CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/220,404 filed on July 9, 2021, and U.S. Provisional Patent Application No. 63/257,896, filed on October 20, 2021, the entire contents of each of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] The IL-17 family consists of six cytokines (IL-17A through IL-17F). Interleukin- 17A (IL- 17A), is an established pro-inflammatory cytokine, which is involved in the induction of IL-6, IL-8, G-CSF, TNF-a, IL-Ib, PGE2, and IFN-g, as well as numerous chemokines and other effectors. IL- 17A can form homodimers or heterodimers with its family member, IL-17F and can bind to both IL-17 receptors, IL-17 RA and IL-17 RC, in order to mediate signaling. IL-17A is a major pathological cytokine expressed by Thl7 cells, which are involved in the pathology of inflammation and autoimmunity, and also CD8+ T cells, gd cells, NK cells, NKT cells, macrophages and dendritic cells. Additionally, IL-17A and Thl7 are necessary for defense against various microbes despite their involvement in inflammation and autoimmune disorders. Further, IL- 17A can act in cooperation with other inflammatory cytokines such as TNF-a, IFN-g, and IL-Ib to mediate pro-inflammatory effects.

[0003] To date, there are a few biologies (Secukinumab and Ixekizumab) that have been approved to modulate IL-17A for the treatment of inflammatory diseases, such as psoriasis, ankylosing spondylitis, and psoriatic arthritis. These treatments require injection to a patient as they are not readily absorbed by the gut when orally ingested. Further, these approved biologic treatments have a high cost of entry for patients, limiting the availability to the patient population in need thereof. [0004] There are a few small molecule modulators of IL-17A that have been approved for oral administration. However, while these have the convenience of oral administration and a lower cost of entry for patients, they lack the efficacy of approved biologies. Therefore, there exists a need for the development of potent small molecule IL-17A modulators for the treatment of inflammatory diseases and other associated disorders.

SUMMARY OF THE INVENTION

[0005] In certain aspects, the present disclosure provides a compound represented by the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

A is selected from a 5- to 6-membered heterocycle optionally substituted with one more substituents independently selected from (i), (ii), and (iii):

(i) halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , C(O)OR ¹¹ , -OC(O)R ¹¹ , - OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , - N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ , and -CN;

(ii) C ₁ -10 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , C(O)OR ¹¹ , -OC(O)R ¹¹ , - OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , - N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ , =O, -CN; and

C _3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, -OR ¹¹ , - SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , - N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), - S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ , =O, and -CN; and (iii) 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , - N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ , =O, -CN; and

C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , - OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , - N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ , =O , and -CN;

B is selected from -CH(R ^A )(R ^B ) and C _3-10 carbocycle, wherein C _3-10 carbocycle is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹² , -SR ¹² , -N(R ¹² ) ₂ , -C(O)R ¹² , -C(O)OR ¹² , -OC(O)R ¹² , -OC(O)N(R ¹² ) _2, -C(O)N(R ¹² ) ₂ , -N(R ¹² )C(O)R ¹² , -N(R ¹² )C(O)OR ¹² , -N(R ¹² )C(O)N(R ¹² ) ₂ , -N(R ¹² )S(O) ₂ (R ¹² ), -S(O)R ¹² , -S(O) ₂ R ¹² , -S(O) ₂ N(R ¹² ) ₂ , -NO ₂ , =,O and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹² , -SR ¹² , -N(R ¹² ) ₂ , -C(O)R ¹² , -C(O)OR ¹² , -OC(O)R ¹² , - OC(O)N(R ¹² ) _2, -C(O)N(R ¹² ) ₂ , -N(R ¹² )C(O)R ¹² , -N(R ¹² )C(O)OR ¹² , -N(R ¹² )C(O)N(R ¹² ) ₂ , - N(R ¹² )S(O) ₂ (R ¹² ), -S(O)R ¹² , -S(O) ₂ R ¹² , -S(O) ₂ N(R ¹² ) ₂ , -NO ₂ , ,= aOnd -CN;

