[00303] In some embodiments, the reduction in hepatic gene expression level of cluster of differentiation 68 ( Cd68 ) is by at least about 1% to at least about 95%. In various other embodiments, the reduction in hepatic gene expression level of cluster of differentiation 68 is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the reduction in hepatic gene expression level of cluster of differentiation 68 is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the reduction in hepatic gene expression level of cluster of differentiation 68 is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In some embodiments, the reduction in hepatic gene expression level of cluster of differentiation 68 ( Cd68 ) is by at least about 37%.

[00304] In some embodiments, the reduction in hepatic gene expression level of vascular cell adhesion protein ( V('AM) is by at least about 1% to at least about 95%. In various other embodiments, the reduction in hepatic gene expression level of vascular cell adhesion protein is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the reduction in hepatic gene expression level of vascular cell adhesion protein is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the reduction in hepatic gene expression level of vascular cell adhesion protein is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, the reduction in hepatic gene expression level of vascular cell adhesion protein (V('AM) is by at least about 33%.

[00305] In some embodiments, the reduction in hepatic gene expression level of interleukin- 12 (11-12) is by at least about 1% to at least about 95%. In various other embodiments, the reduction in hepatic gene expression level of interleukin- 12 is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the reduction in hepatic gene expression level of interleukin- 12 is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the reduction in hepatic gene expression level of interleukin- 12 is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In another embodiment, the reduction in hepatic gene expression level of interleukin- 12 (11-12) is by at least about 44%. [00306] In some embodiments, the reduction in hepatic gene expression level of cluster of differentiation 206 ( Cd206) is by at least about 1% to at least about 95%. In various other embodiments, the reduction in hepatic gene expression level of cluster of differentiation 206 is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the reduction in hepatic gene expression level of cluster of differentiation 206 is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the reduction in hepatic gene expression level of cluster of differentiation 206 is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, the reduction in hepatic gene expression level of cluster of differentiation 206 ( Cd206) is by at least about 24%.

[00307] In some embodiments, hepatic gene expression level of Early growth response protein 2 ( Egr2 ) is by at least about 1% to at least about 95%. In various other embodiments, hepatic gene expression level of Early growth response protein 2 is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, hepatic gene expression level of Early growth response protein 2 is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, hepatic gene expression level of Early growth response protein 2 is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In certain other embodiments of the present disclosure, hepatic gene expression level of Early growth response protein 2 ( Egr2 ) is by at least about 45%.

[00308] In some embodiments, the reduction in hepatic gene expression level of the inducible nitric oxide/arginase 1 ratio ( iNos/Argl ) is by at least about 1% to at least about 95%. In various other embodiments, the reduction in hepatic gene expression level of the inducible nitric oxide/arginase 1 ratio is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the reduction in hepatic gene expression level of the inducible nitric oxide/arginase 1 ratio is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the reduction in hepatic gene expression level of the inducible nitric oxide/arginase 1 ratio is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In yet another embodiment, the reduction in hepatic gene expression level of the inducible nitric oxide/arginase 1 ratio ( iNos/Argl ) is by at least about 26%.

[00309] Besides hepatic inflammation, systemic inflammation is also impacted by the disclosed methods. In some embodiments, the reduction in systemic inflammation is by at least about 1% to at least about 95% relative to a subject with NASH not undergoing treatment about. In various other embodiments, the reduction in systemic inflammation is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the reduction in systemic inflammation is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the reduction in systemic inflammation is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 1 1%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In a specific embodiment, the reduction in systemic inflammation is by at least about 30% relative to a subject with NASH not undergoing treatment.

[00310] Various immune system responses are telling. For instance, in certain embodiments of the present method, the reduction of systemic inflammation is determined by measuring blood leukocyte and CD4 ⁺ T cell levels. In some embodiments, the blood leukocyte level is decreased by at least about 1% to at least about 95%. In various other embodiments, the blood leukocyte level is decreased by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the blood leukocyte level is decreased by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the blood leukocyte level is decreased by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In other embodiments, the blood leukocyte level is decreased by at least about 32%.

[00311] In some embodiments, the CD4 ⁺ T cell level is decreased by at least about 1% to at least about 95%. In various other embodiments, the CD4 ⁺ T cell level is decreased by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the CD4 ⁺ T cell level is decreased by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the CD4 ⁺ T cell level is decreased by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, the CD4 ⁺ T cell level is decreased by at least about 30%.

[00312] Without being bound by any particular theory, it is believed that the benefits of the methods described herein are derived from the proteolytic inhibition of cathepsin D (CTSD) by the inventive compounds disclosed herein. Such inhibition has been found to reduce steatohepatitis (hepatic inflammation) by restoring aberrant lysosomal function to“normal” levels. Thus, the present disclosure affords a method of improving aberrant lysosomal function in a patient suffering from NASH comprising administering a therapeutically effective amount of the compounds described herein, a pharmaceutically acceptable salt thereof, or a composition thereof to a subject in need. In various embodiments, the aberrant lysosomal function is restored to the level found in a subject not afflicted with NASH. In other embodiments, the restoration occurs by reducing one or more of plasma CTSD activity, plasma CTSD levels, and hepatic CTSD activity.

[00313] In some embodiments, the reduction of the plasma CTSD activity is by at least about 1% to at least about 95%. In various other embodiments, the reduction of the plasma CTSD activity is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the reduction of the plasma CTSD activity is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the reduction of the plasma CTSD activity is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, the reduction of the plasma CTSD activity is by at least about 35%. [00314] In some embodiments, the reduction of the plasma CTSD level is by at least about 1% to at least about 95%. In various other embodiments, the reduction of the plasma CTSD level is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the reduction of the plasma CTSD level is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the reduction of the plasma CTSD level is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, the reduction of the plasma CTSD level is by at least about 39%.

