HK1249361B - Small molecule inhibitors of fibrosis - Google Patents

Description

Small molecule inhibitors of fibrosis

Background Art

Fibrosis, generally defined as the production of excess connective tissue, occurs as a result of a variety of underlying diseases. Chronic inflammation or tissue damage/remodeling are typical fibrosis-inducing events. Specific disease examples include idiopathic pulmonary fibrosis (IPF), liver fibrosis associated with the late stages of alcoholic and non-alcoholic cirrhosis, renal fibrosis, cardiac fibrosis, and keloid formation caused by abnormal wound healing [Wynn, T.A. (2004) Nature Reviews Immunology. 4: 583-594; Friedman, S.L. (2013) Science Translation Medicine. 5 (167): 1-17]. In addition, fibrosis is a key pathological feature associated with chronic autoimmune diseases, including rheumatoid arthritis, Crohn's disease, systemic lupus erythematosus, and scleroderma. Diseases representing urgent unmet medical needs include idiopathic pulmonary fibrosis (IPF), scleroderma, and liver fibrosis associated with non-alcoholic steatohepatitis (NASH). The increased incidence of NASH-related liver fibrosis is expected to parallel the incidence of type 2 diabetes and obesity.

Scleroderma is a rare chronic autoimmune disease, characterized in that normal tissue is replaced by dense thick fibrous tissue. Although the exact underlying cause of scleroderma is unknown, the disease is generally related to the activation of skin myofibroblasts mediated by immune cells, thereby causing the deposition of excessive extracellular matrix proteins (e.g., collagen type I), which causes the skin to thicken, and in some cases causes the sclerosis and final failure of multiple organs. At present, there is no curative method for scleroderma. Its treatment is limited to attempting to control symptoms, and usually requires the combination of methods. Although scleroderma confined to the skin is not life-threatening usually, the systemic scleroderma affecting multiple internal organs may be a life-threatening disease.

Summary of the Invention

In one aspect, provided herein is a compound of formula (I) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In another aspect, provided herein is a compound of Formula (Ia) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In some embodiments, the compound of Formula (I) or (Ia) is ^-alkylene (cycloalkyl). In some embodiments, the compound of Formula (I) or (Ia) is ^-CH2- (cycloalkyl). In some embodiments, the compound of Formula (I) or (Ia) is _-CH2- (cyclopentyl). In some embodiments, the compound ^of Formula (I) or (Ia _{) is -CH(CH2CH3)2 . In} ^some embodiments, the compound of Formula (I) or (Ia) _is ^-CH ( _{CH3 ) CH2CH2R2} . In some embodiments, the compound of Formula (I) or (Ia) is ^-CH ( _CH3 ⁾ _CH2CH2R2 ^{and R2} is _-CH3 . In some embodiments, the compound of Formula (I) or (Ia) is n is ₀ . In some embodiments, the compound is of formula (I) or (Ia), wherein n is 1. In some embodiments, the compound is of formula (I) or (Ia), wherein n is 1 and ^R is halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments, the compound is of formula (I) or (Ia), wherein n is 2. In some embodiments, the compound is of formula (I) or (Ia), wherein n is ² and each R is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments, the compound is of formula (I) or (Ia), wherein n is 2 and each R ^{is halogen} . In some embodiments, the compound is of formula (I) or (Ia), wherein n is 2 and each R is ^Cl . In some embodiments, the compound is of formula (I) or (Ia), wherein R is H. In some embodiments, the compound is of formula (I) or (Ia), wherein R is ^halogen . In some embodiments is a compound of Formula (I) or (Ia), wherein R ⁵ is F.

In another aspect, provided herein is a compound of formula (II) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

^R4 is halogen, alkyl,

Each R ⁷ is independently selected from halogen and alkyl;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

n is selected from 0, 1, 2, 3 and 4; and

m is selected from 0, 1 and 2.

In another aspect, provided herein is a compound of formula (IIa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

^R4 is halogen, alkyl,

Each R ⁷ is independently selected from halogen and alkyl;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

n is selected from 0, 1, 2, 3 and 4; and

m is selected from 0, 1 and 2.

In some embodiments, the compound of formula (II) or (IIa) is R ⁴ is -CH ₃ . In some embodiments, the compound of formula (II) or (IIa) is R ⁴ is In some embodiments, the compound of formula (II) or (IIa) is R ¹ is -CH(CH ₂ CH ₃ ) ₂ . In some embodiments, the compound of formula (II) or (IIa) is R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² . In some embodiments, the compound of formula (II) or (IIa) is R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² and R ² is H. In some embodiments, the compound of formula (II) or (IIa) is R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² and R ² is -CH ₃ .

In another aspect, provided herein is a compound of formula (III) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

each R ⁵ is independently selected from haloalkyl, -alkylene(NR ¹³ R ¹⁴ ), -NR ¹³ R ¹⁴ and -SO ₂ R ¹³ ;

Each R ⁶ is independently selected from halogen, alkyl and haloalkyl;

Each R ⁷ is independently selected from halogen, alkyl, haloalkyl and -CN;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

n is selected from 0, 1, 2, 3 and 4;

p is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3, and 4; and

t is independently selected from 0, 1, 2, 3 and 4;

At least one of p, q or t is not zero.

In another aspect, provided herein is a compound of formula (IIIa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

each R ⁵ is independently selected from haloalkyl, -alkylene(NR ¹³ R ¹⁴ ), -NR ¹³ R ¹⁴ and -SO ₂ R ¹³ ;

Each R ⁶ is independently selected from halogen, alkyl and haloalkyl;

Each R ⁷ is independently selected from halogen, alkyl, haloalkyl and -CN;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

n is selected from 0, 1, 2, 3 and 4;

p is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3, and 4; and

t is independently selected from 0, 1, 2, 3 and 4;

At least one of p, q or t is not zero.

In some embodiments, the compound is of formula (III) or (IIIa), wherein p is 1. In some embodiments, the compound is of formula (III) or (IIIa), wherein q is 0. In some embodiments, the compound is of formula (III) or (IIIa), wherein t is 0.

In some embodiments, the compound is of formula (III) or (IIIa), wherein q is 1. In some embodiments, the compound is of formula (III) or (IIIa), wherein q is 1 and ^R is alkyl. In some embodiments, the compound is of formula (III) or (IIIa), wherein q is 1 and t is 0. In some embodiments, the compound is of formula (III) or (IIIa), wherein q is 1, ^R is alkyl, and t is 0.

In some embodiments, the compound is of formula (III) or (IIIa), wherein t is 1. In some embodiments, the compound is of formula (III) or (IIIa), wherein t is 1 and R ^is halogen. In some embodiments, the compound is of formula (III) or (IIIa), wherein t is 1 and q is 0. In some embodiments, the compound is of formula (III) or (IIIa), wherein t is 1, ^R is halogen, and q is 0.

In some embodiments is a compound of Formula (III) or (IIIa), wherein p is 0.

In another aspect, provided herein is a compound of formula (IV) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

^R4 is halogen, alkyl,

R ⁵ and R ⁶ are independently selected from H, alkyl, halo and haloalkyl;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

^R and ^R are independently selected from H, halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl ^{, heterocyclyl} , aryl, ^heteroaryl , ^-SR13 , -SOR13, -SO2R13, -SO2NR13R14, _-NR13R14 , -NR13SO2R14, ^-NR13C (O ₎ ^{R14 , -NR13C} (O ^{) OR14} , ^{-NR13C (} O ⁾ _NR13R14 , ^{-C(O)R14 , -C (} O ^{) OR14} , and -C(O) ^{NR13R 14} , wherein at least one of R ²⁰ and R ²² is not F or Cl;

each R ²¹ is independently selected from H, halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO 2 R 13 , -SO ₂ NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO 2 R ¹⁴ , -NR ¹³ _C (O)R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ^{14 ;} and

^R23 is H.

In another aspect, provided herein is a compound of formula (IVa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

^R4 is halogen, alkyl,

R ⁵ and R ⁶ are independently selected from H, alkyl, halo and haloalkyl;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

^R and ^R are independently selected from H, halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl ^{, heterocyclyl} , aryl, ^heteroaryl , ^-SR13 , -SOR13, -SO2R13, -SO2NR13R14, _-NR13R14 , -NR13SO2R14, ^-NR13C (O ₎ ^{R14 , -NR13C} (O ^{) OR14} , ^{-NR13C (} O ⁾ _NR13R14 , ^{-C(O)R14 , -C (} O ^{) OR14} , and -C(O) ^{NR13R 14} , wherein at least one of R ²⁰ and R ²² is not F or Cl;

each R ²¹ is independently selected from H, halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO 2 R 13 , -SO ₂ NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO 2 R ¹⁴ , -NR ¹³ _C (O)R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ^{14 ;} and

^R23 is H.

In another aspect, provided herein is a compound of formula (IVb) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

^R4 is halogen, alkyl,

R ⁵ and R ⁶ are independently selected from H, alkyl, halo and haloalkyl;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

^R and ^R are independently selected from H, halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl ^{, heterocyclyl} , aryl, ^heteroaryl , ^-SR13 , -SOR13, -SO2R13, -SO2NR13R14, _-NR13R14 , -NR13SO2R14, ^-NR13C (O ₎ ^{R14 , -NR13C} (O ^{) OR14} , ^{-NR13C (} O ⁾ _NR13R14 , ^{-C(O)R14 , -C (} O ^{) OR14} , and -C(O) ^{NR13R 14} , wherein at least one of R ²⁰ and R ²² is not F or Cl;

each R ²¹ is independently selected from H, halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO 2 R 13 , -SO ₂ NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO 2 R ¹⁴ , -NR ¹³ _C (O)R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ^{14 ;} and

^R23 is H.

In some embodiments, the compound is of Formula (IV), (IVa) or (IVb), wherein R ²⁰ and R ²² are independently selected from H, halogen, -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, -SO ₂ R ¹³ , -SO ₂ NR ¹³ R ¹⁴ and -C(O)NR ¹³ R ¹⁴ ; wherein at least one of R ²⁰ and R ²² is not F or Cl. In some embodiments, the compound is of Formula (IV), (IVa) or (IVb), wherein R ²⁰ and R ²² are independently selected from H, Cl, -CN, -CH ₃ , -OCH ₃ and -CF ₃ ; wherein at least one of R ²⁰ and R ²² is not Cl. In some embodiments, the compound is of Formula (IV), (IVa) or (IVb), wherein each R ²¹ is independently selected from H, halogen, -CN, alkyl, alkoxy and haloalkyl. In some embodiments, the compound is of Formula (IV), (IVa) or (IVb), wherein each R ²¹ is independently selected from H, Cl, -CN, -CH ₃ , -OCH ₃ and -CF ₃ . In some embodiments, the compound is of Formula (IV), (IVa) or (IVb), wherein R ⁴ is In some embodiments, the compound is of Formula (IV), (IVa) or (IVb), wherein R 4 is In some embodiments, the compound is of Formula (IV), (IVa) or (IVb), wherein R ⁴ is In some embodiments, the compound is of Formula (IV), (IVa) or (IVb), wherein R ¹ is and R ² is H. In some embodiments, the compound is of Formula (IV), (IVa) or (IVb), wherein R ¹ is and R ² is H. In some embodiments, the compound is of Formula (IV), (IVa) or (IVb), wherein R ¹ is and R 2 is H. In some embodiments, the compound is of Formula (IV), (IVa) or (IVb), wherein R ¹ is and R ² is H. In some embodiments is a compound of Formula (IV), (IVa), or (IVb) wherein R ¹ is —CH(CH ₂ CH ₃ ) ₂ .

In another aspect, provided herein is a compound of formula (V) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH(R ³ )CH ₃ , -CH(CH ₃ )C(O)CH ₃ , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ¹⁰ is H or alkyl;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

R ²⁰ is selected from H, Cl, Br, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO 2 R 13 , -SO ₂ NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O) _R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ and -C(O)NR ^{13 R 14 ;}

R ²¹ , R ²² and R ²³ are independently selected from H, halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ^{13 , -SO 2 R 13} , -SO ₂ NR ¹³ R 14 , -NR ¹³ R 14 , -NR _{13 SO} ² R ¹⁴ , -NR ¹³ C(O) ^{R 14} , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O ⁾ NR ¹³ R ¹⁴ , -C(O) ^{R 14 , -C(O)OR 14 and -C} (O)NR ¹³ R ¹⁴ ; and

^R24 is H.

In another aspect, provided herein is a compound having the following structural formula (Va), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH(R ³ )CH ₃ , -CH(CH ₃ )C(O)CH ₃ , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ¹⁰ is H or alkyl;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

R ²⁰ is selected from H, Cl, Br, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO 2 R 13 , -SO ₂ NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O) _R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ and -C(O)NR ^{13 R 14 ;}

R ²¹ , R ²² and R ²³ are independently selected from H, halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ^{13 , -SO 2 R 13} , -SO ₂ NR ¹³ R 14 , -NR ¹³ R 14 , -NR _{13 SO} ² R ¹⁴ , -NR ¹³ C(O) ^{R 14} , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O ⁾ NR ¹³ R ¹⁴ , -C(O) ^{R 14 , -C(O)OR 14 and -C} (O)NR ¹³ R ¹⁴ ; and

^R24 is H.

In some embodiments, the compound is of formula (V) or (Va), wherein R ²¹ , R ²² , and R ²³ are independently selected from H, halogen, -CN, alkyl, alkoxy, and haloalkyl. In some embodiments, the compound is of formula (V) or (Va), wherein R ²¹ , R ²² , and R ²³ are independently selected from H and halogen. In some embodiments, the compound is of formula (V) or (Va), wherein R ²⁰ is independently selected from H, Cl, Br, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments, the compound is of formula (V) or (Va), wherein R ²⁰ is independently selected from H and Cl.

In another aspect, provided herein is a compound of formula (VI) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

^R1 is

^R2 is H;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In another aspect, provided herein is a compound of formula (VIa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

^R1 is

^R2 is H;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In another aspect, provided herein is a compound of formula (VIb) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

^R1 is

^R2 is H;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In another aspect, provided herein is a compound of formula (VIc) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

^R1 is

^R2 is H;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In some embodiments, the compound is of Formula (VI), (VIa), (VIb), or (VIc), wherein n is 0. In some embodiments, the compound is of Formula (VI), (VIa), (VIb), or (VIc), wherein n is 1. In some embodiments, the compound is of Formula (VI), (VIa), (VIb), or (VIc), wherein ^R is halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments, the compound is of Formula (VI), (VIa), (VIb), or (VIc), wherein R is ^halogen . In some embodiments, the compound is of Formula (VI), (VIa), (VIb), or (VIc), wherein R is ^Cl . In some embodiments, the compound is of Formula (VI), (VIa), (VIb), or (VIc), wherein R is ^H. In some embodiments, the compound is of Formula (VI), (VIa), (VIb), or (VIc), wherein R is ^halogen . In some embodiments, the compound is of formula (VI), (VIa), (VIb) or (VIc), wherein R ⁵ is F. In some embodiments, the compound is of formula (VI), (VIa), (VIb) or (VIc), wherein R ¹ is In some embodiments, the compound is of formula (VI), (VIa), (VIb) or (VIc), wherein R ¹ is

Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient.

Also provided herein is a method of treating fibrosis, a disorder characterized by fibrosis, or a disease characterized by fibrosis in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), or (VIc), as described above and below, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

Also provided herein is a method of treating fibrosis using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), or (VIc), wherein the fibrosis is liver fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, or cardiac fibrosis.

Also provided herein is a method of treating liver fibrosis associated with late stages of alcoholic or non-alcoholic cirrhosis using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), or (VIc).

Also provided herein is a method of using a compound of formula (I) to treat fibrosis, wherein the fibrosis is idiopathic pulmonary fibrosis.

Also provided herein is a method of treating a disease using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), or (VIc), wherein the disease or condition characterized by fibrosis is a chronic autoimmune disease.

Also provided herein is a method of treating a chronic autoimmune disease using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), or (VIc), wherein the chronic autoimmune disease is rheumatoid arthritis, scleroderma, Crohn's disease, and systemic lupus erythematosus.

Also provided herein is a method of treating a chronic autoimmune disease using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb) or (VIc), wherein the chronic autoimmune disease is scleroderma.

Also provided herein is a method of using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), or (VIc) to treat fibrosis, wherein the fibrosis is keloid formation resulting from abnormal wound healing.

Also provided herein is a method of treating fibrosis following organ transplantation using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), or (VIc).

Also provided herein is a method for treating fibrosis, a condition characterized by fibrosis, or a disease characterized by fibrosis, the method comprising administering a composition comprising a therapeutically effective amount of a compound as described herein in combination with one or more pharmaceutical agents. In certain embodiments described above, the one or more pharmaceutical agents are anti-fibrotic agents. In certain embodiments described above, the one or more pharmaceutical agents are antifungal agents.

In another aspect, provided herein is a compound of formula (IX) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug or stereoisomer thereof:

in:

-XY- is -CH ₂ CH ₂ -, -CH=CH-, -CH=N- or -N=CH-;

Z ¹ is selected from O, S, NH and NR ¹³ ;

Z ² is selected from O, S, CH ₂ , NH and NR ¹³ ;

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

^R4 is halogen, alkyl,

Each R ⁷ is independently selected from halogen and alkyl;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

each R ¹⁵ is independently selected from haloalkyl, -alkylene(NR ¹³ R ¹⁴ ), -NR ¹³ R ¹⁴ and -SO ₂ R ¹³ ;

Each R ¹⁶ is independently selected from halogen, alkyl and haloalkyl;

Each R ¹⁷ is independently selected from halogen, alkyl, haloalkyl and -CN;

n is selected from 0, 1, 2, 3 and 4;

m is selected from 0, 1 and 2;

p is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3, and 4; and

t is independently selected from 0, 1, 2, 3 and 4.

In another aspect, provided herein is a compound of Formula (IXa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug or stereoisomer thereof:

in:

-XY- is -CH ₂ CH ₂ -, -CH=CH-, -CH=N- or -N=CH-;

Z ¹ is selected from O, S, NH and NR ¹³ ;

Z ² is selected from O, S, CH ₂ , NH and NR ¹³ ;

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

^R4 is halogen, alkyl,

Each R ⁷ is independently selected from halogen and alkyl;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

each R ¹⁵ is independently selected from haloalkyl, -alkylene(NR ¹³ R ¹⁴ ), -NR ¹³ R ¹⁴ and -SO ₂ R ¹³ ;

Each R ¹⁶ is independently selected from halogen, alkyl and haloalkyl;

Each R ¹⁷ is independently selected from halogen, alkyl, haloalkyl and -CN;

n is selected from 0, 1, 2, 3 and 4;

m is selected from 0, 1 and 2;

p is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3, and 4; and

t is independently selected from 0, 1, 2, 3 and 4.

In some embodiments, the compound of formula (IX) or (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IX) or (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IX) or (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IX) or (IXa) wherein n is 0. In some embodiments, the compound of formula (IX) or (IXa) wherein n is 1. In some embodiments, the compound of formula (IX) or (IXa) wherein n is 1 and R ⁸ is halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments, the compound of formula (IX) or (IXa) wherein n is 2. In some embodiments, the compound of formula (IX) or (IXa) wherein n is 2 and each R ⁸ is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments, the compound of formula (IX) or (IXa) wherein n is 2 and each R ⁸ is halogen. In some embodiments, the compound is of Formula (IX) or (IXa), wherein n is 2 and each R is ^F. In some embodiments, the compound is of Formula (IX) or (IXa), wherein ^R is -CH(CH ₃ ) ₂ . In some embodiments, the compound is of Formula (IX) or (IXa), wherein ^R is -CH(CH ₂ CH ₃ ) ₂ . In some embodiments, the compound is of Formula (IX) or ( ^IXa ), wherein R is In some embodiments, the compound is of Formula (IX) or (IXa), wherein R ^is and R ^is H. In some embodiments, the compound is of Formula (IX) or (IXa), wherein R ^{is and} R is -CH ₃ . In some embodiments, the compound is of Formula (IX) or (IXa), wherein ^R is In some embodiments, the compound is of Formula (IX) or (IXa), wherein ^R is and R ^is H. In some embodiments, the compound is of Formula (IX) or (IXa), wherein R ¹ is and R ² is -CH ₃ . In some embodiments, the compound is of Formula (IX) or (IXa), wherein R ¹ is In some embodiments, the compound is of Formula (IX) or (IXa), wherein R ¹ is and R ² is H. In some embodiments, the compound is of Formula (IX) or (IXa), wherein R ¹ is and R ² is -CH ₃ . In some embodiments, the compound is of Formula (IX) or (IXa), wherein p is 0. In some embodiments, the compound is of Formula (IX) or (IXa), wherein q is 0. In some embodiments, the compound is of Formula (IX) or (IXa), wherein t is 0. In some embodiments, the compound is of Formula (IX) or (IXa), wherein Z ¹ and Z ² are each O. In some embodiments, the compound is of Formula (IX) or (IXa), wherein -XY- is -CH ₂ CH ₂ -. In some embodiments is a compound of Formula (IX) or (IXa) wherein -XY- is -CH=N-.

In another aspect, provided herein is a compound of formula (X) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug or stereoisomer thereof:

in:

-XY- is -CH ₂ CH ₂ -, -CH=CH-, -CH=N- or -N=CH-;

Z ¹ is selected from O, S, NH and NR ¹³ ;

Z ² is selected from O, S, CH ₂ , NH and NR ¹³ ;

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

each R ¹⁵ is independently selected from haloalkyl, -alkylene(NR ¹³ R ¹⁴ ), -NR ¹³ R ¹⁴ and -SO ₂ R ¹³ ;

Each R ¹⁶ is independently selected from halogen, alkyl and haloalkyl;

Each R ¹⁷ is independently selected from halogen, alkyl, haloalkyl and -CN;

n is selected from 0, 1, 2, 3 and 4;

p is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3, and 4; and

t is independently selected from 0, 1, 2, 3 and 4;

When ^Z1 and ^Z2 are both O, -XY- is -CH=CH-, -CH=N- or -N=CH-.

In another aspect, provided herein is a compound of formula (Xa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug or stereoisomer thereof:

in:

-XY- is -CH ₂ CH ₂ -, -CH=CH-, -CH=N- or -N=CH-;

Z ¹ is selected from O, S, NH and NR ¹³ ;

Z ² is selected from O, S, CH ₂ , NH and NR ¹³ ;

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

each R ¹⁵ is independently selected from haloalkyl, -alkylene(NR ¹³ R ¹⁴ ), -NR ¹³ R ¹⁴ and -SO ₂ R ¹³ ;

Each R ¹⁶ is independently selected from halogen, alkyl and haloalkyl;

Each R ¹⁷ is independently selected from halogen, alkyl, haloalkyl and -CN;

n is selected from 0, 1, 2, 3 and 4;

p is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3, and 4; and

t is independently selected from 0, 1, 2, 3 and 4;

When ^Z1 and ^Z2 are both O, -XY- is -CH=CH-, -CH=N- or -N=CH-.

In some embodiments, the compound is of formula (X) or (Xa), wherein n is 0. In some embodiments, the compound is of formula (X) or (Xa), wherein n is 1. In some embodiments, the compound is of formula (X) or (Xa), wherein n is 1 and R ⁸ is halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments, the compound is of formula (X) or (Xa), wherein n is 2. In some embodiments, the compound is of formula (X) or (Xa), wherein n is 2 and each R ⁸ is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments, the compound is of formula (X) or (Xa), wherein n is 2 and each R ⁸ is halogen. In some embodiments, the compound is of formula (X) or (Xa), wherein n is 2 and each R ⁸ is F. In some embodiments, the compound is of formula (X) or (Xa), wherein R ¹ is -CH(CH ₃ ) ₂ . In some embodiments, the compound is of formula (X) or (Xa), wherein R ¹ is -CH(CH ₂ CH ₃ ) ₂ . In some embodiments, the compound is of formula (X) or (Xa), wherein R ¹ is In some embodiments, the compound is of formula (X) or (Xa), wherein R ¹ is and R ² is H. In some embodiments, the compound is of formula (X) or (Xa), wherein R ¹ is and R ² is -CH ₃ . In some embodiments, the compound is of formula (X) or (Xa), wherein R ¹ is In some embodiments, the compound is of formula (X) or (Xa), wherein R ¹ is and R ² is H. In some embodiments, the compound is of formula (X) or (Xa), wherein R ¹ is and R ² is -CH ₃ . In some embodiments, the compound is of formula (X) or (Xa), wherein R ¹ is In some embodiments, the compound is of formula (X) or (Xa), wherein R ¹ is and R ² is H. In some embodiments, the compound is of formula (X) or (Xa), wherein R ¹ is and R ² is -CH ₃ . In some embodiments, the compound is of formula (X) or (Xa), wherein p is 0. In some embodiments, the compound is of formula (X) or (Xa), wherein q is 0. In some embodiments, the compound is of formula (X) or (Xa), wherein t is 0. In some embodiments, the compound is of formula (X) or (Xa), wherein Z ¹ and Z ² are each O. In some embodiments, the compound is of formula (X) or (Xa), wherein -XY- is -CH=N-.

In another aspect, provided herein is a method of treating fibrosis, a condition characterized by fibrosis, or a disease characterized by fibrosis, comprising administering a composition comprising a therapeutically effective amount of a compound of formula (XI), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof:

in:

A ¹ and A ² are independently selected from aryl or heteroaryl;

B is

C is an optionally substituted 5-membered or 6-membered heterocyclyl or an optionally substituted 5-membered or 6-membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 nitrogen atoms;

D is aryl or heteroaryl;

E is aryl, heteroaryl, carbocyclyl, heterocyclyl or alkyl;

Each of R ¹ , R ² , R ³ and R ⁴ is independently selected from H, alkyl, haloalkyl or alkoxy;

X ₁ and X ₂ are independently selected from N and CR ⁵ ;

^R5 is H, OH, alkyl or alkoxy;

Each R ⁶ is independently alkyl, haloalkyl, halo, alkoxy, -alkylene (NR ¹³ R ¹⁴ ) or aryl;

each R ⁸ is independently selected from alkyl, cycloalkyl, heterocyclyl, halo, hydroxy, nitrile, azido, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ₁₃ R ¹⁴ , -NR 13 SO ^{2 R 14 , -NR 13 C (} O)R ¹⁴ , -NR ₁₃ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -C(O)R ¹⁴ , -C(O ⁾ OR ^{14 and} -C(O)NR ¹³ R ^{14 ; or} two adjacent R ⁸ forms a heterocyclyl ring;

each R ¹³ and R ¹⁴ are independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

Y ¹ is selected from O, NH and NR ¹³ ;

Y ² is selected from O, CH ₂ , NH and NR ¹³ ;

n is 1, 2, or 3;

m is 1 or 2;

p is 1, 2, 3, or 4;

q is 1, 2, or 3;

r is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

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

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

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

v is 0, 1, 2, 3, or 4.

In some embodiments described above or below of a compound of formula (XI), X ₁ and X ₂ are N.

In some embodiments described above or below of a compound of Formula (XI), X ₁ is CR ⁵ and X ₂ is N.

In some embodiments described above or below of a compound of Formula (XI), X ₁ is N and X ₂ is CR ⁵ .

In some embodiments described above or below of a compound of Formula (XI), q is 1 and r is 0.

In some embodiments described above or below of a compound of Formula (XI), A ¹ is aryl.

In some embodiments described above or below of the compound of formula (XI), A ¹ is

In some embodiments described above or below of the compound of formula (XI), A ¹ is

In some embodiments described above or below of a compound of Formula (XI), A ¹ is heteroaryl.

In some embodiments described above or below of a compound of Formula (XI), A ² is aryl.

In some embodiments described above or below of compounds of formula (XI), ^A2 is

In some embodiments described above or below of compounds of formula (XI), ^A2 is

In some embodiments described above or below of a compound of Formula (XI), A ² is heteroaryl.

In some embodiments described above or below of a compound of Formula (XI), A ² is pyridine, pyrazine, pyrimidine, pyridazine, or triazine.

In some embodiments described above or below of compounds of formula (XI), C is optionally substituted 5- or 6-membered heteroaryl. In other embodiments described above or below of compounds of formula (XI), C is optionally substituted 5- or 6-membered heterocyclyl.

In some embodiments described above or below of compounds of formula (XI), C is and

R ⁷ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), cycloalkyl, heterocyclyl, -alkylene(cycloalkyl) or -alkylene(heterocyclyl).

In some embodiments described above or below of a compound of Formula (XI), C is and R ⁷ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), cycloalkyl, heterocyclyl, -alkylene(cycloalkyl), or -alkylene(heterocyclyl).

In some embodiments described above or below of a compound of Formula (XI), C is and R ⁷ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), cycloalkyl, heterocyclyl, -alkylene(cycloalkyl), or -alkylene(heterocyclyl).

In some embodiments described above or below of a compound of Formula (XI), E is alkyl.

In some embodiments described above or below of a compound of Formula (XI), E is cycloalkyl.

In some embodiments described above or below of a compound of Formula (XI), E is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments described above or below of a compound of Formula (XI), E is heterocyclyl.

In some embodiments described above or below of a compound of Formula (XI), E is aryl.

In some embodiments described above or below of a compound of Formula (XI), E is and u is 0, 1, 2, 3, 4, or 5.

In some embodiments described above or below of a compound of Formula (XI), E is heteroaryl.

In some embodiments described above or below of a compound of formula (XI), E is selected from:

W ¹ , W ² , W ³ , W ⁴ , W ⁵ , W ⁶ and W ⁷ are independently selected from N and CR ⁹ ;

Z ¹ is NR ¹² , S or O;

Z ² is N or CR ⁹ ;

Each R ⁹ is independently selected from H, halogen, CN, NO ₂ , alkyl, -SR ¹⁰ , -OR ¹⁰ , -NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)(alkyl), -NR ¹⁰ C(O)(cycloalkyl), -NR ¹⁰ C(O)(heterocycloalkyl), -NR ¹⁰ C(O)(aryl), -NR ¹⁰ C(O)(heteroaryl), -C(O)NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ (cycloalkyl), -C(O)NR ¹⁰ (heterocycloalkyl), -C(O)NR ¹⁰ (aryl), -C(O)NR ¹⁰ (heteroaryl), -NR ¹⁰ C(O)NR ¹⁰ R ¹¹ , -NR ¹⁰ C(O)NR ¹¹ (cycloalkyl), -NR ¹⁰ C(O)NR ¹¹ (heterocycloalkyl), -NR ¹⁰ C(O)NR ¹¹ (aryl), -NR ¹⁰ C(O)NR ¹¹ (heteroaryl), -NR ¹⁰ C(O)O(alkyl), -NR ¹⁰ C(O)O(cycloalkyl), -NR ¹⁰ C(O)O(heterocycloalkyl), -NR ¹⁰ C(O)O(aryl), -NR ¹⁰ C(O)O(heteroaryl), -NR ¹⁰ SO ₂ (alkyl), -NR ¹⁰ SO ₂ (cycloalkyl), -NR ¹⁰ SO ₂ (heterocycloalkyl), -NR ¹⁰ SO ₂ (aryl), -NR ¹⁰ SO ₂ (heteroaryl), -SO ₂ NR ¹⁰ R ¹¹ , -SO ₂ NR ¹⁰ (cycloalkyl), -SO ₂ NR ¹⁰ (heterocycloalkyl), -SO ₂ NR ¹⁰ (aryl), -SO ₂ NR ¹⁰ (heteroaryl), haloalkyl, aryl, and heteroaryl;

Each R ¹⁰ and R ¹¹ is independently selected from H and alkyl; or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached form a heterocyclic ring; and

R ¹² is H, alkyl or halogenated alkyl.

In some embodiments described above or below of a compound of Formula (XI), D is aryl.

In some embodiments described above or below of a compound of Formula (XI), E is heteroaryl.

In some embodiments described above or below of compounds of formula (XI), D is selected from:

W ¹ , W ² , W ³ , W ⁴ and W ⁵ are independently selected from N and CR ⁹ ;

^W6 is N or C; and

Each R ⁹ is independently selected from H, halogen, CN, NO ₂ , alkyl, -SR ¹⁰ , -OR ¹⁰ , -NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)(alkyl), -NR ¹⁰ C(O)(cycloalkyl), -NR ¹⁰ C(O)(heterocycloalkyl), -NR ¹⁰ C(O)(aryl), -NR ¹⁰ C(O)(heteroaryl), -C(O)NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ (cycloalkyl), -C(O)NR ¹⁰ (heterocycloalkyl), -C(O)NR ¹⁰ (aryl), -C(O)NR ¹⁰ (heteroaryl), -NR ¹⁰ C(O)NR ¹⁰ R ¹¹ , -NR ¹⁰ C(O)NR ¹¹ (cycloalkyl), -NR ¹⁰ C(O)NR ¹¹ (heterocycloalkyl), -NR ¹⁰ C(O)NR ¹¹ (aryl), -NR ¹⁰ C(O)NR ¹¹ (heteroaryl), -NR ¹⁰ C(O)O(alkyl), -NR ¹⁰ C(O)O(cycloalkyl), -NR ¹⁰ C(O)O(heterocycloalkyl), -NR ¹⁰ C(O)O(aryl), -NR ¹⁰ C(O)O(heteroaryl), -NR ¹⁰ SO ₂ (alkyl), -NR ¹⁰ SO ₂ (cycloalkyl), -NR ¹⁰ SO ₂ (heterocycloalkyl), -NR ¹⁰ SO ₂ (aryl), -NR ¹⁰ SO ₂ (heteroaryl), -SO ₂ NR ¹⁰ R ¹¹ , -SO ₂ NR ¹⁰ (cycloalkyl), -SO ₂ NR ¹⁰ (heterocycloalkyl), -SO ₂ NR ¹⁰ (aryl), -SO ₂ NR ¹⁰ (heteroaryl), haloalkyl, aryl and heteroaryl.

In certain embodiments described above or below of compounds of formula (XI), D is In certain embodiments described above or below of compounds of formula (XI), D is In certain embodiments described above or below of compounds of formula (XI), D is

In some embodiments described above or below of a compound of Formula (XI), Y ¹ and Y ² are O.

In some embodiments described above or below of a compound of Formula (XI), m is 1.

In some embodiments described above or below of a compound of Formula (XI), p is 1, 2, or 3.

In some embodiments described above or below of a compound of Formula (XI), p is 1.

In some embodiments described above or below of a compound of Formula (XI), R ¹ , R ² , R ³ , and R ⁴ are hydrogen.

Further provided herein is a method of treating fibrosis using a compound of formula (XI), wherein the fibrosis is liver fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis, or cardiac fibrosis.

Further provided herein is a method of using a compound of formula (XI) to treat liver fibrosis, wherein the liver fibrosis is associated with late stages of alcoholic or non-alcoholic cirrhosis.

Further provided herein is a method of treating fibrosis using a compound of formula (XI), wherein the fibrosis is idiopathic pulmonary fibrosis.

Further provided herein is a method of treating a disease using a compound of formula (XI), wherein the disease or condition characterized by fibrosis is a chronic autoimmune disease.

Further provided herein is a method of treating a chronic autoimmune disease using a compound of formula (XI), wherein the chronic autoimmune disease is rheumatoid arthritis, scleroderma, Crohn's disease, or systemic lupus erythematosus.

Further provided herein is a method of treating a chronic autoimmune disease using a compound of formula (XI), wherein the chronic autoimmune disease is scleroderma.

Further provided herein is a method of using a compound of formula (XI) to treat fibrosis, wherein the fibrosis is keloid formation resulting from abnormal wound healing.

Further provided herein is a method of using a compound of formula (XI) to treat fibrosis, wherein the fibrosis occurs following organ transplantation.

Also provided herein is a method for treating fibrosis, a condition characterized by fibrosis, or a disease characterized by fibrosis, the method comprising administering a composition comprising a therapeutically effective amount of a compound as described herein in combination with one or more pharmaceutical agents. In certain embodiments described above, the one or more pharmaceutical agents are anti-fibrotic agents. In certain embodiments described above, the one or more pharmaceutical agents are antifungal agents.

Incorporation by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION

Fibrosis is a critically important yet surprisingly neglected health problem. In Western countries, nearly 45% of all natural deaths are attributed to chronic fibroproliferative diseases. However, there is currently only one clinically approved drug (pirfenidone) that specifically targets the pathogenesis of fibrosis and is directly indicated for the treatment of fibrotic diseases. Fibrosis affects almost every tissue in the body and, when highly advanced, can lead to organ dysfunction and death. Clearly, the identification of new anti-fibrotic drugs is an unmet medical need that would have a significant beneficial effect on patients in a variety of disease populations. Furthermore, there is currently no cure for scleroderma, and treatment is limited to symptom control.

Fibrosis, generally defined as the production of excess connective tissue, occurs as a result of a variety of underlying diseases. Chronic inflammation or tissue damage/remodeling are typical fibrosis-inducing events. Fibrosis affects nearly every tissue in the body and, when highly advanced, can lead to organ dysfunction and death. Specific examples of diseases include idiopathic pulmonary fibrosis (IPF); liver fibrosis associated with the late stages of alcoholic and non-alcoholic cirrhosis; renal fibrosis; cardiac fibrosis; and keloid formation caused by abnormal wound healing. In addition, fibrosis is a key pathological feature associated with chronic autoimmune diseases, including rheumatoid arthritis, scleroderma, Crohn's disease, and systemic lupus erythematosus. As such, fibrosis is a critically important yet surprisingly neglected health issue. In fact, in Western countries, nearly 45% of all natural deaths are attributed to chronic fibroproliferative diseases. However, currently only one clinically approved drug (pirfenidone, approved only in Europe for the treatment of IPF) specifically targets the pathogenesis of fibrosis and is directly indicated for the treatment of fibrotic diseases. Unfortunately, pirfenidone has significant hepatic and gastrointestinal side effects, and therefore patients treated with pirfenidone are advised to avoid direct exposure to sunlight, as this is known to cause photosensitivity reactions, resulting in rashes, dry skin, or itching. Recently, lysophosphatidic acid 1 (LPA1) antagonists (e.g., AM-152) have been shown to be effective in preclinical models of IPF. However, the clinical efficacy of AM-152 remains to be demonstrated. Clearly, the identification of new anti-fibrotic drugs is an important unmet medical need that would have a significant beneficial effect on patients in a variety of disease populations.