R ^A and R ^B are each independently selected from: halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , -OC(O)N(R ¹³ ) _2, -C(O)N(R ¹³ ) ₂ , -N(R ¹³ )C(O)R ¹³ , -N(R ¹³ )C(O)OR ¹³ , -N(R ¹³ )C(O)N(R ¹³ ) ₂ , -N(R ¹³ )S(O) ₂ (R ¹³ ), -S(O)R ¹³ , -S(O) ₂ R ¹³ , -S(O) ₂ N(R ¹³ ) ₂ , -NO ₂ , and -CN; C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , - OC(O)N(R ¹³ ) _2, -C(O)N(R ¹³ ) ₂ , -N(R ¹³ )C(O)R ¹³ , -N(R ¹³ )C(O)OR ¹³ , -N(R ¹³ )C(O)N(R ¹³ ) ₂ , - N(R ¹³ ) ₂ S(O) ₂ (R ¹³ ), -S(O)R ¹³ , -S(O) ₂ R ¹³ , -S(O) ₂ N(R ¹³ ) ₂ , -NO ₂ , and -CN; and

C _3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , - OC(O)N(R ¹³ ) _2, -C(O)N(R ¹³ ) ₂ , -N(R ¹³ )C(O)R ¹³ , -N(R ¹³ )C(O)OR ¹³ , -N(R ¹³ )C(O)N(R ¹³ ) ₂ , - N(R ¹³ )S(O) ₂ (R ¹³ ), -S(O)R ¹³ , -S(O) ₂ R ¹³ , -S(O) ₂ N(R ¹³ ) ₂ , -NO ₂ , and -CN;

R ¹ and R ² are each independently selected from (iv), (v), (vi) and (vii):

(iv) hydrogen;

(v) halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , - OC(O)N(R ¹⁴ ) _2, -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , -NO ₂ , and -CN; and

(vi) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , - OC(O)N(R ¹⁴ ) _2, -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , - N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , -NO ₂ , and -CN; and

3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^14B , -SR ^14B , -N(R ^14B ) ₂ , - C(O)R ^14B , -C(O)OR ^14B , -OC(O)R ^14B , -OC(O)N(R ^14B ) _2, -C(O)N(R ^14B ) ₂ , - N(R ^14B )C(O)R ^14B , -N(R ^14B )C(O)OR ^14B , -N(R ^14B )C(O)N(R ^14B ) ₂ , -N(R ^14B )S(O) ₂ (R ^14B ), -S(O)R ^14B , -S(O) ₂ R ^14B , -S(O) ₂ N(R ^14B ) ₂ , -NO ₂ , and -CN; and (vii) 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ^14B , -SR ^14B , -N(R ^14B ) ₂ , -C(O)R ^14B , -C(O)OR ^14B , -OC(O)R ^14B , - OC(O)N(R ^14B ) _2, -C(O)N(R ^14B ) ₂ , -N(R ^14B )C(O)R ^14B , -N(R ^14B )C(O)OR ^14B , - N(R ^14B )C(O)N(R ^14B ) ₂ , -N(R ^14B )S(O) ₂ (R ^14B ), -S(O)R ^14B , -S(O) ₂ R ^14B , -S(O) ₂ N(R ^14B ) ₂ , - NO ₂ , and -CN

R ³ and R ⁴ are each independently selected from (a), (b), (c), and (d):

(a) hydrogen;

(b) C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)NH ₂ , -C(O)-O-C _1-6 -alkyl, - OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , - CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , - OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN;

(c) C _2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C _1-6 -alkyl, -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , - OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; and (d) C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2J -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; or

R ³ and R ⁴ can come together to form a 4- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁶ , -SR ¹⁶ , -N(R ¹⁶ ) ₂ , -C(O)R ¹⁶ , -C(O)OR ¹⁶ , -OC(O)R ¹⁶ , -OC(O)N(R ¹⁶ ) _2, -C(O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ )C(O)R ¹⁶ , -N(R ¹⁶ )C(O)OR ¹⁶ , -N(R ¹⁶ )C(O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ )S(O) ₂ (R ¹⁶ ), -S(O)R ¹⁶ , -S(O) ₂ R ¹⁶ , -S(O) ₂ N(R ¹⁶ ) ₂ , -NO ₂ , =,O and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁶ , -SR ¹⁶ , -N(R ¹⁶ ) ₂ , -C(O)R ¹⁶ , -C(O)OR ¹⁶ , -OC(O)R ¹⁶ , - OC(O)N(R ¹⁶ ) _2, -C(O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ )C(O)R ¹⁶ , -N(R ¹⁶ )C(O)OR ¹⁶ , -N(R ¹⁶ )C(O)N(R ¹⁶ ) ₂ , - N(R ¹⁶ )S(O) ₂ (R ¹⁶ ), -S(O)R ¹⁶ , -S(O) ₂ R ¹⁶ , -S(O) ₂ N(R ¹⁶ ) ₂ , -NO ₂ , ,= aOnd -CN;