[00315] In some embodiments, the reduction of hepatic CTSD activity is by at least about 1% to at least about 95%. In various other embodiments, the reduction of hepatic CTSD activity is by at least about 5% to at least about 95%, at least about 10% to at least about 95%, at least about 15% to at least about 95%, at least about 20% to at least about 95%, at least about 25% to at least about 95%, at least about 30% to at least about 95%, at least about 35% to at least about 95%, at least about 40% to at least about 95%, at least about 45% to at least about 95%, at least about 50% to at least about 95%, at least about 55% to at least about 95%, at least about 60% to at least about 95%, at least about 65% to at least about 95%, at least about 70% to at least about 95%, at least about 75% to at least about 95%, at least about 80% to at least about 95%, at least about 85% to at least about 95%, or at least about 90% to at least about 95%. In certain embodiments, the reduction of hepatic CTSD activity is by at least about 5% to at least about 15%, at least about 10% to at least about 20%, at least about 15% to at least about 25%, at least about 20% to at least about 35%, at least about 25% to at least about 40%, at least about 30% to at least about 45%, at least about 35% to at least about 50%, at least about 40% to at least about 55%, at least about 45% to at least about 60%, at least about 50% to at least about 65%, at least about 55% to at least about 70%, at least about 60% to at least about 75%, at least about 65% to at least about 80%, at least about 70% to at least about 85%, at least about 75% to at least about 90%, or at least about 80% to at least about 85%. In still other embodiments, the reduction of hepatic CTSD activity is by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, or at least about 95%. In specific embodiments, the reduction of hepatic CTSD activity is by at least about 15%. In certain other related embodiments, the reduction in plasma CTSD level correlates with a reduction of the hepatic gene expression levels of one or more of the inflammatory markers TNFa,Ccl2, and Caspasel .

[00316] The methods of the present disclosure provide numerous additional related benefits. In some embodiments, the present disclosure describes methods of reducing the accumulation of liver fat in a subject comprising the administration of a therapeutically effective amount of the compounds described herein, a pharmaceutically acceptable salt thereof, or a composition thereof.

[00317] In other embodiments of the present disclosure, a method of stabilizing, reducing, or slowing the upward progression of the NAFDL activity score (NAS) in a subject, comprising administration of a therapeutically effective amount of the compounds described herein, a pharmaceutically acceptable salt thereof, or a composition thereof is provided.

[00318] NAFLD may be differentiated from NASH by the NAFLD Activity Score (NAS), the sum of the histopathology scores of a liver biopsy for steatosis (0 to 3), lobular inflammation (0 to 2), and hepatocellular ballooning (0 to 2). A NAS of <3 corresponds to NAFLD, 3-4 corresponds to borderline NASH, and >5 corresponds to NASH. The biopsy is also scored for fibrosis (0 to 4).

[00319] The present disclosure also provides a method for reducing in a subject’s blood plasma or blood serum the subject's total cholesterol level, low -density lipoprotein cholesterol concentration, low-density lipoprotein concentration, very low-density lipoprotein cholesterol concentration, very low-density lipoprotein concentration, non-HDL cholesterol concentration, non-HDL concentration, apolipoprotein B level, triglyceride concentration, apolipoprotein C- III level, C-reactive protein level, fibrinogen level, or lipoprotein level, comprising administering to a subject in need thereof an effective amount of the compounds described herein, a pharmaceutically acceptable salt thereof, or a composition thereof.

[00320] In addition to treating liver diseases and other abnormal liver conditions, the present methods are expected to have benefits in other therapeutic areas. For example, in some embodiments, a method is provided that is useful for treating or preventing a cardiovascular disorder or a related vascular disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compounds described herein, a pharmaceutically acceptable salt thereof, or a composition thereof. In certain embodiments, the cardiovascular disorder or a related vascular disorder is atherosclerosis, hypertension, coronary artery disease, myocardial infarction, arrhythmia, atrial fibrillation, heart valve disease, heart failure, cardiomyopathy, myopathy, pericarditis, impotence, or a thrombotic disorder. In a specific embodiment, the method is useful for treating a cardiovascular disorder that is atherosclerosis.

[00321] Tissue fibrosis (scarring) is a leading cause of morbidity and mortality with limited treatment options available. Compounds of the present disclosure are expected to be useful to this end. Therefore, in some embodiments, the present methods are useful in treating fibrotic disorders. In some embodiments, the fibrotic disorders are pulmonary fibrosis, renal fibrosis, cardiac fibrosis or systemic sclerosis. In other embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis. In another embodiment, the cardiac fibrosis is myocardial fibrosis.

[00322] The present disclosure also provides a method for treating or preventing a disorder of glucose metabolism, comprising administering to a subject in need thereof a therapeutically effective amount of the compounds described herein, a pharmaceutically acceptable salt thereof, or a composition thereof. In various embodiments, the disorder of glucose metabolism can be insulin resistance, impaired glucose tolerance, impaired fasting glucose, diabetes mellitus, lipodystrophy, familial partial lipodystrophy, obesity, peripheral lipoatrophy, diabetic nephropathy, diabetic retinopathy, renal disease, or septicemia. In a related embodiment, the disorder of glucose metabolism is diabetes mellitus. In a more specific embodiment, the diabetes mellitus is type 2 diabetes. Compound Formulation

[00323] In some embodiments, the present disclosure provides pharmaceutical compositions comprising an effective amount of a compound of Formula (I), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (I-H _a ), Formula (I-Hb), Formula (I-I), Formula (I-J), Formula (I-K), Formula (I-L), Formula (I-M), or Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein comprise one or more pharmaceutically acceptable carriers or excipients.

[00324] In various embodiments, the pharmaceutical compositions of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.

[00325] The effective amount of a compound of Formula (I), pharmaceutically acceptable salts, esters, prodrugs, hydrates, solvates and isomers thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be determined by one skilled in the art based on known methods.

[00326] In one embodiment, a pharmaceutical composition or a pharmaceutical formulation of the present disclosure comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, and/or excipient. Pharmaceutically acceptable carriers, diluents or excipients include without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[00327] In one embodiment, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.

[00328] Aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like.

[00329] Liquid carriers suitable for use in the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.

[00330] Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration. The liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[00331] Solid carriers suitable for use in the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. A solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier can be a finely divided solid which is in admixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

[00332] Parenteral carriers suitable for use in the present application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.