Despite the diversity of diseases and triggers that can induce the fibrotic process in a given tissue or organ, common biochemical and cellular mechanisms exist in all cases studied to date. Following injury or inflammatory insult, resident fibroblasts (in some cases, recruited circulating fibroblasts or epithelial cells derived from the bone marrow that have undergone an epithelial-to-mesenchymal transition) are activated and "transdifferentiate" into myofibroblasts expressing α-smooth muscle actin (α-SMA), which secrete extracellular matrix (ECM) components required for wound repair. In the case of liver fibrosis, a population of resident pericytes known as quiescent hepatic stellate cells (HSCs) "transdifferentiate" into type I collagen-producing, α-SMA-expressing, fibrogenic, "activated" HSCs. Transforming growth factor β1 (TGF-β1)-mediated Smad 3/4 signaling typically drives the transdifferentiation of resident fibroblasts or HSCs into myofibroblasts or activated HSCs, and stimulates the production of ECM components in the latter population. Platelet-derived growth factor (PDGF) also acts as a common pro-fibrotic cytokine driving cell activation and proliferation.

A therapeutic approach for treating progressive fibrotic diseases is to target one of the many complex etiological immune processes. This approach is limited by the lack of mechanistic clarity and the potential for worsening of the underlying disease. An attractive alternative for treating different fibrotic diseases is to directly target the transdifferentiation pathway, which is responsible for the mutual conversion of resting fibroblasts and activated profibrotic myofibroblasts. Drugs that can block the conversion of fibroblasts to activated myofibroblasts can be administered prophylactically after injury or damage (e.g., myocardial infarction) or therapeutically in the early stages of organ diseases that can be repaired (e.g., liver fibrosis, IPF, or scleroderma). Direct inhibitors of TGF-β1 production (e.g., pirfenidone) are not ideal candidates for chronic administration and are particularly undesirable for the treatment of autoimmune diseases because they have the potential to worsen the autoimmune response. Alternatively, drugs that can induce existing myofibroblasts to reverse their fate to resting cells will have wide applicability in the treatment of fibrosis in multiple tissue types and may potentially be effective in the later stages of the disease.

A high-content imaging assay has been established using primary human lung fibroblasts and primary rodent HSCs that enables the identification of small molecules that inhibit myofibroblast formation/activation or induce reversal of activated myofibroblasts to a quiescent fibroblast state. Conditions that promote robust in vitro transdifferentiation (including serum starvation and subsequent TGF-β treatment) in a miniaturized (384-well plate) format suitable for high-throughput small molecule screening have been identified. The inhibition assay is based on α-SMA immunofluorescence staining and cell morphological changes associated with fibroblast to myofibroblast transdifferentiation. Using a selective ALK-5 TGF-β1 receptor inhibitor (SB-43154) as a positive control, this inhibition assay has been used to begin screening a panel of approximately 100,000 small molecules consisting of bioactive small molecules and a diverse collection based on 2D and 3D structural diversity and intrinsic "drug-like" properties. Initial screening led to the identification of multiple previously identified anti-fibrotic molecules. Most of these molecules have limited clinical utility due to known off-target toxicity issues or lack of demonstrated in vivo efficacy. In addition to these, however, the triazole antifungal agent itraconazole has also been identified as a highly potent inhibitor of myofibroblast formation (at doses far below those associated with toxicity in fibroblasts or other control cell types).

The activity of itraconazole was confirmed in vitro by analyzing changes in the expression of multiple genes associated with the transdifferentiation of fibroblasts to myofibroblasts using biochemical methods (i.e., Western blot and RT-PCR). Using pharmacological methods, the mechanistic basis for the anti-fibrotic activity of this molecule has been determined to be dual inhibition of hedgehog signaling and vascular endothelial growth factor (VEFG) receptor glycosylation/trafficking (neither activity alone is sufficient). Encouragingly, itraconazole's activity was determined to be applicable to human and rodent cell types, as well as cells derived from various tissue types (e.g., lung, liver, skin, heart). Using pirfenidone and AM-152 as benchmark control compounds, itraconazole was demonstrated to be effective in both bleomycin-induced lung and carbon tetrachloride-induced liver fibrosis mouse models. In this regard, the FDA-approved drug itraconazole has been identified as a novel lead for the development of a new class of drugs for the treatment of various fibrosis-related diseases.

A potential limitation to the drug's use as an antifibrotic agent, particularly in the treatment of liver fibrosis, is its known hepatotoxicity profile, which is related to the coordination of the heme iron by the N4 of the 1,2,4-triazole moiety. This leads to inhibition of P450 enzymes (most notably Cyp3A4), an activity distinct from itraconazole's VEGF and Hgh activities. Consequently, medicinal chemistry efforts have begun to identify optimized itraconazole analogs with favorable hepatotoxicity profiles and further improved antifibrotic potency. From an initial panel of approximately 30 itraconazole analogs in which the N4 pKa was lowered or the N4 nitrogen was substituted with carbon, several lead candidates have been identified in which Cyp inhibitory activity was abolished while retaining in vitro antifibrotic activity. Notably, the pharmacokinetic properties of these compounds are comparable to those of the parent compound. Based on observed in vitro activity, in vivo efficacy, rodent serum exposure, and human exposure data, a 5-fold improvement in potency and/or exposure is expected for the final clinical candidate. Preliminary structure-activity relationship studies show that by modifying the distal site of the triazole substituent, potency enhancement can be achieved. Chemical work is underway and will be used to optimize potency, exposure ( _Cmax >5 times in vitro _EC50 ) and toxicity profiles (based on human off-target group profile analysis, hERG and AMES in vitro toxicity tests and Cyp induction/inhibition tests). Reproducible disease-modifying activity (i.e., potency equal to or greater than the potency of existing (pirfenidone) or possible future (AM-152) medical standards) will be demonstrated for the optimized itraconazole analogs using lung and liver rodent fibrosis models.

definition

In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, those skilled in the art will appreciate that the present invention can be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessary ambiguity in the description of the embodiments. Unless the context otherwise requires, throughout this specification and the claims that follow, the words "comprise" and variations thereof, such as "include" and "comprising" should be interpreted in an open, inclusive sense, i.e., as "including but not limited to." In addition, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in conjunction with that embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. In addition, as used in this specification and the appended claims, unless the content clearly indicates otherwise, the singular forms "a," "an," and "the" include plural objects. It should also be noted that, unless the content clearly indicates otherwise, the term "or" is generally used in its sense including "and/or."

Unless otherwise indicated, the following terms as used herein have the following meanings:

"Amino" refers to a _-NH2 group.

"Cyano" or "nitrile" refers to a -CN group.

"Hydroxy" or "hydroxyl" refers to an -OH group.

"Nitro" refers to a _-NO2 group.

"Oxo" refers to a =0 substituent.

"Oxime" refers to a =N-OH substituent.

"Thio" refers to a =S substituent.

"Alkyl" refers to a straight or branched hydrocarbon chain radical having 1 to 30 carbon atoms and connected to the rest of the molecule by a single bond. Alkyl groups containing any number of carbon atoms from 1 to 30 are contemplated. Alkyl groups containing up to 30 carbon atoms are referred to as _C1 - _C30 alkyl groups, and similarly, for example, alkyl groups containing up to 12 carbon atoms are _C1 - _C12 alkyl groups. Alkyl groups containing other numbers of carbon atoms (and other moieties defined herein) are represented in a similar manner. Alkyl groups include, but are not limited to, _C1 - _C30 alkyl groups, _C1 - _C20 alkyl groups, _C1 - _C15 alkyl groups, _C1 - _C10 alkyl groups, _C1 - _C8 alkyl groups, _C1 - _C6 alkyl groups, _C1 - _C4 alkyl groups, _C1 - _C3 alkyl groups, _C1 - _C2 alkyl groups, C2- _C8 alkyl _groups , _C3 - _C8 alkyl groups, and _C4 - _C8 alkyl groups. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, vinyl, allyl, propynyl, and the like. Alkyl groups containing unsaturated bonds include alkenyl and alkynyl. Unless otherwise specifically stated in the specification, alkyl groups may be optionally substituted as described below.

"Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain as described above for alkyl. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted as described below.

"Alkoxy" refers to a radical of the formula -OR _a , where _Ra is an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkoxy radical may be optionally substituted as described below.

"Aryl" refers to a group derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from the hydrocarbon ring systems of aceanthrene, acenaphthene, acephenanthren, anthracene, azulene, benzene, fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenanthren, phenanthren, pyrene and triphenylene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar" (as in "aralkyl") is intended to include optionally substituted aryl groups.

"Cycloalkyl" or "carbocycle" refers to a stable, non-aromatic monocyclic or polycyclic carbocyclic ring that may include a fused or bridged ring system that is saturated or unsaturated. Representative cycloalkyls or carbocycles include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Monocyclic cycloalkyls or carbocycles include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocyclic rings include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane and bicyclo[3.3.2]decane and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specifically stated in the specification, cycloalkyl or carbocyclic groups may be optionally substituted. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:

"Fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced by a nitrogen atom.

"Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

"Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo groups, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

Similarly, "haloalkoxy" refers to a radical of the formula -OR _a , where _Ra is a haloalkyl radical as defined above. Unless stated otherwise specifically in the specification, a haloalkoxy radical may be optionally substituted as described below.

"Heterocycloalkyl" or "heterocyclyl" or "heterocyclic ring" or "heterocycle" refers to a stable 3- to 24-membered non-aromatic ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. Unless otherwise specifically stated in the specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl group may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuranyl, Trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 12-crown-4, 15-crown-5, 18-crown-6, 21-crown-7, aza-18-crown-6, diaza-18-crown-6, aza-21-crown-7 and diaza-21-crown-7. Unless otherwise specifically stated in the specification, the heterocyclic group may be optionally substituted. Heterocycloalkyl is also known as non-aromatic heterocycle, and illustrative examples thereof include:

The term heterocycloalkyl also includes carbohydrates of all ring forms, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise indicated, heterocycloalkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is different from the total number of atoms (including heteroatoms) that constitute the heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring). Unless otherwise specifically stated in the specification, heterocycloalkyl may be optionally substituted.

As used herein, the term "heteroaryl" refers, individually or in combination, to an optionally substituted aromatic monovalent group containing about five to about twelve skeleton ring atoms, wherein one or more ring atoms are heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms, and provided that the ring of the group does not contain two adjacent O or S atoms. In embodiments where there are two or more heteroatoms in the ring, these two or more heteroatoms may be identical to each other, or some or all of these two or more heteroatoms may each be different from the other heteroatoms. The term heteroaryl includes optionally substituted fused and non-fused heteroaryl groups having at least one heteroatom. The term heteroaryl also includes fused and non-fused heteroaryl groups having five to about twelve skeleton ring atoms, and fused and non-fused heteroaryl groups having five to about ten skeleton ring atoms. The heteroaryl group may be bonded to the heteroaryl group via a carbon atom or a heteroatom. Thus, as non-limiting examples, an imidazole group can be connected to the parent molecule by any of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol-5-yl) or its nitrogen atom (imidazol-1-yl or imidazol-3-yl). Similarly, heteroaryl can be further substituted by any or all of its carbon atoms and/or any or all of its heteroatoms. The fused heteroaryl group can contain two to four fused rings, wherein the ring connected is a heteroaromatic ring and each of the other rings can be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof. The non-limiting examples of monocyclic heteroaryl include pyridyl; fused ring heteroaryl includes benzimidazolyl, quinolyl, acridinyl; non-fused bipyridyl includes bipyridyl. Other examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl, indolyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl, purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl, thiadiazolyl, and the like, and oxides thereof, such as pyridyl-N-oxide. Illustrative examples of heteroaryl groups include the following moieties:

The heteroaryl group 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 group can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, aza-, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl or benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carba ...anyl, benzo[b][1,4]dioxanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzo[b][1,4 phenanthroline, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindololinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl -1H-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).

All of the above groups may be substituted or unsubstituted. As used herein, the term "substituted" means that any of the above groups (e.g., alkyl, alkylene, alkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyl and/or heteroaryl) may be further functionalized wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom substituent. Unless otherwise specified in the specification, a substituted group may include one or more substituents selected from the group consisting of oxo, amino, -CO ₂ H, nitrile, nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, dialkylamine, arylamine, alkylarylamine, diarylamine, trialkylammonium (-N ⁺ R ₃ ), N-oxide, imide, and enamine; a silicon atom in a group such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl, a perfluoroalkyl or perfluoroalkoxy group, such as trifluoromethyl or trifluoromethoxy. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher bond (e.g., a double bond or a triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, and nitrogen in groups such as _imine , oxime, hydrazone, and nitrile. For example, "substituted _" includes any of the above groups in which one or _more hydrogen atoms are replaced _{by -NH2} , _-NRgC (=O) _NRgRh , _-NRgC (=O) _ORh , _-NRgSO2Rh , _{-OC (} = _{O)NRgRh, -ORg, -SRg , -SORg , -SO2Rg , -OSO2Rg , -SO2ORg , = NSO2Rg} , and _-SO2NRgRh . In the above, _R and _R are the same or different and are independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and/or heteroarylalkyl. In addition, each of the above substituents may be optionally substituted with one or more of the above substituents. In addition, any of the above groups may be substituted to include one or more internal oxygen, sulfur, or nitrogen atoms. For example, an alkyl group may be substituted with one or more internal oxygen atoms to form an ether or polyether group. Similarly, an alkyl group may be substituted with one or more internal sulfur atoms to form thioethers, disulfides, and the like.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does _not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. In addition, an optionally substituted group can be unsubstituted (e.g., _-CH2CH3 ), fully substituted (e.g., _-CF2CF3 ), monosubstituted (e.g., _-CH2CH2F ), or substituted at any level between fully substituted and _{monosubstituted} (e.g., _-CH2CHF2 , _{-CH2CF3 , -CF2CH3} , _-CFHCHF2 , _{etc. )} . It will be understood by those skilled in the art that for any group containing one or more substituents, these groups are not intended to introduce any substitution or substitution pattern that is sterically unavailable and/or synthetically infeasible (e.g., _substituted alkyl includes optionally substituted cycloalkyl, which in turn is defined to include optionally substituted alkyl, and so on, potentially indefinitely). Thus, any substituent described will generally be understood to have a maximum molecular weight of about 1,000 Daltons, and more typically, up to about 500 Daltons.

An "effective amount" or "therapeutically effective amount" refers to an amount of a compound that is administered to a mammalian subject as a single dose or as part of a series of doses and that is effective to produce the desired therapeutic effect.

"Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used in an attempt to alter the natural course of an individual or cell. In some embodiments, treatment includes administering a pharmaceutical composition after a pathological event or contact with a pathogen has begun, and includes stabilization of the condition (e.g., the condition does not worsen) or alleviation of the condition. In other embodiments, treatment also includes prophylactic treatment (e.g., administering a composition described herein when an individual is suspected of having a bacterial infection).

"Tautomer" refers to a proton transfer from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by the migration of a hydrogen atom with the conversion of a single bond and an adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversion include:

A "metabolite" of a compound disclosed herein is a derivative of that compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of the compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of processes by which a particular substance is altered by an organism, including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions. Thus, enzymes can produce specific structural changes in a compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, 9th edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are well known in the art. In some embodiments, a metabolite of a compound is formed by an oxidative process and corresponds to the corresponding hydroxyl-containing compound. In some embodiments, a compound is metabolized to form a pharmacologically active metabolite.

Compound

In one aspect, provided herein is a compound of formula (I) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² . In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is alkyl. In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is methyl. In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is ethyl. In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is isopropyl. In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is -NH ₂ . In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is -NHCH ₃ . In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of Formula (I ⁾ is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound of Formula (I ⁾ is -CH( _CH3 ) ₂ . In some embodiments, the compound of Formula (I) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 ^. In some embodiments, the compound of Formula (I) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula (I) is ^-CH ( _CH2CH3 )CH ^(R3 _{) CH3} ^, and ^R3 is alkyl. In some embodiments, the compound of _Formula (I) is ^-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is ethyl. In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NR ¹³ R ¹⁴ . In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NH ₂ . In some embodiments, the compound of Formula (I) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NHCH ₃ . In some embodiments, the compound of formula (I) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (I) wherein R ¹ is -alkylene(cycloalkyl). In some embodiments, the compound of formula (I) wherein R ¹ is -CH ₂ CH ₂ (cycloalkyl). In some embodiments, the compound of formula (I) wherein R ¹ is -CH ₂ (cycloalkyl). In some embodiments, the compound of formula (I) wherein R ¹ is -CH ₂ (cyclobutyl). In some embodiments, the compound of formula (I) wherein R ¹ is -CH ₂ (cyclopentyl). In some embodiments, the compound of formula (I) wherein R ¹ is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula (I) wherein R ¹ is

In some embodiments described above or below, the compound of formula (I) is ^H. In some embodiments described above or below, the compound of formula (I) is -CN. In some embodiments described above or ^below , the compound of formula (I) is halogen. In some embodiments described above or below, the compound of formula ( ^I ) is F. In some embodiments described above or below, the compound of formula (I) is ^Cl . In some embodiments described above or below, the compound of formula (I) is ^alkyl . In some embodiments described above or below, the compound of formula (I) is ^methyl . In some embodiments described above or below, the compound of formula (I) is ethyl. In some embodiments described above or below, the compound ^of formula ( ^I) is ^{-NR 13 R 14} . In some embodiments described above or below, the compound of formula (I ⁾ is -NH ₂ . In some embodiments described above or below is a compound of Formula (I) wherein ^R5 is -alkylene ( ^NR13R14 ). In some embodiments described above or below is a compound ^of Formula (I) wherein ^R5 is -alkylene ( _NH2 ). In some embodiments described above or below is a compound _of Formula (I) wherein ^R5 is _-CH2NH2 .

In some embodiments described above or below is a compound of Formula (I) wherein n is 0.

In some embodiments described above or below is a compound of Formula (I) wherein n is 1. In some embodiments described above or below is a compound of Formula (I) wherein n is 1 and ^R8 is selected from halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , -NR13SO2R14 ^{, -NR13C (} O ₎ ^R14 , ^-NR13C (O ⁾ _OR14 , ^-NR13C (O ^{) NR13R14 , -C} (O ^{) R14 ,} -C(O)OR In some embodiments described ^above or below, ^the compound is of formula (I), wherein n is 1 and ^R is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments described above or below, the compound ^is of formula (I), wherein n is 1 and ^R is halogen. In some embodiments described above or below, the compound is of formula (I), wherein n is 1 and R is F. In some embodiments described above or below, the compound is of formula (I), wherein n is 1 and R is ^Cl . In some embodiments described above or below, the compound is of formula (I), wherein n is ¹ and ^R is -CN. In some embodiments described above or below, the compound is of formula (I), wherein n is 1 and ^R is alkyl. In some embodiments described above or below, the compound is of formula (I), wherein n is 1 and ^R is methyl. In some embodiments described above or below, the compound is of formula (I), wherein n is 1 and R ^is ethyl. In some embodiments described above or below, the compound of formula (I) is wherein n is 1 and ^R is alkoxy. In some embodiments described above or below, the compound of formula (I) is wherein n is 1 and ^R is methoxy. In some embodiments described above or below, the compound of formula (I) is wherein n is 1 and ^R is ethoxy. In some embodiments described above or below, the compound of formula (I) is wherein n is 1 and ^R is haloalkoxy. In some embodiments described above or below, the compound of formula (I) is wherein n is 1 and ^R is -OCF ₃ . In some embodiments described above or below, the compound of formula (I) is wherein n is 1 and ^R is haloalkyl. In some embodiments described above or below, the compound of formula (I) is wherein n is 1 and ^R is -CF ₃ .

In some embodiments described above or below is a compound of Formula (I) wherein n is 2. In some embodiments described above or below is a compound of Formula (I) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl ^, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, -NR13R14, ^-NR13SO2R14 , ^-NR13C (O ₎ ^R14 , ^-NR13C (O ^{) OR14} , ^-NR13C (O ₎ ^{NR13R14 , -C} (O) ^R14 , ^{-C (} O)OR In some embodiments described ^above or below, the compound is ^of formula (I), wherein n is 2 and R ^{8 is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments described above or below, the compound is of formula (I), wherein n is 2 and R 8 is} halogen. In some embodiments described above or below, the compound is of formula (I), wherein n is 2 and each R ⁸ is F. In some embodiments described above or below, the compound is of formula (I), wherein n is 2 and each R ⁸ is Cl. In some embodiments described above or below, the compound is of formula (I), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (I), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (I), wherein n is 2 and R ⁸ is independently selected from halogen and alkyl. In some embodiments described above or below, the compound is of formula (I), wherein n is 2 and R ⁸ is independently selected from -CN and alkyl. In some embodiments described above or below is a compound of Formula (I) wherein n is 2 and two adjacent R ⁸ form a heterocyclyl ring.

In another embodiment is a compound of Formula (I) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of Formula (Ia) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In some embodiments, the ^compound of Formula (Ia) is -CH( _CH3 ) _CH2CH2R2 . In _some embodiments, the compound of Formula (Ia) is ^-CH ( _CH3 ) _CH2CH2R2 , ^{and R2} is ^alkyl . In some embodiments, ^the compound of Formula (Ia) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^R2 is methyl. In some embodiments, the compound of Formula (Ia) is ^-CH _{( CH3 ) CH2CH2R2} , ^and _R2 is ^ethyl . In some embodiments, the compound of Formula (Ia) is ^-CH ( _CH3 ) _CH2CH2R2 , ^and _R2 is ^isopropyl . In some embodiments, the compound of Formula (Ia) is R1, wherein ^R1 is -CH( _CH3 ) _CH2CH2R2 , and _R2 ^{is -NR13R14} . In some embodiments, the compound of Formula (Ia) is R1, wherein ^R1 is -CH( _{CH3 )} ^CH2CH2R2 , and _R2 ^{is -NH2} . In some embodiments, the compound of Formula ⁽ Ia) is _R1 , wherein ^R1 is -CH( _CH3 ) _CH2CH2R2 , and ^{R2 is} _-NHCH3 . In some embodiments, the compound of Formula (Ia) is R1, wherein ^R1 is _-CH ( _CH3 ) _CH2CH2R2 , and _R2 ^{is -N} ( _CH3 ) ₂ .

In some embodiments, the ^compound of Formula (Ia) is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound ^of Formula (Ia) is -CH( _CH3 ) ₂ . In some embodiments, _the compound of Formula (Ia) is ^-CH ( _CH2CH3 )CH( _R3 ) ^CH3 . In some embodiments, the compound of Formula (Ia) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula (Ia) is ^-CH ( ^CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of _Formula (Ia) is ^-CH ( _CH2CH3 ) _CH ( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (Ia) is ^-CH ( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^R3 is ethyl. In some embodiments, the compound of ^Formula (Ia) is -CH( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^{R3 is -NR13R14} . In some embodiments, the compound of Formula (Ia) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is _-NH2 . In some embodiments, ^{the compound of Formula (Ia) is -CH(CH2CH3)CH(R3 )} _CH3 ^, _{and R3} ^is _-NHCH3 . In some embodiments, there is a compound of Formula (Ia) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, there is a compound of Formula (Ia) wherein R ¹ is -alkylene(cycloalkyl). In some embodiments, there is a compound of Formula (Ia) wherein R ¹ is -CH ₂ CH ₂ (cycloalkyl). In some embodiments, there is a compound of Formula (Ia) wherein R ¹ is -CH ₂ (cycloalkyl). In some embodiments, there is a compound of Formula (Ia) wherein R ¹ is -CH ₂ (cyclobutyl). In some embodiments, there is a compound of Formula (Ia) wherein R ¹ is -CH ₂ (cyclopentyl). In some embodiments, there is a compound of Formula (Ia) wherein R ¹ is -CH ₂ (cyclohexyl). In some embodiments, there is a compound of Formula (Ia) wherein R ¹ is

In some embodiments described above or below, there is a compound of formula (Ia), wherein R is ^H. In some embodiments described above or below, there is a compound of formula (Ia), wherein ^R is -CN. In some embodiments described above or below, there is a compound of formula (Ia), wherein R is ^halogen . In some embodiments described above or below, there is a compound of formula (Ia), wherein ^R is F. In some embodiments described above or below, there is a compound of formula (Ia), wherein ^R is Cl. In some embodiments described above or below, there is a compound of formula (Ia), wherein ^R is alkyl. In some embodiments described above or below, there is a compound of formula (Ia), wherein ^R is methyl. In some embodiments described above or below, there is a compound of formula (Ia), wherein R is ^ethyl . In some embodiments described above or below, there is a compound of formula (Ia), wherein ^R is -NR ¹³ R ¹⁴ . In some embodiments described above or below, there is a compound of formula (Ia), wherein ^R is -NH ₂ . In some embodiments described above or below is a compound of Formula (Ia) wherein R ⁵ is -alkylene (NR ¹³ R ¹⁴ ). In some embodiments described above or below is a compound of Formula (Ia) wherein R ⁵ is -alkylene (NH ₂ ). In some embodiments described above or below is a compound of Formula (Ia) wherein R ⁵ is -CH ₂ NH ₂ .

In some embodiments described above or below is a compound of Formula (Ia) wherein n is 0.

In some embodiments described above or below is a compound of Formula (Ia) wherein n is 1. In some embodiments described above or below is a compound of Formula (Ia) wherein n is 1 and ^R8 is selected from halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , -NR13SO2R14 ^{, -NR13C (} O ₎ ^R14 , ^-NR13C (O ⁾ _OR14 , ^-NR13C (O ^{) NR13R14 , -C} (O ^{) R14 ,} -C(O)OR In some embodiments described ^above or below, ^the compound is of formula (Ia), wherein n is 1 and ^R is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments described above or below, the compound ^is of formula (Ia), wherein n is 1 and ^R is halogen. In some embodiments described above or below, the compound is of formula (Ia), wherein n is 1 and R is F. In some embodiments described above or below, the compound is of formula (Ia), wherein n is 1 and R is ^Cl . In some embodiments described above or below, the compound is of formula (Ia), wherein n is ¹ and ^R is -CN. In some embodiments described above or below, the compound is of formula (Ia), wherein n is 1 and ^R is alkyl. In some embodiments described above or below, the compound is of formula (Ia), wherein n is 1 and ^R is methyl. In some embodiments described above or below, the compound of formula (Ia) is wherein n is 1 and R ^is ethyl. In some embodiments described above or below, the compound of formula (Ia) is wherein n is 1 and ^R is alkoxy. In some embodiments described above or below, the compound of formula (Ia) is wherein n is 1 and ^R is methoxy. In some embodiments described above or below, the compound of formula (Ia) is wherein n is 1 and ^R is ethoxy. In some embodiments described above or below, the compound of formula (Ia) is wherein n is 1 and ^R is haloalkoxy. In some embodiments described above or below, the compound of formula (Ia) is wherein n is 1 and ^R is -OCF ₃ . In some embodiments described above or below, the compound of formula (Ia) is wherein n is 1 and ^R is haloalkyl. In some embodiments described above or below, the compound of formula (Ia) is wherein n is 1 and R is -CF ³ _.

In some embodiments described above or below is a compound of Formula (Ia) wherein n is 2. In some embodiments described above or below is a compound of Formula (Ia) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl ^, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, -NR13R14, ^-NR13SO2R14 , ^-NR13C (O ₎ ^R14 , ^-NR13C (O ^{) OR14} , ^-NR13C ( ^O ₎ ^{NR13R14 , -C} (O) ^R14 , -C ⁽ O)OR In some embodiments described ^above or below, the compound is ^of formula (Ia), wherein n is 2 and R ^{8 is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments described above or below, the compound is of formula (Ia), wherein n is 2 and R 8 is} halogen. In some embodiments described above or below, the compound is of formula (Ia), wherein n is 2 and each R ⁸ is F. In some embodiments described above or below, the compound is of formula (Ia), wherein n is 2 and each R ⁸ is Cl. In some embodiments described above or below, the compound is of formula (Ia), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (Ia), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (Ia), wherein n is 2 and R ⁸ is independently selected from halogen and alkyl. In some embodiments described above or below, the compound is of formula (Ia), wherein n is 2 and R ⁸ is independently selected from -CN and alkyl. In some embodiments described above or below is a compound of Formula (Ia) wherein n is 2 and two adjacent R ⁸ form a heterocyclyl ring.

In another embodiment is a compound of Formula (Ia) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (II) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In some embodiments, the compound of formula (II) wherein R ⁴ is halogen. In some embodiments, the compound of formula (II) wherein R ⁴ is F. In some embodiments, the compound of formula (II) wherein R ⁴ is Cl. In some embodiments, the compound of formula (II) wherein R 4 is alkyl. In some embodiments, the compound of formula (II) wherein R ⁴ is methyl. In some embodiments, the compound of formula (II) wherein R ⁴ is ethyl. In some embodiments, the compound of formula (II) wherein R 4 is In some embodiments, the compound of formula (II) wherein R ⁴ is In some embodiments, the compound of formula (II) wherein R ⁴ is In some embodiments, the compound of formula (II) wherein R 4 is In some embodiments, the compound of formula (II) wherein R ⁴ is In some embodiments, the compound of formula (II) wherein R 4 is In some embodiments, the compound of formula (II) wherein R ⁴ is In some embodiments, the compound of formula (II) wherein R ⁴ is In some embodiments, the compound of formula (II) wherein R 4 is In some embodiments, the compound of formula (II) wherein R ⁴ is In some embodiments, the compound of formula (II) wherein R 4 is In some embodiments, the compound of formula (II) wherein R ⁴ is In some embodiments, the compound of formula (II) wherein R ⁴ is In some embodiments, the compound of formula (II) wherein R 4 is In some embodiments, the compound of formula (II) wherein R ⁴ is In some embodiments, the compound of formula (II) wherein R ⁴ is In some embodiments, the compound of formula (II) wherein R ⁴ is

In some embodiments, the compound of formula (II) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² . In some embodiments, the compound of formula (II) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is H. In some embodiments, the compound of formula (II) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is alkyl. In some embodiments, the compound of formula (II) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is methyl. In some embodiments, the compound of formula (II) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is ethyl. In some embodiments, the compound of formula (II) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is isopropyl. In some embodiments, the compound of Formula (II) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of Formula (II) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is -NH ₂ . In some embodiments, the compound of Formula (II) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is -NHCH ₃ . In some embodiments, the compound of Formula (II) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (II ⁾ is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound of formula (II ⁾ is -CH( _CH3 ) ₂ . In some embodiments, _the compound of formula (II) is -CH( _CH2CH3 )CH( _R3 ) ^CH3 . In some embodiments, the compound of formula ( ^II ) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of formula ( ^II ) is -CH( ^CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of formula (II) is ^-CH ( _CH2CH3 ) _CH ( ^R3 ) _CH3 , and _R3 ^is methyl. In some embodiments, the compound of Formula (II) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is ethyl. In some embodiments, the compound of Formula (II) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NR ¹³ R ¹⁴ . In some embodiments, the compound of Formula (II) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NH ₂ . In some embodiments, the compound of Formula (II) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NHCH ₃ . In some embodiments, the compound of formula (II) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (II) wherein R ¹ is -alkylene(cycloalkyl). In some embodiments, the compound of formula (II) wherein R ¹ is -CH ₂ CH ₂ (cycloalkyl). In some embodiments, the compound of formula (II) wherein R ¹ is -CH ₂ (cycloalkyl). In some embodiments, the compound of formula (II) wherein R ¹ is -CH ₂ (cyclobutyl). In some embodiments, the compound of formula (II) wherein R ¹ is -CH ₂ (cyclopentyl). In some embodiments, the compound of formula (II) wherein R ¹ is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula (II) wherein R ¹ is

In some embodiments described above or below is a compound of Formula (II) wherein n is 0.

In some embodiments described above or below is a compound of Formula (II) wherein n is 1. In some embodiments described above or below is a compound of Formula (II) wherein n is 1 and ^R8 is selected from halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , -NR13SO2R14 ^{, -NR13C (} O ₎ ^R14 , ^-NR13C (O ⁾ _OR14 , ^-NR13C (O ^{) NR13R14 , -C} (O ^{) R14 ,} -C(O)OR In some embodiments described ^above or below, ^the compound is of formula (II), wherein n is 1 and ^R is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments described above or below, the compound ^is of formula (II), wherein n is 1 and ^R is halogen. In some embodiments described above or below, the compound is of formula (II), wherein n is 1 and R is F. In some embodiments described above or below, the compound is of formula (II), wherein n is 1 and R is ^Cl . In some embodiments described above or below, the compound is of formula (II), wherein n is ¹ and ^R is -CN. In some embodiments described above or below, the compound is of formula (II), wherein n is 1 and ^R is alkyl. In some embodiments described above or below, the compound is of formula (II), wherein n is 1 and R ^is methyl. In some embodiments described above or below, the compound is of formula (II), wherein n is 1 and R is ^ethyl . In some embodiments described above or below, the compound of formula (II) is wherein n is 1 and ^R is alkoxy. In some embodiments described above or below, the compound of formula (II) is wherein n is 1 and ^R is methoxy. In some embodiments described above or below, the compound of formula (II) is wherein n is 1 and ^R is ethoxy. In some embodiments described above or below, the compound of formula (II) is wherein n is 1 and ^R is haloalkoxy. In some embodiments described above or below, the compound of formula (II) is wherein n is 1 and ^R is -OCF ₃ . In some embodiments described above or below, the compound of formula (II) is wherein n is 1 and ^R is haloalkyl. In some embodiments described above or below, the compound of formula (II) is wherein n is 1 and ^R is -CF ₃ .

In some embodiments described above or below is a compound of Formula (II) wherein n is 2. In some embodiments described above or below is a compound of Formula (II) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl ^, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, -NR13R14, ^-NR13SO2R14 , ^-NR13C (O ₎ ^R14 , ^-NR13C (O ^{) OR14} , ^-NR13C (O ₎ ^{NR13R14 , -C} (O) ^R14 , ^{-C (} O)OR In some embodiments described ^above or below, the compound is ^of formula (II), wherein n is 2 and R 8 is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and ^haloalkyl . In some embodiments described above or below, the compound is of formula (II), wherein n is 2 and R ⁸ is halogen. In some embodiments described above or below, the compound is of formula (II), wherein n is 2 and each R ⁸ is F. In some embodiments described above or below, the compound is of formula (II), wherein n is ² and each R ⁸ is Cl. In some embodiments described above or below, the compound is of formula (II), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (II), wherein n is 2 and R ⁸ is independently selected from halogen and alkyl. In some embodiments described above or below, the compound is of formula (II), wherein n is 2 and R ⁸ is independently selected from -CN and alkyl. In some embodiments described above or below is a compound of Formula (II) wherein n is 2 and two adjacent R ⁸ form a heterocyclyl ring.

In another embodiment is a compound of formula (II) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (IIa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In some embodiments, the compound of formula (IIa) is wherein R ⁴ is halogen. In some embodiments, the compound of formula (IIa) is wherein R ⁴ is F. In some embodiments, the compound of formula (IIa) is wherein R ⁴ is Cl. In some embodiments, the compound of formula (IIa) is wherein R ⁴ is alkyl. In some embodiments, the compound of formula (IIa) is wherein R ⁴ is methyl. In some embodiments, the compound of formula (IIa) is wherein R ⁴ is ethyl. In some embodiments, the compound of formula (IIa) wherein R ⁴ is In some embodiments, the compound of formula (IIa) wherein R ⁴ is In some embodiments, the compound of formula (IIa) wherein R ⁴ is In some embodiments, the compound of formula (IIa) wherein R 4 is In some embodiments, the compound of formula (IIa) wherein R ⁴ is In some embodiments, the compound of formula (IIa) wherein R ⁴ is In some embodiments, the compound of formula (IIa) wherein R ⁴ is In some embodiments, the compound of formula (IIa) wherein R ⁴ is In some embodiments, the compound of formula (IIa) wherein R 4 is In some embodiments, the compound of formula (IIa) wherein R ⁴ is In some embodiments, the compound of formula (IIa) wherein R ⁴ is In some embodiments, the compound of formula (IIa) wherein R ⁴ is

In some embodiments, ^the compound of Formula (IIa) is ^-CH ( _CH3 ) _CH2CH2R2 . In _some embodiments, the compound of Formula (IIa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^R2 is H. In some embodiments, ^the compound ^of Formula ( ^IIa ) is -CH( _CH3 ) _CH2CH2R2 , and ^R2 is alkyl. In some embodiments, the compound of Formula (IIa) is ^-CH ( _{CH3 ) CH2CH2R2} , ^{and R2} _is ^methyl . In some embodiments, the compound of Formula ( _IIa ) is ^-CH ( _CH3 ) _CH2CH2R2 , and _R2 ^{is ethyl} . In some embodiments, the ^compound of Formula (IIa) is -CH( _CH3 ) _CH2CH2R2 , and _R2 is ^isopropyl . In some embodiments, the compound of Formula (IIa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^{R2 is -NR13R14 .} In some embodiments, the compound of Formula (IIa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^{R2 is} _-NH2 . In some embodiments, the compound of Formula ⁽ _IIa ) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^{R2 is} _-NHCH3 . In some embodiments, the compound of Formula (IIa) is ^-CH ( _{CH3 ) CH2CH2R2} , and _R2 ^is _-N ( ^CH3 ₎ ² _.

In some embodiments, the compound of Formula (IIa ⁾ is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound of Formula ( ^IIa ) is -CH( _CH3 ) ₂ . In some embodiments, _the compound of Formula (IIa) is -CH( _CH2CH3 )CH( _R3 ) ^CH3 . In some embodiments, the compound of Formula ( ^IIa ) is ^-CH ( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula ( ^IIa ) is -CH( _CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of _Formula (IIa) is ^-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (IIa) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is ethyl. In _some embodiments, the compound of Formula ( _IIa ) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^{R3 is -NR13R14} . In some embodiments, the compound of Formula (IIa) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is _-NH2 . _In some embodiments, the compound of Formula ( ^IIa ) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is _-NHCH3 . In some embodiments, the compound of formula (IIa) is R 1, wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (IIa) is R 1, wherein R ¹ is -alkylene(cycloalkyl). In some embodiments, the compound of formula (IIa) is R 1, wherein R ¹ is -CH ₂ CH ₂ (cycloalkyl). In some embodiments, the compound of formula (IIa) is R 1, wherein R ¹ is -CH ₂ (cycloalkyl). In some embodiments, the compound of formula (IIa) is R 1, wherein R ¹ is -CH ₂ (cyclobutyl). In some embodiments, the compound of formula (IIa) is R 1, wherein R ¹ is -CH ₂ (cyclopentyl). In some embodiments, the compound of formula (IIa) is R 1, wherein R ¹ is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula (IIa) is R ¹ , wherein R 1 is -CH 2 (cyclohexyl).

In some embodiments described above or below is a compound of Formula (IIa) wherein n is 0.