R ⁵ is selected from: halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ , -C(O)OR ¹⁷ , -OC(O)R ¹⁷ , -OC(O)N(R ¹⁷ ) _2, -C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )C(O)R ¹⁷ , -N(R ¹⁷ )C(O)OR ¹⁷ , -N(R ¹⁷ )C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁷ , -S(O) ₂ R ¹⁷ , -S(O) ₂ N(R ¹⁷ ) ₂ , -NO ₂ , and -CN; C _1-6 alkyl and C _2-6 alkenyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ , - C(O)OR ¹⁷ , -OC(O)R ¹⁷ , -OC(O)N(R ¹⁷ ) _2, -C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )C(O)R ¹⁷ , -N(R ¹⁷ )C(O)OR ¹⁷ , - N(R ¹⁷ )C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁷ , -S(O) ₂ R ¹⁷ , -S(O) ₂ N(R ¹⁷ ) ₂ , -NO ₂ , , a=nOd - CN; and

C _3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^17B , -SR ^17B , -N(R ^17B ) ₂ , -C(O)R ^17B , -C(O)OR ^17B , -OC(O)R ^17B , - OC(O)N(R ^17B ) _2, -C(O)N(R ^17B ) ₂ , -N(R ^17B )C(O)R ^17B , -N(R ^17B )C(O)OR ^17B , - N(R ^17B )C(O)N(R ^17B ) ₂ , -N(R ^17B )S(O) ₂ (R ^17B ), -S(O)R ^17B , -S(O) ₂ R ^17B , -S(O) ₂ N(R ^17B ) ₂ , -NO ₂ , and -CN; R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ^14B , R ¹⁵ , R ¹⁶ , R ¹⁷ , and R ^17B are independently selected at each occurrence from

(I), (II) and (III):

(I) hydrogen;

(II) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ haloalkyl -NH ₂ , -NO ₂ , =O, -CN, C _3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C _3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents selected from: halogen, -OH, C ₁ -C ₆ haloalkyl, -O-C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ haloalkyl -NH ₂ , -NO ₂ , =O, and -CN; and

(III) C _3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, C ₁ -C ₆ haloalkyl, -O-C1-C ₆ alkyl, -O-C1-C ₆ haloalkyl -NH2, -NO2, =O, and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C ₁ -C ₆ alkyl, -O-C1-C ₆ haloalkyl -NH2, -NO2, =O, and -CN; and n is selected from 0, 1, 2, 3, and 4, wherein n is selected from 1, 2, 3, and 4; or at least one of R ¹ or R ² is hydrogen.

[0006] In certain embodiments, the disclosure provides a pharmaceutical composition comprising pharmaceutically acceptable excipient and a compound or salt of Formula (I) or (I-a).

[0007] In certain embodiments, the disclosure provides a method of modulating IL-17 A in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (I) or (I-a), or a pharmaceutical composition thereof.

[0008] In certain embodiments, the disclosure provides a method treating an inflammatory disease or condition comprising administering to the subject a compound or salt of Formula (I) or (I-a), or a pharmaceutical composition thereof. In some embodiments, the inflammatory disease or condition is selected from plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, Palmoplantar Psoriasis, Spondyloarthritis, and Non-infectious Uveitis.