[00333] Carriers suitable for use in the present application can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art. The carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art.

[00334] Diluents may be added to the formulations of the present invention. Diluents increase the bulk of a solid pharmaceutical composition and/or combination, and may make a pharmaceutical dosage form containing the composition and/or combination easier for the patient and care giver to handle. Diluents for solid compositions and/or combinations include, for example, microcrystalline cellulose (e.g., AVICEL), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT(r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc. [00335] The pharmaceutical composition of the present invention may be prepared into any type of formulation and drug delivery system by using any of the conventional methods well- known in the art. The inventive pharmaceutical composition may be formulated into injectable formulations, which may be administered by routes including intrathecal, intraventricular, intravenous, intraperitoneal, intranasal, intraocular, intramuscular, subcutaneous or intraosseous. Also, it may also be administered orally, or parenterally through the rectum, the intestines or the mucous membrane in the nasal cavity ( see Gennaro, A. R., ed. (1995) Remington's Pharmaceutical Sciences). Preferably, the composition is administered topically, instead of enterally. For instance, the composition may be injected, or delivered via a targeted drug delivery system such as a reservoir formulation or a sustained release formulation.

[00336] The pharmaceutical formulation of the present invention may be prepared by any well-known methods in the art, such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. As mentioned above, the compositions of the present invention may include one or more physiologically acceptable carriers such as excipients and adjuvants that facilitate processing of active molecules into preparations for pharmaceutical use.

[00337] Proper formulation is dependent upon the route of administration chosen. For injection, for example, the composition may be formulated in an aqueous solution, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. Fortransmucosal or nasal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. In a one embodiment of the present invention, the inventive compound may be prepared in an oral formulation. For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the disclosed compound to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[00338] Pharmaceutical preparations for oral use may be obtained as solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable adjuvants, if desired, to obtain tablets or dragee cores. Suitable excipients may be, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose formulation such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP) formulation. Also, disintegrating agents may be employed, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Also, wetting agents, such as sodium dodecyl sulfate and the like, may be added.

[00339] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compounds doses.

[00340] The present disclosure also relates to the afore-described compound, pharmaceutically acceptable salt thereof, or composition thereof for use as a medicament.

[00341] The present disclosure also relates to use of the afore-described compound, pharmaceutically acceptable salt thereof, or composition thereof in the manufacture of a medicament.

[00342] The present disclosure also relates to the afore-described compound, pharmaceutically acceptable salt thereof, or composition thereof for use as a medicament for treating or preventing a liver disease or an abnormal liver condition.

[00343] The present disclosure also relates to use of the afore-described compound, pharmaceutically acceptable salt thereof, or composition thereof in the manufacture of a medicament for treating or preventing a liver disease or an abnormal liver condition.

[00344] In an embodiment, the said medicament is administered to a subject in need thereof.

[00345] The present disclosure also relates to the afore-described compound, pharmaceutically acceptable salt thereof, or composition thereof for use in treating or preventing a liver disease or an abnormal liver condition.

[00346] In an embodiment, the compound, pharmaceutically acceptable salt thereof, or composition of the present disclosure is useful for treating or preventing a liver disease or an abnormal liver condition, wherein the liver disease or abnormal liver condition includes, non alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic steatohepatitis, cirrhosis, inflammation, fibrosis, partial fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, liver failure, hepatocellular carcinoma, liver cancer, hepatic steatosis, hepatocyte ballooning, hepatic lobular inflammation, and hepatic triglyceride accumulation. In an embodiment, the liver disease or abnormal liver condition is non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. In an embodiment, the liver disease or abnormal liver condition is non-alcoholic steatohepatitis.

[00347] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto; inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[00348] The above-described embodiments can be implemented in any of numerous ways. Also, various inventive concepts may be embodied as one or more methods, of which an example has been provided. The acts performed as part of the method may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.

[00349] All cited documents are herein incorporated by reference in their entirety for all purposes. Examples

[00350] Example 1 : Preparation of Library Compounds

[00351] Various derivatives of the above described formulas can be prepared from the appropriate starting materials and intermediates using the general methods described herein, as shown below in Scheme 1, Scheme 2, and Scheme 3.

Scheme 1. Synthesis of D-library guanidine compounds

□ _' Variants

Scheme 2. Synthesis of D-library amide compounds

O-Vsfii ti

Scheme 3. Synthesis of D-library modified guanidine compounds

o-m Representative procedure for the synthesis of D-002 (Scheme 1)

[00352] Synthesis of intermediate 3

[00353] To a solution of compound 1 (lOg, 36.3 mmol, 1.0 equiv.) in DCM at 0 °C under nitrogen, oxalyl chloride (5.5 g, 43.6 mmol, 1.2 equiv.) and cat. DMF were added in to it. The reaction mixture was allowed to stir at rt. Progress of the reaction was monitored with TLC. After completion of the reaction the reaction mixture was evaporated to dryness, further diluted with DCM and used as such for next reaction. In another RBF, N-Boc-guanidine (7.5 g, 47.2 mmol, 1.3 equiv.) was added and dissolved in DCM. To this solution, DIPEA (7.0 g, 54.4 mmol, 1.5 equiv.) was added at 0 °C under nitrogen. After 30 min. intermediate 2 was added in to it at the same temperature. The reaction mixture was allowed to warm at rt. Progress of the reaction was monitored with TLC. After completion of the reaction, the reaction mixture was washed with sat. aqueous NaHCCb and brine. The organic layer was evaporated to dryness. The crude residue was purified through column chromatography using hexane:EtOAc (80:20) as the eluent to afford compound 3 as light yellow solid (9.5 g, 62.9%); ¹ HNMR (400 MHz, CDCb) S 1.48 (s, 9H), 3.77 (s, 3H), 3.88 (s, 6H), 6.77 (s, 1H), 6.90 (s, 1H).