In some embodiments described above or below is a compound of Formula (IIa) wherein n is 1. In some embodiments described above or below is a compound of Formula (IIa) wherein n is 1 and R ⁸ is selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R ¹³ , -SO ₂ NR ¹³ R ¹⁴ , -NR ¹³ R 14 , -NR 13 SO ₂ R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O) ^{NR 13 R 14} , -C(O)R ¹⁴ , -C(O) ^OR In some embodiments described ^above or below, ^the compound is of formula (IIa), wherein n is 1 and ^R is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments described above or below, the compound ^is of formula (IIa), wherein n is 1 and ^R is halogen. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 and R is F. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 and R is ^Cl . In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 ^{and R} is -CN. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 and ^R is alkyl. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 and ^R is methyl. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 and R ⁸ is ethyl. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 and R ⁸ is alkoxy. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 and R ⁸ is methoxy. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 and R ⁸ is ethoxy. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 and R ⁸ is haloalkoxy. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 and R ⁸ is -OCF ₃ . In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 and R ⁸ is haloalkyl. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 1 and R ⁸ is -CF ₃ .

In some embodiments described above or below is a compound of Formula (IIa) wherein n is 2. In some embodiments described above or below is a compound of Formula (IIa) wherein n is 2 and R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO ₂ NR ¹³ R ¹⁴ , -NR 13 R ¹⁴ , -NR ¹³ SO 2 R ¹⁴ , -NR ¹³ C(O ₎ R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14 ,} -C(O)R ¹⁴ , -C(O ⁾ OR In some embodiments described ^above or below, the compound is ^of formula (IIa), wherein n is 2 and R ^{8 is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 2 and R 8 is} halogen. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 2 and each R ⁸ is F. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 2 and each R ⁸ is Cl. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 2 and R ⁸ is independently selected from halogen and alkyl. In some embodiments described above or below, the compound is of formula (IIa), wherein n is 2 and R ⁸ is independently selected from -CN and alkyl. In some embodiments described above or below is a compound of Formula (IIa) wherein n is 2 and two adjacent R ⁸ form a heterocyclyl ring.

In another aspect, provided herein is a compound of formula (III) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

each R ⁵ is independently selected from haloalkyl, -alkylene(NR ¹³ R ¹⁴ ), -NR ¹³ R ¹⁴ and -SO ₂ R ¹³ ;

Each R ⁶ is independently selected from halogen, alkyl and haloalkyl;

Each R ⁷ is independently selected from halogen, alkyl, haloalkyl and -CN;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

n is selected from 0, 1, 2, 3 and 4;

p is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3, and 4; and

t is selected from 0, 1, 2, 3 and 4;

At least one of p, q or t is not zero.

In some embodiments, the compound of formula (III) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² . In some embodiments, the compound of formula (III) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is H. In some embodiments, the compound of formula (III) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is alkyl. In some embodiments, the compound of formula (III) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is methyl. In some embodiments, the compound of formula (III) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is ethyl. In some embodiments, the compound of formula (III) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is isopropyl. In some embodiments, the compound of Formula (III) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of Formula (III) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is -NH ₂ . In some embodiments, the compound of Formula (III) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is -NHCH ₃ . In some embodiments, the compound of Formula (III) wherein R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (III ⁾ is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound of formula (III ⁾ is -CH( _CH3 ) ₂ . In some embodiments, the compound of formula (III) is -CH( _CH2CH3 )CH( _R3 ) _CH3 ^. In some embodiments, the compound of formula ( ^III ) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of formula ( _III ) is ^-CH ( ^CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of formula (III) is ^-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and _R3 ^is methyl. In some embodiments, the compound of Formula (III) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is ethyl. In some embodiments, the compound of Formula (III) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NR ¹³ R ¹⁴ . In some embodiments, the compound of Formula (III) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NH ₂ . In some embodiments, the compound of Formula (III) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NHCH ₃ . In some embodiments, the compound of formula (III) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (III) wherein R ¹ is -alkylene(cycloalkyl). In some embodiments, the compound of formula (III) wherein R ¹ is -CH ₂ CH ₂ (cycloalkyl). In some embodiments, the compound of formula (III) wherein R ¹ is -CH ₂ (cycloalkyl). In some embodiments, the compound of formula (III) wherein R ¹ is -CH ₂ (cyclobutyl). In some embodiments, the compound of formula (III) wherein R ¹ is -CH ₂ (cyclopentyl). In some embodiments, the compound of formula (III) wherein R ¹ is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula (III) wherein R ¹ is

In some embodiments described above or below is a compound of Formula (III) wherein n is 0.

In some embodiments described above or below is a compound of Formula (III) wherein n is 1. In some embodiments described above or below is a compound of Formula (III) wherein n is 1 and ^R8 is selected from halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , -NR13SO2R14 ^{, -NR13C (} O ₎ ^R14 , ^-NR13C (O ⁾ _OR14 , ^-NR13C (O ^{) NR13R14 , -C} (O ^{) R14 ,} -C(O)OR In some embodiments described ^above or below, ^the compound is of formula (III), wherein n is 1 and ^R is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments described above or below, the compound ^is of formula (III), wherein n is 1 and ^R is halogen. In some embodiments described above or below, the compound is of formula (III), wherein n is 1 and R is F. In some embodiments described above or below, the compound is of formula (III), wherein n is 1 and R is ^Cl . In some embodiments described above or below, the compound is of formula (III), wherein n is ¹ and ^R is -CN. In some embodiments described above or below, the compound is of formula (III), wherein n is 1 and ^R is alkyl. In some embodiments described above or below, the compound is of formula (III), wherein n is 1 and ^R is methyl. In some embodiments described above or below, the compound is of formula (III), wherein n is 1 and R is ^ethyl . In some embodiments described above or below, the compound of formula (III) wherein n is 1 and R ⁸ is alkoxy. In some embodiments described above or below, the compound of formula (III) wherein n is 1 and R ⁸ is methoxy. In some embodiments described above or below, the compound of formula (III) wherein n is 1 and R ⁸ is ethoxy. In some embodiments described above or below, the compound of formula (III) wherein n is 1 and R ⁸ is haloalkoxy. In some embodiments described above or below, the compound of formula (III) wherein n is 1 and R ⁸ is -OCF ₃ . In some embodiments described above or below, the compound of formula (III) wherein n is 1 and R ⁸ is haloalkyl. In some embodiments described above or below, the compound of formula (III) wherein n is 1 and R ⁸ is -CF ₃ .

In some embodiments described above or below is a compound of Formula (III) wherein n is 2. In some embodiments described above or below is a compound of Formula (III) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl ^, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, -NR13R14, ^-NR13SO2R14 , ^-NR13C (O ₎ ^R14 , ^-NR13C (O ^{) OR14} , ^-NR13C (O ₎ ^{NR13R14 , -C} (O) ^R14 , ^{-C (} O)OR In some embodiments described ^above or below, the compound is ^of formula (III), wherein n is 2 and R ^{8 is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments described above or below, the compound is of formula (III), wherein n is 2 and R 8 is} halogen. In some embodiments described above or below, the compound is of formula (III), wherein n is 2 and each R ⁸ is F. In some embodiments described above or below, the compound is of formula (III), wherein n is 2 and each R ⁸ is Cl. In some embodiments described above or below, the compound is of formula (III), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (III), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (III), wherein n is 2 and R ⁸ is independently selected from halogen and alkyl. In some embodiments described above or below, the compound is of formula (III), wherein n is 2 and R ⁸ is independently selected from -CN and alkyl. In some embodiments described above or below is a compound of Formula (III) wherein n is 2 and two adjacent R ⁸ form a heterocyclyl ring.

In some embodiments described above or below is a compound of Formula (III), wherein each R ⁵ is independently selected from -CH ₂ NH ₂ , -CF ₃ , and -SO ₂ Me. In some embodiments described above or below is a compound of Formula (III), wherein p is 1 and R ⁵ is selected from -CH ₂ NH ₂ , -CF ₃ , and -SO ₂ Me. In some embodiments described above or below is a compound of Formula (III), wherein q is 0. In some embodiments described above or below is a compound of Formula (III), wherein t is 0. In some embodiments described above or below is a compound of Formula (III), wherein q is 0, t is 0, p is 1, and R ⁵ is selected from -CH ₂ NH ₂ , -CF ₃ , and -SO ₂ Me.

In some embodiments described above or below is a compound of Formula (III), wherein q is 1. In some embodiments described above or below is a compound of Formula (III), wherein q is 1 and ^R is alkyl. In some embodiments described above or below is a compound of Formula (III), wherein q is 1, t is ⁰ , and R is alkyl. In some embodiments described above or below is a compound of Formula (III), wherein q is 1, t is 0, and ^R is alkyl.

In some embodiments described above or below is a compound of Formula (III), wherein t is 1. In some embodiments described above or below is a compound of Formula (III), wherein t is 1 and R is ^halogen . In some embodiments described above or below is a compound of Formula (III), wherein t is 1, q is 0, ^and R is alkyl. In some embodiments described above or below is a compound of Formula (III), wherein t is 1, q is 0, p is 0, and R ^is halogen.

In another embodiment is a compound of formula (III) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (IIIa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

each R ⁵ is independently selected from haloalkyl, -alkylene(NR ¹³ R ¹⁴ ), -NR ¹³ R ¹⁴ and -SO ₂ R ¹³ ;

Each R ⁶ is independently selected from halogen, alkyl and haloalkyl;

Each R ⁷ is independently selected from halogen, alkyl, haloalkyl and -CN;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

n is selected from 0, 1, 2, 3 and 4;

p is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3, and 4; and

t is selected from 0, 1, 2, 3 and 4;

At least one of p, q or t is not zero.

In some embodiments, ^the compound of Formula (Ilia) is R1, wherein ^R1 is -CH( _CH3 ) _{CH2CH2R2 .} In some embodiments, the compound of Formula (Ilia) is R1, wherein ^R1 is _-CH ( _CH3 ⁾ _CH2CH2R2 , and ^R2 is H. In some embodiments, the compound of Formula (Ilia) is ^R1 , wherein ^R1 is -CH( _CH3 ) _CH2CH2R2 , and ^R2 is alkyl. In some embodiments, the compound of Formula (Ilia) is R1, wherein ^R1 is -CH( _{CH3 ) CH2CH2R2} , ^and _R2 is ^methyl . In some embodiments, the compound of Formula (Ilia) is R1, wherein ^R1 is -CH( _CH3 ) _CH2CH2R2 , and ^{R2 is} _ethyl . In some embodiments, the ^compound of Formula (IIIa) is -CH( _CH3 ) _CH2CH2R2 , and _R2 is ^isopropyl . In some embodiments, the compound of Formula (IIIa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^{R2 is -NR13R14 .} In some embodiments, the compound of Formula (IIIa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^{R2 is} _-NH2 . In some embodiments, the compound of Formula ⁽ _IIIa ) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^{R2 is} _-NHCH3 . In some embodiments, the compound of Formula (IIIa) is ^-CH ( _{CH3 ) CH2CH2R2} , and _R2 ^is _-N ( ^CH3 ₎ ² _.

In some embodiments, the ^compound of Formula (IIIa) is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound ^of Formula (IIIa) is -CH( _CH3 ) ₂ . In some embodiments, _the compound of Formula (IIIa) is -CH( _CH2CH3 )CH( _R3 ) ^CH3 . In some embodiments, the compound of Formula ( ^IIIa ) is ^-CH ( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula ( ^IIIa ) is -CH( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is alkyl. In some embodiments, the compound of _Formula ( ^IIIa ) is ^-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments ^, the compound of Formula (Ilia) is ^R1 , wherein -CH( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is ethyl. In some embodiments, the compound of Formula (Ilia) is ^R1 , wherein -CH( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^{R3 is -NR13R14} . In some embodiments, the compound of Formula (Ilia) is ^R1 , wherein -CH( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is _-NH2 . In some embodiments, the compound of Formula (Ilia) is ^R1 , wherein -CH ^{(CH2CH3)CH(R3} ₎ ^CH3 _{, and} ^R3 is _-NHCH3 . In some embodiments, the compound of formula (IIIa) is R ^{1, wherein R 1} is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (IIIa) is R 1, wherein R ¹ is -alkylene(cycloalkyl). In some embodiments, the compound of formula (IIIa) is R 1, wherein R ¹ is -CH ₂ CH ₂ (cycloalkyl). In some embodiments, the compound of formula (IIIa) is R 1, wherein R ¹ is -CH ₂ (cycloalkyl). In some embodiments, the compound of formula (IIIa) is R 1, wherein R ¹ is -CH ₂ (cyclobutyl). In some embodiments, the compound of formula (IIIa) is R 1, wherein R ¹ is -CH ₂ (cyclopentyl). In some embodiments, the compound of formula (IIIa) is R 1, wherein R ¹ is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula (IIIa) is R ¹ , wherein R 1 is -CH 2 (cyclohexyl).

In some embodiments described above or below is a compound of Formula (IIIa) wherein n is 0.

In some embodiments described above or below is a compound of Formula (IIIa) wherein n is 1. In some embodiments described above or below is a compound of Formula (IIIa) wherein n is 1 and ^R8 is selected from halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , -NR13SO2R14 ^{, -NR13C (} O ₎ ^R14 , ^-NR13C (O ⁾ _OR14 , ^-NR13C (O ^{) NR13R14 , -C} (O ^{) R14 ,} -C(O)OR In some embodiments described ^above or below, ^the compound is of formula (IIIa), wherein n is 1 and ^R is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments described above or below, the compound ^is of formula (IIIa), wherein n is 1 and ^R is halogen. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 and R is F. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 and R is ^Cl . In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 ^{and R} is -CN. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 and ^R is alkyl. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 and ^R is methyl. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 and R ⁸ is ethyl. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 and R ⁸ is alkoxy. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 and R ⁸ is methoxy. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 and R ⁸ is ethoxy. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 and R ⁸ is haloalkoxy. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 and R ⁸ is -OCF ₃ . In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 and R ⁸ is haloalkyl. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 1 and R ⁸ is -CF ₃ .

In some embodiments described above or below is a compound of Formula (IIIa) wherein n is 2. In some embodiments described above or below is a compound of Formula (IIIa) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl ^, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, -NR13R14, ^-NR13SO2R14 , ^-NR13C (O ₎ ^R14 , ^-NR13C (O ^{) OR14} , ^-NR13C (O ₎ ^{NR13R14 , -C} (O) ^R14 , ^{-C (} O)OR In some embodiments described ^above or below, the compound is ^of formula (IIIa), wherein n is 2 and R ^{8 is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 2 and R 8 is} halogen. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 2 and each R ⁸ is F. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 2 and each R ⁸ is Cl. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 2 and R ⁸ is independently selected from halogen and alkyl. In some embodiments described above or below, the compound is of formula (IIIa), wherein n is 2 and R ⁸ is independently selected from -CN and alkyl. In some embodiments described above or below is a compound of Formula (IIIa) wherein n is 2 and two adjacent R ⁸ form a heterocyclyl ring.

In some embodiments described above or below is a compound of Formula (IIIa), wherein each R ⁵ is independently selected from -CH ₂ NH ₂ , -CF ₃ , and -SO ₂ Me. In some embodiments described above or below is a compound of Formula (IIIa), wherein p is 1 and R ⁵ is selected from -CH ₂ NH ₂ , -CF ₃ , and -SO ₂ Me. In some embodiments described above or below is a compound of Formula (IIIa), wherein q is 0. In some embodiments described above or below is a compound of Formula (IIIa), wherein t is 0. In some embodiments described above or below is a compound of Formula (IIIa), wherein q is 0, t is 0, p is 1, and R ⁵ is selected from -CH ₂ NH ₂ , -CF ₃ , and -SO ₂ Me.

In some embodiments described above or below is a compound of Formula (IIIa), wherein q is 1. In some embodiments described above or below is a compound of Formula (IIIa), wherein q is 1 and ^R is alkyl. In some embodiments described above or below is a compound of Formula (IIIa), wherein q is 1, t is ⁰ , and R is alkyl. In some embodiments described above or below is a compound of Formula (IIIa), wherein q is 1, t is 0, and ^R is alkyl.

In some embodiments described above or below is a compound of Formula (IIIa), wherein t is 1. In some embodiments described above or below is a compound of Formula (IIIa), wherein t is 1 and R is ^halogen . In some embodiments described above or below is a compound of Formula (IIIa), wherein t is 1, q is 0, ^and R is alkyl. In some embodiments described above or below is a compound of Formula (IIIa), wherein t is 1, q is 0, p is 0, and ^R is halogen.

In another aspect, provided herein is a compound of formula (IV) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

^R4 is halogen, alkyl,

R ⁵ and R ⁶ are independently selected from H, alkyl, halo and haloalkyl;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

^R and ^R are independently selected from H, halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl ^{, heterocyclyl} , aryl, ^heteroaryl , ^-SR13 , -SOR13, -SO2R13, -SO2NR13R14, _-NR13R14 , -NR13SO2R14, ^-NR13C (O ₎ ^{R14 , -NR13C} (O ^{) OR14} , ^{-NR13C (} O ⁾ _NR13R14 , ^{-C(O)R14 , -C (} O ^{) OR14} , and -C(O) ^{NR13R 14} , wherein at least one of R ²⁰ and R ²² is not F or Cl;

each R ²¹ is independently selected from H, halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO 2 R 13 , -SO ₂ NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO 2 R ¹⁴ , -NR ¹³ _C (O)R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ^{14 ;} and

^R23 is H.

In some embodiments, the compound of formula (IV) is selected from ^the group consisting of H, halogen, -CN, ^alkyl , alkoxy, haloalkoxy, haloalkyl, _-SO2R13 , ^{-SO2NR13R14 , and} -C( _O ) ^NR13R14 ; wherein at least one ^{of R20} and ^R22 is not F or Cl. In some embodiments, the compound of formula (IV) is selected from the group consisting of H and halogen; wherein at least one ^{of R20 and R22} is not F or Cl. In some embodiments, the compound of formula (IV) is selected from the group consisting of H and -CN. In some embodiments, the compound ^of formula (IV) is selected from ^the group consisting of H and ^alkyl . In some embodiments, the compound ^of formula ( ^IV ) is selected from the group consisting of H and ^alkoxy . In some embodiments, the compound of formula (IV) is R ²⁰ and R ²² are independently selected from H and haloalkoxy. In some embodiments, the compound of formula (IV) is R ²⁰ and R ²² are independently selected from H and haloalkyl. In some embodiments, the compound of formula (IV) is R ²⁰ and R ²² are independently selected from H and -SO ₂ R ¹³ . In some embodiments, the compound of formula (IV) is R ²⁰ and R ²² are independently selected from H and -SO ₂ NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IV) is R ²⁰ and R ²² are independently selected from H and -C(O)NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IV) is R ²⁰ and R ²² are independently selected from -CN and alkyl. In some embodiments is a compound of Formula (IV), wherein R ²⁰ and R ²² are independently selected from H, Cl, -CN, -CH ₃ , -OCH ₃ , and -CF ₃ ; wherein at least one of R ²⁰ and R ²² is not Cl.

In some embodiments is a compound of Formula (IV) wherein R ²⁰ and R ²² are each H.

In some embodiments, the compound ^of formula (IV) is independently selected from H, halogen, -CN, alkyl, alkoxy, and haloalkyl. In some embodiments, the compound of formula (IV ⁾ is independently selected from H and -CN. In some embodiments, the compound of formula ( ^IV ) is independently selected from H and alkyl. In some embodiments, the compound of formula ( ^IV ) is independently selected from H and alkoxy. In some embodiments, the compound of formula ( ^IV ) is independently selected from H and haloalkoxy. In some embodiments, the compound of formula (IV) is independently selected from H and haloalkyl. In some embodiments, the compound of formula (IV ⁾ is independently selected from H and -SO ₂ R ¹³ . In some embodiments, the compound of formula (IV ⁾ is independently selected from H and -SO ₂ NR ^{13 R 14 .} In some embodiments, the compound of formula (IV ⁾ is independently selected from H and -C(O)NR ¹³ R ^14. In some embodiments, the compound of formula (IV) is independently selected from -CN and alkyl. In some embodiments, the compound of formula (IV) is independently selected from H, Cl ^, -CN, -CH ₃ , -OCH ₃ and -CF ^3. In some embodiments, the compound of formula (IV) is independently selected from H, Cl, -CN and -CH _3. In some embodiments, the compound ^of formula (IV) is independently selected from H. In some embodiments, the compound of formula (IV) _is independently ^selected from H. In some embodiments, the compound of formula (IV) is ^Cl .

In some embodiments, the compound of formula (IV) is ^halogen . In some embodiments, the compound of formula (IV) is F. In some embodiments, the compound of formula (IV) is ^Cl . In some embodiments, the compound of formula ( ^IV ) is alkyl. In some embodiments, the compound of formula (IV) is methyl. In some embodiments, the compound of formula (IV) is ethyl. In some embodiments, the compound of formula ( ^{IV) is R 4. In} some embodiments, the compound of formula (IV) is R ^4. In some embodiments, the compound of formula (IV) is R ^4. In some embodiments, the compound of formula (IV) is R 4. In some embodiments, the compound of formula (IV) is R ^4. In some embodiments, the compound of formula (IV) is R ^4. In some embodiments, the compound of formula (IV) is R 4. In some embodiments, the compound of formula (IV) is R ^4. In some embodiments, the compound of formula (IV) is R ^4. In some embodiments, the compound of formula (IV) is R ^4. In some embodiments, the compound of formula (IV) is R 4. In some embodiments, the compound of formula (IV) is R ^4. In some embodiments, the compound of formula (IV) is R ^4. In some embodiments, the compound of formula (IV) is R ^4. In some embodiments, the compound of formula (IV) is R ⁴ .

In some embodiments, the compound of formula (IV) wherein R ¹ is In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is -NR ¹³ R ^14. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is -NH _2. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is -NHCH _3. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (IV) wherein R ¹ is In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is -NR ¹³ R ^14. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is -NH _2. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is -NHCH _3. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (IV) wherein R ¹ is In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is -NR ¹³ R ^14. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is -NH _2. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is -NHCH _3. In some embodiments, the compound of formula (IV) wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (IV ⁾ is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound of formula (IV ⁾ is -CH( _CH3 ) ₂ . In some embodiments, the compound of formula (IV) is -CH( _CH2CH3 )CH( _R3 ) _CH3 ^. In some embodiments, the compound of formula ( ^IV ) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of formula (IV) is ^-CH ( _CH2CH3 )CH ^(R3 _{) CH3} ^, and ^R3 is alkyl. In some embodiments, the compound of formula (IV) is ^-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and _R3 ^is methyl. In some embodiments, the compound of Formula (IV) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is ethyl. In some embodiments, the compound of Formula (IV) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NR ¹³ R ¹⁴ . In some embodiments, the compound of Formula (IV) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NH ₂ . In some embodiments, the compound of Formula (IV) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NHCH ₃ . In some embodiments, the compound of formula (IV) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (IV) wherein R ¹ is -alkylene(cycloalkyl). In some embodiments, the compound of formula (IV) wherein R ¹ is -CH ₂ CH ₂ (cycloalkyl). In some embodiments, the compound of formula (IV) wherein R ¹ is -CH ₂ (cycloalkyl). In some embodiments, the compound of formula (IV) wherein R ¹ is -CH ₂ (cyclobutyl). In some embodiments, the compound of formula (IV) wherein R ¹ is -CH ₂ (cyclopentyl). In some embodiments, the compound of formula (IV) wherein R ¹ is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula (IV) wherein R ¹ is

In another embodiment is a compound of formula (IV) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (IVa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

^R4 is halogen, alkyl,

R ⁵ and R ⁶ are independently selected from H, alkyl, halo and haloalkyl;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

^R and ^R are independently selected from H, halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl ^{, heterocyclyl} , aryl, ^heteroaryl , ^-SR13 , -SOR13, -SO2R13, -SO2NR13R14, _-NR13R14 , -NR13SO2R14, ^-NR13C (O ₎ ^{R14 , -NR13C} (O ^{) OR14} , ^{-NR13C (} O ⁾ _NR13R14 , ^{-C(O)R14 , -C (} O ^{) OR14} , and -C(O) ^{NR13R 14} , wherein at least one of R ²⁰ and R ²² is not F or Cl;

each R ²¹ is independently selected from H, halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO 2 R 13 , -SO ₂ NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO 2 R ¹⁴ , -NR ¹³ _C (O)R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ^{14 ;} and

^R23 is H.

In some embodiments, the compound of formula (IVa) is wherein R ²⁰ and R ²² are independently selected from H, halogen, -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, -SO ₂ R ¹³ , -SO ₂ NR ¹³ R ¹⁴ and -C(O)NR ¹³ R ¹⁴ ; wherein at least one of R ²⁰ and R ²² is not F or Cl. In some embodiments, the compound of formula (IVa) is wherein R ²⁰ and R ²² are independently selected from H and halogen; wherein at least one of R ²⁰ and R ²² is not F or Cl. In some embodiments, the compound of formula (IVa) is wherein R ²⁰ and R ²² are independently selected from H and -CN. In some embodiments, the compound of formula (IVa) is wherein R ²⁰ and R ²² are independently selected from H and alkyl. In some embodiments, the compound of formula (IVa) is wherein R ²⁰ and R ²² are independently selected from H and alkoxy. In some embodiments, the compound of formula (IVa) is wherein R ²⁰ and R ²² are independently selected from H and haloalkoxy. In some embodiments, the compound of formula (IVa) is wherein R ²⁰ and R ²² are independently selected from H and haloalkyl. In some embodiments, the compound of formula (IVa) is wherein R ²⁰ and R ²² are independently selected from H and -SO ₂ R ¹³ . In some embodiments, the compound of formula (IVa) is wherein R ²⁰ and R ²² are independently selected from H and -SO ₂ NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IVa) is wherein R ²⁰ and R ²² are independently selected from H and -C(O)NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IVa) is wherein R ²⁰ and R ²² are independently selected from -CN and alkyl. In some embodiments is a compound of Formula (IVa), wherein R ²⁰ and R ²² are independently selected from H, Cl, —CN, —CH ₃ , —OCH ₃ , and —CF ₃ ; wherein at least one of R ²⁰ and R ²² is not Cl.

In some embodiments is a compound of Formula (IVa) wherein R ²⁰ and R ²² are each H.

In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is independently selected from H, halogen, -CN, alkyl, alkoxy, and haloalkyl. In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is independently selected from H and -CN. In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is independently selected from H and alkyl. In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is independently selected from H and alkoxy. In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is independently selected from H and haloalkoxy. In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is independently selected from H and haloalkyl. In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is independently selected from H and -SO ₂ R ¹³ . In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is independently selected from H and -SO ₂ NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is independently selected from H and -C(O)NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is independently selected from -CN and alkyl. In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is independently selected from H, Cl, -CN, -CH ₃ , -OCH ₃ and -CF ₃ . In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is independently selected from H, Cl, -CN and -CH ₃ . In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is H. In some embodiments, the compound of formula (IVa) is wherein each R ²¹ is Cl.

In some embodiments, the compound of formula (IVa) is wherein R ⁴ is halogen. In some embodiments, the compound of formula (IVa) is wherein R ⁴ is F. In some embodiments, the compound of formula (IVa) is wherein R ⁴ is Cl. In some embodiments, the compound of formula (IVa) is wherein R ⁴ is alkyl. In some embodiments, the compound of formula (IVa) is wherein R ⁴ is methyl. In some embodiments, the compound of formula (IVa) is wherein R ⁴ is ethyl. In some embodiments, the compound of formula (IVa) wherein R ⁴ is In some embodiments, the compound of formula (IVa) wherein R ⁴ is In some embodiments, the compound of formula (IVa) wherein R ⁴ is In some embodiments, the compound of formula (IVa) wherein R 4 is In some embodiments, the compound of formula (IVa) wherein R ⁴ is In some embodiments, the compound of formula (IVa) wherein R ⁴ is In some embodiments, the compound of formula (IVa) wherein R ⁴ is In some embodiments, the compound of formula (IVa) wherein R ⁴ is In some embodiments, the compound of formula (IVa) wherein R 4 is In some embodiments, the compound of formula (IVa) wherein R ⁴ is In some embodiments, the compound of formula (IVa) wherein R ⁴ is In some embodiments, the compound of formula (IVa) wherein R ⁴ is

In some embodiments, the compound of formula (IVa) is wherein R ¹ is In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is -NR ¹³ R ^14. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is -NH _2. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (IVa) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (IVa) is wherein R ¹ is In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is -NR ¹³ R ^14. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is -NH _2. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (IVa) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (IVa) is wherein R ¹ is In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is -NR ¹³ R ^14. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is -NH _2. In some embodiments, the compound of formula (IVa) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (IVa) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of Formula (IVa ⁾ is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound of Formula ( ^IVa ) is -CH( _CH3 ) ₂ . In some embodiments, _the compound of Formula (IVa) is -CH( _CH2CH3 )CH( _R3 ) ^CH3 . In some embodiments, the compound of Formula ( ^IVa ) is ^-CH ( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula ( ^IVa ) is -CH( _CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of _Formula (IVa) is ^-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (IVa) is ^-CH ( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^R3 is ethyl. In some embodiments, the compound of Formula (IVa) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^{R3 is -NR13R14} . In some embodiments, the compound of Formula ( ^IVa ) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is _-NH2 . In some embodiments, ^{the compound of Formula (IVa) is -CH(CH2CH3)CH(R3 )} _{CH3 , and} ^{R3 is} _-NHCH3 . In some embodiments, the compound of formula (IVa) is R ^{1, wherein R 1} is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (IVa) is R 1, wherein R ¹ is -alkylene(cycloalkyl). In some embodiments, the compound of formula (IVa) is R 1, wherein R ¹ is -CH ₂ CH ₂ (cycloalkyl). In some embodiments, the compound of formula (IVa) is R 1, wherein R ¹ is -CH ₂ (cycloalkyl). In some embodiments, the compound of formula (IVa) is R 1, wherein R ¹ is -CH ₂ (cyclobutyl). In some embodiments, the compound of formula (IVa) is R 1, wherein R ¹ is -CH ₂ (cyclopentyl). In some embodiments, the compound of formula (IVa) is R 1, wherein R ¹ is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula (IVa) is R ¹ , wherein R 1 is -CH 2 (cyclohexyl).

In another embodiment is a compound of Formula (IVa) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (IVb) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

^R4 is halogen, alkyl,

R ⁵ and R ⁶ are independently selected from H, alkyl, halo and haloalkyl;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

^R and ^R are independently selected from H, halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl ^{, heterocyclyl} , aryl, ^heteroaryl , ^-SR13 , -SOR13, -SO2R13, -SO2NR13R14, _-NR13R14 , -NR13SO2R14, ^-NR13C (O ₎ ^{R14 , -NR13C} (O ^{) OR14} , ^{-NR13C (} O ⁾ _NR13R14 , ^{-C(O)R14 , -C (} O ^{) OR14} , and -C(O) ^{NR13R 14} , wherein at least one of R ²⁰ and R ²² is not F or Cl;

each R ²¹ is independently selected from H, halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO 2 R 13 , -SO ₂ NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO 2 R ¹⁴ , -NR ¹³ _C (O)R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ^{14 ;} and

^R23 is H.

In some embodiments, the compound of formula (IVb) is selected from H, halogen, -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, _-SO2R13 , ^{-SO2NR13R14 , and} -C( _O ^{) NR13R14} ; wherein at least one ^{of R20 and R22} is not F or Cl. In some embodiments, the compound of formula (IVb) is selected ^from H and halogen; wherein at least one of ^R20 and ^R22 is not F or Cl. In some embodiments, the compound of formula ( ^IVb ) is selected from H and ^-CN . In some embodiments, the compound of formula ( ^IVb ) is selected from H and ^alkyl . In some embodiments, the compound of formula ( ^{IVb )} is selected from H and ^alkoxy . In some embodiments, the compound of formula (IVb) is wherein R ²⁰ and R ²² are independently selected from H and haloalkoxy. In some embodiments, the compound of formula (IVb) is wherein R ²⁰ and R ²² are independently selected from H and haloalkyl. In some embodiments, the compound of formula (IVb) is wherein R ²⁰ and R ²² are independently selected from H and -SO ₂ R ¹³ . In some embodiments, the compound of formula (IVb) is wherein R ²⁰ and R ²² are independently selected from H and -SO ₂ NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IVb) is wherein R ²⁰ and R ²² are independently selected from H and -C(O)NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IVb) is wherein R ²⁰ and R ²² are independently selected from -CN and alkyl. In some embodiments is a compound of Formula (IVb) wherein R ²⁰ and R ²² are independently selected from H, Cl, —CN, —CH ₃ , —OCH ₃ , and —CF ₃ ; wherein at least one of R ²⁰ and R ²² is not Cl.

In some embodiments is a compound of Formula (IVb) wherein R ²⁰ and R ²² are each H.

In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is independently selected from H, halogen, -CN, alkyl, alkoxy, and haloalkyl. In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is independently selected from H and -CN. In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is independently selected from H and alkyl. In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is independently selected from H and alkoxy. In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is independently selected from H and haloalkoxy. In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is independently selected from H and haloalkyl. In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is independently selected from H and -SO ₂ R ¹³ . In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is independently selected from H and -SO ₂ NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is independently selected from H and -C(O)NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is independently selected from -CN and alkyl. In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is independently selected from H, Cl, -CN, -CH ₃ , -OCH ₃ and -CF ₃ . In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is independently selected from H, Cl, -CN and -CH ₃ . In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is H. In some embodiments, the compound of formula (IVb) is wherein each R ²¹ is Cl.

In some embodiments, the compound of formula (IVb) is wherein ^R is halogen. In some embodiments, the compound of formula (IVb) is wherein R is ^F. In some embodiments, the compound of formula (IVb) is wherein R is ^Cl . In some embodiments, the compound of formula (IVb) is wherein ^R is alkyl. In some embodiments, the compound of formula (IVb) is wherein ^R is methyl. In some embodiments, the compound of formula (IVb) is wherein R is ^ethyl . In some embodiments, the compound of formula (IVb) wherein R ⁴ is In some embodiments, the compound of formula (IVb) wherein R ⁴ is In some embodiments, the compound of formula (IVb) wherein R ⁴ is In some embodiments, the compound of formula (IVb) wherein R 4 is In some embodiments, the compound of formula (IVb) wherein R ⁴ is In some embodiments, the compound of formula (IVb) wherein R ⁴ is In some embodiments, the compound of formula (IVb) wherein R ⁴ is In some embodiments, the compound of formula (IVb) wherein R ⁴ is In some embodiments, the compound of formula (IVb) wherein R 4 is In some embodiments, the compound of formula (IVb) wherein R ⁴ is In some embodiments, the compound of formula (IVb) wherein R ⁴ is In some embodiments, the compound of formula (IVb) wherein R ⁴ is

In some embodiments, the compound of formula (IVb) is wherein R ¹ is In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (IVb) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (IVb) is wherein R ¹ is In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (IVb) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (IVb) is wherein R ¹ is In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (IVb) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (IVb) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of Formula (IVb) is ^R1 , wherein -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound of Formula (IVb) is ^R1 , wherein -CH( _CH3 ) ₂ . In some embodiments, the compound of Formula (IVb) is ^R1 , wherein -CH( _CH2CH3 )CH( _R3 ) _CH3 ^. In some embodiments, the compound of Formula (IVb) is ^R1 , wherein -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula (IVb) is ^R1 , wherein -CH( _{CH2CH3 )} CH( _R3 ⁾ _CH3 , and ^R3 is alkyl. In some embodiments, the compound of Formula (IVb) is ^R1 , wherein _-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (IVb) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is ethyl. In _some embodiments, the compound of Formula ( _IVb ) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^{R3 is -NR13R14} . In some embodiments, the compound of Formula (IVb) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is _-NH2 . _In some embodiments, the compound of Formula (IVb) is R1, ^{wherein R1} is -CH( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is _-NHCH3 . In some embodiments, the compound ^of formula (IVb) is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (IVb) is -alkylene(cycloalkyl). In some embodiments, the compound ^of formula (IVb) is -CH ² CH ₂ (cycloalkyl) _. In some embodiments, the compound of formula (IVb) is -CH ² (cycloalkyl). In some embodiments, the compound ^of formula (IVb) is -CH ₂ (cyclobutyl). In some embodiments, the compound of formula (IVb) is -CH ₂ (cyclopentyl). In some embodiments, ^the compound ^of formula (IVb) is _{-CH 2 (} cyclohexyl). In some embodiments, the compound of formula (IVb) is -CH ² (cyclohexyl).

In another embodiment is a compound of Formula (IVb) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (V) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH(R ³ )CH ₃ , -CH(CH ₃ )C(O)CH ₃ , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ¹⁰ is H or alkyl;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

R ²⁰ is selected from H, Cl, Br, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO 2 R 13 , -SO ₂ NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O) _R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ and -C(O)NR ^{13 R 14 ;}

R ²¹ , R ²² and R ²³ are independently selected from H, halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ^{13 , -SO 2 R 13} , -SO ₂ NR ¹³ R 14 , -NR ¹³ R 14 , -NR _{13 SO} ² R ¹⁴ , -NR ¹³ C(O) ^{R 14} , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O ⁾ NR ¹³ R ¹⁴ , -C(O) ^{R 14 , -C(O)OR 14 and -C} (O)NR ¹³ R ¹⁴ ; and

^R24 is H.

In some embodiments, the compound is represented by Formula (V), wherein R ¹⁰ is H. In some embodiments, the compound is represented by Formula (V), wherein R ¹⁰ is alkyl. In some embodiments, the compound is represented by Formula (V), wherein R ¹⁰ is methyl. In some embodiments, the compound is represented by Formula (V), wherein R ¹⁰ is ethyl.

In some embodiments, the compound of formula (V) is selected from the group consisting of H, halogen, -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, -SO ₂ R ¹³ , -SO ₂ NR ^{13 R 14} and -C(O)NR ¹³ R ^14. In some embodiments, the compound of formula (V) is selected from the group consisting of H, ^halogen , -CN, ^{alkyl, alkoxy and haloalkyl} . In some embodiments, the compound of formula (V) is selected from the group consisting of H, halogen, -CN, alkyl, alkoxy and haloalkyl. In some embodiments, the compound ^of formula (V) is selected from the group consisting of H and halogen. In some embodiments, the compound of formula (V) is selected from the group consisting of ^H , ^{R 21} , R ²² and R ²³ are independently selected from the group consisting of H and -CN. In some embodiments, the compound of formula (V) is selected from the group consisting of H, R ²¹ , R ²² and R ²³ are independently selected from the ^group consisting of H and alkyl. ^In some embodiments, the compound of formula (V) is selected from H and ^alkoxy . ^In some embodiments, the compound ^of formula (V) is selected from H ^and haloalkoxy. ^In some embodiments, the compound of formula (V) is selected from H and haloalkyl. In some embodiments, the compound ^of formula (V) is selected from H and haloalkyl. ^In some embodiments, ^the compound ^of formula ( ^V ) is selected ^{from H} _{and -SO2R13} ^. In some embodiments, the compound of formula ( ^V ) is selected from ^H and _-SO2NR13R14 . ^{In some} embodiments, the compound ^of formula ( ^V ) is selected ^from H and -C(O ^{) NR13R14} . In some embodiments, the compound is represented by Formula (V), wherein R ²¹ , R ²² , and R ²³ are independently selected from —CN and alkyl. In some embodiments, the compound is represented by Formula (V), wherein R ²¹ , R ²² , and R ²³ are independently selected from H, Cl, —CN, —CH ₃ , —OCH ₃ , and —CF ₃ .