[00354] Synthesis of intermediate 4

[00355] To a solution of compound 3 (3 g, 7.21 mmol, 1.0 equiv.) in DCM at -78 °C under nitrogen, was added triethylamine (1.59 g, 10.81 mmol, 2.0 equiv.) After 15 min, triflic anhydride (2.64 g, 9.36 mmol, 1.3 equiv.) was slowly added in to it. Progress of the reaction was monitored with TLC. After completion of the reaction the reaction mixture was washed with 2M sodium bisulfate and brine. The organic layer was evaporated to dryness. The crude residue was purified through column chromatography using hexane: EtOAc (75:25) as the eluent to afford compound 4as white solid (0.9 g, 22.8%); ¹ HNMR (400 MHz, CDCb) S 1.50 (s, 9H), 3.89 (s, 3H), 3.91 (s, 6H), 6.78 (s, 1H), 7.0 (s, 1H).

[00356] Synthesis of intermediate 6

[00357] To a solution of compound 5 (2.71 g, 9.98 mmol, 1.0 equiv.) and 3 -Amino-4, N,N- trimethylbenzene sulfonamide (2g, 9.98 mmol, 1.0 equiv.) in ACN at 0 °C under nitrogen, were added DIPEA (3.4 mL, 19.97 mmol, 2.0 equiv.) and HOBt (1.35 g, 9.98 mmol, 1.0 equiv.). After 30 min, EDC-HC1 (2.1 g, 10.98 mmol, 1.1 equiv.) was slowly added in to it. Progress of the reaction was monitored with TLC. After completion of the reaction the reaction mixture was evaporated to dryness. The crude residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was evaporated to dryness. The crude residue was purified through column chromatography using hexane: EtOAc (80:20) as the eluent to afford compound6as white solid( 1.8 g, 41%); TfNMR ^OO MHz, CDCb) d 0.92-1.29 (m, 5H), 1.40- 1.48 (m, 12H), 1.51-1.89 (m, 5 H), 2.35 (s, 3H), 2.74 (s, 6H), 4.26-4.32 (m, 1H), 4.85-4.92 (m, 1H), 7.32-7.34 (m, 1H), 7.47-7.49 (m, 1H), 8.36 (s, 1H), 8.42 (brs, 1H).

[00358] Synthesis of intermediate 7

[00359] To a solution of compound 6 (1.7 g, 3.6 mmol, 1.0 equiv.) in MeOH at 0 °C, was added cone. HC1 (5 mL). The reaction mixture was allowed to stir at rt. Progress of the reaction was monitored with TLC. After completion of the reaction the reaction mixture was evaporated to dryness. The crude residue was purified through ethyl acetate washing and used as such without further purification. ¹ HNMR (400 MHz, CDCb) d 0.97-1.47 (m, 6H), 1.61-1.91 (m, 8H), 2.32 (s, 3H), 2.67 (s, 6H), 4.26-4.30 (m, 1H), 7.59 (d, J= 8.8 Hz, 1H), 7.66-7.68 (m, 2H).

[00360] Synthesis of intermediate D-002a

[00361] To a solution of compound 7 (0.875 g, 2.16 mmol, 1.15 equiv.) in THF at 0 °C under nitrogen, was added DIPEA (0.73 g, 5.65 mmol, 3.0 equiv.). After 30 min, compound 4 (1.0 g, 1.88 mmol, 1.0 equiv.) was added in to it. The reaction mixture was allowed to stir at rt. Progress of the reaction was monitored with TLC. After completion of the reaction the reaction mixture was evaporated to dryness. The crude residue was dissolved in EtOAc and washed with water followed by brine. The organic layer was evaporated to dryness. The crude residue was purified through column chromatography using hexane: EtOAc (75:25) as the eluent to afford compound D-002a as white solid (0.54 g, 37.5 %).

[00362] Synthesis of D-002

[00363] To a solution of compound D-002a (0.52 g, 0.68 mmol, 1.0 equiv.) in DCM at 0 °C under nitrogen, was added TFA (2 mL). The reaction mixture was allowed to stir at rt. Progress of the reaction was monitored with TLC. After completion of the reaction the reaction mixture was evaporated to dryness. The crude residue was purified through column chromatography using DCM: MeOH (98:02) as the eluent to afford compound D-002 as light brown solid (450 mg, 83.7%). ¹ HNMR (400 MHz, CDCb) d 0.89-1.40 (m, 8H), 1.63-1.89 (m, 5H), 1.99 (s, 3H), 2.59 (s, 6H), 3.76 (s, 6H), 3.79 (s, 2H), 4.62-4.63 (m, 1H), 7.05 (d, J= 4.8 Hz, 2H), 7.50-7.55 (m, 2H), 7.75 (s, 1H), 9.02-9.10 (m, 3H), 9.81 (s, 1H), 11.49 (s, 1H).

Representative procedure for the synthesis of D-008 (Scheme 2)

D-40®

[00364] Synthesis of intermediate 3

[00365] To a solution of compound 1 (0.5 g, 2.5 mmol, 1.0 equiv.) and 2 (0.35 g, 2.5 mmol, 1.0 equiv.) in ACN at 0 °C under nitrogen, were added DIPEA (1.1 mL, 6.4 mmol, 2.5 equiv.) and HOBt (0.38 g, 2.8 mmol, 1.1 equiv.). After 15 min, EDC-HC1 (0.54 g, 2.8 mmol, 1.1 equiv.) was slowly added in to it. The reaction mixture was allowed to stir at rt. Progress of the reaction was monitored with TLC. After completion of the reaction the reaction mixture was evaporated to dryness. The crude residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was evaporated to dryness. The crude residue was used for next step without further purification.

[00366] Synthesis of intermediate 4

[00367] To a solution of compound 3 (0.5 g, 1.8 mmol, 1.0 equiv.) in THF:H20 (1 : 1) at 0 °C, was added LiOH-HiO (0.11 g, 2.7 mmol, 1.5 equiv.). The reaction mixture was allowed to stir at rt. Progress of the reaction was monitored with TLC. After completion of the reaction the reaction mixture was evaporated to dryness. The crude residue was dissolved in ethyl acetate and washed with water. The aqueous layer was made acidic with 1N HC1 and further extracted with ethyl acetate. The organic layer was evaporated to dryness afforded compound 4 as white solid which was used in next step without further purification.

[00368] Synthesis of D-008

[00369] To a solution of compound 4 (0.2 g, 0.75 mmol, 1.0 equiv.) and 3-Amino-4-/V,/V- trimethylbenzenesulfonamide (0.16 g, 0.75 mmol, 1.0 equiv.) in ACN at 0 °C, were added DIPEA (0.32 mL, 1.9 mmol, 2.5 equiv.) and HOBt (0.11 g, 0.82 mmol, 1.1 equiv.). After 30 min. EDC-HC1 (0.16 g, 0.82 mmol, 1.1 equiv.) was added in to it. The reaction mixture was allowed to stir at rt. Progress of the reaction was monitored with TLC. After completion of the reaction the reaction mixture was evaporated to dryness. The crude residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was evaporated to dryness. The crude residue was purified through column chromatography using hexane: EtOAc (80:20) as the eluent to afford D-008 as white solid (160 mg, 46%) ¹ HNMR (400 MHz, CDCb) S 1.39 (d, J = 7.2 Hz, 3H), 2.28 (s, 3H), 2.72 (s, 6H), 3.58 (s, 2H), 3.86-3.89 (m, 6H), 4.63-4.70 (m, 1H), 6.0 (brs, 1H), 6.76-6.86 (m, 3H), 7.32 (d, J= 8.0 Hz, 1H), 7.45-7.47 (m, 1H), 8.36 (s, 1H), 8.74 (s, 1H).

Representative procedure for the synthesis of D-176 (Scheme 3)

[00370] Synthesis of intermediate 2

[00371] To a solution of compound 1 (10 g, 50.9 mmol., 1 equiv.) and N-Boc guanidine (8.5 g, 53.5 mmol., 1.05 equiv.) in DMF (100 mL) at 0 °C, DIPEA (21.9 mL, 127.4 mmol., 2.5 equiv.) was added. The reaction mixture was allowed to stir for 30 min at the same temperature and then HATU (29 g, 76.5 mmol., 1.5 equiv.) was added in to it. The reaction mixture was allowed to stir overnight at room temperature. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured in to cold water and extracted twice with ethyl acetate. The combined organic layer was washed with brine and evaporated to dryness. The crude residue was purified through flash chromatography using hexane: ethyl acetate (80:20) as the eluent. Yield: 14 g (82%); 'H NMR (400 MHz, CDCb) d = 11.01 (brs, 1H), 8.81 (brs, 1H), 8.73 (brs, 1H), 6.88-6.91 (m, 2H), 6.80 (dd, J= 2.0 Hz, 6.0 Hz, 1H), 3.73 (d, J= 4.8 Hz, 6H), 3.55 (s, 1H), 1.38 (s, 9H).

[00372] Synthesis of intermediate 3

[00373] To a solution of compound 2 (4 g, 11.8 mmol., 1 equiv.) in DCM (40 mL) at -78 °C, DIPEA (5 mL, 29.5 mmol., 2.5 equiv.) was added. The reaction mixture was allowed to stir for 30 min at the same temperature. Triflic anhydride (3 mL, 17.7 mmol., 1.5 equiv.) was added slowly at the same temperature. Progress of the reaction was monitored by TLC. After completion of the reaction, sodium bisulfite solution was added. The reaction mixture was separated and washed with brine. The organic layer was evaporated to dryness. The crude residue was purified through flash chromatography using hexane: ethyl acetate (85: 15) as the eluent. Yield: 2.8 g (50%); 'H NMR (400 MHz, CDCb) <5 = 11.48 (brs, 1H), 11.31 (brs, 1H), 6.89-6.91 (m, 2H), 6.77-6.80 (m, 1H), 3.72-3.74 (m, 8H), 1.45 (s, 9H). [00374] Synthesis of intermediate 6

[00375] To a solution of compound 4 (0.7 g, 3.7 mmol., 1.0 equiv.) and 5 (0.756 g, 3.75 mmol., 1.0 equiv.) in DMF (10 mL) at 0 °C, DIPEA (1.6 mL, 9.4 mmol., 2.5 equiv.) was added. The reaction mixture was allowed to stir for 30 min at the same temperature and then HATU (2.1 g, 7.1 mmol., 2.0 equiv.) was added in to it. The reaction mixture was allowed to stir overnight at room temperature. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured in to cold water and extracted twice with ethyl acetate. The combined organic layer was washed with brine and evaporated to dryness. The crude residue was purified through flash chromatography using hexane: ethyl acetate (60:40) as the eluent. Yield: 0.9 g (64%); ¾ NMR (400 MHz, CDCh) S = 9.64 (s, 1H), 7.55 (d, J= 7.6 Hz, 1H), 7.42 (d, J= 8.0 Hz, 1H), 7.35 (s, 2H), 7.05-7.08 (m, 1 H), 4.74 (brs,

1 H), 3.85-3.90 (m, 2H), 2.26 (s, 3H), 2.08-2.20 (m, 2H), 1.38 (s, 9H).

[00376] Synthesis of intermediate 7

[00377] To a solution of compound 6 (0.9 g, 2.43 mmol., 1 equiv.) in MeOH (10 mL) at 0 °C, 6N HC1 (3 mL) was added. The reaction mixture was allowed to stir overnight at room temperature. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The crude residue was purified through washing using hexane and diethylether and used as such without further purification.

[00378] Synthesis of intermediate 7a

[00379] To a solution of compound 7 (0.2 g, 0.65 mmol., 1 equiv.) in THF: DMF (5: 1 mL) at 0 °C, DIPEA (0.34 mL, 1.96 mmol., 3.0 equiv.) was added. The reaction mixture was allowed to stir for 30 min at the same temperature and then compound 3 (0.3 g, 0.65 mmol., 1.0 equiv.) was added in to it. The reaction mixture was allowed to stir overnight at room temperature. Progress of the reaction was monitored by TLC. After completion of the reaction, water was added and the reaction mixture was extracted twice with ethyl acetate. The combined organic layer was washed with brine and evaporated to dryness. The crude residue was purified through flash chromatography using hexane: ethyl acetate (20:80) as the eluent. Yield: .18 g (46%); Ή NMR (400 MHz, CDCb) d = 10.74 (brs, 1H), 9.76 (brs, 1H), 8.12 (brs, 1H), 7.33-7.53 (m, 4H), 6.68-6.92 (m, 3 H), 5.04 (brs, 1 H), 3.94-4.12 (m, 2H), 3.50-3.74 (m, 8H), 2.18-2.27 (m, 2H), 1.33 (s, 9H).