In some embodiments is a compound of Formula (V) wherein R ²¹ , R ²² , and R ²³ are each H.

In some embodiments, the compound of formula (V) is selected from H, ^halogen , -CN, alkyl, alkoxy, and haloalkyl. In some embodiments, the compound ^of formula (V) is selected from H and -CN. In some embodiments, the compound ^of formula (V) is selected from H and alkyl. In some embodiments, the compound ^of formula (V) is selected from H and alkoxy. In some embodiments, the compound of formula ( ^V ) is selected from H and haloalkoxy. In some embodiments, the compound of formula ( ^V ) is selected from H and haloalkyl. In some embodiments, the compound of formula ( ^V ) is selected from ^H and _-SO2R13 . In some embodiments, the compound of formula (V ⁾ is ^selected from H _{and -SO2NR13R14} ^. In some embodiments, the compound of formula (V) is selected from -CN and ^alkyl . In some embodiments, the compound ^of formula (V) is selected from H, Cl, -CN, -CH ₃ , -OCH ₃ and -CF ₃ . In some embodiments, the compound ^of formula (V) is selected from H, Cl, -CN and -CH _{3 . In some embodiments, the compound of formula (V) is selected from H, Cl, -CN and -CH 3} . In some embodiments, the compound ^of formula (V) is H. In some embodiments, the compound of formula (V ⁾ is Cl.

In some embodiments, the compound of formula (V) is wherein R ¹ is In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (V) is wherein R ¹ is In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (V) is wherein R ¹ is In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments, the compound of formula (V) is wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of Formula (V ⁾ is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound ^of Formula (V) is -CH( _CH3 ) ₂ . In some embodiments, _the compound of Formula (V) is ^-CH ( _CH2CH3 )CH( _R3 ) ^CH3 . In some embodiments, the compound of Formula (V) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula (V) is ^-CH ( ^CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of _Formula (V) is ^-CH ( _CH2CH3 ) _CH ( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (V) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is ethyl. In some embodiments, the compound of Formula (V) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NR ¹³ R ¹⁴ . In some embodiments, the compound of Formula (V) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NH ₂ . In some embodiments, the compound of Formula (V) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NHCH ₃ . In some embodiments, the compound ^of formula (V) is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (V) is -alkylene(cycloalkyl). In some embodiments, the compound of formula (V ⁾ is -CH ² _{CH 2} (cycloalkyl). In some embodiments, the compound of formula (V) is -CH ² (cycloalkyl). In some embodiments, the compound of formula (V) is -CH ² (cyclobutyl ₎ . In some embodiments, the compound of formula (V ⁾ is -CH ₂ (cyclopentyl ₎ . In some embodiments, the compound of formula (V ⁾ is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula ( ^V ) is

In another embodiment is a compound of Formula (V) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of Formula (Va) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH(R ³ )CH ₃ , -CH(CH ₃ )C(O)CH ₃ , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ¹⁰ is H or alkyl;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

R ²⁰ is selected from H, Cl, Br, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO 2 R 13 , -SO ₂ NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O) _R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ and -C(O)NR ^{13 R 14 ;}

R ²¹ , R ²² and R ²³ are independently selected from H, halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ^{13 , -SO 2 R 13} , -SO ₂ NR ¹³ R 14 , -NR ¹³ R 14 , -NR _{13 SO} ² R ¹⁴ , -NR ¹³ C(O) ^{R 14} , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O ⁾ NR ¹³ R ¹⁴ , -C(O) ^{R 14 , -C(O)OR 14 and -C} (O)NR ¹³ R ¹⁴ ; and

^R24 is H.

In some embodiments, the compound is represented by formula (Va), wherein R ¹⁰ is H. In some embodiments, the compound is represented by formula (Va), wherein R ¹⁰ is alkyl. In some embodiments, the compound is represented by formula (Va), wherein R ¹⁰ is methyl. In some embodiments, the compound is represented by formula (Va), wherein R ¹⁰ is ethyl.

In some embodiments, the compound of formula (Va) is wherein R ²¹ , R ²² and R ²³ are independently selected from H, halogen, -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, -SO ₂ R ¹³ , -SO ₂ NR ¹³ R ¹⁴ and -C(O)NR ¹³ R ^14. In some embodiments, the compound of formula (Va) is wherein R ²¹ , R ²² and R ²³ are independently selected from H, halogen, -CN, alkyl, alkoxy and haloalkyl. In some embodiments, the compound of formula (Va) is wherein R ²¹ , R ²² and R ²³ are independently selected from H and halogen. In some embodiments, the compound of formula (Va) is wherein R ²¹ , R ²² and R ²³ are independently selected from H and -CN. In some embodiments, the compound of formula (Va) is wherein R ²¹ , R ²² and R ²³ are independently selected from H and alkyl. In some embodiments, the compound of formula (Va) is R ²¹ , R ²² , and R ²³ are independently selected from H and alkoxy. In some embodiments, the compound of formula (Va) is R ²¹ , R ²² , and R ²³ are independently selected from H and haloalkoxy. In some embodiments, the compound of formula (Va) is R ²¹ , R ²² , and R ²³ are independently selected from H and haloalkyl. In some embodiments, the compound of formula (Va) is R ²¹ , R ²² , and R ²³ are independently selected from H and -SO ₂ R ^13. In some embodiments, the compound of formula (Va) is R ²¹ , R ²² , and R ²³ are independently selected from H and -SO ₂ NR ¹³ R ^14. In some embodiments, the compound of formula (Va) is R ²¹ , R ²² , and R ²³ are independently selected from H and -C(O)NR ¹³ R ¹⁴ . In some embodiments is a compound of Formula (Va) wherein R ²¹ , R ²² and R ²³ are independently selected from —CN and alkyl. In some embodiments is a compound of Formula (Va) wherein R ²¹ , R ²² and R ²³ are independently selected from H, Cl, —CN, —CH ₃ , —OCH ₃ and —CF ₃ .

In some embodiments is a compound of Formula (Va) wherein R ²¹ , R ²² , and R ²³ are each H.

In some embodiments, the compound of formula (Va) is selected from H, ^halogen , -CN, alkyl, alkoxy, and haloalkyl. In some embodiments, the compound of formula (Va ⁾ is selected from H and -CN. In some embodiments, the compound ^of formula (Va) is selected from H and alkyl. In some embodiments, the compound ^of formula (Va) is selected from H and alkoxy. In some embodiments, the compound of formula (Va) is selected from H and ^haloalkoxy . In some embodiments, the compound of formula (Va) is selected from H and haloalkyl. In some embodiments, the compound of formula (Va) is selected from H and -SO ² R ¹³ . In some embodiments, the compound of formula (Va ⁾ is selected from H _{and -SO 2 NR} ^{13 R 14 .} In some embodiments, the compound ^of formula (Va) is selected from -CN and alkyl. In some embodiments, the compound of formula (Va) is wherein R ²⁰ is selected from H, Cl, -CN, -CH ₃ , -OCH ₃ and -CF ₃ . In some embodiments, the compound of formula (Va) is wherein R ²⁰ is selected from H, Cl, -CN and -CH ₃ . In some embodiments, the compound of formula (Va) is wherein R ²⁰ is H. In some embodiments, the compound of formula (Va) is wherein R ²⁰ is Cl.

In some embodiments, there is a compound of formula (Va) wherein R ¹ is In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is H. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is alkyl. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is methyl. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is ethyl. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is isopropyl. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (Va) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, there is a compound of formula (Va) wherein R ¹ is In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is H. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is alkyl. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is methyl. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is ethyl. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is isopropyl. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (Va) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, there is a compound of formula (Va) wherein R ¹ is In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is H. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is alkyl. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is methyl. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is ethyl. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is isopropyl. In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, there is a compound of formula (Va) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (Va) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of Formula (Va ⁾ is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound of Formula (Va ⁾ is -CH( _CH3 ) ₂ . In some embodiments, the compound of Formula (Va) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 ^. In some embodiments, the compound of Formula (Va) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula (Va) is ^-CH ( ^CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of _Formula (Va) is ^-CH ( _CH2CH3 ) _CH ( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (Va) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is ethyl. In some embodiments, the compound of Formula (Va) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NR ¹³ R ¹⁴ . In some embodiments, the compound of Formula (Va) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NH ₂ . In some embodiments, the compound of Formula (Va) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NHCH ₃ . In some embodiments, the compound of formula (Va) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (Va) wherein R ¹ is -alkylene(cycloalkyl). In some embodiments, the compound of formula (Va) wherein R ¹ is -CH ₂ CH ₂ (cycloalkyl). In some embodiments, the compound of formula (Va) wherein R ¹ is -CH ₂ (cycloalkyl). In some embodiments, the compound of formula (Va) wherein R ¹ is -CH ₂ (cyclobutyl). In some embodiments, the compound of formula (Va) wherein R ¹ is -CH ₂ (cyclopentyl). In some embodiments, the compound of formula (Va) wherein R ¹ is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula (Va) wherein R ¹ is

In another aspect, provided herein is a compound of formula (VI) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

^R1 is

^R2 is H;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In some embodiments described above or below is a compound of Formula (VI) wherein n is 0.

In some embodiments is a compound of Formula (VI) wherein n is 1. In some embodiments, it is a compound of Formula (VI) wherein n is 1 and ^R8 is selected from halogen, _-OH , -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene(cycloalkyl), -alkylene( ^heterocyclyl ), cycloalkyl, heterocyclyl, ^aryl , heteroaryl, ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , ^-NR13SO2R14 , _-NR13C(O ^{) R14} , ^{-NR13C(O)OR14, -NR13C ( O ) NR13R14} _, ^-C (O) ^{R14 , -C(O)OR14 ,} or ^-C (O ⁾ _NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (VI) wherein n is 1 and R ⁸ is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy or haloalkyl. In some embodiments, the compound of formula (VI) wherein n is 1 and R ⁸ is halogen. In some embodiments, the compound of formula (VI) wherein n is 1 and R ⁸ is F. In some embodiments, the compound of formula (VI) wherein n is 1 and R ⁸ is Cl. In some embodiments, the compound of formula (VI) wherein n is 1 and R ⁸ is -CN. In some embodiments, the compound of formula (VI) wherein n is 1 and R ⁸ is alkyl. In some embodiments, the compound of formula (VI) wherein n is 1 and R ⁸ is methyl. In some embodiments, the compound of formula (VI) wherein n is 1 and R ⁸ is ethyl. In some embodiments, the compound of formula (VI) wherein n is 1 and R ⁸ is alkoxy. In some embodiments, the compound of formula (VI) wherein n is 1 and R ⁸ is methoxy. In some embodiments, the compound of formula (VI) is wherein n is 1 and R ⁸ is ethoxy. In some embodiments, the compound of formula (VI) is wherein n is 1 and R ⁸ is haloalkoxy. In some embodiments, the compound of formula (VI) is wherein n is 1 and R ⁸ is -OCF ₃ . In some embodiments, the compound of formula (VI) is wherein n is 1 and R ⁸ is haloalkyl. In some embodiments, the compound of formula (VI) is wherein n is 1 and R ⁸ is -CF ₃ .

In some embodiments is a compound of Formula (VI) wherein n is 2. In some embodiments, it is a compound of Formula (VI) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, ^aryl , _heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13 ^{, -SO2NR13R14} , -NR13R14, ^-NR13SO2R14 , ^-NR13C ₍ O ^{) R14} , ^-NR13C (O) _OR14 , ^-NR13C (O ^{) NR13R14} , -C(O) ^{R14 ,} -C(O ^{) OR} In some embodiments, the compound of formula (VI) is ² , wherein n is 2 and ^R is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments, the compound of formula (VI) ^{is 2 ,} wherein n is 2 and R is halogen. In some embodiments, the compound of formula (VI) is ² , wherein n is 2 and each R is ^F. In some embodiments, the compound of formula (VI) is 2, wherein n is 2 and each R is ^Cl . In some embodiments, the compound of formula (VI) is 2, wherein n is 2 and ^R is independently selected from halogen and -CN. In some embodiments, the compound of formula (VI) is 2, wherein n is 2 and ^R is independently selected from halogen and alkyl. In some embodiments, the compound of formula (VI) is 2, wherein n is 2 and ^R is independently selected from -CN and alkyl. In some embodiments, the compound of formula (VI) is 2, wherein n is 2 and two adjacent ^R form a heterocyclyl ring.

In some embodiments described above or below, the compound is of formula (VI), wherein R is ^H. In some embodiments described above or below, the compound is of formula (VI), wherein ^R is -CN. In some embodiments described above or below, the compound is of formula (VI), wherein R is ^halogen . In some embodiments described above or below, the compound is of formula (VI), wherein ^R is F. In some embodiments described above or below, the compound is of formula (VI), wherein ^R is Cl. In some embodiments described above or below, the compound is of formula (VI), wherein ^R is alkyl. In some embodiments described above or below, the compound is of formula (VI), wherein R is ^methyl . In some embodiments described above or below, the compound is of formula (VI), wherein R is ^ethyl . In some embodiments described above or below, the compound is of formula (VI), wherein ^R is -NR ¹³ R ¹⁴ . In some embodiments described above or below, the compound is of formula (VI), wherein ^R is -NH ₂ . In some embodiments described above or below is a compound of Formula (VI) wherein ^R5 is -alkylene ( ^NR13R14 ). In some embodiments described above or below is a compound ^of Formula (I) wherein ^R5 is -alkylene ( _NH2 ). In some embodiments described above or below is a compound _of Formula (VI) wherein ^R5 is _-CH2NH2 .

In some embodiments is a compound of Formula (VI) wherein R ¹ is and R ² is H.

In some embodiments is a compound of Formula (VI) wherein R ¹ is and R ² is H.

In another embodiment is a compound of formula (VI) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (VIa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

^R1 is

^R2 is H;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In some embodiments described above or below is a compound of Formula (VIa) wherein n is 0.

In some embodiments is a compound of Formula (VIa) wherein n is 1. In some embodiments, it is a compound of Formula (VIa) wherein n is 1 and ^R8 is selected from halogen, _-OH , -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene(cycloalkyl), -alkylene( ^heterocyclyl ), cycloalkyl, heterocyclyl, ^aryl , heteroaryl, ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , ^-NR13SO2R14 , _-NR13C(O ^{) R14} , ^{-NR13C(O)OR14, -NR13C ( O ) NR13R14} _, ^-C (O) ^{R14 , -C(O)OR14 ,} or ^-C (O ⁾ _NR ¹³ R ¹⁴ . In some embodiments, it is a compound of formula (VIa), wherein n is 1 and R ⁸ is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy or haloalkyl. In some embodiments, it is a compound of formula (VIa), wherein n is 1 and R ⁸ is halogen. In some embodiments, it is a compound of formula (VIa), wherein n is 1 and R ⁸ is F. In some embodiments, it is a compound of formula (VIa), wherein n is 1 and R ⁸ is Cl. In some embodiments, it is a compound of formula (VIa), wherein n is 1 and R ⁸ is -CN. In some embodiments, it is a compound of formula (VIa), wherein n is 1 and R ⁸ is alkyl. In some embodiments, it is a compound of formula (VIa), wherein n is 1 and R ⁸ is methyl. In some embodiments, it is a compound of formula (VIa), wherein n is 1 and R ⁸ is ethyl. In some embodiments, it is a compound of formula (VIa), wherein n is 1 and R ⁸ is alkoxy. In some embodiments, the compound of formula (VIa) is n 1 and R ⁸ is methoxy. In some embodiments, the compound of formula (VIa) is n 1 and R ⁸ is ethoxy. In some embodiments, the compound of formula (VIa) is n 1 and R ⁸ is haloalkoxy. In some embodiments, the compound of formula (VIa) is n 1 and R ⁸ is -OCF _3. In some embodiments, the compound of formula (VIa) is n 1 and R ⁸ is haloalkyl. In some embodiments, the compound of formula (VIa) is n 1 and R ⁸ is -CF ₃ .

In some embodiments is a compound of Formula (VIa) wherein n is 2. In some embodiments, it is a compound of Formula (VIa) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, ^aryl , _heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13 ^{, -SO2NR13R14} , -NR13R14, ^-NR13SO2R14 , ^-NR13C ₍ O ^{) R14} , ^-NR13C (O) _OR14 , ^-NR13C (O ^{) NR13R14} , -C(O) ^{R14 ,} -C(O ^{) OR} In some embodiments, the compound of formula (VIa) is ² and ^R is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy and haloalkyl. In some embodiments, the compound of formula (VIa) is ² and R is ^halogen . In some embodiments, the compound of formula (VIa) is 2 and ^each R is F. In some embodiments, the compound of formula (VIa) is 2 and each R is ^Cl . In some embodiments, the compound of formula (VIa) is 2 and R is independently selected from halogen and ^-CN . In some embodiments, the compound of formula (VIa) is 2 and R ^is independently selected from halogen and alkyl. In some embodiments, the compound of formula (VIa) is 2 and ^R is independently selected from -CN and alkyl. In some embodiments, the compound of formula (VIa) is 2 and ^two adjacent ^R form a heterocyclyl ring.

In some embodiments described above or below, the compound of formula (VIa) is ^H. In some embodiments described above or below, the compound of formula (VIa) is -CN. In some embodiments described above or ^below , the compound of formula (VIa) is halogen. In some embodiments described above or below, the compound of formula ( ^VIa ) is F. In some embodiments described above or below, the compound of formula (VIa) is ^Cl . In some embodiments described above or below, the compound of formula (VIa) is ^alkyl . In some embodiments described above or below, the compound of formula (VIa) is ^methyl . In some embodiments described above or below, the compound of formula (VIa) is ^ethyl . In some embodiments described above or below, the compound ^{of formula (VIa) is -NR 13 R 14 . In some} embodiments described above or below, the compound of formula ( ^VIa) is -NH ₂ . In some embodiments described above or below is a compound of Formula (VIa) wherein ^R5 is -alkylene ( ^NR13R14 ). In some embodiments described above or below is a compound ^of Formula (I) wherein ^R5 is -alkylene ( _NH2 ). In some embodiments described above or below is a compound _of Formula (VIa) wherein ^R5 is _-CH2NH2 .

In some embodiments is a compound of Formula (VIa) wherein R ¹ is and R ² is H.

In some embodiments is a compound of Formula (VIa) wherein R ¹ is and R ² is H.

In another embodiment is a compound of Formula (VIa) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (VIb) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

^R1 is

^R2 is H;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and n is selected from 0, 1, 2, 3, and 4.

In some embodiments described above or below is a compound of Formula (VIb) wherein n is 0.

In some embodiments is a compound of Formula (VIb) wherein n is 1. In some embodiments, the compound of Formula (VIb) wherein n is 1 and ^R is selected from halogen, _-OH , -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene(cycloalkyl), -alkylene( ^heterocyclyl ), cycloalkyl, heterocyclyl, aryl, heteroaryl ^{, -SR13} , ^-SOR13 , ^{-SO2R13 ,} -SO2NR13R14, -NR13R14, ^-NR13SO2R14 , _-NR13C(O ^{) R14} , ^-NR13C (O ⁾ _OR14 , ^-NR13C (O ^{) NR13R14} , -C(O) ^{R14 ,} -C(O) ^OR14 , or ^-C (O ⁾ _NR ¹³ R ¹⁴ . In some embodiments, it is a compound of formula (VIb), wherein n is 1 and R ⁸ is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy or haloalkyl. In some embodiments, it is a compound of formula (VIb), wherein n is 1 and R ⁸ is halogen. In some embodiments, it is a compound of formula (VIb), wherein n is 1 and R ⁸ is F. In some embodiments, it is a compound of formula (VIb), wherein n is 1 and R ⁸ is Cl. In some embodiments, it is a compound of formula (VIb), wherein n is 1 and R ⁸ is -CN. In some embodiments, it is a compound of formula (VIb), wherein n is 1 and R ⁸ is alkyl. In some embodiments, it is a compound of formula (VIb), wherein n is 1 and R ⁸ is methyl. In some embodiments, it is a compound of formula (VIb), wherein n is 1 and R ⁸ is ethyl. In some embodiments, it is a compound of formula (VIb), wherein n is 1 and R ⁸ is alkoxy. In some embodiments, the compound of formula (VIb) is wherein n is 1 and R ⁸ is methoxy. In some embodiments, the compound of formula (VIb) is wherein n is 1 and R ⁸ is ethoxy. In some embodiments, the compound of formula (VIb) is wherein n is 1 and R ⁸ is haloalkoxy. In some embodiments, the compound of formula (VIb) is wherein n is 1 and R ⁸ is -OCF ₃ . In some embodiments, the compound of formula (VIb) is wherein n is 1 and R ⁸ is haloalkyl. In some embodiments, the compound of formula (VIb) is wherein n is 1 and R ⁸ is -CF ₃ .

In some embodiments is a compound of Formula (VIb) wherein n is 2. In some embodiments, it is a compound of Formula (VIb) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, ^aryl , _heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13 ^{, -SO2NR13R14} , -NR13R14, ^-NR13SO2R14 , ^-NR13C ₍ O ^{) R14} , ^-NR13C (O) _OR14 , ^-NR13C (O ^{) NR13R14} , -C(O) ^{R14 ,} -C(O ^{) OR} In some embodiments, the compound of formula (VIb) is ² and ^R is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments, the compound of formula (VIb) is ² and R is ^halogen . In some embodiments, the compound of formula (VIb) is 2 and ^each R is F. In some embodiments, the compound of formula (VIb) is 2 and each R is ^Cl . In some embodiments, the compound of formula (VIb) is 2 and R is independently selected from halogen and ^-CN . In some embodiments, the compound of formula (VIb) is 2 and R ^is independently selected from halogen and alkyl. In some embodiments, the compound of formula (VIb) is 2 and ^R is independently selected from -CN and alkyl. In some embodiments, the compound of formula (VIb) is ² and two adjacent ^R form a heterocyclyl ring.

In some embodiments described above or below, the compound of formula (VIb) is ^H. In some embodiments described above or below, the compound of formula (VIb) is -CN. In some embodiments described above or ^below , the compound of formula (VIb) is halogen. In some embodiments described above or below, the compound of formula ( ^VIb ) is F. In some embodiments described above or below, the compound of formula (VIb) is ^Cl . In some embodiments described above or below, the compound of formula (VIb) is ^alkyl . In some embodiments described above or below, the compound of formula (VIb) is ^methyl . In some embodiments described above or below, the compound of formula (VIb) is ethyl. In some embodiments described above or below, the compound ^{of formula (VIb) is -NR 13 R 14 . In some embodiments} described above or below, the compound of formula ( ^VIb) is -NH ₂ . In some embodiments described above or below is a compound of Formula (VIb) wherein ^R5 is -alkylene ( ^NR13R14 ). In some embodiments described above or below is a compound ^of Formula (I) wherein ^R5 is -alkylene ( _NH2 ). In some embodiments described above or below is a compound _of Formula (VIb) wherein ^R5 is _-CH2NH2 .

In some embodiments is a compound of Formula (VIb) wherein R ¹ is and R ² is H.

In some embodiments is a compound of Formula (VIb) wherein R ¹ is and R ² is H.

In another embodiment is a compound of Formula (VIb) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (VIc) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

^R1 is

^R2 is H;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a heterocycle; and

n is selected from 0, 1, 2, 3 and 4.

In some embodiments described above or below is a compound of Formula (VIc) wherein n is 0.

In some embodiments is a compound of Formula (VIc) wherein n is 1. In some embodiments, it is a compound of Formula (VIc) wherein n is 1 and ^R is selected from halogen, _-OH , -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene(cycloalkyl), -alkylene( ^heterocyclyl ), cycloalkyl, heterocyclyl, ^aryl , heteroaryl, ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , ^-NR13SO2R14 , _-NR13C(O ^{) R14} , ^{-NR13C(O)OR14, -NR13C ( O ) NR13R14} _, ^-C (O) ^{R14 , -C(O)OR14 ,} or ^-C (O ⁾ _NR ¹³ R ¹⁴ . In some embodiments, it is a compound of formula (VIc), wherein n is 1 and R ⁸ is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy or haloalkyl. In some embodiments, it is a compound of formula (VIc), wherein n is 1 and R ⁸ is halogen. In some embodiments, it is a compound of formula (VIc), wherein n is 1 and R ⁸ is F. In some embodiments, it is a compound of formula (VIc), wherein n is 1 and R ⁸ is Cl. In some embodiments, it is a compound of formula (VIc), wherein n is 1 and R ⁸ is -CN. In some embodiments, it is a compound of formula (VIc), wherein n is 1 and R ⁸ is alkyl. In some embodiments, it is a compound of formula (VIc), wherein n is 1 and R ⁸ is methyl. In some embodiments, it is a compound of formula (VIc), wherein n is 1 and R ⁸ is ethyl. In some embodiments, it is a compound of formula (VIc), wherein n is 1 and R ⁸ is alkoxy. In some embodiments, the compound of formula (VIc) is wherein n is 1 and R ⁸ is methoxy. In some embodiments, the compound of formula (VIc) is wherein n is 1 and R ⁸ is ethoxy. In some embodiments, the compound of formula (VIc) is wherein n is 1 and R ⁸ is haloalkoxy. In some embodiments, the compound of formula (VIc) is wherein n is 1 and R ⁸ is -OCF ₃ . In some embodiments, the compound of formula (VIc) is wherein n is 1 and R ⁸ is haloalkyl. In some embodiments, the compound of formula (VIc) is wherein n is 1 and R ⁸ is -CF ₃ .

In some embodiments is a compound of Formula (VIc) wherein n is 2. In some embodiments, it is a compound of Formula (VIc) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, ^aryl , _heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13 ^{, -SO2NR13R14} , -NR13R14, ^-NR13SO2R14 , ^-NR13C ₍ O ^{) R14} , ^-NR13C (O) _OR14 , ^-NR13C (O ^{) NR13R14} , -C(O) ^{R14 ,} -C(O ^{) OR} In some embodiments, the compound of formula (VIc) is ² and ^R is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments, the compound of formula (VIc) is ² and R is ^halogen . In some embodiments, the compound of formula (VIc) is 2 and ^each R is F. In some embodiments, the compound of formula (VIc) is 2 and each R is ^Cl . In some embodiments, the compound of formula (VIc) is 2 and R is independently selected from halogen and ^-CN . In some embodiments, the compound of formula (VIc) is 2 and R ^is independently selected from halogen and alkyl. In some embodiments, the compound of formula (VIc) is 2 and ^R is independently selected from -CN and alkyl. In some embodiments, the compound of formula (VIc) is ² and two adjacent ^R form a heterocyclyl ring.

In some embodiments described above or below, the compound of formula ( ^VIc ) is H. In some embodiments described above or below, the compound of formula (VIc) is -CN. In some embodiments described above or below, the compound of formula ( ^VIc ) is halogen. In some embodiments described above or below, the compound of formula ( ^VIc ) is F. In some embodiments described above or below, the compound of formula (VIc) is ^Cl . In some embodiments described above or below, the compound of formula (VIc) is ^alkyl . In some embodiments described above or below, the compound of formula (VIc) is ^methyl . In some embodiments described above or below, the compound of formula (VIc) is ^ethyl . In some embodiments described above or below, the compound ^of formula ( ^VIc ) is -NR ¹³ R ¹⁴ . In some embodiments described above or below, the compound of formula ( ^VIc) is -NH ₂ . In some embodiments described above or below is a compound of Formula (VIc) wherein ^R5 is -alkylene ( ^NR13R14 ). In some embodiments described above or below is a compound ^of Formula (I) wherein ^R5 is -alkylene ( _NH2 ). In some embodiments described above or below is a compound _of Formula (VIc) wherein ^R5 is _-CH2NH2 .

In some embodiments is a compound of Formula (VIc) wherein R ¹ is and R ² is H.

In some embodiments is a compound of Formula (VIc) wherein R ¹ is and R ² is H.

In another embodiment is a compound of Formula (VIc) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (VII) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

n is selected from 0, 1, 2, 3 and 4;

X ₁ and X ₂ are each independently selected from -O-, -S-, -S(O) ₂ -, -N(R ¹⁵ )-, and -(CH ₂ )-, wherein at least one X ¹ or X ² is not -O-; and

^R15 is H or alkyl.

In some embodiments, the compound of formula (VII) wherein R ¹ is In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is -NR ¹³ R ^14. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is -NH _2. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is -NHCH _3. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (VII) wherein R ¹ is In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is -NR ¹³ R ^14. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is -NH _2. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is -NHCH _3. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (VII) wherein R ¹ is In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is -NR ¹³ R ^14. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is -NH _2. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is -NHCH _3. In some embodiments, the compound of formula (VII) wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of Formula (VII ⁾ is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound of Formula (VII ⁾ is -CH( _CH3 ) ₂ . In some embodiments, the compound of Formula (VII) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 ^. In some embodiments, the compound of Formula (VII) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula ( _VII ) is ^-CH ( ^CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of _Formula (VII) is ^-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (VII) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is ethyl. In some embodiments, the compound of Formula (VII) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NR ¹³ R ¹⁴ . In some embodiments, the compound of Formula (VII) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NH ₂ . In some embodiments, the compound of Formula (VII) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NHCH ₃ . In some embodiments, the compound of formula (VII) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (VII) wherein R ¹ is -alkylene(cycloalkyl). In some embodiments, the compound of formula (VII) wherein R ¹ is -CH ₂ CH ₂ (cycloalkyl). In some embodiments, the compound of formula (VII) wherein R ¹ is -CH ₂ (cycloalkyl). In some embodiments, the compound of formula (VII) wherein R ¹ is -CH ₂ (cyclobutyl). In some embodiments, the compound of formula (VII) wherein R ¹ is -CH ₂ (cyclopentyl). In some embodiments, the compound of formula (VII) wherein R ¹ is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula (VII) wherein R ¹ is

In some embodiments described above or below, the compound of formula ( ^VII ) is H. In some embodiments described above or below, the compound of formula (VII) is -CN. In some embodiments described above or ^below , the compound of formula (VII) is halogen. In some embodiments described above or below, the compound of formula ( ^VII ) is F. In some embodiments described above or below, the compound of formula (VII) is ^Cl . In some embodiments described above or below, the compound of formula (VII) is ^alkyl . In some embodiments described above or below, the compound of formula (VII) is ^methyl . In some embodiments described above or below, the compound of formula (VII) is ^ethyl . In some embodiments described above or below, the compound ^of formula ( ^VII) is -NR ¹³ R ^14. In some embodiments described above or below, the compound of formula (VII ⁾ is -NH ₂ . In some embodiments described above or below is a compound of Formula (VII) wherein ^R5 is -alkylene ( ^NR13R14 ). In some embodiments described above or below is a compound ^of Formula (VII) wherein ^R5 is -alkylene ( _NH2 ). In some embodiments described above or below is a compound _of Formula (VII) wherein ^R5 is _-CH2NH2 .

In some embodiments described above or below is a compound of Formula (VII) wherein n is 0.

In some embodiments described above or below is a compound of Formula (VII) wherein n is 1. In some embodiments described above or below is a compound of Formula (VII) wherein n is 1 and ^R8 is selected from halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , -NR13SO2R14 ^{, -NR13C (} O ₎ ^R14 , ^-NR13C (O ⁾ _OR14 , ^-NR13C (O ^{) NR13R14 , -C} (O ^{) R14 ,} -C(O)OR In some embodiments described ^above or below, ^the compound is of formula (VII), wherein n is 1 and ^R is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments described above or below, the compound ^is of formula (VII), wherein n is 1 and ^R is halogen. In some embodiments described above or below, the compound is of formula (VII), wherein n is 1 and R is F. In some embodiments described above or below, the compound is of formula (VII), wherein n is 1 and R is ^Cl . In some embodiments described above or below, the compound is of formula (VII), wherein n is ¹ and ^R is -CN. In some embodiments described above or below, the compound is of formula (VII), wherein n is 1 and ^R is alkyl. In some embodiments described above or below, the compound is of formula (VII), wherein n is 1 and ^R is methyl. In some embodiments described above or below, the compound is of formula (VII), wherein n is 1 and R is ^ethyl . In some embodiments described above or below, the compound of formula (VII) is wherein n is 1 and ^R is alkoxy. In some embodiments described above or below, the compound of formula (VII) is wherein n is 1 and ^R is methoxy. In some embodiments described above or below, the compound of formula (VII) is wherein n is 1 and ^R is ethoxy. In some embodiments described above or below, the compound of formula (VII) is wherein n is 1 and ^R is haloalkoxy. In some embodiments described above or below, the compound of formula (VII) is wherein n is 1 and ^R is -OCF ₃ . In some embodiments described above or below, the compound of formula (VII) is wherein n is 1 and ^R is haloalkyl. In some embodiments described above or below, the compound of formula (VII) is wherein n is 1 and ^R is -CF ₃ .

In some embodiments described above or below is a compound of Formula (VII) wherein n is 2. In some embodiments described above or below is a compound of Formula (VII) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl ^, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, -NR13R14, ^-NR13SO2R14 , ^-NR13C (O ₎ ^R14 , ^-NR13C (O ^{) OR14} , ^-NR13C ( ^O ₎ ^{NR13R14 , -C} (O) ^R14 , -C ⁽ O)OR In some embodiments described ^above or below, the compound is ^of formula (VII), wherein n is 2 and R ^{8 is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments described above or below, the compound is of formula (VII), wherein n is 2 and R 8 is} halogen. In some embodiments described above or below, the compound is of formula (VII), wherein n is 2 and each R ⁸ is F. In some embodiments described above or below, the compound is of formula (VII), wherein n is 2 and each R ⁸ is Cl. In some embodiments described above or below, the compound is of formula (VII), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (VII), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (VII), wherein n is 2 and R ⁸ is independently selected from halogen and alkyl. In some embodiments described above or below, the compound is of formula (VII), wherein n is 2 and R ⁸ is independently selected from -CN and alkyl. In some embodiments described above or below is a compound of Formula (VII) wherein n is 2 and two adjacent R ⁸ form a heterocyclyl ring.

In another embodiment is a compound of formula (VII) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (VIIa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ⁵ is H, -CN, halogen, haloalkyl, alkyl, -NR ¹³ R ¹⁴ , -alkylene (NR ¹³ R ¹⁴ ) and -SO ₂ R ¹³ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

n is selected from 0, 1, 2, 3 and 4;

X ₁ and X ₂ are each independently selected from -O-, -S-, -S(O) ₂ -, -N(R ¹⁵ )-, and -(CH ₂ )-, wherein at least one X ¹ or X ² is not -O-; and

^R15 is H or alkyl.

In some embodiments, the compound of formula (VIIA) is wherein R ¹ is In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is -NR ¹³ R ^14. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is -NH _2. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (VIIA) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (VIIA) is wherein R ¹ is In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is -NR ¹³ R ^14. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is -NH _2. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (VIIA) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (VIIA) is wherein R ¹ is In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is -NR ¹³ R ^14. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is -NH _2. In some embodiments, the compound of formula (VIIA) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (VIIA) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the ^compound of Formula (VIIA) is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound ^of Formula (VIIA) is -CH( _CH3 ) ₂ . In some embodiments, _the compound of Formula (VIIA) is -CH( _CH2CH3 )CH( _R3 ) ^CH3 . In some embodiments, the compound of Formula ( ^VIIA ) is ^-CH ( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula (VIIA) is ^-CH ( _CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of _Formula (VIIA) is ^-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (VIIA) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is ethyl. In _some embodiments, the compound of Formula ( _VIIA ) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^{R3 is -NR13R14} . In some embodiments, the compound of Formula (VIIA) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is _-NH2 . _In some embodiments, the compound of Formula ( _VIIA ) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is _-NHCH3 . In some embodiments, the compound of Formula (VIIA) is R ¹ , wherein R 1 is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of Formula (VIIA) is R 1, wherein R ¹ is -alkylene(cycloalkyl). In some embodiments, the compound of Formula (VIIA) is R 1, wherein R ¹ is -CH ₂ CH ₂ (cycloalkyl). In some embodiments, the compound of Formula (VIIA) is R 1, wherein R ¹ is -CH ₂ (cycloalkyl). In some embodiments, the compound of Formula (VIIA) is R 1, wherein R ¹ is -CH ₂ (cyclobutyl). In some embodiments, the compound of Formula (VIIA) is R 1, wherein R ¹ is -CH ₂ (cyclopentyl). In some embodiments, the compound of Formula (VIIA) is R 1, wherein R ¹ is -CH ₂ (cyclohexyl). In some embodiments, the compound of Formula (VIIA) is R ¹ , wherein R 1 is -CH 2 (cyclohexyl).

In some embodiments described above or below, the compound is of formula (VIIA), wherein R is ^H. In some embodiments described above or below, the compound is of formula (VIIA), wherein ^R is -CN. In some embodiments described above or below, the compound is of formula (VIIA), wherein R is ^halogen . In some embodiments described above or below, the compound is of formula (VIIA), wherein ^R is F. In some embodiments described above or below, the compound is of formula (VIIA), wherein ^R is Cl. In some embodiments described above or below, the compound is of formula (VIIA), wherein ^R is alkyl. In some embodiments described above or below, the compound is of formula (VIIA), wherein ^R is methyl. In some embodiments described above or below, the compound is of formula (VIIA), wherein R is ^ethyl . In some embodiments described above or below, the compound is of formula (VIIA), wherein ^R is -NR ¹³ R ¹⁴ . In some embodiments described above or below, the compound is of formula (VIIA), wherein ^R is -NH ₂ . In some embodiments described above or below is a compound of Formula (VIIA) wherein ^R5 is -alkylene ( ^NR13R14 ). In some embodiments described above or below is a compound ^of Formula (VIIA) wherein ^R5 is -alkylene ( _NH2 ). In some embodiments described above or below is a compound _of Formula (VIIA) wherein ^R5 is _-CH2NH2 .

In some embodiments described above or below is a compound of Formula (VIIA) wherein n is 0.

In some embodiments described above or below is a compound of Formula (VIIA) wherein n is 1. In some embodiments described above or below is a compound of Formula (VIIA) wherein n is 1 and ^R8 is selected from halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , -NR13SO2R14 ^{, -NR13C (} O ₎ ^R14 , ^-NR13C (O ⁾ _OR14 , ^-NR13C (O ^{) NR13R14 , -C} (O ^{) R14 ,} -C(O)OR In some embodiments described ^above or below, ^the compound is of formula (VIIA), wherein n is 1 and ^R is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments described above or below, the compound ^is of formula (VIIA), wherein n is 1 and ^R is halogen. In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 and R is F. In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 and R is ^Cl . In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 ^{and R} is -CN. In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 and ^R is alkyl. In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 and ^R is methyl. In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 and R ^is ethyl. In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 and ^R is alkoxy. In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 and ^R is methoxy. In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 and ^R is ethoxy. In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 and ^R is haloalkoxy. In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 and ^R is -OCF ₃ . In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 and ^R is haloalkyl. In some embodiments described above or below, the compound is of formula (VIIA), wherein n is 1 and ^R is -CF ₃ .

In some embodiments described above or below is a compound of Formula (VIIA) wherein n is 2. In some embodiments described above or below is a compound of Formula (VIIA) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl ^, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, -NR13R14, ^-NR13SO2R14 , ^-NR13C (O ₎ ^R14 , ^-NR13C (O ^{) OR14} , ^-NR13C (O ₎ ^{NR13R14 , -C} (O) ^R14 , ^{-C (} O)OR In some embodiments described ^above or below, ^the compound is a compound ^of formula (VIIA), wherein n is 2 and R 8 is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments described above or below, the compound is a compound of formula (VIIA), wherein n is 2 and R ⁸ is halogen. In some embodiments described above or below, the compound is a compound of formula (VIIA), wherein n is 2 and each R ⁸ is F. In some embodiments described above or below, the compound is a compound of formula (VIIA), wherein n is 2 and each R ⁸ is Cl. In some embodiments described above or below, the compound is a compound of formula (VIIA), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is a compound of formula (VIIA), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is a compound of formula (VIIA), wherein n is 2 and R ⁸ is independently selected from halogen and alkyl. In some embodiments described above or below, the compound is a compound of formula (VIIA), wherein n is 2 and R ⁸ is independently selected from -CN and alkyl. In some embodiments described above or below is a compound of Formula (VIIA) wherein n is 2 and two adjacent R ⁸ form a heterocyclyl ring.

In another embodiment is a compound of Formula (VIIa) having the structure: or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (VIII) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH(R ³ )CH ₃ , -CH(CH ₃ )C(O)CH ₃ , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ¹⁰ and R ¹¹ are independently selected from H or alkyl, wherein at least one of R ¹⁰ and R ¹¹ is alkyl;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

R ²⁰ is selected from H, F, Cl, Br, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO 2 R 13 , -SO ₂ NR 13 R ¹⁴ , -NR ₁₃ R ¹⁴ , -NR ¹³ SO 2 ^{R 14 ,} -NR ¹³ _C (O) ^{R 14} , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -C(O)R ¹⁴ , -C(O ⁾ OR ¹⁴ and -C(O)NR ¹³ R ¹⁴ ;

R ²¹ , R ²² and R ²³ are independently selected from H, halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ^{13 , -SO 2 R 13} , -SO ₂ NR ¹³ R 14 , -NR ¹³ R 14 , -NR _{13 SO} ² R ¹⁴ , -NR ¹³ C(O) ^{R 14} , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O ⁾ NR ¹³ R ¹⁴ , -C(O) ^{R 14 , -C(O)OR 14 and -C} (O)NR ¹³ R ¹⁴ ; and

^R24 is H.

In some embodiments, the compound of formula (VIII) is ^H and ^R is alkyl. In some embodiments, the compound ^of formula (VIII) is H and R is methyl. In some embodiments, the compound of formula (VIII) is H and R ^is ethyl. In some embodiments, the compound of formula (VIII) is ^H and R is ^isopropyl . In some embodiments, the compound of formula (VIII) is ^R and ^R is alkyl. In some embodiments, the compound of formula (VIII) is methyl and R is H. In some embodiments, the compound of formula (VIII) is ^R and R is ^ethyl . In some embodiments, the compound of formula (VIII) is ^R and R is isopropyl. In some embodiments, the compound of formula (VIII) is R and R is ^alkyl . In some embodiments, the compound of formula (VIII) is ^R and R is ^ethyl . In some embodiments, the compound of formula (VIII) is ^R and ^R is H. In some embodiments, the compound of formula (VIII) is R and R is isopropyl. In some embodiments, the compound of formula ( ^VIII ) is R and ^R is alkyl. In some embodiments is a compound of Formula (VIII) wherein R ¹⁰ is methyl and R ¹¹ is methyl.

In some embodiments, the compound of formula (VIII) is R ²¹ , R ²² , and R ²³ are independently selected from H, halogen, -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, -SO ₂ R ¹³ , -SO ₂ NR ¹³ R ¹⁴ , and -C(O)NR ¹³ R ^14. In some embodiments, the compound of formula (VIII) is R ²¹ , R ²² , and R ²³ are independently selected from H, halogen, -CN, alkyl, alkoxy, and haloalkyl. In some embodiments, the compound of formula (VIII) is R ²¹ , R ²² , and R ²³ are independently selected from H and halogen. In some embodiments, the compound of formula (VIII) is R ²¹ , R ²² , and R ²³ are independently selected from H and -CN. In some embodiments, the compound of formula (VIII) is R ²¹ , R ²² , and R ²³ are independently selected from H and alkyl. In some embodiments, the compound of formula (VIII) is R ²¹ , R ²² , and R ²³ are independently selected from H and alkoxy. In some embodiments, the compound of formula (VIII) is R ²¹ , R ²² , and R ²³ are independently selected from H and haloalkoxy. In some embodiments, the compound of formula (VIII) is R ²¹ , R ²² , and R ²³ are independently selected from H and haloalkyl. In some embodiments, the compound of formula (VIII) is R ²¹ , R ²² , and R ²³ are independently selected from H and -SO ₂ R ^13. In some embodiments, the compound of formula (VIII) is R ²¹ , R ²² , and R ²³ are independently selected from H and -SO ₂ NR ¹³ R ^14. In some embodiments, the compound of formula (VIII) is R ²¹ , R ²² , and R ²³ are independently selected from H and -C(O)NR ¹³ R ¹⁴ . In some embodiments, the compound is represented by formula (VIII), wherein R ²¹ , R ²² , and R ²³ are independently selected from —CN and alkyl. In some embodiments, the compound is represented by formula (VIII), wherein R ²¹ , R ²² , and R ²³ are independently selected from H, Cl, —CN, —CH ₃ , —OCH ₃ , and —CF ₃ .

In some embodiments is a compound of Formula (VIII) wherein R ²¹ , R ²² , and R ²³ are each H.

In some embodiments, the compound of formula (VIII) wherein R ²⁰ is selected from H, halogen, -CN, alkyl, alkoxy, and haloalkyl. In some embodiments, the compound of formula (VIII) wherein R ²⁰ is selected from H and -CN. In some embodiments, the compound of formula (VIII) wherein R ²⁰ is selected from H and alkyl. In some embodiments, the compound of formula (VIII) wherein R ²⁰ is selected from H and alkoxy. In some embodiments, the compound of formula (VIII) wherein R ²⁰ is selected from H and haloalkoxy. In some embodiments, the compound of formula (VIII) wherein R ²⁰ is selected from H and haloalkyl. In some embodiments, the compound of formula (VIII) wherein R ²⁰ is selected from H and -SO ₂ R ¹³ . In some embodiments, the compound of formula (VIII) wherein R ²⁰ is selected from H and -SO ₂ NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (VIII) wherein R ²⁰ is selected from -CN and alkyl. In some embodiments, the compound of formula (VIII) is R ²⁰ selected from H, Cl, -CN, -CH ₃ , -OCH ₃ and -CF ₃ . In some embodiments, the compound of formula (VIII) is R ²⁰ selected from H, Cl, -CN and -CH ₃ . In some embodiments, the compound of formula (VIII) is R ²⁰ is H. In some embodiments, the compound of formula (VIII) is R ²⁰ is Cl.

In some embodiments, the compound of formula (VIII) wherein R ¹ is In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (VIII) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (VIII) wherein R ¹ is In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (VIII) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (VIII) wherein R ¹ is In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (VIII) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (VIII) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (VIII ⁾ is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound of formula (VIII ⁾ is -CH( _CH3 ) ₂ . In some embodiments, the compound of formula (VIII) is -CH( _CH2CH3 )CH( _R3 ) _CH3 ^. In some embodiments, the compound of formula ( ^VIII ) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of formula ( _VIII ) is ^-CH ( ^CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of formula (VIII) is ^-CH ( _{CH2CH3 )} CH( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (VIII) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is ethyl. In some embodiments, the compound of Formula (VIII) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NR ¹³ R ¹⁴ . In some embodiments, the compound of Formula (VIII) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NH ₂ . In some embodiments, the compound of Formula (VIII) wherein R ¹ is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , and R ³ is -NHCH ₃ . In some embodiments, the compound of formula (VIII) is R ^{1, wherein R 1} is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (VIII) is R 1, wherein R ¹ is -alkylene(cycloalkyl). In some embodiments, the compound of formula (VIII) is R 1, wherein R ¹ is -CH ₂ CH ₂ (cycloalkyl). In some embodiments, the compound of formula (VIII) is R 1, wherein R ¹ is -CH ₂ (cycloalkyl). In some embodiments, the compound of formula (VIII) is R 1, wherein R ¹ is -CH ₂ (cyclobutyl). In some embodiments, the compound of formula (VIII) is R 1, wherein R ¹ is -CH ₂ (cyclopentyl). In some embodiments, the compound of formula (VIII) is R 1, wherein R ¹ is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula (VIII) is R ¹ , wherein R 1 is -CH 2 (cyclohexyl).

In another embodiment is a compound of formula (VIII) having the structure:

A pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (VIIIa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:

in:

R ¹ is -CH(CH ₃ )CH(R ³ )CH ₃ , -CH(CH ₃ )C(O)CH ₃ , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

R ¹⁰ and R ¹¹ are independently selected from H or alkyl, wherein at least one of R ¹⁰ and R ¹¹ is alkyl;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

R ²⁰ is selected from H, F, Cl, Br, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO 2 R 13 , -SO ₂ NR 13 R ¹⁴ , -NR ₁₃ R ¹⁴ , -NR ¹³ SO 2 ^{R 14 ,} -NR ¹³ _C (O) ^{R 14} , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -C(O)R ¹⁴ , -C(O ⁾ OR ¹⁴ and -C(O)NR ¹³ R ¹⁴ ;

R ²¹ , R ²² and R ²³ are independently selected from H, halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ^{13 , -SO 2 R 13} , -SO ₂ NR ¹³ R 14 , -NR ¹³ R 14 , -NR _{13 SO} ² R ¹⁴ , -NR ¹³ C(O) ^{R 14} , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O ⁾ NR ¹³ R ¹⁴ , -C(O) ^{R 14 , -C(O)OR 14 and -C} (O)NR ¹³ R ¹⁴ ; and

^R24 is H.

In some embodiments, the compound of formula (VIIIa) is ^H and ^R is alkyl. In some embodiments, the compound ^of formula (VIIIa) is H and R is methyl. In some embodiments, the compound of formula (VIIIa) is ^{H and R} is ethyl. In some embodiments, the compound of formula (VIIIa) is ^H and ^R is isopropyl. In some embodiments, the compound of formula (VIIIa) is ^R is alkyl and R is ^H. In some embodiments, the compound of formula (VIIIa) is ^{R is} methyl and R ^{is H.} In some embodiments, the compound of formula ( ^VIIIa ) is R isopropyl and R is ^H. In some embodiments is a compound of Formula (VIIIa) wherein R ¹⁰ is alkyl and R ¹¹ is alkyl. In some embodiments is a compound of Formula (VIIIa) wherein R ¹⁰ is methyl and R ¹¹ is methyl.

In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from H, halogen, -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, -SO ₂ R ¹³ , -SO ₂ NR ¹³ R ¹⁴ and -C(O)NR ¹³ R ^14. In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from H, halogen, -CN, alkyl, alkoxy and haloalkyl. In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from H and halogen. In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from H and -CN. In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from H and alkyl. In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from H and alkoxy. In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from H and haloalkoxy. In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from H and haloalkyl. In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from H and -SO ₂ R ¹³ . In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from H and -SO ₂ NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from H and -C(O)NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from -CN and alkyl. In some embodiments, the compound of formula (VIIIa) is wherein R ²¹ , R ²² and R ²³ are independently selected from H, Cl, -CN, -CH ₃ , -OCH ₃ and -CF ₃ .

In some embodiments is a compound of Formula (VIIIa) wherein R ²¹ , R ²² , and R ²³ are each H.

In some embodiments, the compound of formula (VIIIa) wherein R ²⁰ is selected from H, halogen, -CN, alkyl, alkoxy, and haloalkyl. In some embodiments, the compound of formula (VIIIa) wherein R ²⁰ is selected from H and -CN. In some embodiments, the compound of formula (VIIIa) wherein R ²⁰ is selected from H and alkyl. In some embodiments, the compound of formula (VIIIa) wherein R ²⁰ is selected from H and alkoxy. In some embodiments, the compound of formula (VIIIa) wherein R ²⁰ is selected from H and haloalkoxy. In some embodiments, the compound of formula (VIIIa) wherein R ²⁰ is selected from H and haloalkyl. In some embodiments, the compound of formula (VIIIa) wherein R ²⁰ is selected from H and -SO ₂ R ¹³ . In some embodiments, the compound of formula (VIIIa) wherein R ²⁰ is selected from H and -SO ₂ NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (VIIIa) wherein R ²⁰ is selected from -CN and alkyl. In some embodiments, the compound of formula (VIIIa) is wherein R ²⁰ is selected from H, Cl, -CN, -CH ₃ , -OCH ₃ and -CF ₃ . In some embodiments, the compound of formula (VIIIa) is wherein R ²⁰ is selected from H, Cl, -CN and -CH ₃ . In some embodiments, the compound of formula (VIIIa) is wherein R ²⁰ is H. In some embodiments, the compound of formula (VIIIa) is wherein R ²⁰ is Cl.

In some embodiments, the compound of formula (VIIIa) wherein R ¹ is In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (VIIIa) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (VIIIa) wherein R ¹ is In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (VIIIa) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (VIIIa) wherein R ¹ is In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (VIIIa) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (VIIIa) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the ^compound of Formula (VIIIa) is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound ^of Formula (VIIIa) is -CH( _CH3 ) ₂ . In some embodiments, _the compound of Formula (VIIIa) is -CH( _CH2CH3 )CH( _R3 ) ^CH3 . In some embodiments, the compound of Formula ( ^VIIIa ) is ^-CH ( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula (VIIIa) is ^-CH ( _CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of _Formula (VIIIa) is ^-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (VIIIa) is ^R1 , wherein -CH( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^R3 is ethyl. In some embodiments, the compound of Formula (VIIIa) is ^R1 , wherein -CH( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^{R3 is -NR13R14} . In some embodiments, the compound of Formula (VIIIa) is ^R1 , wherein -CH( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is _-NH2 . In some embodiments, the compound of Formula ( _VIIIa ) is ^R1 , wherein -CH( _CH2CH3 ⁾ CH( ^R3 ) _CH3 , and ^R3 is _-NHCH3 . In some embodiments, the compound of formula (VIIIa) is R ¹ , wherein -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (VIIIa) is R ¹ , wherein -alkylene(cycloalkyl). In some embodiments, the compound of formula (VIIIa) is R ¹ , wherein -CH ₂ CH ₂ (cycloalkyl). In some embodiments, the compound of formula (VIIIa) is R ¹ , wherein -CH ₂ (cycloalkyl). In some embodiments, the compound of formula (VIIIa) is R ¹ , wherein -CH ₂ (cyclobutyl). In some embodiments, the compound of formula (VIIIa) is R ¹ , wherein -CH ₂ (cyclopentyl). In some embodiments, the compound of formula (VIIIa) is R ¹ , wherein -CH ₂ (cyclohexyl). In some embodiments, the compound of formula (VIIIa) is R ¹ , wherein -CH 2 (cyclohexyl).

In another embodiment is a compound of Formula (VIIIa) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect are compounds having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (IX) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug or stereoisomer thereof:

in:

-XY- is -CH ₂ CH ₂ -, -CH=CH-, -CH=N- or -N=CH-;

Z ¹ is selected from O, S, NH and NR ¹³ ;

Z ² is selected from O, S, CH ₂ , NH and NR ¹³ ;

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

^R4 is halogen, alkyl,

Each R ⁷ is independently selected from halogen and alkyl;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

each R ¹⁵ is independently selected from haloalkyl, -alkylene(NR ¹³ R ¹⁴ ), -NR ¹³ R ¹⁴ and -SO ₂ R ¹³ ;

Each R ¹⁶ is independently selected from halogen, alkyl and haloalkyl;

Each R ¹⁷ is independently selected from halogen, alkyl, haloalkyl and -CN;

n is selected from 0, 1, 2, 3 and 4;

m is selected from 0, 1 and 2;

p is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3, and 4; and

t is independently selected from 0, 1, 2, 3 and 4.

In some embodiments, the compound of formula (IX) is wherein R ⁴ is halogen. In some embodiments, the compound of formula (IX) is wherein R ⁴ is F. In some embodiments, the compound of formula (IX) is wherein R ⁴ is Cl. In some embodiments, the compound of formula (IX) is wherein R ⁴ is alkyl. In some embodiments, the compound of formula (IX) is wherein R ⁴ is methyl. In some embodiments, the compound of formula (IX) is wherein R ⁴ is ethyl. In some embodiments, the compound of formula (IX) is wherein

wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R 4 is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R 4 is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R 4 is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R 4 is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is in some embodiments a compound of formula (IX), wherein R ⁴ is

In some embodiments, ^the compound of Formula (IX) is ^-CH ( _CH3 ) _CH2CH2R2 . In _some embodiments, the compound of Formula (IX) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^R2 is H. In some embodiments, ^the compound ^of Formula (IX) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^R2 is alkyl. In some embodiments, the compound of Formula (IX) is ^-CH ( _{CH3 ) CH2CH2R2} , ^{and R2} _is ^methyl . In some embodiments, the compound of Formula ( _IX ) is ^-CH ( _CH3 ) _CH2CH2R2 , and R2 is ^ethyl . In some embodiments, _the compound of Formula (IX) is ^-CH ( _{CH3 ) CH2CH2R2} , and ^{R2 is isopropyl} . In some embodiments, the compound of Formula (IX) is R1, wherein ^R1 is -CH( _CH3 ) _CH2CH2R2 , and _R2 ^{is -NR13R14} . In some embodiments, the compound ^of Formula (IX) is R1, wherein ^R1 is -CH( _{CH3 )} ^CH2CH2R2 , and _R2 ^{is -NH2} . In some embodiments, the compound of Formula (IX) is _R1 , wherein ^R1 is -CH( _CH3 ) _CH2CH2R2 , and ^{R2 is} _-NHCH3 . In some embodiments, the compound of Formula (IX) is R1, wherein ^R1 is _-CH ( _CH3 ) _CH2CH2R2 , and _R2 ^{is -N} ( _CH3 ) ₂ .

In some embodiments, the compound of Formula (IX ⁾ is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound of Formula ( ^IX ) is -CH( _CH3 ) ₂ . In some embodiments, the compound of Formula (IX) is -CH( _CH2CH3 )CH( _R3 ) _CH3 ^. In some embodiments, the compound of Formula ( ^IX ) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula ( _IX ) is ^-CH ( ^CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of _Formula (IX) is ^-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (IX) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is ethyl. In _some embodiments, the compound of Formula ( _IX ) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^{R3 is -NR13R14} . In some embodiments, the compound of Formula (IX) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is _-NH2 . _In some embodiments, the compound of Formula ( ^IX ) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is _-NHCH3 . In some embodiments, the compound of formula ( ^IX ) is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (IX) is -alkylene(cycloalkyl). In some embodiments, the compound of formula (IX ⁾ is -CH ² _{CH 2} (cycloalkyl). In some embodiments, the compound of formula (IX) is -CH ² (cycloalkyl). In some embodiments, the compound of formula (IX) is -CH ₂ (cyclobutyl ₎ . In some embodiments, the compound of formula ( ^IX ) is -CH ² (cyclopentyl ₎ . In some embodiments, the compound of formula ( ^IX) is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula ( ^IX ) is

In some embodiments, the compound of formula (IX) wherein R ¹ is In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (IX) wherein R ¹ is In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (IX) wherein R ¹ is In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments, the compound of formula (IX) wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments described above or below is a compound of Formula (IX) wherein n is 0.

In some embodiments described above or below is a compound of Formula (IX) wherein n is 1. In some embodiments described above or below is a compound of Formula (IX) wherein n is 1 and ^R8 is selected from halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , -NR13SO2R14 ^{, -NR13C (} O ₎ ^R14 , ^-NR13C (O ⁾ _OR14 , ^-NR13C (O ^{) NR13R14 , -C} (O ^{) R14 ,} -C(O)OR In some embodiments described ^above or below, ^the compound is of formula (IX), wherein n is 1 and ^R is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments described above or below, the compound ^is of formula (IX), wherein n is 1 and ^R is halogen. In some embodiments described above or below, the compound is of formula (IX), wherein n is 1 and R is F. In some embodiments described above or below, the compound is of formula (IX), wherein n is 1 and R is ^Cl . In some embodiments described above or below, the compound is of formula (IX), wherein n is ¹ and ^R is -CN. In some embodiments described above or below, the compound is of formula (IX), wherein n is 1 and ^R is alkyl. In some embodiments described above or below, the compound is of formula (IX), wherein n is 1 and ^R is methyl. In some embodiments described above or below, the compound is of formula (IX), wherein n is 1 and R is ^ethyl . In some embodiments described above or below, the compound of formula (IX) is wherein n is 1 and ^R is alkoxy. In some embodiments described above or below, the compound of formula (IX) is wherein n is 1 and ^R is methoxy. In some embodiments described above or below, the compound of formula (IX) is wherein n is 1 and ^R is ethoxy. In some embodiments described above or below, the compound of formula (IX) is wherein n is 1 and ^R is haloalkoxy. In some embodiments described above or below, the compound of formula (IX) is wherein n is 1 and ^R is -OCF ₃ . In some embodiments described above or below, the compound of formula (IX) is wherein n is 1 and ^R is haloalkyl. In some embodiments described above or below, the compound of formula (IX) is wherein n is 1 and ^R is -CF ₃ .

In some embodiments described above or below is a compound of Formula (IX) wherein n is 2. In some embodiments described above or below is a compound of Formula (IX) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl ^, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, -NR13R14, ^-NR13SO2R14 , ^-NR13C (O ₎ ^R14 , ^-NR13C (O ^{) OR14} , ^-NR13C (O ₎ ^{NR13R14 , -C} (O) ^R14 , ^{-C (} O)OR In some embodiments described ^above or below, the compound is ^of formula (IX), wherein n is 2 and R ^{8 is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments described above or below, the compound is of formula (IX), wherein n is 2 and R 8 is} halogen. In some embodiments described above or below, the compound is of formula (IX), wherein n is 2 and each R ⁸ is F. In some embodiments described above or below, the compound is of formula (IX), wherein n is 2 and each R ⁸ is Cl. In some embodiments described above or below, the compound is of formula (IX), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (IX), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (IX), wherein n is 2 and R ⁸ is independently selected from halogen and alkyl. In some embodiments described above or below, the compound is of formula (IX), wherein n is 2 and R ⁸ is independently selected from -CN and alkyl. In some embodiments described above or below is a compound of Formula (IX) wherein n is 2 and two adjacent R ⁸ form a heterocyclyl ring.

In some embodiments described above or below, the compound is of formula (IX), wherein Z ¹ is O. In some embodiments described above or below, the compound is of formula (IX), wherein Z ¹ is S. In some embodiments described above or below, the compound is of formula (IX), wherein Z ¹ is NR ¹³ . In some embodiments described above or below, the compound is of formula (IX), wherein Z ¹ is N(CH ₃ ). In some embodiments described above or below, the compound is of formula (IX), wherein Z ¹ is NH.

In some embodiments described above or below, the compound is of formula (IX), wherein ^Z is O. In some embodiments described above or below, the compound is of formula (IX), wherein ^Z is S. In some embodiments described above or below, the compound is of formula (IX), wherein ^Z is NR ¹³ . In some embodiments described above or below, the compound is of formula (IX), wherein ^Z is N(CH ₃ ). In some embodiments described above or below, the compound is of formula (IX), wherein ^Z is NH. In some embodiments described above or below, the compound is of formula (IX), wherein ^Z is CH ₂ .

In some embodiments described above or below is a compound of Formula (IX) wherein Z ¹ and Z ² are each O.

In some embodiments described above or below is a compound of Formula (IX), _wherein -XY- is _-CH2CH2- . In some embodiments described above or below is a compound of Formula (IX), wherein -XY- is -CH=CH-. In some embodiments described above or below is a compound of Formula (IX), wherein -XY- is -CH=N-. In some embodiments described above or below is a compound of Formula (IX), wherein -XY- is -N=CH-.

In another embodiment is a compound of formula (IX) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of Formula (IXa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug or stereoisomer thereof:

in:

-XY- is -CH ₂ CH ₂ -, -CH=CH-, -CH=N- or -N=CH-;

Z ¹ is selected from O, S, NH and NR ¹³ ;

Z ² is selected from O, S, CH ₂ , NH and NR ¹³ ;

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

^R4 is halogen, alkyl,

Each R ⁷ is independently selected from halogen and alkyl;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

each R ¹⁵ is independently selected from haloalkyl, -alkylene(NR ¹³ R ¹⁴ ), -NR ¹³ R ¹⁴ and -SO ₂ R ¹³ ;

Each R ¹⁶ is independently selected from halogen, alkyl and haloalkyl;

Each R ¹⁷ is independently selected from halogen, alkyl, haloalkyl and -CN;

n is selected from 0, 1, 2, 3 and 4;

m is selected from 0, 1 and 2;

p is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3, and 4; and

t is independently selected from 0, 1, 2, 3 and 4.

In some embodiments, the compound of formula (IXa) is wherein R ^is halogen. In some embodiments, the compound of formula (IXa) is wherein R ^is F. In some embodiments, the compound of formula (IXa) is wherein R is ^Cl . In some embodiments, the compound of formula (IXa) is wherein ^R is alkyl. In some embodiments, the compound of formula (IXa) is wherein ^R is methyl. In some embodiments, the compound of formula (IXa) is wherein R is ^ethyl . In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R 4 is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R 4 is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R 4 is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R 4 is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R 4 is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R 4 is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R 4 is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R 4 is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R 4 is In some embodiments, the compound of formula (IXa) wherein R ⁴ is In some embodiments, the compound of formula (IXa) wherein R 4 is ⁴ is in some embodiments a compound of formula (IXa), wherein R ⁴ is in some embodiments a compound of formula (IXa), wherein R ⁴ is in some embodiments a compound of formula (IXa), wherein R ⁴ is in some embodiments a compound of formula (IXa), wherein R ⁴ is

In some embodiments, ^the compound of Formula (IXa) is ^-CH ( _CH3 ) _CH2CH2R2 . In _some embodiments, the compound of Formula (IXa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^{R2 is} H. In some embodiments, ^the compound of Formula (IXa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^R2 is alkyl. In some embodiments, the compound of Formula (IXa) is ^-CH ( _{CH3 ) CH2CH2R2} , ^and _R2 is ^methyl . In some embodiments, the compound of Formula ( _IXa ) is ^-CH ( _CH3 ) _CH2CH2R2 , and _R2 ^{is ethyl} . In some embodiments, the ^compound of Formula (IXa) is -CH( _CH3 ) _CH2CH2R2 , and _R2 is ^isopropyl . In some embodiments, the compound of Formula (IXa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^{R2 is -NR13R14 .} In some embodiments, the compound of Formula (IXa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^{R2 is} _-NH2 . In some embodiments, the compound of Formula ⁽ _IXa ) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^{R2 is} _-NHCH3 . In some embodiments, the compound of Formula (IXa) is ^-CH ( _{CH3 ) CH2CH2R2} , and _R2 ^is _-N ( ^CH3 ₎ ² _.

In some embodiments, the ^compound of Formula (IXa) is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound ^of Formula (IXa) is -CH( _CH3 ) ₂ . In some embodiments, _the compound of Formula (IXa) is -CH( _CH2CH3 )CH( _R3 ) ^CH3 . In some embodiments, the compound of Formula ( ^IXa ) is ^-CH ( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula (IXa) is ^-CH ( _CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of _Formula (IXa) is ^-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (IXa) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is ethyl. In _some embodiments, the compound of Formula ( _IXa ) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^{R3 is -NR13R14} . In some embodiments, the compound of Formula (IXa) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is _-NH2 . _In some embodiments, the compound of Formula ( _IXa ) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is _-NHCH3 . In some embodiments, the compound of formula (IXa) is ^-CH (CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (IXa) is -alkylene(cycloalkyl). In some embodiments, the compound ^of formula (IXa) is -CH ² _{CH 2} (cycloalkyl). In some embodiments, the compound of formula (IXa) is -CH ² (cycloalkyl). In some embodiments, the compound of formula (IXa) is -CH ₂ (cyclobutyl ₎ . In some embodiments, the compound of formula (IXa) is -CH ² (cyclopentyl). In some embodiments, the compound ^of formula (IXa) ^is -CH ₂ (cyclohexyl ₎ . In some embodiments, the compound of formula (IXa) is -CH ² (cyclohexyl).

In some embodiments, the compound of formula (IXa) is wherein R ¹ is In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (IXa) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (IXa) is wherein R ¹ is In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (IXa) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (IXa) is wherein R ¹ is In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (IXa) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (IXa) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments described above or below is a compound of Formula (IXa) wherein n is 0.

In some embodiments described above or below is a compound of Formula (IXa) wherein n is 1. In some embodiments described above or below is a compound of Formula (IXa) wherein n is 1 and ^R8 is selected from halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , -NR13SO2R14 ^{, -NR13C (} O ₎ ^R14 , ^-NR13C (O ⁾ _OR14 , ^-NR13C (O ^{) NR13R14 , -C} (O ^{) R14 ,} -C(O)OR In some embodiments described ^above or below, ^the compound is of formula (IXa), wherein n is 1 and ^R is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments described above or below, the compound ^is of formula (IXa), wherein n is 1 and ^R is halogen. In some embodiments described above or below, the compound is of formula (IXa), wherein n is 1 and R is F. In some embodiments described above or below, the compound is of formula (IXa), wherein n is 1 and R is ^Cl . In some embodiments described above or below, the compound is of formula (IXa), wherein n is 1 ^{and R} is -CN. In some embodiments described above or below, the compound is of formula (IXa), wherein n is 1 and ^R is alkyl. In some embodiments described above or below, the compound is of formula (IXa), wherein n is 1 and ^R is methyl. In some embodiments described above or below, the compound of formula (IXa) is wherein n is 1 and ^R is ethyl. In some embodiments described above or below, the compound of formula (IXa) is wherein n is 1 and ^R is alkoxy. In some embodiments described above or below, the compound of formula (IXa) is wherein n is 1 and ^R is methoxy. In some embodiments described above or below, the compound of formula (IXa) is wherein n is 1 and ^R is ethoxy. In some embodiments described above or below, the compound of formula (IXa) is wherein n is 1 and ^R is haloalkoxy. In some embodiments described above or below, the compound of formula (IXa) is wherein n is 1 and ^R is -OCF ₃ . In some embodiments described above or below, the compound of formula (IXa) is wherein n is 1 and ^R is haloalkyl. In some embodiments described above or below, the compound of formula (IXa) is wherein n is 1 and R is -CF ³ _.

In some embodiments described above or below is a compound of Formula (IXa) wherein n is 2. In some embodiments described above or below is a compound of Formula (IXa) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl ^, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, -NR13R14, ^-NR13SO2R14 , ^-NR13C (O ₎ ^R14 , ^-NR13C (O ^{) OR14} , ^-NR13C (O ₎ ^{NR13R14 , -C} (O) ^R14 , ^{-C (} O)OR In some embodiments described ^above or below, the compound is ^of formula (IXa), wherein n is 2 and R ^{8 is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments described above or below, the compound is of formula (IXa), wherein n is 2 and R 8 is} halogen. In some embodiments described above or below, the compound is of formula (IXa), wherein n is 2 and each R ⁸ is F. In some embodiments described above or below, the compound is of formula (IXa), wherein n is 2 and each R ⁸ is Cl. In some embodiments described above or below, the compound is of formula (IXa), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (IXa), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (IXa), wherein n is 2 and R ⁸ is independently selected from halogen and alkyl. In some embodiments described above or below, the compound is of formula (IXa), wherein n is 2 and R ⁸ is independently selected from -CN and alkyl. In some embodiments described above or below is a compound of Formula (IXa) wherein n is 2 and two adjacent R ⁸ form a heterocyclyl ring.

In some embodiments described above or below, the compound is of Formula (IXa), wherein Z ¹ is O. In some embodiments described above or below, the compound is of Formula (IXa), wherein Z ¹ is S. In some embodiments described above or below, the compound is of Formula (IXa), wherein Z ¹ is NR ¹³ . In some embodiments described above or below, the compound is of Formula (IXa), wherein Z ¹ is N(CH ₃ ). In some embodiments described above or below, the compound is of Formula (IXa), wherein Z ¹ is NH.

In some embodiments described above or below, the compound is of formula (IXa), wherein ^Z is O. In some embodiments described above or below, the compound is of formula (IXa), wherein ^Z is S. In some embodiments described above or below, the compound is of formula (IXa), wherein ^Z is NR ¹³ . In some embodiments described above or below, the compound is of formula (IXa), wherein ^Z is N(CH ₃ ). In some embodiments described above or below, the compound is of formula (IXa), wherein ^Z is NH. In some embodiments described above or below, the compound is of formula (IXa), wherein ^Z is CH ₂ .

In some embodiments described above or below is a compound of Formula (IXa) wherein Z ¹ and Z ² are each O.

In some embodiments described above or below is a compound of Formula (IXa), _wherein -XY- is _-CH2CH2- . In some embodiments described above or below is a compound of Formula (IXa), wherein -XY- is -CH=CH-. In some embodiments described above or below is a compound of Formula (IXa), wherein -XY- is -CH=N-. In some embodiments described above or below is a compound of Formula (IXa), wherein -XY- is -N=CH-.

In another embodiment is a compound of Formula (IXa) having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (X) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug or stereoisomer thereof:

in:

-XY- is -CH ₂ CH ₂ -, -CH=CH-, -CH=N- or -N=CH-;

Z ¹ is selected from O, S, NH and NR ¹³ ;

Z ² is selected from O, S, CH ₂ , NH and NR ¹³ ;

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

each R ¹⁵ is independently selected from haloalkyl, -alkylene(NR ¹³ R ¹⁴ ), -NR ¹³ R ¹⁴ and -SO ₂ R ¹³ ;

Each R ¹⁶ is independently selected from halogen, alkyl and haloalkyl;

Each R ¹⁷ is independently selected from halogen, alkyl, haloalkyl and -CN;

n is selected from 0, 1, 2, 3 and 4;

p is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3, and 4; and

t is independently selected from 0, 1, 2, 3 and 4;

When ^Z1 and ^Z2 are both O, -XY- is -CH=CH-, -CH=N- or -N=CH-.

In some embodiments, ^{the compound} of Formula (X) is -CH( _CH3 ) _CH2CH2R2 . In _some embodiments, the compound of Formula (X) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^R2 is H. In some embodiments, ^the compound ^of Formula (X) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^R2 is alkyl. In some embodiments, the compound of Formula (X) is ^-CH ( _{CH3 ) CH2CH2R2} , ^{and R2} _is ^methyl . In some embodiments, the compound of Formula ( _X ) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^R2 is ^ethyl . In some embodiments, _the compound of Formula (X) is ^-CH ( _{CH3 ) CH2CH2R2} , and ^R2 is ^isopropyl . In some embodiments, the compound of Formula (X) is R1, wherein ^R1 is -CH( _CH3 ) _CH2CH2R2 , and _R2 ^{is -NR13R14} . In some embodiments, the compound ^of Formula (X) is R1, wherein ^R1 is -CH( _{CH3 )} ^CH2CH2R2 , and _R2 ^{is -NH2} . In some embodiments, the compound of Formula (X) is _R1 , wherein ^R1 is -CH( _CH3 ) _CH2CH2R2 , and ^{R2 is} _-NHCH3 . In some embodiments, the compound of Formula (X) is R1, wherein ^R1 is _-CH ( _CH3 ) _CH2CH2R2 , and _R2 ^{is -N} ( _CH3 ) ₂ .

In some embodiments, the compound of Formula (X ⁾ is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound ^of Formula (X) is -CH( _CH3 ) ₂ . In some embodiments, the compound of Formula (X) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 ^. In some embodiments, the compound of Formula (X) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula (X) is ^-CH ( _CH2CH3 )CH ^(R3 _{) CH3} ^, and ^R3 is alkyl. In some embodiments, the compound of _Formula (X) is ^-CH ( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (X) is ^-CH ( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^R3 is ethyl. In some embodiments, the compound of ^Formula (X) is -CH( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^{R3 is -NR13R14} . In some embodiments, the compound of Formula (X) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is _-NH2 . In some embodiments, ^{the compound of Formula (X) is -CH(CH2CH3)CH(R3 )} _CH3 ^, _{and R3} ^is _-NHCH3 . In some embodiments, the compound ^of formula (X) is -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (X) is -alkylene(cycloalkyl). In some embodiments, the compound of formula (X ⁾ is -CH ² _{CH 2} (cycloalkyl). In some embodiments, the compound of formula (X) is -CH ² (cycloalkyl). In some embodiments, the compound of formula (X) is -CH ₂ (cyclobutyl ₎ . In some embodiments, the compound of formula (X ⁾ is -CH ² (cyclopentyl ₎ . In some embodiments, the compound of formula (X ⁾ is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula ( ^X ) is

In some embodiments, the compound of formula (X) is wherein R ¹ is In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (X) is wherein R ¹ is In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments, the compound of formula (X) is wherein R ¹ is In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is H. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is alkyl. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is methyl. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is ethyl. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is isopropyl. In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is -NH ₂ . In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments, the compound of formula (X) is wherein R ¹ is and R ² is -N(CH ₃ ) ₂ .

In some embodiments described above or below is a compound of Formula (X) wherein n is 0.