[00380] Synthesis of D- 176 [00381] To a solution of compound 7a (0.18 g, 0.3 mmol., 1 equiv.) in DCM (5 mL) at 0 °C, TFA (0.8 mL) was added. The reaction mixture was allowed to stir overnight at room temperature. Progress of the reaction was monitored by TLC. After completion of the reaction, water was added and the reaction mixture was extracted twice with DCM. The combined organic layer was washed with brine and evaporated to dryness. The crude residue was purified through flash chromatography using DCM: MeOH (90: 10) as the eluent. Yield: 130 mg (70%); ¾ NMR (400 MHz, CDCb) d = 10.74 (brs, 1H), 9.76 (brs, 1H), 8.12 (brs, 1H), 7.33-7.53 (m, 4H), 6.68-6.92 (m, 3 H), 5.04 (brs, 1 H), 3.94-4.12 (m, 2H), 3.50-3.74 (m, 8H), 2.18-2.27 (m, 2H), 1.33 (s, 9H); [M+Hf: 490.30.

[00382] In addition, those of ordinary skill in the art recognize that some functional groups can be protected/deprotected using various protecting groups before a certain reaction takes place. Suitable conditions for protecting and/or deprotecting specific functional group, and the use of protecting groups are well-known in the art.

[00383] For example, various kinds of protecting groups are described in T.W. Greene and G.M. Wuts, Protecting Groups in Organic Synthesis, Second edition, Wiley, New York, 1991, and other references cited above.

[00384] Example 2: Evaluation of CTSD Inhibitory Activity of Library Compounds

[00385] The IC50 values of the compounds were determined by an inhibition assay as described herein. Purified Cathepsin D (CTSD) was treated with compounds of interest at a suitable pH. A substrate of Cathepsin D was added, which upon cleavage by Cathepsin D releases a fluorescent molecule. Cathepsin D activity is directly proportional to the fluorescence intensity. The reduction in the fluorescence caused due to the effect of the compound on Cathepsin D is calculated as percentage of inhibition, by considering Cathepsin D activity as 100% in the absence of compound.

[00386] 10 ng of Cathepsin D purified enzyme was taken in a 96 well plate and mixed with increasing concentration of compounds and Pepstatin A (positive control) was taken in single concentration. The plate was incubated at 37 °C.52 pL of (Reaction Buffer 50 pL + 2 pL of substrate mixed) substrate mix was added to each well including the control and mixed well. The plate was incubated at 37°C for 1-2 hours in the dark. Samples were read in a fluorimeter equipped with a 328nm excitation filter and 460nm emission filter. IC50 was determined for the compounds that exhibited dose dependent inhibition of Cathepsin D by plotting % inhibition versus concentration.

inhibition of CTSD at 100 mih d. 55% inhibition of CTSD at 100 mih e. 32% inhibition of CTSD at 100 mih f. 30% inhibition of CTSD at 100 mih g. <50% inhibition of CTSD at 100 mih

[00387] Example 3: Methods for Evaluating the Biological Properties of the Inventive

Compounds

[00388] Mice, diet and intervention

[00389] Ldlr ^/ mice on a C57BL/6 background are housed under standard conditions and given free access to food and water. Female 12 week-old Ldlr ^/ mice are fed either regular chow or a high-fat, high-cholesterol (HFC) diet (SAFE, Augy, France) for 3 weeks and are divided into multiple groups. The HFC diet contains approximately 21% milk butter, 0.2% cholesterol, 46% carbohydrates and 17% casein. To examine whether proteolytic inhibition of circulating CTSD decreases hepatic inflammation, Ldlr mice are injected intraperitoneally with any of the compounds of the present disclosure two times in the final week of the experiment. Control mice receive DMSO (8%). Collection of blood and tissue specimens, biochemical determination of lipids in plasma and liver, liver histology, RNA isolation, cDNA synthesis, qPCR and oxysterol levels are determined as described previously (4, 14, 46).

[00390] Cathensin D Activity Assay

[00391] Cathepsin D activity are measured using the cathepsin D activity assay kit (JM- K143-100; MBF International, Woburn, MA) according to the manufacturer's protocol. In summary, 50 pg of liver homogenate are lysed in cathepsin D lysis buffer on ice for 10 minutes. Following centrifugation for 5 minutes at top speed, 5 mE of clear cell lysate is transferred to a well of a 96-well plate, and the total volume is made up to 50 mE with cathepsin D cell lysis buffer. To each assay, 52 mE of master mix (50 mE of CD Reaction Buffer and 2 mE of CD Substrate) are added, and the plate is incubated at 37°C for 1 hour. Samples are then measured using a fluorescence plate reader with a 328-nm excitation filter and 460-nm emission filter. Cathepsin D activity is expressed by the relative fluorescence units.

[00392] Acid phosphatase activity assay

[00393] Hepatic acid phosphatase (AP) activity is determined by the acid phosphatase assay kit (10008051, Cayman Chemical Company, USA). Liver homogenates are diluted 20 times in assay buffer, and transferred to a 96-well plate containing 20 mΐ assay buffer. Next, 20 mΐ AP substrate solution is added to each well to initiate the reaction. After 20 minutes incubation at 37°C, the reaction is stopped by adding 100 mΐ of stop solution to all wells. The absorbance is measured using a Bio-Rad Benchmark 550 Micro-plate reader at 405-414 nm (170-6750XTU, Bio-Rad Laboratories, Veenendaal, the Netherlands).