In some embodiments described above or below is a compound of Formula (X) wherein n is 1. In some embodiments described above or below is a compound of Formula (X) wherein n is 1 and ^R8 is selected from halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , -NR13SO2R14 ^{, -NR13C (} O ₎ ^R14 , ^-NR13C (O ⁾ _OR14 , ^-NR13C (O ^{) NR13R14 , -C} (O ^{) R14 ,} -C(O)OR In some embodiments described ^above or below, ^the compound is of formula (X), wherein n is 1 and ^R is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments described above or below, the compound ^is of formula (X), wherein n is 1 and ^R is halogen. In some embodiments described above or below, the compound is of formula (X), wherein n is 1 and R is F. In some embodiments described above or below, the compound is of formula (X), wherein n is 1 and R is ^Cl . In some embodiments described above or below, the compound is of formula (X), wherein n is ¹ and ^R is -CN. In some embodiments described above or below, the compound is of formula (X), wherein n is 1 and ^R is alkyl. In some embodiments described above or below, the compound is of formula (X), wherein n is 1 and ^R is methyl. In some embodiments described above or below, the compound is of formula (X), wherein n is 1 and R is ^ethyl . In some embodiments described above or below, the compound of formula (X) is wherein n is 1 and ^R is alkoxy. In some embodiments described above or below, the compound of formula (X) is wherein n is 1 and ^R is methoxy. In some embodiments described above or below, the compound of formula (X) is wherein n is 1 and ^R is ethoxy. In some embodiments described above or below, the compound of formula (X) is wherein n is 1 and ^R is haloalkoxy. In some embodiments described above or below, the compound of formula (X) is wherein n is 1 and ^R is -OCF ₃ . In some embodiments described above or below, the compound of formula (X) is wherein n is 1 and ^R is haloalkyl. In some embodiments described above or below, the compound of formula (X) is wherein n is 1 and ^R is -CF ₃ .

In some embodiments described above or below is a compound of Formula (X) wherein n is 2. In some embodiments described above or below is a compound of Formula (X) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl ^, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, -NR13R14, ^-NR13SO2R14 , ^-NR13C (O ₎ ^R14 , ^-NR13C (O ^{) OR14} , ^-NR13C ( ^O ₎ ^{NR13R14 , -C} (O) ^R14 , -C ⁽ O)OR In some embodiments described ^above or below, the compound is ^of formula (X), wherein n is 2 and R ^{8 is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments described above or below, the compound is of formula (X), wherein n is 2 and R 8 is} halogen. In some embodiments described above or below, the compound is of formula (X), wherein n is 2 and each R ⁸ is F. In some embodiments described above or below, the compound is of formula (X), wherein n is 2 and each R ⁸ is Cl. In some embodiments described above or below, the compound is of formula (X), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (X), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (X), wherein n is 2 and R ⁸ is independently selected from halogen and alkyl. In some embodiments described above or below, the compound is of formula (X), wherein n is 2 and R ⁸ is independently selected from -CN and alkyl. In some embodiments described above or below is a compound of Formula (X) wherein n is 2 and two adjacent R ⁸ form a heterocyclyl ring.

In some embodiments described above or below is a compound of Formula (X), wherein Z ¹ is O. In some embodiments described above or below is a compound of Formula (X), wherein Z ¹ is S. In some embodiments described above or below is a compound of Formula (X), wherein Z ¹ is NR ¹³ . In some embodiments described above or below is a compound of Formula (X), wherein Z ¹ is N(CH ₃ ). In some embodiments described above or below is a compound of Formula (X), wherein Z ¹ is NH.

In some embodiments described above or below, the compound is of formula (X), wherein ^Z is O. In some embodiments described above or below, the compound is of formula (X), wherein ^Z is S. In some embodiments described above or below, the compound is of formula (X), wherein ^Z is NR ¹³ . In some embodiments described above or below, the compound is of formula (X), wherein ^Z is N(CH ₃ ). In some embodiments described above or below, the compound is of formula (X), wherein ^Z is NH. In some embodiments described above or below, the compound is of formula (X), wherein ^Z is CH ₂ .

In some embodiments described above or below is a compound of Formula (X) wherein Z ¹ and Z ² are each O.

In some embodiments described above or below is a compound of formula (X), _wherein -XY- is _-CH2CH2- . In some embodiments described above or below is a compound of formula (X), wherein -XY- is -CH=CH-. In some embodiments described above or below is a compound of formula (X), wherein -XY- is -CH=N-. In some embodiments described above or below is a compound of formula (X), wherein -XY- is -N=CH-.

In another embodiment is a compound of formula (X) having the structure:

A pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of formula (Xa) having the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug or stereoisomer thereof:

in:

-XY- is -CH ₂ CH ₂ -, -CH=CH-, -CH=N- or -N=CH-;

Z ¹ is selected from O, S, NH and NR ¹³ ;

Z ² is selected from O, S, CH ₂ , NH and NR ¹³ ;

R ¹ is -CH(CH ₃ )CH ₂ CH ₂ R ² , -CH(CH ₂ CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(R ³ )CH ₃ , -alkylene (cycloalkyl) or

R ² is H, alkyl or -NR ¹³ R ¹⁴ ;

R ³ is -OH, alkyl or -NR ¹³ R ¹⁴ ;

Each R ⁸ is independently selected from halogen, -OH, -NO ₂ , -N ₃ , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ₁₃ SO ² R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , ^{-NR 13} _C (O)OR ¹⁴ , -NR ¹³ C(O)NR ^{13 R 14} , -C(O)R ¹⁴ , -C(O)OR ^{14 ,} and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ⁸ form a heterocyclyl ring;

each R ¹³ and each R ¹⁴ are each independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

each R ¹⁵ is independently selected from haloalkyl, -alkylene(NR ¹³ R ¹⁴ ), -NR ¹³ R ¹⁴ and -SO ₂ R ¹³ ;

Each R ¹⁶ is independently selected from halogen, alkyl and haloalkyl;

Each R ¹⁷ is independently selected from halogen, alkyl, haloalkyl and -CN;

n is selected from 0, 1, 2, 3 and 4;

p is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3, and 4; and

t is independently selected from 0, 1, 2, 3 and 4;

When ^Z1 and ^Z2 are both O, -XY- is -CH=CH-, -CH=N- or -N=CH-.

In some embodiments, ^the compound of Formula (Xa) is ^-CH ( _CH3 ) _CH2CH2R2 . In _some embodiments, the compound of Formula (Xa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^R2 is H. In some embodiments, ^the compound ^of Formula (Xa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^R2 is alkyl. In some embodiments, the compound of Formula (Xa) is ^-CH ( _{CH3 ) CH2CH2R2} , ^{and R2} _is ^methyl . In some embodiments, the compound of Formula (Xa) is ^-CH ( _CH3 ) _CH2CH2R2 , ^and _R2 ^is _ethyl . In some embodiments, the ^compound of Formula (Xa) is -CH( _CH3 ) _CH2CH2R2 , and _R2 is ^isopropyl . In some embodiments, the compound of Formula (Xa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^{R2 is -NR13R14 .} In some embodiments, the compound of Formula (Xa) is ^-CH ( _{CH3 ) CH2CH2R2} , and ^{R2 is} _-NH2 . In some embodiments, the compound of Formula ⁽ Xa) is ^-CH ( _CH3 ) _CH2CH2R2 , and ^{R2 is} _-NHCH3 . In some embodiments, the compound of Formula (Xa) is ^-CH ( _{CH3 ) CH2CH2R2} , and _R2 ^is _-N ( ^CH3 ₎ ² _.

In some embodiments, the ^compound of Formula (Xa) is -CH( _CH2CH3 ) ₂ . In _some embodiments, the compound of Formula (Xa) is -CH( _CH3 ) ² _. In some embodiments, the compound of Formula (Xa) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 ^. In some embodiments, the compound of Formula (Xa) is ^-CH ( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is -OH. In some embodiments, the compound of Formula (Xa) is ^-CH ( ^CH2CH3 )CH ^(R3 _{) CH3} , and ^R3 is alkyl. In some embodiments, the compound of _Formula (Xa) is ^-CH ( _CH2CH3 ) _CH ( ^R3 ) _CH3 , and ^R3 is methyl. In some embodiments, the compound of Formula (Xa) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is ethyl. In _some embodiments, the compound of Formula (Xa) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( _R3 ⁾ _CH3 , and ^{R3 is -NR13R14} . In some embodiments, the compound of Formula (Xa) is R1, wherein ^R1 is -CH( _CH2CH3 )CH( ^R3 ) _CH3 , and ^R3 is _-NH2 . In some embodiments _, the compound of Formula (Xa) is R1, ^{wherein R1} is -CH( _CH2CH3 )CH( _R3 ) _CH3 , and ^R3 is _-NHCH3 . In some embodiments, the compound of formula (Xa) is ^-CH (CH ₂ CH ₃ )CH(R ³ )CH ₃ and R ³ is -N(CH ₃ ) ₂ . In some embodiments, the compound of formula (Xa) is -alkylene(cycloalkyl). In some embodiments, the compound of formula (Xa ⁾ is -CH ² CH ₂ (cycloalkyl) _. In some embodiments, the compound of formula (Xa) is -CH ² (cycloalkyl). In some embodiments, the compound of formula (Xa) is -CH ₂ (cyclobutyl ₎ . In some embodiments, the compound of formula (Xa) is -CH ² (cyclopentyl). In some embodiments, the compound ^of formula (Xa) ^is -CH ₂ (cyclohexyl). In some embodiments, the compound of formula (Xa) is -CH ₂ (cyclohexyl ⁾ .

In some embodiments, there is a compound of formula (Xa) wherein R ¹ is In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is H. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is alkyl. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is methyl. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is ethyl. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is isopropyl. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (Xa) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, there is a compound of formula (Xa) wherein R ¹ is In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is H. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is alkyl. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is methyl. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is ethyl. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is isopropyl. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (Xa) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments, there is a compound of formula (Xa) wherein R ¹ is In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is H. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is alkyl. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is methyl. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is ethyl. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is isopropyl. In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is -NR ¹³ R ¹⁴ . In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is -NH ₂ . In some embodiments, there is a compound of formula (Xa) wherein R ¹ is and R ² is -NHCH ₃ . In some embodiments is a compound of Formula (Xa) wherein R ¹ is and R ² is —N(CH ₃ ) ₂ .

In some embodiments described above or below is a compound of Formula (Xa) wherein n is 0.

In some embodiments described above or below is a compound of Formula (Xa) wherein n is 1. In some embodiments described above or below is a compound of Formula (Xa) wherein n is 1 and ^R8 is selected from halogen, -OH, -NO2, _-N3 , _-CN , alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, ^-NR13R14 , -NR13SO2R14 ^{, -NR13C (} O ₎ ^R14 , ^-NR13C (O ⁾ _OR14 , ^-NR13C (O ^{) NR13R14 , -C} (O ^{) R14 ,} -C(O)OR In some embodiments described ^above or below, ^the compound is of formula (Xa), wherein n is 1 and ^R is selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, or haloalkyl. In some embodiments described above or below, the compound ^is of formula (Xa), wherein n is 1 and ^R is halogen. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 1 and R is F. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 1 and R is ^Cl . In some embodiments described above or below, the compound is of formula (Xa), wherein n is ¹ and ^R is -CN. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 1 and ^R is alkyl. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 1 and ^R is methyl. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 1 and R ⁸ is ethyl. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 1 and R ⁸ is alkoxy. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 1 and R ⁸ is methoxy. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 1 and R ⁸ is ethoxy. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 1 and R ⁸ is haloalkoxy. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 1 and R ⁸ is -OCF ₃ . In some embodiments described above or below, the compound is of formula (Xa), wherein n is 1 and R ⁸ is haloalkyl. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 1 and R ⁸ is -CF ₃ .

In some embodiments described above or below is a compound of Formula (Xa) wherein n is 2. In some embodiments described above or below is a compound of Formula (Xa) wherein n is ₂ and ^R8 is independently selected from halogen, -OH, -NO2, _-N3 , -CN, alkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene( ^NR13R14 ), -alkylene( ^cycloalkyl ), -alkylene(heterocyclyl), cycloalkyl, heterocyclyl ^, _aryl , ^heteroaryl , ^-SR13 , ^-SOR13 , -SO2R13, -SO2NR13R14, -NR13R14, ^-NR13SO2R14 , ^-NR13C (O ₎ ^R14 , ^-NR13C (O ^{) OR14} , ^-NR13C (O ₎ ^{NR13R14 , -C} (O) ^R14 , ^{-C (} O)OR In some embodiments described ^above or below, the compound is ^of formula (Xa), wherein n is 2 and R ^{8 is independently selected from halogen, -CN, alkyl, alkoxy, haloalkoxy, and haloalkyl. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 2 and R 8 is} halogen. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 2 and each R ⁸ is F. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 2 and each R ⁸ is Cl. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 2 and R ⁸ is independently selected from halogen and -CN. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 2 and R ⁸ is independently selected from halogen and alkyl. In some embodiments described above or below, the compound is of formula (Xa), wherein n is 2 and R ⁸ is independently selected from -CN and alkyl. In some embodiments described above or below is a compound of Formula (Xa) wherein n is 2 and two adjacent R ⁸ form a heterocyclyl ring.

In some embodiments described above or below is a compound of Formula (Xa), wherein Z ¹ is O. In some embodiments described above or below is a compound of Formula (Xa), wherein Z ¹ is S. In some embodiments described above or below is a compound of Formula (Xa), wherein Z ¹ is NR ¹³ . In some embodiments described above or below is a compound of Formula (Xa), wherein Z ¹ is N(CH ₃ ). In some embodiments described above or below is a compound of Formula (Xa), wherein Z ¹ is NH.

In some embodiments described above or below, the compound is of formula (Xa), wherein ^Z is O. In some embodiments described above or below, the compound is of formula (Xa), wherein ^Z is S. In some embodiments described above or below, the compound is of formula (Xa), wherein ^Z is NR ¹³ . In some embodiments described above or below, the compound is of formula (Xa), wherein ^Z is N(CH ₃ ). In some embodiments described above or below, the compound is of formula (Xa), wherein ^Z is NH. In some embodiments described above or below, the compound is of formula (Xa), wherein ^Z is CH ₂ .

In some embodiments described above or below is a compound of Formula (Xa) wherein Z ¹ and Z ² are each O.

In some embodiments described above or below is a compound of Formula (Xa), _wherein -XY- is _-CH2CH2- . In some embodiments described above or below is a compound of Formula (Xa), wherein -XY- is -CH=CH-. In some embodiments described above or below is a compound of Formula (Xa), wherein -XY- is -CH=N-. In some embodiments described above or below is a compound of Formula (Xa), wherein -XY- is -N=CH-.

In another embodiment is a compound of Formula (Xa) having the structure:

A pharmaceutically acceptable salt, a pharmaceutically acceptable solvate or a pharmaceutically acceptable prodrug thereof.

Further provided herein is a method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject one or more compounds identified herein. The disease or condition can be fibrosis. The fibrosis can be liver fibrosis. The liver fibrosis can be idiopathic pulmonary fibrosis.

Further provided herein is a method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject one or more compounds identified herein. The disease or condition can be fibrosis. The fibrosis can be a chronic autoimmune disease. The chronic autoimmune disease can be rheumatoid arthritis, scleroderma, Crohn's disease, or systemic lupus erythematosus.

Preparation of compounds

Described herein are compounds for treating fibrosis, conditions characterized by fibrosis, or diseases characterized by fibrosis, and methods for their preparation. Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs of these compounds. Also provided are pharmaceutical compositions comprising at least one such compound, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite, or pharmaceutically acceptable prodrug of such a compound, and a pharmaceutically acceptable excipient.

Compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) described herein can be synthesized using standard synthetic reactions known to those skilled in the art or using methods known in the art. The reactions can be employed in a linear sequence to provide the compounds, or these reactions can be used to synthesize fragments that are subsequently linked by methods known in the art.

Starting materials used to synthesize the compounds described herein may be synthesized or may be obtained from commercial sources such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma Chemical Co. (St. Louis, Mo.). The compounds described herein and other related compounds having various substituents can be synthesized using techniques and materials known to those skilled in the art, for example, using techniques and materials described in, for example, March, ADVANCED ORGANIC CHEMISTRY, 4th ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, 4th ed., Vols. A and B (Plenum 2000, 2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3rd ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1990); Sons, 1991); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). (All of which are incorporated herein by reference in their entirety.) Other methods for synthesizing the compounds described herein can be found in International Patent Publication No. WO 01/01982901, Arnold et al., Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170; Burchat et al., Bioorganic & Medicinal Chemistry Letters 12 (2002) 1687-1690. General methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and to introduce the various moieties found in the general formulas provided herein, the reactions can be modified by using appropriate reagents and conditions, as recognized by those skilled in the art.

The reaction products can be isolated and purified, if desired, using conventional techniques including, but not limited to, filtration, distillation, crystallization, and chromatography. Such materials can be characterized using conventional means including physical constants and spectral data.

The compounds described herein can be prepared as a single isomer or as a mixture of isomers.

Other forms of the compounds disclosed herein

Isomers

In addition, in some embodiments, the compounds described herein exist in the form of geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis, trans, same side, opposite side, E type (E) and Z type (Z) isomers and their corresponding mixtures. In some cases, the compounds exist in the form of tautomers. The compounds described herein include all possible tautomers within the general formula described herein. In some cases, the compounds described herein have one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereoisomers, enantiomers and epimeric forms and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, the enantiomers and/or diastereoisomer mixtures obtained by a single preparation step, combination or mutual conversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting the racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereoisomers and recovering optically pure enantiomers. In some embodiments, separable complexes (e.g., crystalline diastereomeric salts) are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.), and these differences are utilized to separate. In some embodiments, diastereomers are separated by chiral chromatography or preferably by separation/resolution techniques based on solubility differences. In some embodiments, optically pure enantiomers and resolving agents are then recovered by any practical means that do not cause racemization.

Labeled compounds

In some embodiments, the compounds described herein exist in the form of their isotopic labels. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such isotopically labeled compounds in the form of pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, and except that one or more atoms are replaced with atoms having atomic masses or mass numbers different from those commonly found in nature, the isotopically labeled compounds are identical to the compounds described herein. Examples of isotopes that can be introduced into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively. Compounds described herein containing other isotopes of the above-mentioned isotopes and/or other atoms and their metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives are within the scope of the present invention. Certain isotopically labeled compounds, for example, those into which radioactive isotopes such as ³ H and ¹⁴ C are introduced, can be used for drug and/or substrate tissue distribution analysis. Tritiated (i.e. ³ H) and carbon-14 (i.e. ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavy isotopes such as deuterium (i.e. ² H) produces certain therapeutic advantages caused by higher metabolic stability, such as an extension of half-life in vivo or a reduction in dosage requirements. In some embodiments, isotopically labeled compounds, their pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives are prepared by any suitable method.

In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically acceptable salts

In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts in the form of pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the purified compound in free form with a suitable acid or base, respectively, and isolating the salt thus formed.

Examples of pharmaceutically acceptable salts include those prepared by reacting a compound described herein with an inorganic acid, an organic acid, or an inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride salt, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, such pharmaceutically acceptable inorganic or organic acids include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzyl alcohol, benzoic acid ... [0014] Examples of the present invention include, but are not limited to, oxalic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids such as oxalic acid, while not pharmaceutically acceptable per se, are used to prepare salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

In some embodiments, compounds described herein that contain free acid groups are reacted with a suitable base, such as a pharmaceutically acceptable hydroxide, carbonate, bicarbonate, sulfate of a metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N ⁺ (C _1-4 alkyl) ₄ , and the like.

Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.

Solvates

In some embodiments, the compounds described herein exist in the form of solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates in the form of pharmaceutical compositions.

Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed in the processes described herein. By way of example only, organic solvents including but not limited to dioxane, tetrahydrofuran, or methanol can be conveniently used to prepare hydrates of the compounds described herein by recrystallization from an aqueous/organic solvent mixture. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, for the compounds and methods provided herein, the solvated forms are considered to be equivalent to the unsolvated forms.

polymorphs

In some embodiments, the compounds described herein exist in the form of polymorphs. The present invention provides methods of treating diseases by administering such polymorphs. The present invention further provides methods of treating diseases by administering such polymorphs in the form of pharmaceutical compositions.

Thus, the compounds described herein include all crystalline forms thereof, referred to as polymorphs. Polymorphs include different crystal packing arrangements of a compound having the same elemental composition. In some cases, polymorphs have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. In some cases, various factors such as recrystallization solvent, crystallization rate, and storage temperature cause a single crystalline form to predominate.

Prodrug

In some embodiments, the compounds described herein exist in the form of prodrugs. The present invention provides methods of treating diseases by administering such prodrugs. The present invention further provides methods of treating diseases by administering such prodrugs in the form of pharmaceutical compositions.

Prodrugs are generally drug precursors that, after being administered to an individual and subsequently absorbed, are converted into active or more active substances via a process such as conversion through metabolic pathways. Some prodrugs have chemical groups on the prodrug that make it less active and/or impart drug solubility or some other properties. Once the chemical group is cleaved and/or modified from the prodrug, an active drug is produced. Because prodrugs are easier to administer than the parent drug in some cases, prodrugs are generally available. For example, they can be bioavailable by oral administration, while the parent drug cannot. In some cases, prodrugs also have improved solubility in pharmaceutical compositions than the parent drug. An example of a prodrug is, but is not limited to, a compound as described herein, which is administered in the form of an ester ("prodrug") to facilitate transport across cell membranes where water solubility is unfavorable for mobility, but which is then metabolically hydrolyzed into a carboxylic acid (active entity) once inside the cell where water solubility is favorable. Another example of a prodrug can be a short peptide (polyamino acid) bonded to an acid group, wherein the peptide is metabolized to reveal the active portion. (See, e.g., Bundgaard, "Design and Application of Prodrugs", A Textbook of Drug Design and Development, eds. Krosgaard-Larsen and Bundgaard, 1991, Chapter 5, 113-191, which is incorporated herein by reference).

In some embodiments, prodrugs are designed as reversible drug derivatives to act as modulators that enhance drug delivery to site-specific tissues. To date, prodrugs have been designed to enhance the effective aqueous solubility of therapeutic compounds targeted to regions where water is the primary solvent.

In addition, prodrug derivatives of the compounds described herein can be prepared by methods described herein or known in the art (for more details, see Saulnier et al., Bioorganic and Medicinal Chemistry Letters, 1994, 4, 1985). By way of example only, suitable prodrugs can be prepared by reacting the underivatized compound with a suitable carbamoylating agent such as, but not limited to, 1,1-acyloxyalkyl chloroformate, p-nitrophenyl carbonate, or the like. Prodrug forms of the compounds described herein (wherein the prodrug is metabolized in vivo to produce a derivative as described herein) are included within the scope of the claims. In fact, some of the compounds described herein are prodrugs of another derivative or active compound.

In some embodiments, prodrugs include compounds in which amino acid residues or polypeptide chains with two or more (e.g., 2, 3, or 4) amino acid residues are covalently attached to the free amino groups, hydroxyl groups, or carboxylic acid groups of the compounds of the invention via amide bonds or ester bonds. Amino acid residues include, but are not limited to, 20 naturally occurring amino acids, and also include 4-hydroxyproline, hydroxylysine, demosine, isodesine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. In other embodiments, prodrugs include compounds in which nucleic acid residues or oligonucleotides with two or more (e.g., 2, 3, or 4) nucleic acid residues are covalently attached to the compounds of the invention.

Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternized derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphates, metal salts, and sulfonates. Compounds having free amino, amide, hydroxyl, or carboxyl groups can be converted into prodrugs. For example, a free carboxyl group can be derivatized into an amide or alkyl ester. In some cases, groups including, but not limited to, ether, amine, and carboxylic acid functional groups are introduced into all of these prodrug moieties.

Hydroxy prodrugs include esters such as, but not limited to, acyloxyalkyl (e.g., acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphates, sulfonates, sulfates, and disulfide-containing esters; ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates, and phosphooxymethoxycarbonyl, as summarized in Advanced Drug Delivery Reviews 1996, 19, 115.

Amine-derived prodrugs include, but are not limited to, the following groups and combinations of groups:

and sulfonamides and phosphamides.

In certain instances, sites on any aromatic ring moiety are susceptible to various metabolic reactions, and thus incorporation of appropriate substituents on the aromatic ring structure can reduce, minimize, or eliminate this metabolic pathway.

metabolites

In some embodiments, compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), or (Xa) are susceptible to various metabolic reactions. Thus, in some embodiments, incorporating suitable substituents into the structure will reduce, minimize, or eliminate metabolic pathways. In specific embodiments, by way of example only, suitable substituents that reduce or eliminate the susceptibility of the aromatic ring to metabolic reactions are halogen or alkyl.

In additional or further embodiments, a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa), upon administration to an organism in need thereof, is metabolized to produce a metabolite which is subsequently used to produce a desired effect, including a desired therapeutic effect.

Pharmaceutical compositions/preparations

In another aspect, provided herein are pharmaceutical compositions comprising a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) as described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the compounds described herein are formulated as pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into a pharmaceutically usable formulation. The appropriate formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference.

Provided herein are pharmaceutical compositions comprising a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), or (Xa) and at least one pharmaceutically acceptable inactive ingredient. In some embodiments, the compounds described herein are administered as pharmaceutical compositions in which a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), or (Xa) is mixed with other active ingredients, such as in a combination therapy. In other embodiments, the pharmaceutical composition comprises other medical or pharmaceutical preparations, carriers, adjuvants, preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts and/or buffers for regulating osmotic pressure. In still other embodiments, the pharmaceutical composition comprises other therapeutically valuable substances.

As used herein, a pharmaceutical composition refers to a mixture of a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), or (Xa) with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, antioxidants, preservatives, or one or more combinations thereof. Pharmaceutical compositions facilitate administration of the compound to an organism. In practicing the methods of treatment or uses provided herein, a therapeutically effective amount of a compound described herein is administered in the form of a pharmaceutical composition to a mammal suffering from a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. The therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound can be used alone or in combination with one or more therapeutic agents as a component of a mixture.

The pharmaceutical formulations described herein are administered to a subject via an appropriate route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, lozenges, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and immediate and controlled release mixed formulations.

Pharmaceutical compositions comprising a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) are manufactured in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, embedding or compression methods.

The pharmaceutical compositions will comprise at least one compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), or (Xa) as an active ingredient in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides (if appropriate), crystalline forms, amorphous phases, and active metabolites of these compounds having the same type of activity. In some embodiments, the compounds described herein exist in unsolvated form or in solvated form with a pharmaceutically acceptable solvent such as water, ethanol, or the like. The solvated forms of the compounds provided herein are also considered to be disclosed herein.

Pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants (if necessary) to obtain tablets or lozenge cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other excipients, such as polyvinyl pyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked sodium carboxymethylcellulose, polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate are added. In some embodiments, dyes or pigments are added to the tablet or lozenge coating for identification or characterization of different combinations of active compound doses.

Pharmaceutical formulations for oral administration include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Push-fit capsules contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

In certain embodiments, delivery systems for pharmaceutical compounds may be employed, such as liposomes and emulsions. In certain embodiments, the compositions provided herein may further comprise a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate, and dextran.

Combination therapy

The compounds according to Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) described herein can be used in combination with one or more additional anti-fibrotic agents. The anti-fibrotic agent can be a lysophosphatidic acid 1 (LPA1) antagonist. The anti-fibrotic agent can be selected from pirfenidone, nintedanib, thalidomide, carlumab, FG-3019, fusumab, interferon α, lecithinized superoxide dismutase, simtuzumab, tanzisertib, tralokinumab, hu3G9, huTBTl3_2_1, 2126458, AM-152, IFN-γ-1b, IW-001, PRM-151, PX S-25, pentoxifylline/N-acetyl-cysteine, pentoxifylline/vitamin E, salbutamol sulfate, [Sar9,Met(O2)11]-substance P, pentoxifylline, cysteamine bitartrate, obeticholic acid, aramchol, GFT-505, eicosapentaenoic acid ethyl ester, metformin hydrochloride, metreleptin, muromonab-CD3, oltipraz, IMM-124-E, MK-4074, PX-102, and RO-5093151.

The compounds according to Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) described herein can be used in combination with one or more additional azole antifungal agents. The azole antifungal agent can be selected from an imidazole antifungal agent, a triazole antifungal agent or a thiazole antifungal agent. Examples of such antifungal agents include, but are not limited to, imidazole derivatives such as miconazole, ketoconazole, clotrimazole, clomidazole, cloconazole, econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, miconazole, neticonazole, oxiconazole, sertaconazole, sulconazole, tioconazole; triazole derivatives such as fluconazole, fosfluconazole, hexaconazole, itraconazole, isavuconazole, posaconazole, voriconzaole, terconazole, albaconazole; and thiazole derivatives such as abafungin.

Administration of the pharmaceutical composition

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, spray, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ear, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

In some embodiments, the compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), or (Xa), and compositions thereof, are administered in any suitable manner. The mode of administration can be selected based on, for example, whether local or systemic treatment is desired and the area to be treated. For example, the compositions can be administered orally, parenterally (e.g., by intravenous, subcutaneous, intraperitoneal, or intramuscular injection), by inhalation, in vitro, topically (including transdermal, ocular, vaginal, rectal, intranasal), and the like.

If used, parenteral administration of the composition is typically characterized by injection. Injections can be prepared in conventional forms, as liquid solutions or suspensions, solid forms suitable for dissolution or suspension in liquids prior to injection, or as emulsions. Recent revisions to parenteral administration methods include the use of slow-release or delayed-release systems to maintain a constant dose.

Treatment

Also provided herein is a method of treating fibrosis, a disorder characterized by fibrosis, or a disease characterized by fibrosis in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), or (Xa) as described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient.

Also provided herein is a method of treating fibrosis using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) as described herein, wherein the fibrosis is liver fibrosis, idiopathic pulmonary fibrosis, renal fibrosis or cardiac fibrosis.

Also provided herein is a method of treating liver fibrosis associated with late stages of alcoholic or non-alcoholic cirrhosis using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) as described herein.

Also provided herein is a method of treating fibrosis using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) as described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, wherein the fibrosis is idiopathic pulmonary fibrosis.

Also provided herein is a method of treating a disease using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) as described herein, wherein the disease or condition characterized by fibrosis is a chronic autoimmune disease.

Also provided herein is a method of treating a chronic autoimmune disease using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) as described herein, wherein the chronic autoimmune disease is rheumatoid arthritis, scleroderma, Crohn's disease and systemic lupus erythematosus.

Also provided herein is a method of treating a chronic autoimmune disease using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) as described herein, wherein the chronic autoimmune disease is scleroderma.

Also provided herein is a method of treating fibrosis using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) as described herein, wherein the fibrosis is keloid formation resulting from abnormal wound healing.

Also provided herein is a method of treating fibrosis following organ transplantation using a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa).

Also provided herein is a method for treating fibrosis, a disease characterized by fibrosis, or a disease characterized by fibrosis, the method comprising administering a composition comprising a therapeutically effective amount of a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), or (Xa) as described herein in combination with one or more pharmaceutical agents. In certain embodiments described above, the one or more pharmaceutical agents are anti-fibrotic agents. In certain embodiments described above, the one or more pharmaceutical agents are antifungal agents.

In another aspect, provided herein is a method of treating fibrosis, a condition characterized by fibrosis, or a disease characterized by fibrosis, comprising administering a composition comprising a therapeutically effective amount of a compound of formula (XI), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof:

in:

A ¹ and A ² are independently selected from aryl or heteroaryl;

B is

C is an optionally substituted 5-membered or 6-membered heterocyclyl or an optionally substituted 5-membered or 6-membered heteroaryl, wherein the heterocyclyl or heteroaryl contains 1 to 4 nitrogen atoms;

D is aryl or heteroaryl;

E is aryl, heteroaryl, carbocyclyl, heterocyclyl or alkyl;

Each of R ¹ , R ² , R ³ and R ⁴ is independently selected from H, alkyl, haloalkyl or alkoxy;

X ₁ and X ₂ are independently selected from N and CR ⁵ ;

^R5 is H, OH, alkyl or alkoxy;

Each R ⁶ is independently alkyl, haloalkyl, halo, alkoxy, -alkylene (NR ¹³ R ¹⁴ ) or aryl;

each R ⁸ is independently selected from alkyl, cycloalkyl, heterocyclyl, halo, hydroxy, nitrile, azido, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), -alkylene(cycloalkyl), -alkylene(heterocyclyl), aryl, heteroaryl, -SR ¹³ , -SOR ¹³ , -SO ₂ R 13 , -SO 2 NR 13 R ¹⁴ , -NR ₁₃ R ¹⁴ , -NR 13 SO ^{2 R 14 , -NR 13 C (} O)R ¹⁴ , -NR ₁₃ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -C(O)R ¹⁴ , -C(O ⁾ OR ^{14 and} -C(O)NR ¹³ R ^{14 ; or} two adjacent R ⁸ forms a heterocyclyl ring;

each R ¹³ and R ¹⁴ are independently selected from H, alkyl, cycloalkyl, heterocyclylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl; or R ¹³ and R ¹⁴ , together with the atoms to which they are attached, form a heterocycle;

Y ¹ is selected from O, NH and NR ¹³ ;

Y ² is selected from O, CH ₂ , NH and NR ¹³ ;

n is 1, 2, or 3;

m is 1 or 2;

p is 1, 2, 3, or 4;

q is 1, 2, or 3;

r is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

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

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

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

v is 0, 1, 2, 3, or 4.

In some embodiments described above or below of a compound of formula (XI), X ₁ and X ₂ are N.

In some embodiments described above or below of a compound of Formula (XI), X ₁ is CR ⁵ and X ₂ is N.

In some embodiments described above or below of a compound of Formula (XI), X ₁ is N and X ₂ is CR ⁵ .

In some embodiments described above or below of a compound of Formula (XI), q is 1 and r is 0.

In some embodiments described above or below of a compound of Formula (XI), A ¹ is aryl.

In some embodiments described above or below of the compound of formula (XI), A ¹ is

In some embodiments described above or below of the compound of formula (XI), A ¹ is

In some embodiments described above or below of a compound of Formula (XI), A ¹ is heteroaryl.

In some embodiments described above or below of a compound of Formula (XI), A ² is aryl.

In some embodiments described above or below of compounds of formula (XI), ^A2 is

In some embodiments described above or below of compounds of formula (XI), ^A2 is

In some embodiments described above or below of a compound of Formula (XI), A ² is heteroaryl.

In some embodiments described above or below of a compound of Formula (XI), A ² is pyridine, pyrazine, pyrimidine, pyridazine, or triazine.

In some embodiments described above or below of compounds of formula (XI), C is optionally substituted 5- or 6-membered heteroaryl. In other embodiments described above or below of compounds of formula (XI), C is optionally substituted 5- or 6-membered heterocyclyl.

In some embodiments described above or below of compounds of formula (XI), C is and

R ⁷ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), cycloalkyl, heterocyclyl, -alkylene(cycloalkyl) or -alkylene(heterocyclyl).

In some embodiments described above or below of a compound of Formula (XI), C is and R ⁷ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), cycloalkyl, heterocyclyl, -alkylene(cycloalkyl), or -alkylene(heterocyclyl).

In some embodiments described above or below of a compound of Formula (XI), C is and R ⁷ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylene(NR ¹³ R ¹⁴ ), cycloalkyl, heterocyclyl, -alkylene(cycloalkyl), or -alkylene(heterocyclyl).

In some embodiments described above or below of a compound of Formula (XI), E is alkyl.

In some embodiments described above or below of a compound of Formula (XI), E is cycloalkyl.

In some embodiments described above or below of a compound of Formula (XI), E is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments described above or below of a compound of Formula (XI), E is heterocyclyl.

In some embodiments described above or below of a compound of Formula (XI), E is aryl.

In some embodiments described above or below of a compound of Formula (XI), E is and u is 0, 1, 2, 3, 4, or 5.

In some embodiments described above or below of a compound of Formula (XI), E is heteroaryl.

In some embodiments described above or below of a compound of formula (XI), E is selected from:

W ¹ , W ² , W ³ , W ⁴ , W ⁵ , W ⁶ and W ⁷ are independently selected from N and CR ⁹ ;

Z ¹ is NR ¹² , S or O;

Z ² is N or CR ⁹ ;

Each R ⁹ is independently selected from H, halogen, CN, NO ₂ , alkyl, -SR ¹⁰ , -OR ¹⁰ , -NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)(alkyl), -NR ¹⁰ C(O)(cycloalkyl), -NR ¹⁰ C(O)(heterocycloalkyl), -NR ¹⁰ C(O)(aryl), -NR ¹⁰ C(O)(heteroaryl), -C(O)NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ (cycloalkyl), -C(O)NR ¹⁰ (heterocycloalkyl), -C(O)NR ¹⁰ (aryl), -C(O)NR ¹⁰ (heteroaryl), -NR ¹⁰ C(O)NR ¹⁰ R ¹¹ , -NR ¹⁰ C(O)NR ¹¹ (cycloalkyl), -NR ¹⁰ C(O)NR ¹¹ (heterocycloalkyl), -NR ¹⁰ C(O)NR ¹¹ (aryl), -NR ¹⁰ C(O)NR ¹¹ (heteroaryl), -NR ¹⁰ C(O)O(alkyl), -NR ¹⁰ C(O)O(cycloalkyl), -NR ¹⁰ C(O)O(heterocycloalkyl), -NR ¹⁰ C(O)O(aryl), -NR ¹⁰ C(O)O(heteroaryl), -NR ¹⁰ SO ₂ (alkyl), -NR ¹⁰ SO ₂ (cycloalkyl), -NR ¹⁰ SO ₂ (heterocycloalkyl), -NR ¹⁰ SO ₂ (aryl), -NR ¹⁰ SO ₂ (heteroaryl), -SO ₂ NR ¹⁰ R ¹¹ , -SO ₂ NR ¹⁰ (cycloalkyl), -SO ₂ NR ¹⁰ (heterocycloalkyl), -SO ₂ NR ¹⁰ (aryl), -SO ₂ NR ¹⁰ (heteroaryl), haloalkyl, aryl, and heteroaryl;

Each R ¹⁰ and R ¹¹ is independently selected from H and alkyl; or R ¹⁰ and R ¹¹ together with the nitrogen to which they are attached form a heterocyclic ring; and

R ¹² is H, alkyl or halogenated alkyl.

In some embodiments described above or below of a compound of Formula (XI), D is aryl.

In some embodiments described above or below of a compound of Formula (XI), E is heteroaryl.

In some embodiments described above or below of compounds of formula (XI), D is selected from:

W ¹ , W ² , W ³ , W ⁴ and W ⁵ are independently selected from N and CR ⁹ ;

^W6 is N or C; and

Each R ⁹ is independently selected from H, halogen, CN, NO ₂ , alkyl, -SR ¹⁰ , -OR ¹⁰ , -NR ¹⁰ R ¹¹ , NR ¹⁰ C(O)(alkyl), -NR ¹⁰ C(O)(cycloalkyl), -NR ¹⁰ C(O)(heterocycloalkyl), -NR ¹⁰ C(O)(aryl), -NR ¹⁰ C(O)(heteroaryl), -C(O)NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ (cycloalkyl), -C(O)NR ¹⁰ (heterocycloalkyl), -C(O)NR ¹⁰ (aryl), -C(O)NR ¹⁰ (heteroaryl), -NR ¹⁰ C(O)NR ¹⁰ R ¹¹ , -NR ¹⁰ C(O)NR ¹¹ (cycloalkyl), -NR ¹⁰ C(O)NR ¹¹ (heterocycloalkyl), -NR ¹⁰ C(O)NR ¹¹ (aryl), -NR ¹⁰ C(O)NR ¹¹ (heteroaryl), -NR ¹⁰ C(O)O(alkyl), -NR ¹⁰ C(O)O(cycloalkyl), -NR ¹⁰ C(O)O(heterocycloalkyl), -NR ¹⁰ C(O)O(aryl), -NR ¹⁰ C(O)O(heteroaryl), -NR ¹⁰ SO ₂ (alkyl), -NR ¹⁰ SO ₂ (cycloalkyl), -NR ¹⁰ SO ₂ (heterocycloalkyl), -NR ¹⁰ SO ₂ (aryl), -NR ¹⁰ SO ₂ (heteroaryl), -SO ₂ NR ¹⁰ R ¹¹ , -SO ₂ NR ¹⁰ (cycloalkyl), -SO ₂ NR ¹⁰ (heterocycloalkyl), -SO ₂ NR ¹⁰ (aryl), -SO ₂ NR ¹⁰ (heteroaryl), haloalkyl, aryl and heteroaryl.

In certain embodiments described above or below of compounds of formula (XI), D is In certain embodiments described above or below of compounds of formula (XI), D is In certain embodiments described above or below of compounds of formula (XI), D is

In some embodiments described above or below of a compound of Formula (XI), Y ¹ and Y ² are O.

In some embodiments described above or below of a compound of Formula (XI), m is 1.

In some embodiments described above or below of a compound of Formula (XI), p is 1, 2, or 3.

In some embodiments described above or below of a compound of Formula (XI), p is 1.

In some embodiments described above or below of a compound of Formula (XI), R ¹ , R ² , R ³ , and R ⁴ are hydrogen.

Further provided herein is a method of treating fibrosis using a compound described herein, wherein the fibrosis is liver fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis, or cardiac fibrosis.

Further provided herein is a method of using the compounds described herein to treat liver fibrosis, wherein the liver fibrosis is associated with late stages of alcoholic or non-alcoholic cirrhosis.

Further provided herein is a method of treating fibrosis using the compounds described herein, wherein the fibrosis is idiopathic pulmonary fibrosis.

Further provided herein is a method of treating a disease using a compound described herein, wherein the disease or disorder characterized by fibrosis is a chronic autoimmune disease.

Further provided herein is a method of treating a chronic autoimmune disease using a compound described herein, wherein the chronic autoimmune disease is rheumatoid arthritis, scleroderma, Crohn's disease, or systemic lupus erythematosus.

Further provided herein is a method of treating a chronic autoimmune disease using a compound described herein, wherein the chronic autoimmune disease is scleroderma.

Further provided herein is a method of using the compounds described herein to treat fibrosis, wherein the fibrosis is keloid formation resulting from abnormal wound healing.

Further provided herein is a method of using the compounds described herein to treat fibrosis, wherein the fibrosis occurs following organ transplantation.

Example

List of abbreviations

As used above, and throughout the specification of the present invention, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings:

ACN acetonitrile

Bn phenyl

BOC or Boc tert-butyl carbamate

BOP Benzotriazol-1-yl-oxytris(dimethylamino)phosphonium

t-Bu tert-butyl

Cbz benzyl carbamate

Cy cyclohexyl

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCC Dicyclohexylcarbodiimide

DCM dichloromethane (CH2Cl2)

DIC 1,3-Diisopropylcarbodiimide

DEAD Diethyl azodicarboxylate

DIAD Diisopropyl azodicarboxylate

DIEA Diisopropylethylamine

DMAP 4-(N,N-dimethylamino)pyridine

DMP reagent Dess-Martin Periodinane reagent

DMF dimethylformamide

DMA N,N-dimethylacetamide

DME 1,2-dimethoxyethane

DMSO dimethyl sulfoxide

Dppf 1,1'-bis(diphenylphosphino)ferrocene

EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl

eq equivalent

Et ethyl

Et2O diethyl ether

EtOH

EtOAc

HOAt 1-Hydroxy-7-azabenzotriazole

HOBT 1-Hydroxybenzotriazole

HOSu N-hydroxysuccinamide

HPLC high-performance liquid chromatography

LAH Lithium Aluminum Anhydride

Me methyl

MeI iodomethane

MeOH methanol

MOMCl Methoxymethyl chloride

MOM methoxymethyl

MS

NMP N-Methyl-2-pyrrolidinone

NMR Nuclear Magnetic Resonance

PyBOP Benzotriazol-1-yl-oxytris-pyrrolidinyl-phosphonium hexafluorophosphate

SPHOS 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

TBD 1,5,7-Triazabicyclo[4.4.0]-dec-5-ene

RP-HPLC reversed-phase high-pressure liquid chromatography

RT Room temperature

TBS tert-butyldimethylsilyl

TBSCl tert-Butyldimethylsilyl chloride

TBTU O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethylolmium

TEOC 2-trimethylsilylethylcarbamate

TFA trifluoroacetic acid

Tf2O trifluoromethanesulfonic anhydride

TMG 1,1,3,3-tetramethylguanidine

THF Tetrahydrofuran

THP Tetrahydropyran

TLC thin layer chromatography

XPHOS 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

General Examples for the Preparation of Compounds of the Invention

The starting materials and intermediates for the compounds of the present invention can be prepared by applying or modifying the methods described below, their obvious chemical equivalents, or, for example, as described in The Science of Synthesis, Volumes 1-8. E.M. Carreira et al., eds. Thieme publishers (2001-2008). Details of reagents and reaction options can also be obtained by structure and reaction searches using commercial computer search engines such as Scifinder (www.cas.org) or Reaxys (www.reaxys.com).

The following reaction schemes A, B, and C detail the syntheses of intermediates relevant to the synthesis of compounds described herein.

Process A: Synthesis of racemic diol (E):

To a 250 mL three-necked round-bottom flask equipped with a condenser and Dean-stark filter was added Intermediate-A (25.0 g), acetone (75.0 mL), PTSA.H ₂ O (0.75 g), and petroleum ether (75.0 mL). The mixture was stirred at reflux for 12 h and monitored by TLC (hexane:ethyl acetate (5:5)). The reaction mixture was cooled to room temperature and 0.75 g of sodium acetate was added. The mixture was stirred at room temperature for 30 minutes. The organic layer was decanted and concentrated under reduced pressure to obtain a crude liquid, Intermediate-B (27.0 g, 75.2%).

To a 500 mL three-necked round-bottom flask equipped with a calcium chloride protective tube was added Intermediate-B (25.0 g) in chloroform (185 mL). TEA (79.0 mL) was added and the reaction was cooled to 0° C. Intermediate-C (47.0 g) was added batchwise to the mixture and stirred at room temperature for 5 h. The reaction was monitored by TLC (hexane:ethyl acetate (5:5)). The reaction mixture was washed with water (200 mL) and the aqueous layer was back-extracted with CHCl ₃ (50 mL x 2). The organic layers were combined, dried over Na ₂ SO ₄ , and concentrated under reduced pressure to give a crude oil. The oil was purified by column chromatography (hexane containing 6% ethyl acetate) to obtain Intermediate-D (21.0 g, 38.6%).

To a 250 mL three-necked round-bottom flask equipped with a magnetic stirrer was added Intermediate-D (21.0 g) in THF (100 mL). The reaction solution was cooled to 0°C, mixed with 6N HCl (25.0 mL), and stirred at room temperature for 6 h. The reaction was monitored by TLC (hexane:ethyl acetate (5:5)). The reaction mixture was diluted with water (100 mL) and neutralized with saturated sodium bicarbonate solution. The product was extracted with _CHCl₃ (50 mL* ₂ ). The organic layers were combined, dried over _Na₂SO₄ , and concentrated under reduced pressure to give Intermediate-E (16.0 g, 88.8%) as a thick oil. Intermediate-E was used in the next stage of the synthesis without further purification.

Intermediate spectral data:

Process B: Synthesis of Intermediate-K:

To be equipped with the 100mL three-necked round-bottom flask of calcium chloride tube, add intermediate-F (5.0g) in DMA (25.0mL).Phenyl chloroformate (2.8mL) is added dropwise, and the reaction mixture is stirred at room temperature for 30 minutes.By TLC (hexane: ethyl acetate (5:5)) monitoring reaction.The reaction mixture is poured into ice water.Gained precipitate is collected by filtration, washed with water, and dried under vacuum to obtain pure product--intermediate-G (4.4g, 61.1%).

To a 100mL three-necked round-bottom flask equipped with a calcium chloride tube was added intermediate-G (4.4g) in 1,4-dioxane (20.0mL). Hydrazine hydrate (1.37mL) was added dropwise, and the reaction mixture was stirred at room temperature for 24h. The reaction was monitored by TLC (hexane: ethyl acetate (5:5)). The reaction mixture was poured into ice water. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to obtain the pure product, intermediate-H (2.80g, 53.8%).

To a 100mL three-necked round-bottom flask equipped with a condenser, intermediate-H (2.80g) in n-BuOH (25.0mL) was added. Formamidine acetate (4.47g) was added and the reaction mixture was stirred at 90°C for 4h. The reaction was monitored by TLC (EtOAc). The reaction mixture was cooled to room temperature and the precipitate was collected by filtration, washed with ethyl acetate, and dried to obtain the pure product, intermediate-I (2.5g, 86.8%).

To a 100mL three-necked round-bottom flask equipped with a condenser was added intermediate-I (2.50g) in DMF (30.0mL). NaOH (1.50g) and secondary bromobutane (5.11g) were added and the reaction mixture was stirred at 90°C for 8h. The reaction was monitored by TLC (EtOAc). The reaction mixture was poured into ice water. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to obtain the pure product, intermediate-J (1.45g, 49.8%).

In 100mL hydrogenator container, be added the intermediate-J (1.45g) in MeOH (25.0mL).Add 10%Pd/C (0.15g) and with reaction mixture at room temperature under 10kg H ₂ pressure hydrogenation spends the night.By TLC (EtOAc) monitoring reaction.After reaction is completed, by filtering catalyst, and evaporating solvent to obtain viscous oil.By column chromatography (MDC containing 5%MeOH) purification of crude product to obtain intermediate-K (0.75g, 67.5%).

Intermediate spectral data:

■Process C: Synthesis of Intermediate-N

To a stirred solution of intermediate-L (2.0 g) in toluene (30.0 mL) was added 1H-1,2,3 triazole (1.96 g) and Na ₂ CO ₃ (3.01 g) at room temperature. The reaction mixture was stirred at 100 ° C for 3 h. The reaction was monitored for completion by TLC (hexane: ethyl acetate (5:5)). After the reaction was complete, the mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The obtained organic layer was washed with water (50 mL x 2). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane containing 20% ethyl acetate) to obtain intermediate-M (0.70 g, 19.2%).

Under room temperature, argon atmosphere, intermediate-M (1.30g) in toluene (15.0ml) of stirring is charged with intermediate-E (1.50g). The gained mixture is cooled to 0 ℃ and trifluoromethanesulfonic acid (1.80mL) is added dropwise thereto. The mixture is warmed to room temperature and stirred for 60h. The completion of the reaction is monitored by TLC (hexane: ethyl acetate (5:5)). After the reaction is completed, the gained mixture is poured into water (25mL) and neutralized with saturated sodium bicarbonate solution. The aqueous layer is extracted with ethyl acetate (25mL x 2). The organic layers are merged, through Na ₂ SO ₄ drying and concentrating under reduced pressure to obtain thick oil. The crude product is purified by column chromatography (hexane containing 10% ethyl acetate) to obtain intermediate-N (0.32g, 24.6%).

Intermediate spectral data:

■Process D: Synthesis of Intermediate-O

A mixture of isopropylamine and 2-bromo-1,1-dimethoxyethane in a sealed tube was heated at 80° C. The reaction mixture was cooled and purified to give Intermediate-O (92%).

Example 1: Synthesis of 4-(4-(4-(4-(((2S,4R)-2-((2H-1,2,3-triazol-2-yl)methyl)-2-phenyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-(S)-1-sec-butyl-1H-1,2,4-triazol-5(4H)-one (180)

To a solution of compound 1a (10 g, 35.3 mmol) and pyridine (3.12 mL, 38.8 mmol) in anhydrous DCM (40 mL) at 0 ° C, phenyl chloroformate (4.87 mL, 38.8 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for 2 h. After the reaction was completed, the reaction mixture was poured into ice water (100 mL). The resulting precipitate was collected by filtration, washed with water and dried to obtain compound 2a (13.1 g, 92%) as a brown solid, which was used directly in the next step without further purification. LC-MS: m/z 404.1 (M+H); ¹ H NMR (400MHz, CDCl ₃ ): δ7.32-7.43(m,4H),7.16-7.26(m,3H),6.97(d,J＝8.4Hz,4H),6.87(d,J＝8.8Hz,2H),6.81(s,1H),3.79(s,3H),3.31(br s,4H),3.24(br s,4H).

To a solution of compound 2a (13.1 g, 32.4 mmol) in 1,4-dioxane (50 mL) was added hydrazine hydrate (50-60%, 9.72 mL, 97.2 mmol). The reaction mixture was heated to reflux (110 ° C) for 1 h, cooled to room temperature, and then poured into water (150 mL). The obtained precipitate was collected by filtration, washed with water and dried to give compound 3a (10.5 g, 95%) as a brown solid, which was used directly in the next step without further purification. LC-MS: m/z 342.2 (M+H); ¹ H NMR (400MHz, DMSO-d ₆ )δ8.41(s,1H),7.46-7.30(m,2H),7.25(s,1H),6.99-6.92(m,2H),6.93-6. 88(m,2H),6.88-6.81(m,2H),4.31(s,2H),3.70(s,3H),3.18-3.17(m,8H).

To a solution of compound 3a (7.65 g, 22 mmol) in anhydrous DMF (25 mL) was added formamidine acetate (7.0 g, 67.0 mmol). The reaction mixture was heated at 130 ° C for 3 h, cooled to room temperature, and then water (100 mL) was added. The precipitate was collected by filtration, washed with water and dried to give the product 4a (6.70 g, 85%) as a brown solid, which was used directly in the next step without further purification. LC-MS: m/z 352.0 (M+H); ¹ H NMR (400MHz, DMSO-d ₆ )δ8.25(s,1H),7.55-7.42(m,2H),7.14-7.05(m,2H),7.03-6.91(m,2H),6.91-6.81(m,2H),3.70(s,3H),3.35-3.29(m,4H),3.21(br s,1H),3.20-3.11(m,4H).

To a solution of (R)-2-butanol 5a (5 g, 67.3 mmol), _Et3N (18.8 mL, 134.6 mmol), and DMAP (822 mg, 6.73 mmol) in DCM (30 mL) at 0°C was slowly added a solution of p-toluenesulfonyl chloride (TsCl) (15.4 g, 80.7 _mmol ) in DCM. The reaction mixture was warmed to room temperature and stirred overnight. After dilution with water, the reaction mixture was extracted with DCM. The combined organic layers were dried over _Na2SO4 , filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: hexane/EtOAc = 10/1) to give the product 6a (10.5 g, 69%) as a colorless liquid. ¹ H NMR (400MHz, CDCl ₃ )δ7.90-7.74(m,2H),7.43-7.31(m,2H),4.58(m,1H),2.46(s,3H),1.68-1.49(m,2H),1.27(d,J＝6.3Hz,3H),0.83(t,J＝7.5Hz,3H).

To a solution of compound 4a (5 g, 14.2 mmol) in DMSO (50 mL) were added _K2CO3 (3.9 g, 28.4 mmol), 18-crown- ₆ (3.4 g, 14.2 mmol), and 6a (3.89 g, 17.0 mmol) sequentially. The reaction mixture was stirred at room temperature overnight, then diluted with water and extracted with DCM. The combined organic layers were dried over _Na2SO4 , _filtered , and concentrated. The crude product was purified by silica gel column chromatography (eluent: hexane/EtOAc = 1/1) to give the product 7a (2.1 g, 36%) as an off-white solid. LC-MS: m/z 408.2 (M+H); ¹ H NMR (400MHz, CDCl ₃ ): δ7.62 (s, 1H), 7.42 (d, J = 7.2Hz, 2H), 7.03 (d, J = 7.2Hz, 2H), 6.98 (br s,2H),6.86(d,J＝7.2Hz,2H),,4.29(m,1H),3.79(s,3H),3.37(br s,4H),3.23(br s, 4H), 1.89 (m, 1H), 1.70 (m, 1H), 1.39 (d, J = 5.6Hz, 3H), 0.90 (t, J = 6.0Hz, 3H).

A mixture of 7a (2.0 g, 4.91 mmol) and 48% HBr solution (10 mL) was heated under reflux overnight, and the reaction mixture was then cooled to room temperature. The reaction mixture was diluted with DCM and then neutralized with saturated NaHCO _3. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: hexane/EtOAc=1/3) to give product 8a (1.26 g, 65%) as an off-white solid. LC-MS: m/z 394.2 (M+H); ¹ H NMR (400MHz, CDCl ₃ ):7.64(s,1H),7.41(d,J＝8.8Hz,2H),7.00(d,J＝9.2Hz,2H),6.86(d,J＝9.2Hz,2H),6.74(d,J＝8.8Hz,2H),5.77(br s,1H),4.33(m,1H),3.48-3.31(m,4H),3.31-3.07(m,4H),1.89(m,1H),1.75(m,1H),1.42(d,J＝6.7Hz,3H),0.93(t,J＝7.4Hz,3H).

To a solution of (R)-2,2-dimethyl-1,3-dioxolane-4-methanol 9a (5 g, 37.8 mmol), _Et3N (10.5 mL, 75.6 mmol) and DMAP (462 mg, 3.78 mmol) in DCM (20 mL) at 0°C was slowly added a solution of p-toluenesulfonyl chloride (TsCl) (10.8 g, 56.7 mmol) in DCM. The reaction mixture was warmed to room temperature and stirred overnight. After dilution with water, the reaction mixture was extracted with DCM. The combined organic layers were dried over _Na2SO4 , filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: hexane/EtOAc = 5/1) to give the product 10a (9.39 g, 87%) as _a colorless liquid. ¹ HNMR (400MHz, CDCl ₃ )δ7.82(d,J＝8.4Hz,2H),7.40(d,J＝8.4Hz,2H),4.30(tt,J＝6.0,5.1Hz,1H),4.12-3. 91(m,3H),3.79(ddd,J＝8.8,5.1,0.7Hz,1H),2.47(s,3H),1.36(s,3H),1.33(s,3H).

A mixture of 10a (9.39 g, 32.7 mmol) in methanol (20 mL) and 1 M aqueous HCl (31 mL) was stirred at room temperature for 3 h. The solvent was partially removed under vacuum, diluted with EtOAc, and neutralized with saturated NaHCO _3. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: hexane/EtOAc=1/3) to obtain product 11a (6.9 g, 85%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.82(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,2H),4.18-4.06(m,2H),4.96(m,1H),3.78-3.59(m,2H),2.48(s,3H),2.26(br s,2H).

To a solution of 2-bromoacetophenone 12a (10 g, 50 mmol) in CH ₃ CN (50 mL) was added 1,2,3-triazole (3.48 mL, 60 mmol) and DIEA (13.2 mL, 75 mmol). The mixture was heated to reflux for 1 h, cooled to room temperature, and then the solvent was removed under vacuum. The residue was redissolved in EtOAc (150 mL), washed with water (50 mL), 10% citric acid (50 mL), and brine, then dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (eluent: hexane/EtOAc = 3/1) to give product 13a (1.50 g, 8.0%) as a yellow solid, and product 13b (7.05 g, 75%) as a yellow solid (eluent: hexane/EtOAc = 1/3). 13a: ¹ H NMR (400MHz, CDCl ₃ ): δ8.05-7.93(m,2H),7.76(s,2H),7.72-7.60(m,1H),7.60-7.51(m,2H),5.95(s,2H). 13b: ¹ H NMR (400MHz, CDCl ₃ ): δ8.03 (dd, J=8.0, 1.5Hz, 2H), 7.83 (s, 1H), 7.77 (s, 1H), 7.72-7.68 (m, 1H), 7.59-7.55 (m, 2H), 5.92 (s, 2H).

Under nitrogen, TfOH (0.93 mL, 10.6 mmol) was slowly added to a solution of ketone 13a (0.5 g, 2.67 mmol) and compound 11a (0.72 g, 2.93 mmol) in anhydrous toluene (10 mL) at 0 ° C. After addition, the mixture was warmed to room temperature and stirred for 60 h. The reaction was quenched by adding saturated NaHCO ₃ at 0 ° C. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (eluent: hexane/EtOAc=3/1) to obtain cis product 14a (0.52 g, 47.2%) as a white solid, and trans product 14b (0.15 g, 14.0%) as a light yellow liquid was obtained under (eluent: hexane/EtOAc=1/1). 14a: LC-MS: m/z 416.0 (M+H); ¹ H NMR (400MHz, CDCl ₃ ): δ7.82-7.75(m,2H),7.57(s,2H),7.50-7.44(m,2H),7.43-7.34(m,5H),4.77(dd,J＝17.6,14.4Hz,2H) ,4.21(m,1H),3.85-3.75(m,2H),3.70(dd,J＝8.8,4.0Hz,1H),3.37(dd,J＝10.0,7.2Hz,1H),2.50(s,3H). The ee (>98%) was determined by chiral HPLC analysis using a Phenomenex LuxCellulose-3 column: 5 uL injection of 1 mg/mL (ethanol): flow rate, 1.0 mL/min; mobile phase, water: _CH3CN :acetic acid (40:60:0.1); RT = 3.24 min. 14b: LC-MS: m/z416.1 (M+H); ¹ H NMR (400MHz, CDCl ₃ ): δ7.67-7.59(m,2H),7.58(s,2H),7.44-7.32(m,2H),7.31-7.23(m,5H),4.70(s,2H),4.06(m,1H),3.90(dd,J＝10 .3, 5.3Hz, 1H), 3.81 (dd, J = 8.6, 6.2Hz, 1H), 3.72 (dd, J = 10.3, 6.3Hz, 1H), 3.55 (dd, J = 8.6, 6.5Hz, 1H), 2.42 (s, 3H).

To a solution of tosylate 14a (49 mg, 0.12 mmol) and phenol 8a (43 mg, 0.11 mmol) in anhydrous DMF (2 mL) was added KOH (25 mg, 0.44 mmol). The reaction mixture was stirred at 50°C overnight. After cooling to room temperature, the reaction mixture was diluted with water and DCM, and the organic phase was separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried _{over Na2SO4} , filtered, and concentrated on a rotary evaporator. The crude product was purified by silica gel column chromatography (eluent: hexane/EtOAc = 1/1 to 1/3) to give 180 (32 mg, 46%) as an off-white solid. LC-MS: m/z 637.2 (M+H); ¹ H NMR (400MHz, CDCl ₃ )δ7.64-7.63(m,3H),7.62-7.54(m,2H),7.50-7.43(m,2H),7.43-7.36(m,3H),7.11-7.03(m,2H),6.96(br s,2H),6.84-6.78(m,2H),4.87(s,2H),4.38(m,1H),4.31(m,1H),3.92(dd,J＝8.5,6.5Hz, 1H),3.85(dd,J＝8.5,4.4Hz,1H),3.78(dd,J＝9.4,5.1Hz,1H),3.49-3.33(m,5H),3.27(br s, 4H), 1.89 (m, 1H), 1.75 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H); Elemental analysis: theoretical (C, 66.02; H, 6.33; N, 17.60); found (C, 65.95; H, 6.39; N, 17.40).

Example 2: Synthesis of 4-(4-(4-(4-(((2S,4R)-2-((2H-1,2,3-triazol-2-yl)methyl)-2-phenyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-(R)-1-sec-butyl-1H-1,2,4-triazol-5(4H)-one (179)

Using a method similar to that described in Example 1 for preparing compound 8a, starting from (S)-2-butanol 5b, compound 8b was obtained as an off-white solid in 3 steps with a yield of 18.6%. LC-MS: m/z 394.2 (M+H); ¹ H NMR (400MHz, CDCl ₃ ): δ7.64(s,1H),7.40(d,J＝8.8Hz,2H),7.00(d,J＝9.2Hz,2H),6.89(d,J＝9.2Hz,2H),6.74(d,J＝8.8Hz,2H),5.81(br s,1H),4.33(m,1H),3.43-3.29(m,4H),3.29-3.14(m,4H),1.90(m,1H),1.75(m,1H),1.41(d,J＝6.8Hz,3H),0.93(t,J＝7.4Hz,3H).

Compound 179 was obtained from tosylate 14a and phenol 8b in a manner similar to that described in Example 1 for the preparation of compound 180. LC-MS: m/z 637.2 (M+H); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (m, 3H), 7.57 (dt, J=10.1, 5.5 Hz, 2H), 7.50-7.34 (m, 5H), 7.05 (t, J=9.8 Hz, 2H), 6.94 (m, 2H), 6.80 (d, J=8.8 Hz, 2H), 4.87 (s, 2H), 4.42-4.28 (m, 2H), 3.92 (dd, J=1. 7.5,8.8Hz,1H),3.85(m,1H),3.78(dd,J＝9.4,5.0Hz,1H),3.37(m,5H),3.27(m,4H) ,1.94-1.82(m,1H),1.82-1.70(m,1H),1.42(d,J＝6.7Hz,3H),0.95(t,J＝7.4Hz,3H).

Example 3: Synthesis of 4-(4-(4-(4-(((2R,4S)-2-((2H-1,2,3-triazol-2-yl)methyl)-2-phenyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-(R)-1-sec-butyl-1H-1,2,4-triazol-5(4H)-one (182)

Starting from (S)-2,2-dimethyl-1,3-dioxolane-4-methanol 9b, 11b was obtained as a white solid in 72.2% yield over two steps using a procedure similar to that described in Example 1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 4.16-4.04 (m, 2H), 3.99 (m, 1H), 3.78-3.60 (m, 2H), 2.48 (s, 3H), 2.17 (br s, 2H).

Compounds 15a and 15b were prepared in a manner similar to that described in Example 1 for the preparation of compounds 14a and 14b. 15a was obtained as a white solid in 45.4% yield. LC-MS: m/z416.1(M+H); ¹ H NMR (400MHz, CDCl ₃ )δ7.81-7.74(m,2H),7.57(s,2H),7.50-7.43(m,2H),7.42-7.33(m,5H),4.77(dd,J＝17.6,14.4Hz,2H),4.21(m ,1H),3.85-3.75(m,2H),3.70(dd,J＝8.8,4.0Hz,1H),3.37(dd,J＝10.0,7.2Hz,1H),2.50(s,3H); using Phenomenex Lux Chiral HPLC analysis on a Cellulose-3 column revealed an ee of >98%: 5 μL injection of 1 mg/mL (ethanol); flow rate, 1.0 mL/min; mobile phase, water: CH ₃ CN: acetic acid (40:60:0.1); RT = 2.86 min. 15b was obtained as a light yellow solid in 13.5% yield. LC-MS: m/z 416.1 (M+H); ¹ H NMR (400MHz, CDCl ₃ )δ7.72-7.65(m,2H),7.63(s,2H),7.44-7.38(m,2H),7.36-7.29(m,5H),4.74(s,2H),4.11(m,1H),3.96(dd,J＝10. 3,5.2Hz,1H),3.86(dd,J＝8.6,6.2Hz,1H),3.75(dd,J＝10.2,6.5Hz,1H),3.60(dd,J＝8.6,6.6Hz,1H),2.47(s,3H).

Compound 182 was obtained from tosylate 15a and phenol 8b in a manner similar to that described in Example 1 for the preparation of compound 180. LC-MS: m/z 637.1 (M+H); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70-7.62 (m, 3H), 7.63-7.53 (m, 2H), 7.53-7.32 (m, 5H), 7.04 (t, J=9.3 Hz, 2H), 6.95 (d, J=7.5 Hz, 2H), 6.79 (d, J=9.0 Hz, 2H), 4.88 (s, 2H), 4.43-4.25 (m, 2H), 3.92 (dd, J=8.4 ,6.6Hz,1H),3.88-3.81(m,1H),3.77(dd,J＝9.4,5.0Hz,1H),3.45-3.31(m,5H),3.26(m, 4H), 1.96-1.82 (m, 1H), 1.82-1.71 (m, 1H), 1.42 (d, J = 6.7Hz, 3H), 0.93 (t, J = 7.4Hz, 3H).

Example 4: Synthesis of 4-(4-(4-(4-(((2R,4S)-2-((2H-1,2,3-triazol-2-yl)methyl)-2-phenyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-(S)-1-sec-butyl-1H-1,2,4-triazol-5(4H)-one (182)

Compound 183 was obtained from tosylate 15a and phenol 8a in a manner similar to that described in Examples 1-3. LC-MS: m/z 637.1 (M+H); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67-7.61 (m, 3H), 7.57 (m, 2H), 7.47-7.33 (m, 5H), 7.04 (t, J=9.2 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H), 6.79 (d, J=9.0 Hz, 2H), 4.86 (s, 2H), 4.42-4.26 (m, 2H), 3.92 (dd, J=8.4, 6 .6Hz,1H),3.85(dd,J＝8.5,4.4Hz,1H),3.78(dd,J＝9.4,5.0Hz,1H),3.37(m,5H),3.26 (m,4H),1.96-1.82(m,1H),1.74(m,1H),1.42(d,J＝6.7Hz,3H),0.93(t,J＝7.4Hz,3H).

Example 5: Synthesis of 4-((2S,4R)-4-((4-(4-(1-sec-butyl-5-oxo-1H-1,2,4-triazol-4(5H)-yl)phenyl)piperazin-1-yl)phenoxy)methyl)-2-(pyridazin-4-ylmethyl)-1,3-dioxolane-2-yl)benzamide (121)

Compound 121 was obtained by a method similar to that described in Example 1-4 starting from ethyl 4-bromobenzoate and 4-methylpyridazine. LC-MS: m/z 691.4 (M+H); ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.90-0.94 (t, 3H), 1.40-1.42 (d, 3H), 1.70-1.77 (m, 1H), 1.86-1.88 (m, 1H), 3.17-3.27 (m, 5H), 3.35-3.40 (m, 4H), 3.55-3.72 (m, 1H), 3.67-3.69 (m, 1H), 3.81-3.84 (m, 2H), 4.29-4.32 (m, 3H) ,5.51-5.68(m,1H),6.09-6.21(m,1H),6.66-6.77.(m,2H),6.88-6.97(m,2H),7.02-7.06(m,2H) ,7.32-7.33(m,1H),7.53-7.59(m,2H),7.63-7.64(m,1H),7.78-7.85(m,2H),9.02-9.08(m,2H).

The compounds in Table 1 were prepared using procedures similar to those described in Examples 1-5.

Table 1

Example 6: Synthesis of cis(±)-4-(4-(4-(4-((4-((2H-1,2,3-triazol-2-yl)methyl)-4-(2,4-difluorophenyl)-1,3-dioxolan-2-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1-sec-butyl-1H-1,2,4-triazol-5(4H)-one (199)

To a solution of 2-chloro-2',4'-difluoroacetophenone (20 g, 10.5 mol) in CH ₃ CN (100 mL) was added 1,2,3-triazole (9.12 mL, 15.7 mol) and DIEA (18.0 mL, 21 mol). The reaction mixture was heated to reflux for 1 h and then cooled to room temperature. The reaction mixture was concentrated, and the residue was redissolved in EtOAc (150 mL), washed with water (50 mL), 10% citric acid (50 mL), and brine, then dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (eluent: hexane/EtOAc = 3/1) to give Compound 195 (3.97 g, 17.2%) as a yellow solid. LC-MS: m/z 224.0 (M+H); ¹ H NMR (400MHz, CDCl ₃ )δ8.06(td,J＝8.5,6.5Hz,1H),7.77(s,2H),7.12-7.04(m,1H),7.04-6.94(m,1H),5.87(d,J＝3.8Hz,2H).

To a solution of 195 (3.97 g, 17.7 mmol) in toluene (40 mL) was added trimethylsulfoxonium iodide (5.19 g, 23 mmol), followed by 20% sodium hydroxide solution (4.6 mL). The reaction mixture was then heated at 60 ° C for 4 h. After completion of the reaction, it was diluted with ethyl acetate (60 mL) and poured into chilled water. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column (eluent: hexane/EtOAc=3/1) to give compound 196 (3.68 g, 87.6%) as a yellow solid. LC-MS: m/z 238.01 (M+H); ¹ H NMR (400MHz, CDCl ₃ )δ7.52(s,2H),7.55(m,1H),6.80-6.65(m,2H),4.77(dd,J＝14.8,1.4Hz,1H),4.45 (dd, J=14.8, 1.3Hz, 1H), 2.89 (dd, J=4.7, 1.4Hz, 1H), 2.81 (dd, J=4.7, 1.5Hz, 1H).

To compound 196 (3.68 g, 15.5 mmol) was added a 10% v/v H ₂ SO ₄ /H ₂ O solution (20 mL) at 0°C. The reaction solution was stirred at room temperature overnight. The solution was basified by the addition of saturated NaHCO ₃ and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (eluent: hexane/EtOAc = 1/1) to give compound 197 (2.24 g, 56.7%) as a light yellow solid. LC-MS: m/z 256.0 (M+H); ¹ H NMR (400MHz, CDCl ₃ ): δ7.52(s,2H),7.50-7.42(m,1H),6.78(ddt,J＝9.7,8.4,1.5Hz,2H),5.18(dd,J＝14.1,1.2Hz, 1H),4.98(d,J＝14.1Hz,1H),4.03(dt,J＝11.7,1.4Hz,1H),3.79(dd,J＝11.7,0.6Hz,1H),2.22(br s,1H).

Bromoacetaldehyde diethyl acetal (1.70 mL, 11.0 mmol) was added dropwise to a stirred solution of 197 (2.24 g, 8.78 mmol) in methanesulfonic acid (5.7 mL) and DCM (50 mL) at 0°C. After the addition, the mixture was warmed to room temperature, stirred for 3 h, and then poured into a mixture of ice/saturated NaHCO _3. The mixture was extracted with DCM. The combined organic solvents were dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash silica gel column (eluent: hexane/EtOAc=10/1) to give 198a (1.72 g, 54.5%) as a colorless oil. LC-MS: m/z 360.0 (M+H); ¹ H NMR (400MHz, CDCl ₃ ): δ ¹ H NMR(400MHz, CDCl3)δ7.61(s,2H),7.55(td,J＝8.7,6.4Hz,1H),6.91(m,1H),6.85(m,1H),5.16(dd,J＝5.1,3.6Hz,1H),4.9 6-4.90(m,1H),4.86-4.70(m,2H),4.05(dd,J＝9.3,1.8Hz,1H),3.45(dd,J＝11.0,3.6Hz,1H),3.28(dd,J＝11.0,5.1Hz,1H).

To a solution of 198a (55 mg, 0.15 mmol) and racemic 8a/8b (60 mg, 0.15 mmol) in anhydrous DMF (1.5 mL) was added KOH (25 mg, 0.44 mmol). The reaction mixture was stirred at 50 ° C for 2 h. After cooling to room temperature, the reaction mixture was diluted with water and DCM, and the organic phase was separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: hexane/EtOAc=1/3) to give the title compound 199 (22 mg, 21%) as an off-white solid. LC-MS: m/z 637.2 (M+H); 1H NMR(400MHz, CDCl3)δ7.81(s,1H),7.65(s,2H),7.51-7.43(m,2H),7.43-7.32(m,1H) ,7.26(s,1H),7.07(d,J＝8.9Hz,2H),6.99(d,J＝8.6Hz,2H),6.93-6.80(m,2H),5.33(t ,J＝3.1Hz,1H),4.73(dd,J＝9.3,3.2Hz,1H),4.67(d,J＝14.3Hz,1H),4.55(d,J＝14.3H z,1H),4.39-4.23(m,1H),4.13(d,J＝3.2Hz,2H),4.05(dd,J＝9.4,1.4Hz,1H),3.56(br s, 4H), 3.40 (brs, 4H), 1.89 (m, 1H), 1.74 (m, 1H), 1.41 (d, J = 6.8, 3H), 0.92 (t, J = 7.4Hz, 3H).

The compounds in Table 2 were prepared using procedures similar to those described in Example 6.

Table 2

Example 7: Synthesis of cis(±)-1-(4-(4-(4-((4-((2H-1,2,3-triazol-2-yl)methyl)-4-(2,4-difluorophenyl)-1,3-dioxolan-2-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-3-isopropylimidazolidin-2-one (203)

As outlined in the above scheme, compound 203 was prepared using a procedure analogous to that described in the previous examples. LC-MS: m/z 660.3 (M+H).

The compounds in Table 3 were prepared using procedures similar to those described in Examples 1-7.

Table 3

Biological Examples

Example 1: Biological test

A high-content imaging assay based on α-SMA staining and cell morphological changes associated with fibroblast-to-myofibroblast transdifferentiation was established using primary human lung fibroblasts and primary rodent HSCs. Conditions (including serum starvation and subsequent TGF-β treatment) that promote robust in vitro transdifferentiation in a miniaturized (384-well plate) format suitable for high-throughput small molecule screening were identified. A selective ALK-5 TGF-β1 receptor inhibitor (SB-431542) was used as a positive control. The 4-day assay is suitable for screening on the order of 100,000 wells and facilitates the identification of compounds that selectively inhibit fibroblast-to-myofibroblast transdifferentiation. This assay is used to evaluate compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X) or (Xa) generated from medicinal chemistry work.

The activity of itraconazole and compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIb), (VIc), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), or (Xa) was confirmed by analyzing changes in gene expression of multiple genes associated with fibroblast to myofibroblast transdifferentiation using biochemical methods (i.e., Western blot and RT-PCR). Groups of six compounds were evaluated at a time in a four-point dose response format using these four-day assays.