[00394] Fluorescence-activated cell sorting

[00395] Blood is drawn from the tail vein of mice at week 2 and 3 of the experiment. Staining is performed using Trucount beads (BD Biosciences, San Jose, CA, USA) according to the manufacturer’s instructions. In short, CD16/32 antibody (eBioscience, San Diego, CA, USA; (1 : 100)) is added to anti-coagulated whole blood to block the Fc-receptor and incubated for 10 minutes in the dark at room temperature (RT). All antibodies are diluted in FACS buffer (PBS, 0.1% BSA, 0.01% sodium azide) and then added to the blood, shaken gently and incubated for 20 min in the dark at RT. To lyse the red blood cells, erylysis solution (8.4 g NH4CI/O.84 g NaHCCb solution in 1 L Milli-Q; 7.2- 7.4 pH) is added and incubated for 15 min in the dark at RT. Samples are measured within 1 h by FACS (BD FACS Canto II flow cytometer). Leukocytes are described as CD45 ⁺ , T cells as CD45 ⁺ CD3 ⁺ NK1. T, NK cells as CD45 ⁺ CD3 NK1. U, B cells as CD45 ⁺ CD3 NKl . U B220 ⁺ , granulocytes as CD45 ⁺ CD3 NKI . G B220 CD l lb ⁺ Ly6G ⁺ and monocytes as CD45 ⁺ CD3 NK1. G B220 CDl lb ⁺ Ly6G . Inflammatory and resident monocytes are divided as being LyhC ¹ "·" ¹ '. Ly6C ^mt and Ly6C ^low respectively. T- helper cells are defined as CD45 ⁺ CD3 ⁺ CD4 ⁺ and cytotoxic T cells as CD45 ⁺ CD3 ⁺ CD8 ⁺ . Graphs showing the absolute difference between the leukocytes measured after 3 weeks (T3) and 2 weeks (T2), meaning A# cells = # cells T3 - # cells T2are prepared.

[00396] Lipoprotein profiles

[00397] Lipoprotein profiles are determined on plasma samples from using an AKTA Basic 10 chromatography system (GE Healthcare Life Sciences, Eindhoven, the Netherlands). Briefly, 20 mΐ of plasmapool is loaded on a Superose6PC 3.2/30 column (GE Healthcare Life Sciences) using PBS-EDTA as a mobile phase (50ul/min) and automatically fractionated into 24 portions of 20 mΐ. In the collected fractions, the total cholesterol levels are determined by using the Cholesterol CHOD-PAP method (10028; CHOLESTEROL liquicolor, Human, Wiesbaden, Germany) and measured at 490nm in a 96 well plate (655101, Greiner Bio-One, Alphen aan de Rijn, the Netherlands) on a Bio-Rad Benchmark 550 Micro-plate reader (170- 6750XTU, Bio-Rad Laboratories, Veenendaal, the Netherlands).

[00398] Bone marrow-derived macrophages

[00399] Bone marrow-derived macrophages were isolated from the tibiae and femurs of C57BL/6 mice. Cells were cultured in RPMI-1640 (GIBCO Invitrogen, Brede, the Netherlands) with 10% heat-inactivated fetal calf serum (Bondinco B.V. Alkmaar, the Netherlands), penicillin (100 U/ml), streptomycin (100 pg/ml) and L-glutamine 2 mM (GIBCO Invitrogen, Breda, the Netherlands), supplemented with 20% L929-conditioned medium (LCM) for 8-9 days to generate bone marrow-derived macrophages. After attachment, macrophages were seeded at about 350,000 cells per well in 24-well plates and incubated for 24h with oxLDL (25 pg/ml) or medium (control). Afterwards, cells were exposed to any of the compounds of the present disclosure or DMSO (0.06%) for 4h. Next, cells are washed and stimulated with LPS (100 ng/ml) for 4h. Finally, medium is used for enzyme-linked immunosorbent assays and cells are lysed for mRNA expression analysis. All in vitro data is the result of three independent, biological experiments with each time 3 technical replicates included.

[00400] Enzyme-linked immunosorbent assay (ELISA)

[00401] TNFa and IL10 ELISA assays (resp. 88-7324-88 and 88-7105-88, eBioscience, Frankfurt, Germany) are performed on supernatant according to manufacturer’s instructions. Analysis is performed on a Bio-Rad Benchmark 550 Micro-plate reader 450 nm.

[00402] Statistics

[00403] Data is statistically analyzed by performing two-tailed unpaired t test using GraphPad Prism version 5 for Windows. Data is expressed as the mean and standard error of the mean and is considered significantly different compared to control-treated mice on chow diet ( ^* P £ 0.05; ^** p< 0.01; ^*** p< 0.001) and compared to control-treated mice on HFC diet ( ^# p < 0.05; ^## p< 0.01; ^### >< 0.001). Pearson correlation coefficients (r) and respective p values are calculated to assess the statistical significance of the correlation. [00404] Example 3a: Evaluating the inflammatory effect of CTSD inhibitory activity of the inventive compounds described herein in bone marrow -derived macrophages

[00405] In order to explore the specific role of macrophages on the reduced inflammatory response upon inhibition of circulating CTSD with the compounds of the present disclosure, bone marrow cells of wild-type (wt) mice were isolated, differentiated to macrophages and incubated with oxLDL for 24 h. Subsequently, cells were treated with D-002 for 4 h, followed by 4 h stimulation with lipopolysaccharide (LPS). Upon incubation with D-002, the cytokine level of the pro-inflammatory marker TNFa, measured in the supernatant of the BMDMs, was significantly reduced compared to carrier (dimethyl sulfoxide (DMSO)-treated cells; FIG. 2) confirming the reduction in inflammation upon D-002 treatment and the pro-inflammatory properties of CTSD in lipid-induced inflammation. Note: Cytokine levels of the anti inflammatory marker IL10 can also be measured to examine the reduction in inflammation.

[00406] Consistent with the above finding, gene expression levels of Ccl2, TNFa, and caspase 1 that encode for the respective pro-inflammatory markers were decreased after incubation of oxLDL-loaded macrophages with D-002 (100 uM) and LPS (FIG. 3a-c). Together these data demonstrate a reduced inflammatory response upon inhibition of extracellular CTSD by inventive compounds such as D-002 that is indicative of a reduction in hepatic inflammation.