α-SMA test

Resting rat hepatic stellate cells were plated in poly-D-lysine-coated 384-well plates (350 cells per well) in astrocyte culture medium (Sciencell). After a 24-hour incubation, the cells were treated with itraconazole for 48 hours in the presence of 10 ng/mL TGF-β1 in the hepatic stellate cell culture medium. After fixation and staining with an anti-smooth muscle actin antibody, cell morphology was analyzed using a Cellomics fluoroscopic imaging reader. The cells were then analyzed for mean cell area of α-SMA staining or mean fluorescence intensity of SMA staining. In this assay, itraconazole reproducibly induced a dose-dependent decrease in both mean cell area and α-smooth muscle actin staining, indicating inhibition of myofibroblast transdifferentiation and activation.

Western blot analysis of fibrosis-related proteins in cells exposed to TGFβ and itraconazole (Itra)

Human lung fibroblasts were seeded at 10 ⁵ cells/well in assay medium (2% fetal bovine serum, DMEM) in 6-well dishes. After 24 hours of incubation, the culture medium was replaced with assay medium containing TGF-β1 (10 ng/mL) and simultaneously treated with itraconazole (10 μM) or vehicle control. After 48 hours of incubation, cells were harvested by brief trypsinization and centrifugation. The cells were lysed in Cell Lytic M (Sigma) and the lysate concentration was normalized by absorbance reading at 260 nm. The samples were boiled in 2X sample buffer and 10% β-mercaptoethanol. Three micrograms of lysate were loaded into each gel lane and then separated on a 10% Bis-Tris gel by SDS-PAGE and then transferred to a PVDF membrane by a semi-dry transfer apparatus. After blocking in 5% milk in TRIS-buffered saline containing Tween-20 (0.1%), the membrane was exposed to the appropriate primary antibody. The blots were incubated with HRP-conjugated secondary antibodies and visualized using membranes and SuperSignal WestDura chemiluminescent substrate (Pierce).In this assay, itraconazole reproducibly induced a dose-dependent reduction in induced α-smooth muscle actin levels, indicating inhibition of myofibroblast transdifferentiation and activation.

Gene expression analysis of human lung fibroblasts treated with itraconazole

Human lung fibroblasts were seeded in assay medium (2% fetal bovine serum in DMEM) in 6-well dishes at 10 ⁵ cells/well. After 24 hours, the culture medium was replaced with assay medium containing TGF-β1 (10 ng/mL) and itraconazole (500 nM). After incubation at 37°C for 48 hours, the cells were harvested by brief trypsinization and centrifugation. RNA was extracted using an RNeasy kit (Qiagen) and cDNA was amplified using a SuperScript III first-strand synthesis kit (Life Technologies). qPCR reactions were then performed using an RT2Profiler PCR array kit focused on fibrosis, which was provided with plates and reagents. Data were analyzed using N=1 per reaction for each treatment condition. Data are expressed as the fold adjustment relative to samples not treated with TGF-β1. In this experiment, itraconazole reproducibly induced dose-dependent changes in multiple fibrosis-related genes, indicating inhibition of myofibroblast transdifferentiation and activation.

The antifibrotic activity of itraconazole is not due to P450 inhibition, which is associated with antifungal activity. Itraconazole inhibits VEGF and Hedgehog profibrotic signaling pathways.

qPCR analysis of Hedgehog-related genes in rat hepatic stellate cells treated with itraconazole

Rat hepatic stellate cells were seeded at ¹⁰ cells/well in astrocyte culture medium (Sciencell) in 6-well dishes coated with poly-D-lysine and allowed to proliferate to full confluence (approximately 2 weeks). The medium was then replaced with DMEM containing 1 μg/mL SHH-N (R&D systems) and 0.5% fetal bovine serum. Cells were treated with SHH-N and compounds (5 μM cyclopamine (positive control), 1 μM itraconazole) for 24 hours. Cells were harvested by brief trypsinization and centrifugation. RNA was extracted using the RNeasy kit (Qiagen), and cDNA was amplified using the SuperScript III First Strand Synthesis Kit (Life Technologies). qPCR was performed using SYBR Green Master Mix (Takara). Relative levels of PTCH1 (protein patch homolog 1) and GLI1 (GLI family zinc finger 1) mRNA indicated that itraconazole inhibits Hedgehog signaling in rat hepatic stellate cells.

Western blot analysis of COL1-GFP HSCs after Smoothened knockdown

COL1-GFP HSC (an immortalized mouse hepatic stellate cell line with GFP knocked into the collagen locus) was seeded into assay medium (10% fetal bovine serum, DMEM) at ^7.55 cells/well. After 24 hours, the cells were transduced with lentiviral particles. After incubation with viral particles for 24 hours, the cells were switched to fresh assay medium and incubated for 48 hours. The cells were lysed in Cell Lytic M (Sigma) and the lysate concentration was normalized by absorbance reading at 260 nm. The samples were boiled in 2X sample buffer and 10% β-mercaptoethanol. Equal amounts of lysate were loaded into each gel lane and then separated on a 10% Bis-Tris gel by SDS-PAGE and then transferred to a PVDF membrane by a semi-dry transfer apparatus. After blocking in 5% milk in TRIS-buffered saline containing Tween-20 (0.1%), the membrane was exposed to the appropriate primary antibody. The blot was incubated with an HRP-conjugated secondary antibody and visualized using a membrane and SuperSignal West Dura chemiluminescent substrate (Pierce). Constructs for lentiviral delivery of shRNA were obtained from Sigma in the form of MISSION glycerol stocks. Lentivirus was packaged using 293T cells and packaging vectors pMD2.G and pSPAX2. Clones 71, 12, and 95 correspond to shRNAs targeting SMO, and pLKO is a plasmid SCH002 encoding a non-targeting shRNA. shRNA-mediated SMO knockdown and the resulting inhibition of Hedgehog signaling in rat hepatic stellate cells partially recapitulated the anti-fibrotic activity of itraconazole.

Western blot analysis of VEGFR2 migration pattern after treatment with itraconazole

Resting rat hepatic stellate cells were seeded at 10 ⁵ cells/well in astrocyte culture medium (Sciencell) in 6-well dishes coated with poly-D-lysine. After incubation for 24 hours, the cells were treated with different doses of itraconazole for 24 hours. The cells were harvested by brief trypsinization and centrifugation. The cells were lysed in Cell Lytic M (Sigma), and the lysate concentration was normalized by absorbance reading at 260 nm. The samples were boiled in 2X sample buffer and 10% β-mercaptoethanol. Equal amounts of lysate were loaded into each gel lane and then separated by SDS-PAGE on a 10% Bis-Tris gel and transferred to a PVDF membrane using a semi-dry blotting apparatus. After blocking in 5% milk in TRIS-buffered saline containing Tween-20 (0.1%), the membrane was exposed to the appropriate primary antibody. Blots were incubated with HRP-conjugated secondary antibodies and visualized using membrane and SuperSignal West Dura chemiluminescent substrate (Pierce).Itraconazole inhibits VEGFR2 glycosylation and trafficking, thereby leading to inhibition of pro-fibrotic VEGF signaling in rat hepatic stellate cells.

Western blot analysis of rat hepatic stellate cells treated with a combination of VEGFR and Hedgehog inhibitory compounds

Resting rat hepatic stellate cells were seeded at 10 ⁵ cells/well in astrocyte culture medium (Sciencell) in 6-well dishes coated with poly-D-lysine. After 24 hours of incubation, cells were switched to astrocyte culture medium containing 10 ng/mL TGF-β1 and the indicated compound combination. After 48 hours of treatment, cells were harvested by brief trypsinization and centrifugation. Cells were lysed in Cell Lytic M (Sigma) and lysate concentrations were normalized by absorbance readings at 260 nm. Samples were boiled in 2X sample buffer and 10% β-mercaptoethanol. Three micrograms of lysate were loaded into each gel lane and then separated by SDS-PAGE on a 10% Bis-Tris gel and transferred to a PVDF membrane by semi-dry blotting. After blocking in 5% milk in TRIS-buffered saline containing Tween-20 (0.1%), the membranes were exposed to the appropriate primary antibodies. Blots were incubated with HRP-conjugated secondary antibodies and visualized using membrane and SuperSignal West Dura chemiluminescent substrate (Pierce).Dual pharmacological inhibition of VEGF and Hedgehog signaling in rat hepatic stellate cells demonstrates the antifibrotic activity of itraconazole.

Western blot analysis of LX2 human hepatic stellate cells after VEFGR1, VEGFR2, or SMO knockdown

LX2 cells (immortalized human hepatic stellate cell line, Scot Friedman laboratory) were seeded at 10 ⁵ cells/well into assay medium (10% fetal bovine serum, DMEM). After 24 hours, the cells were transduced with lentiviral particles. After incubation with viral particles for 24 hours, the cells were switched to fresh assay medium and incubated for 48 hours. The cells were lysed in Cell LyticM (Sigma) and the lysate concentration was normalized by absorbance reading at 260 nm. The samples were boiled in 2X sample buffer and 10% β-mercaptoethanol. Equal amounts of lysate were loaded into each gel lane and then separated on a 10% Bis-Tris gel by SDS-PAGE and then transferred to a PVDF membrane by a semi-dry transfer apparatus. After blocking in 5% milk in TRIS-buffered saline containing Tween-20 (0.1%), the membrane was exposed to the appropriate primary antibody. The blot was incubated with an HRP-conjugated secondary antibody and visualized using a thin film and SuperSignal West Dura chemiluminescent substrate (Pierce). Constructs for lentiviral delivery of shRNA were obtained from Sigma as MISSION glycerol stocks. Lentivirus was packaged using 293T cells and the packaging vectors pMD2.G and pSPAX2. Clone 65 corresponds to an shRNA targeting SMO, 31 and 32 correspond to shRNA targeting VEGFR1, clones 86 and 87 correspond to shRNA targeting VEGFR2, and pLKO is the plasmid SCH002 encoding a non-targeting shRNA.

Table 3 below shows the biological activities ( _EC50 ) of compounds described herein. _EC50s for activities (based on imaging and Western) were ranked as follows: +++ = <500 nM; ++ = 500 nM to 5 μM; + = 5 to 30 μM; - = >30 μM; NT = not measured.

Table 3

Cyp reversible inhibition assay

The purpose of this assay is to determine reversible inhibition of the Cyp enzyme by a given compound using substrate probe turnover as a surrogate for inhibition. The assay is performed using human liver microsomes rather than isolated enzymes to account for potential drug-drug interactions caused by metabolites of the parent drug through Cyp inhibition. Substrate turnover (e.g., conversion of midazolam to hydroxymidazolam) is monitored by LCMSMS (Q1/Q2 = 342.2/203.2). Test compounds are tested in a 7-point dose-response curve starting from 50 μM to 50 nM (approximately a 3-fold dilution series). For Cyp 3A4, the positive control compound is ketoconazole.

The detailed plan is as follows:

• Prepare test compound and standard inhibitor working solutions (100×).

• Remove the microsomes from the -80°C freezer to thaw on ice, label with the date and return to the freezer immediately after use.

• Add 20 μL of substrate solution to the corresponding wells.

• Add 20 μL PB to the blank wells.

• Add 2 μL of test compound and positive control working solutions to the corresponding wells.

• Add 2 μL of MeOH to the no inhibitor wells and blank wells.

Prepare HLM working solution.

• Add 158 μL of HLM working solution to all wells of the incubation plate.

Preheat the plate in a 37°C water bath for approximately 10 minutes.

Prepare NADPH cofactor solution.

• Add 20 μL of NADPH cofactor to all incubation wells.

• Mix and incubate in a 37°C water bath for 10 minutes.

- At this time point, the reaction was stopped by adding 400 μL of cold stop solution (200 ng/mL tolbutamide in ACN).

• Centrifuge the sample at 4000 rpm for 20 minutes to precipitate the protein.

• Transfer 200 μL of supernatant to 200 μL of HPLC water and shake for 10 min.

• Analyze samples by LC/MS/MS.

Cyp time-dependent inhibition (TDI) assay

The purpose of this assay is to determine the ability of compounds to form irreversibly inhibited cytochrome P450 adducts (also known as mechanism-based inhibition (MBI)) in human liver microsomes. MBI is recognized as a greater concern in drug discovery and development than competitive CYP inhibition because CYP inactivation can lead to nonlinear pharmacokinetics and underestimate the potential for drug-drug interactions. Data from this assay are used in conjunction with reversible inhibition assays. TDI assays are commonly performed in liver microsomes to evaluate the PDI potential of parent drugs and metabolites. The readout is the change in IC50 in the presence of NADPH (inactivated/TDI group), which allows conversion of the compound to a reactive species, and in the absence of NADPH (control group, used to correct for protein degradation during a ₂₀ -minute preincubation). Both incubation groups are then diluted with fresh assay buffer containing a Cyp-specific substrate for NADPH (midazolam for Cyp3A4), and inhibition of midazolam hydroxylation is measured by LC-MS/MS (Q1/Q2 = m/z 342.2/203.2). _IC50 changes > 1.5-fold were considered positive for time-dependent inhibition, with a 20-min pre-incubation resulting in increased potency. Troleandomycin was used as a positive control compound, exhibiting a TDI _IC50 change > 20. Test compounds were tested in a 7-point dose response curve starting from 50 μM to 50 nM (approximately a 3-fold dilution series).

The detailed plan is as follows:

• Prepare test compound and positive control working solutions 100× in 1:1 DMSO/MeOH.

• Remove the microsomes from the -80°C freezer to thaw.

• Prepare incubation mix and add 147.5 μL to all wells of the incubation plate.

Prepare cofactor solution and substrate dilution solution.

o Add 2.5 μL of test compound and positive control working solutions to corresponding wells. Final compound concentrations are in a 7-point dose response ranging from 50 μM to 50 nM.

o Add 2.5 μL of 1:1 DMSO/MeOH to the NIC wells.

• Preheat the plate at 37°C for approximately 10 min.

• Add 50 μL of cofactor to the pre-incubated wells.

• Add 50 μL of substrate dilution solution to the incubation wells.

• Mix and pre-incubate in a 37°C water bath for 20 minutes.

Add 50 μL of cofactor to the incubation wells;

o Add 50 μL of substrate dilution solution to the pre-incubated wells.

• Mix and incubate in a 37°C water bath for 5 minutes.

• At this time point, the reaction was stopped by adding 250 μL of IS-spiked cold stop solution to all wells.

• Centrifuge the incubation plate at 4000 rpm for 20 minutes.

• Transfer 200 μL of supernatant to 200 μL of HPLC water and shake for 10 min.

• Analyze samples by LCMS.

PXR (Cyp 3A4) activation assay

CYP3A4 metabolism was assessed using the P450-Glo ^™ CYP3A4 assay using luciferin-IPA as a CYP3A4 substrate and expressed as RLU (relative luminescence units). PXR activation was assessed using the luciferase detection reagent ONE-Glo ^™ and expressed as RLU. The intensity of luminescence is proportional to the degree of PXR activation and concomitant gene transcription in DPX2 cells. Compounds were tested at 10, 1, and 0.1 μM in this assay. Induction fold = (RLU/RFU of compound-treated sample) / (RLU/RFU of vehicle-treated sample), with RFU being a proxy for cell viability. RLU is a proxy for CYP3A metabolism and PXR activation. 0.1% DMSO was used as a vehicle. Cell viability was measured using CellTiter-Fluor ^™ and expressed as RFU (relative fluorescence units).

Activation potency was determined as negative, weak, moderate, and strong. Negative, weak, moderate, and strong activators were those that achieved <15%, <40%, <69%, and >70%, respectively, of the response produced by 10 μM RIF at 10 μM.

Determination of antifungal MIC efficacy of Candida albicans

Wild-type Candida albicans (ATCC 10231) was used, and fluconazole, amphotericin B, itraconazole, and terbinafine were purchased from Sigma and used as positive controls.

The highest assay concentration for all test compounds and fluconazole was 100 μM. Fluconazole was also tested at a maximum concentration of 64 μg/ml, while amphotericin B and terbinafine were tested at 16 and 64 μg/ml. The test compounds were present in DMSO stock solutions at a concentration of 10 mM. Two stock solutions of fluconazole in DMSO were prepared at 10 mM and 6.4 mg/ml. Stock solutions of amphotericin B and terbinafine in DMSO were prepared at 1.6 mg/ml and 6.4 mg/ml, respectively.

Serial dilution of 100X stock solution: 4 μl of stock solution is added to 196 μl RPMI1640 (MOPS buffered and without HEPES and sodium bicarbonate) in the first well of a row of a sterile u-shaped 96-well plate. The other wells are filled with 100 μl RPMI1640. By transferring 100 μl of solution to the next well and mixing by pipetting, a 2-fold serial dilution is continuously made until the 11th well. The extra 100 μl in the 11th well is discarded. Therefore, the compound well contains 100 μl of 2× test concentrations of drug in RPMI1640. The 12th well is filled with only 100 μl RPMI1640.

A frozen glycerol stock of Candida albicans 3147 (ATCC 10231) was streaked onto Sabouraud dextrose agar (SDA). The plates were incubated at 35°C in ambient atmosphere for 20 hours. A single colony was suspended in sterile saline until the turbidity reached 0.1 (1-5 x ¹⁰⁶ CFU/ml) as measured using a Siemens turbidimeter. This suspension was diluted 50x in RPMI1640 in a 15 ml conical tube and then further diluted 20x in RPMI1640 in a 50 ml conical tube. This yielded a suspension of 1-5 x ¹⁰³ CFU/ml, which was used as the inoculum. A plate count of the cell density in the inoculum was performed and found to be 4.94 x ¹⁰³ CFU/ml.

MIC Assay: Over 15 minutes, 100 μl of the prepared bacterial inoculum was added to each well of a plate containing compound/RPMI 1640. The plates were incubated at 35°C under ambient atmosphere. Photos were taken at 24 and 48 hours. The MIC endpoints for fluconazole and amphotericin B were read according to the M27-A3 protocol (Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard - 3rd Edition, published by the Clinical and Laboratory Standards Institute on January 1, 2008, M27-A3). The MICs for the test compounds and terbinafine (not mentioned in the M27-A3 protocol) were read as azoles.

Pharmacokinetic (PK) studies in mice

Compounds with suitable in vitro ADME properties are further subjected to in vivo PK studies. A snapshot format in mice is used to rapidly evaluate the oral availability of lead candidates. The snapshot format involves a single dose (typically 20 mg/kg) administered orally in a standard vehicle (e.g., 5% PEG/DMSO aqueous solution). The compound is directly injected into the MS analysis to determine a unique MRM (multiple reaction monitoring) signal that is concentration-dependent in ESI positive or negative mode. HPLC analysis is performed using a variety of solvent gradients from an organic solution to an aqueous solution to ensure good peak shape for the desired Q1/Q2 mass. The formulation includes an aqueous solution of 45% cyclodextrin (such as that used clinically for itraconazole). Other formulations that can be used are solutol, Eudragit, MC/Tween, etc. Using heparinized plasma from female mice, a standard curve is generated using plasma spiked with compounds at different concentrations (10 ng/mL to 2000 ng/mL) to determine the linear range of the Q1/Q2 mass signal relative to the compound concentration. Mice were orally administered the compound and plasma samples were collected by retroorbital bleeding. Plasma samples were collected into heparinized collection tubes at 5 time points (30 min, 1 h, 4 h, 8 h, and 24 h). Protein precipitation was performed. The compound was extracted in cold acetonitrile and analyzed by MS. Nonwinlin was used for PK modeling as needed.

Example II: Animal Model

To demonstrate in vivo anti-fibrotic activity, carbon tetrachloride (CCl ₄ )-induced liver fibrosis and bleomycin-induced lung and skin rodent fibrosis models were established. These in vivo experiments took 6-8 weeks to complete (including complete histological analysis). Typical experiments consisted of groups of 6-8 animals each, which were treated with itraconazole (2-4 doses), 1 or 2 test compounds (2-4 doses), vehicle, and baseline treatment (pirfenidone and AM-152). AM-152 (Amira Pharmaceuticals) is an LPA1 (lysophosphatidic acid 1) receptor antagonist. This target has been described as being associated with the exacerbation of the IPF system in the mouse bleomycin model (British Journal of Pharmacology (2010), 160, 1699–1713). As previously described in more detail in WO 2012/078805, AM-152 is an advanced compound in this target.

Bleomycin-induced pulmonary fibrosis model

Nine-week-old B6 male mice (Taconic farms) were surgically implanted with an osmotic pump that delivered 25 mg/kg bleomycin for 7 days. 17 days after surgery, mice were treated with drugs for two weeks. Drug treatment was administered. The anti-fibrotic drug AM-152 and pirfenidone described previously were used as positive control drugs. Lung sections were stained with Masson's trichrome staining, and after scanning, eight random areas were taken for analysis for each animal. Data are expressed as mean and standard deviation (s.e.m.). According to the improved Ashcroft scoring system, the stained lung sections were analyzed using an unbiased automated image analysis method. The automated image analysis macro in ImageJ was used to generate the Masson's trichrome staining total area. Each image was then converted into an RGB stack, and the threshold of the staining area was set so that only lung tissue was included in the analysis and empty spaces such as respiratory ducts and alveoli were excluded. The total staining area was then determined using the area measurement function in ImageJ. The average Ashcroft score and the average staining area percentage value were analyzed to determine the severity of pulmonary fibrosis.

Carbon tetrachloride-induced liver fibrosis model

Drug treatment was administered. Liver sections were stained with Sirius Red solution. After scanning, 5 random images were generated for each animal. The percentage of the total area positive for Sirius Red staining was generated using the automated image macro in Image J. In short, each image was converted into an RGB stack, and the threshold of the stained area was set so that the nuclei were not included in the analysis. The total red area was quantitatively determined using the area measurement function in Image J. Small pieces of liver from the CCl ₄ -induced liver fibrosis model were homogenized in PBS using a homogenizer and a steel ball. The residue was discarded by centrifugation, and the concentrated lysate was determined by Nanodrop absorbance measurement at 260nm. Equal amounts of lysate were loaded into each gel lane and then separated on a 10% Bis-Tris gel by SDS-PAGE, and then transferred to a PVDF membrane by a semi-dry transfer apparatus. After blocking in 5% milk in TRIS-buffered saline containing Tween-20 (0.1%), the membrane was exposed to the appropriate primary antibody. The blots were incubated with HRP-conjugated secondary antibodies and visualized using membrane and SuperSignal West Dura chemiluminescent substrate (Pierce).

Rodent wound healing model

Using rodent wound healing model, the impact of test compound on normal wound healing was evaluated. The model started the first five days, and mice were anesthetized and the back skin hair was removed with Nair. On the 1st day, mice were weighed, and a sterile biopsy punch (5mm diameter) was made by piercing the entire thickness of the folded back skin (2x 5mm turntable (dial) holes in total). The size of the wound was measured using a caliper every day. Body weight was monitored twice weekly during the entire study. From the 1st day until the end of the study, drug treatment (itraconazole was 25mg/kg, SID, and test compound or vehicle were 25mg/kg SID) was administered every day using a dosing volume of 5ml/kg. At the 7th, 11th and 14th day, the animals from each group were euthanized, and wounds were collected for histological analysis. When collecting wounds, wounds were cut out together with the surrounding skin of several mm. For each animal, two wounds were collected and fixed for histological analysis.

Example III: Phase II clinical study of scleroderma

A randomized, double-blind, placebo-controlled Phase II clinical trial showed proof of concept for an optimized anti-fibrotic itraconazole analog in patients with diffuse cutaneous scleroderma or systemic scleroderma with diffuse skin involvement. Patients who met the inclusion criteria formed two equal groups of 30 people each. The experimental group was given a single high dose of the drug every day for 6 months, while the placebo comparison group was given a placebo every day for 6 months. The single high dose of the drug was determined based on preclinical efficacy, target engagement in preclinical cynomolgus monkey toxicology studies, and Phase I safety studies. The primary outcome measure was a comparison of the efficacy of the drug with placebo based on the percentage change in m-RSS (score 0-51, 17 sites) between enrollment and monthly visits. Secondary outcome measures included comparison of drug efficacy with placebo based on change in m-RSS between enrollment and follow-up time points (1, 3, and 6 months); assessment of target fit, determined by expression profiling of hedgehog and VEGFR target genes using skin biopsies obtained at enrollment and 6 months; assessment of skin thickness at enrollment and 6 months using skin biopsies; assessment of treatment of non-cutaneous symptoms in patients with systemic sclerosis; assessment of quality of life using the Health Assessment Questionnaire and the Dermatology Quality of Life Index; and assessment of treatment tolerability using clinical and laboratory monitoring of side effects (including assessment of negative inotropic effects using echocardiography). Proof of concept success would be determined if >40% of patients had an improvement in m-RSS (defined as a decrease of ≥5.3 units in m-RSS between baseline and the last study visit at 6 months).

The precise target patient population consisted of patients diagnosed with diffuse (or severe) cutaneous scleroderma (modified Rodnan Skin Score m-RSS ≥ 16/51). Patients diagnosed with localized diffuse cutaneous scleroderma or systemic scleroderma with diffuse cutaneous involvement (as defined by the American College of Rheumatology) were known patient subgroups.

The inclusion and exclusion criteria for patient recruitment in the Phase II proof-of-concept study are as follows. Patients are 18 years of age or older with a documented diagnosis of cutaneous or systemic scleroderma. A baseline m-RSS of ≥16/51 indicative of diffuse cutaneous scleroderma is required. Enrollment requires a cardiac ultrasound ejection fraction score greater than 55% (i.e., normal) prior to enrollment. Patients will be excluded if they have received medications that may interfere with the course of their disease (e.g., methotrexate, corticosteroids, cyclophosphamide, bosentan) within 3 months prior to the start of the trial. Patients with severe organ failure, chronic liver disease (e.g., cirrhosis, chronic hepatitis), cancer, chronic diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, diabetes, HIV), or abnormal blood chemistry will be excluded. Patients who have undergone major surgery less than 4 weeks prior to enrollment will be excluded. Patients with contraindications to itraconazole will be excluded, as stated in the product instructions. Specifically, patients with signs of ventricular dysfunction (eg, congestive heart failure, CHF), at risk for CHF, or already receiving inotropic medications will be excluded. Patients with a myocardial infarction less than 6 months before enrollment will be excluded.

Patients were identified and selected for inclusion in the Phase II proof-of-concept study for treatment in collaboration with dermatology clinicians at multiple sites in the United States. A coordinating investigator, who is a member of the Scleroderma Clinical Trials Consortium, oversaw patient recruitment and served as chair of the study. Patients were diagnosed with localized diffuse cutaneous scleroderma or systemic scleroderma with diffuse skin involvement. Patients were stratified based on scleroderma diagnosis (i.e., localized or systemic), gender, and age to ensure equal distribution within the treatment population. In addition, patients were stratified based on the severity of skin involvement to ensure that an equal number of patients within the treatment population had severe skin involvement (m-RSS ≥ 20/51). This stratification requires an initial diagnostic test that includes skin sclerosis measurement and skin biopsy. Patients were required to undergo a cardiac ultrasound diagnostic test before enrollment to ensure normal heart function (ejection fraction score> 55%).

Because there are currently no treatments directly indicated for inhibiting fibrosis in patients with scleroderma, no comparator agents were used in the patient studies. The new agent was administered alone. Patients taking any medication were monitored to ensure that the new agent did not alter the pharmacokinetic and metabolic properties of the medication being used.

The modified Rodnan Skin Score (m-RSS) was established to evaluate clinical efficacy in patients with scleroderma using measurable and validated biomarkers. Briefly, the total skin surface was arbitrarily divided into 17 areas. In each area, manual palpation was used to estimate the skin score. The skin score varied from 0 to 3 based on the degree of skin thickening (1, not involved; 2, mild; 2, moderate; 3, severe). The total skin score was the sum of the scores for each of the 17 areas (maximum score of 51). Patients with a score between 16 and 19 were classified as diffuse, while patients with a score ≥20 were classified as severe. This skin scoring system has been shown to correlate very well with the degree of dermal fibrosis and also correlates well with the degree of fibrosis/dysfunction of internal organs (in patients with systemic scleroderma). Target engagement in the skin can be assessed by monitoring changes in the expression of hedgehog and VEGFR target genes using skin biopsies.

Example IV: Phase II clinical study of idiopathic pulmonary fibrosis

The purpose of this study is to determine the safety and efficacy of Formula (I) and Formula (II) compounds compared to placebo in the treatment of idiopathic pulmonary fibrosis. This clinical trial is interventional. The allocation of the clinical study participants is randomized; the intervention model is parallel designation; and the study is double-blind masking (subjects, caregivers, researchers). This clinical study primarily measures the rate of change of forced vital capacity, and secondarily evaluates safety based on adverse events, vital signs, and clinical laboratory tests.

The inclusion criteria for patient recruitment were as follows:

At the time of randomization, gender was not limited and age ranged from 40 to 80 years (inclusive).

Have clinical symptoms consistent with idiopathic pulmonary fibrosis (IPF).

Have received a first diagnosis of IPF at least 6 months and no more than 48 months before randomization. The date of diagnosis was defined as the date of the first available HRCT or surgical lung biopsy consistent with IPF/UIP.

Usual interstitial pulmonary fibrosis (UIP) or IPF diagnosed by high-resolution computed tomography (HRCT) or surgical lung biopsy (SLB).

On HRCT scans, the degree of fibrotic changes (honeycomb, reticular changes) is greater than that of emphysema.

If performed, there are no features on endobronchial biopsy, BAL, or SLB that support an alternative diagnosis.

At screening, the predicted post-bronchodilator FVC percentage is 50% to 80% (inclusive).

A change in post-bronchodilator FVC (measured in litres) between Screening and Day 1 that is less than a 10% relative difference, calculated as: 100% absolute value (Screening FVC (L) - Day 1 FVC (L))/Screening FVC (L).

Diffusion capacity for carbon monoxide (DLCO) 30% to 80% inclusive (adjusted for hemoglobin and altitude) at screening.

In the investigators' opinion, measures of IPF disease severity had not improved in the previous year.

At screening, be able to walk 150 meters or more in the 6-minute walk test (6MWT).

At screening, demonstrated a decrease in oxygen saturation of 2 percentage points or more during the 6MWT (which may be titrated with supplemental oxygen to maintain an oxygen saturation level >88%).

·Be able to understand and sign written informed consent.

Understand the importance of adhering to the study treatment and study protocol and be willing to comply with all study requirements, including concomitant medication restrictions, throughout the study.

Women of childbearing potential (WOCBP) and sexually active men with WOCBP must use an acceptable method of contraception.

The exclusion criteria for patient recruitment were as follows:

i) Target disease exclusion

(1) In the investigator's opinion, there is a significant clinical worsening of IPF between screening and Day 1 (during the screening process).

(2) At screening, the forced expiratory volume in 1 second (FEV1)/FVC ratio after bronchodilator administration was less than 0.8.

(3) At screening, had a bronchodilator response, which was defined as an absolute increase of 12% or more in FEV1 or FVC or both after bronchodilator use compared to the pre-bronchodilator value, and an increase of 200 mL.

ii) Medical history and concurrent diseases

(1) A history of clinically significant environmental exposure known to cause pulmonary fibrosis.

(2) Have a known explanation for interstitial lung disease.

(3) Any clinical diagnosis of connective tissue disease.

(4) Current clinically significant asthma or chronic obstructive pulmonary disease.

(5) Clinical evidence of active infection.

(6) Any history of malignancy that may result in significant disability or require significant medical or surgical intervention within the next 2 years. This does not include minor surgical procedures for localized cancers (e.g., basal cell carcinoma).

(7) In the opinion of the researcher, there is any condition other than IPF that may cause the subject's death within the next 2 years.

(8) History of end-stage liver disease.

(9) History of end-stage renal disease requiring dialysis.

(10) History of unstable or worsening heart or lung disease (except IPF) within the previous 6 months.

(11) History of alcohol or drug abuse in the past two years.

(12) Family or personal history of long QT syndrome and/or torsades de pointes (polymorphic ventricular tachycardia).

(13) Any of the following specific therapies have been used within 7 days before screening:

(a) Investigational therapy, which is defined as any drug that has not been approved for marketing for any indication in the country of the participating site.

(b) any cytotoxic, immunosuppressive, cytokine modulating or receptor-antagonist agent, including but not limited to azathioprine, bosentan, ambrisentan, cyclophosphamide, cyclosporine, etanercept, iloprost, infliximab, leukotriene antagonists, methotrexate, mycophenolate mofetil, tacrolimus, montelukast, tetrathiomolybdate, tumor necrosis factor alpha inhibitors, NAC, imatinib mesylate, interferon gamma-1b, pirfenidone and tyrosine kinase inhibitors.

(c) Colchicine, heparin, and warfarin. If there is no clinically acceptable alternative therapy for the same indication, sildenafil (daily use) may be used if given for a non-IPF indication; intermittent use for erectile dysfunction is permitted.

(d) Intermittent use of corticosteroids for acute respiratory exacerbations is permitted.

(e) Ketoconazole, cyclosporine, and steroids for topical and ophthalmic use are permitted.

Claims (16)

1. Compounds of formula (Ia) having the following structure or pharmaceutically acceptable salts thereof: in: R ¹ is -CH(CH ₃ )CH ₂ CH ₂ CH ₃ or -CH(CH ₂ CH ₃ ) ₂ ; ^R5 can be H, -CN, halogen, _C1 - _C10 haloalkyl, _C1 - _C10 ^alkyl , ^-NR13R14 , _-C1 - _C10 alkylene ( ^NR13R14 ) _and ^{-SO2R13 ;} Each ^R8 is independently selected from halogens, -OH, _-NO2 , _-N3 , -CN, _C1 - _C10 alkyl, _C1 - _C10 alkoxy, _C1 - _C10 haloalkoxy, _C1 - _{C10 haloalkyl, C1-C10 hydroxyalkyl , C1} - _C10 alkoxy- _C1 - _C10 alkyl, ^-C1 _{- C10} alkylene ( ^NR13R14 ), _-C1 - _C10 alkylene ( _C3 - _C8 cycloalkyl), _-SR13 , ^-SOR13 , -SO2R13, ^{-SO2NR13R14 ,} -NR13R14, ^-NR13SO2R14 , ^-NR13C ( _O ^{) R14} , ^-NR13C (O) ^{OR14 , -NR13C} (O) _OR14 ^{, -NR 13C} (O)NR ^{13R 14} , -C(O)R ¹⁴ , -C(O)OR ¹⁴ and -C(O)NR ^{13R 14} ; or two adjacent R ⁸ form a -C ₂ -C ₁₀ heterocyclic base ring; Each R ¹³ and each R ¹⁴ are independently selected from H, _C1 - _C10 alkyl, _C3 - _C8 cycloalkyl, _C2 - _C10 heterocyclic alkyl, _C1 - _C10 haloalkyl, _C1 - _C10 hydroxyalkyl, _C1 - _C10 alkoxyC1 _{-C10 alkyl} , and _C6 - _C30 arylC1- _C10 alkyl; or R ¹³ and R ₁₄ together with the atoms to which they are attached form ^a _C2 - _C10 heterocycle; and n is selected from 0, 1, 2, 3, and 4. 2. Compounds of formula (I) having the following structure or pharmaceutically acceptable salts thereof: in: R ¹ is -CH(CH ₃ )CH ₂ CH ₂ CH ₃ or -CH(CH ₂ CH ₃ ) ₂ ; ^R5 can be H, -CN, halogen, _C1 - _C10 haloalkyl, _C1 - _C10 ^alkyl , ^-NR13R14 , _-C1 - _C10 alkylene ( ^NR13R14 ) _and ^{-SO2R13 ;} Each ^R8 is independently selected from halogens, -OH, _-NO2 , _-N3 , -CN, _C1 - _C10 alkyl, _C1 - _C10 alkoxy, _C1 - _C10 haloalkoxy, _C1 - _{C10 haloalkyl, C1-C10 hydroxyalkyl , C1} - _C10 alkoxy- _C1 - _C10 alkyl, _-C1 - _C10 alkylene ( ^NR13R14 ), _-C1 - _C10 alkylene ( _C3 - _C8 cycloalkyl ⁾ , _-C1 - _C10 alkylene ( _C2 - _C10 heterocyclic), _C3 - _C8 cycloalkyl, _{C2 -C10} ^heterocyclic , _C6 - _C30 ^aryl , ^-SR13 , _-SOR13 , ^{-SO2R13 ,} _-SO2NR13R14 -NR ¹³ R ¹⁴ , -NR ¹³ SO ₂ R ¹⁴ , -NR ¹³ C(O)R ¹⁴ , -NR ¹³ C(O)OR ¹⁴ , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ and -C(O)NR ¹³ R ¹⁴ ; or two adjacent R ^8s form a C ₂ -C ₁₀ heterocyclic base ring; Each R ¹³ and each R ¹⁴ is independently selected from H, _C1 - _C10 alkyl, _C3 - _C8 cycloalkyl, _C2 - _C10 heterocyclic _C1 - _C10 alkyl, _C1 -C10 haloalkyl, _C1 - _C10 hydroxyalkyl, _C1 - _C10 alkoxy _C1 - _C10 alkyl, _C6 - _C30 aryl _C1 - _C10 alkyl, heteroaryl _C1 - _C10 alkyl _, and _C6 - _C30 aryl; or R ¹³ and R ¹⁴ together with the atoms to which they are attached form a _C2 - _C10 heterocycle; and n is selected from 0, 1, 2, 3, and 4. 3. The compound of claim 1, wherein ^R1 is _-CH ( _CH2CH3 ) ₂ . 4. _The compound of claim 1, wherein ^R1 is -CH _{( CH3} ) _CH2CH2CH3 . 5. The compound of claim 1, wherein n is 0. 6. The compound of claim 1, wherein n is 1. 7. The compound of claim 6, wherein ^R8 is a halogen, -CN, _C1 - _C10 alkyl, _C1 - _C10 alkoxy, _C1 - _C10 haloalkoxy, or _C1 - _C10 haloalkyl. 8. The compound of claim 1, wherein n is 2. 9. The compound of claim 8, wherein each R ⁸ is independently selected from halogen, -CN, _C1 - _C10 alkyl, _C1 - _C10 alkoxy, _C1 - _C10 haloalkoxy and _C1 - _C10 haloalkyl. 10. The compound of claim 9, wherein each R ⁸ is a halogen. 11. The compound of claim 10, wherein each R ⁸ is Cl. 12. The compound according to any one of claims 1-11, wherein ^R5 is H. 13. The compound according to any one of claims 1-11, wherein ^R5 is a halogen. 14. The compound of claim 13, wherein ^R5 is F. 15. The compound of claim 2, having the following structure: Or its pharmaceutically acceptable salt. 16. The compound of claim 1, having the following structure: Or its pharmaceutically acceptable salt.