[00407] To further study whether the reduction in inflammation in BMDMs upon treatment with any of the compounds of the present disclosure was accompanied by an improvement in cholesterol metabolism Cyp27, the main gene that encodes for the enzyme responsible for the degradation of cholesterol in macrophages was studied. A finding that this gene is upregulated would be indicative of higher levels of cholesterol degradation in BMDMs. After incubation of oxLDL-loaded macrophages with D-002 (100 uM) and LPS, the Cyp27gene expression level was in fact increased (FIG. 3d). Thus, oxLDL-loaded BMDMs demonstrate a reduced inflammatory response upon proteolytic inhibition of CTSD, likey caused by improved cholesterol metabolism.

[00408] To provide further support, gene expression analysis is performed for Cd36, Lxra, Abcal, and HmG-CoAR. Expression of Lxra and Abcal, genes involved in cholesterol efflux, are examined in oxLDL-loaded BMDMs treated with any of the inventive compounds and compared to DMSO-treated BMDM. [00409] Example 3b: Determining the effect on systemic and hepatic inflammation in Ldlr- /- upon treatment with the compounds described herein

[00410] To elucidate the systemic immune effects of proteolytic inhibition of CTSD in Ldlr -/- mice upon treatment with compounds of the present disclosure, the change in blood leukocyte levels between week 2 and 3 of the experiment is determined via fluorescence-activated cell sorting .

[00411] To determine the effect of the proteolytic inhibition of circulating CTSD on hepatic inflammation, immunohistochemical staining is performed on liver sections for the inflammatory cell markers Mac-l (infiltrated macrophages and neutrophils), CD3 (T cells) and CD68 (resident macrophages/monocytes). Quantification of all immunohistochemical staining in control-treated Ldlr-/- mice on HFC is compared to control-treated Ldlr-/- mice on chow diet, to confirm the effectiveness of the HLC diet in inducing hepatic inflammation in Ldlr-/- mice.

[00412] As inflammatory changes at histological level usually require administration of the therapeutic agent for more than one week before they can be observed, hepatic gene expression analysis on the inflammatory markers tumor necrosis factor alpha ( TNFa ), chemokine(C-X-C motif ligand-2 ( Ccl2 ), Caspaseland cluster of differentiation 68 (Cd68) is performed. Ldlr -/- mice on HLC diet are treated with any of the compounds of the present disclosure, and compared to hepatic gene expression levels of TNFa, Ccl2, Caspasel and CD68in control- treated Ldlr-/- mice on HLC diet. Similarly studies are carried out for hepatic gene expression of IL12 and for the M2 markers cluster of differentiation 206 ( Cd206 ), Early growth response protein 2(Egr2)and ratio of inducible nitric oxide ( iNos ) and arginase 1 ( Argl ) Altogether, these data are used to demonstrate that inhibition of the proteolytic site of CTSD in Ldlr ^~ mice reduces the development of systemic inflammation and hepatic inflammatory gene expression

[00413] Example 3c: Determining the extent improvement in hepatic lysosomal function upon treatment with the compounds described herein

[00414] To investigate the effect of the compound of the present disclosure on hepatic lysosomal function in diet-induced hepatic inflammation, plasma and hepatic CTSD activity as well as the activity the lysosomal enzyme acid phosphatase (AP) are measured in total liver. Ldlr ^f~ mice on HLC diet are treated with the inventive compounds and compared to control mice. Subsequently, the activity of AP is measured in the liver.

[00415] To confirm the effects on lysosomal function, hepatic gene expression is measured for the lysosomal enzymes cathepsin D (CTSD), cathepsin S (CTSS) and acid phosphatase (AP). Additionally, to validate whether plasma CTSD levels correlate with the level of hepatic inflammation, plasma CTSD levels are also measured. Moreover, the level of hepatic gene expression of the inflammatory markers TNFa, Ccl2 and Caspasel are compared to the plasma levels of CTSD to better understand the correlation under the described test conditions.

[00416] Example 3d: Determining the effects on lipid and lipoprotein metabolism upon treatment with the compounds described herein

[00417] To determine the extent that inhibition of CTSD, and in particular circulating CTSD affects lipid metabolism, plasma and liver lipid levels are measured in LdlC micc on HFC diet treated with any of the compounds of the present disclosure. Plasma cholesterol and triglycerides are measured after 3 weeks on HFC diet, and compared to mice on a chow diet. Fast protein liquid chromatography (FPFC) profiles is used in the analysis.

[00418] Similar to plasma cholesterol and triglyceride levels, hepatic cholesterol and triglyceride levels are evaluated in control-treated Fdlr -/- mice on a HFC diet and upon treatment with any of the compounds of the present disclosure. Changes in hepatic lipid levels are confirmed by Oil red O staining.

[00419] To further define the influences of circulating CTSD inhibition on hepatic lipid metabolism, hepatic gene expression analysis is performed on markers involved in lipid homeostasis (i.e., Cluster of differentiation 36 ( Cd36 ), Niemann-Pick C2 ( Npc2 ), Liver X receptor alpha ( Lxra ) and ATP -binding cassette transporter Al ( Abcal )) In addition, peroxisome proliferator-activated receptor gamma ( Ppar-y ) expression levels, a lipid-activated transcription factor of genes controlling lipid metabolism, is also tested

[00420] As the proteolytic inhibition of CTSD also appears to influence hepatic cholesterol metabolism, hepatic synthesis and degradation of cholesterol are investigated in more detail. The effect of inhibition of CTSD by any of the compounds of the present disclosure on hepatic cholesterol synthesis is explored using measurements of hepatic desmosterol levels. Besides cholesterol synthesis, cholesterol degradation is also evaluated upon inhibition of CTSD by the inventive compounds. Specifically, looking at 27-hydroxcholesterol (27HC) and 7 alpha- hydroxycholesterol (7aHC) levels in compound-injected Fdlr-/- mice on a HFC diet compared to control-injected mice on HFD diet. Also, hepatic gene expression levels of the enzyme responsible for this conversion, cytochrome P450 7A1 (Cyp7al) is examined in compound- treated Fdlr-/- mice on a HFC diet.