INCORPORATION BY REFERENCE

[0009] 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 OF THE INVENTION [0010] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Definitions

[0011] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0012] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0013] "Alkyl" refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms {i.e., C ₁ -C ₁₂ alkyl). The alkyl is attached to the remainder of the molecule through a single bond. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C ₁ -C ₁₂ alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C ₁ -Cx alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C ₁ -C ₅ alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C ₁ -C ₄ alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C ₁ -C ₃ alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C ₁ -C ₂ alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C ₁ alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C ₅ -C ₁₅ alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., Cs-Cx alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C ₂ -C ₅ alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C ₃ -C ₅ alkyl). For example, the alkyl group may be attached to the rest of the molecule by a single bind, such as, methyl, ethyl, 1 -propyl (//-propyl), 1-methylethyl (No-propyl),

1 -butyl (//-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (No-butyl), 1,1-dimethylethyl (tert- butyl), 1 -pentyl (//-pentyl), and the like.

[0014] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C ₂ -C ₁₂ alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C ₂ -C ₈ alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C ₂ -C ₆ alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C ₂ -C ₄ alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like.

[0015] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C ₂ -C ₁₂ alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C ₂ -C ₈ alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C ₂ -C ₆ alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C ₂ -C ₄ alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0016] "Alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C ₁ - C ₁₀ alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C ₁ -C ₈ alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C ₁ -C ₅ alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C ₁ -C ₄ alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C ₁ -C ₃ alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C ₁ -C ₂ alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C ₁ alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., Cs-Cx alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C ₂ -C ₅ alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C ₃ -C ₅ alkylene).

[0017] "Alkenylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C ₂ -C ₁₀ alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C ₂ -C ₈ alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C ₂ -C ₅ alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C ₂ -C ₄ alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C ₂ -C ₃ alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C ₂ alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C ₅ -Cx alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C ₃ -C ₅ alkenylene).

[0018] "Alkynylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C ₂ -C ₁₀ alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C ₂ -C ₈ alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C ₂ -C ₅ alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C ₂ -C ₄ alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C ₂ -C ₃ alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C ₂ alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C ₅ -C ₈ alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C ₃ -C ₅ alkynylene).

[0019] The term “C _x-y ” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C _1-6 alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term - C _x-y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example, -C _1-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted. [0020] The terms “C _x.y alkenyl” and “C _x.y alkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -C _x.y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, -C ₂ -6 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -C _x.y alkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain. For example, -C ₂ -6 alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0021] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiro-ring systems. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0022] "Cycloalkyl" refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl). In certain embodiments, a cycloalkyl comprises three to ten carbon atoms (i.e., C _3-10 cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkyl). The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein. [0023] "Cycloalkenyl" refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond (i.e., C _3-12 cycloalkenyl). In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms (i.e., C _3-10 cycloalkenyl). In other embodiments, a cycloalkenyl comprises five to seven carbon atoms (i.e., C _5-7 cycloalkenyl). The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0024] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Aryl may be optionally substituted by one or more substituents such as those substituents described herein.

[0025] A “C _x-y carbocycle” is meant to include groups that contain from x to y carbons in a ring.

For example, the term “C _3-6 carbocycle” can be a saturated, unsaturated or aromatic ring system that contains from 3 to 6 carbon atoms — any of which is optionally substituted as provided herein.

[0026] The term “heterocycle” as used herein refers to a saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein. Bicyclic heterocycles may be fused, bridged or spiro-ring systems. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0027] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0028] The term “heteroaryl” refers to a radical derived from a 3- to 12-membered aromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Heteroaryl includes aromatic single ring structures, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein. Heteroaryl also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein.

[0029] An “X-membered heterocycle” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0030] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0031] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0032] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, di chi orom ethyl, bromom ethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluorom ethane, iodomethane), di-and trihalomethane (e.g., tri chi orom ethane, tribromom ethane, trifluorom ethane, triiodom ethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3- dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, and I). When an alkyl group is sub stituted with more than one halogen radicals, each halogen may be independently selected for example, l-chloro,2-fluoroethane.

[0033] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH ₂ of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0034] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N-

NH ₂ ), -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C (O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -O-R ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a ) S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2), and -R ^b -S(O) _t N(R ^a ) ₂ (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO ₂ ), imino (=N- H), oximo(=N-OH), hydrazine(=N-

NH ₂ ), -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C (O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -O-R ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a ) S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2) and -R ^b -S(O) _t N(R ^a ) ₂ (where t is 1 or 2); wherein each R ^a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R ^a , valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO ₂ ), imino (=N-H), oximo (=N-OH), hydrazine(=N- NH ₂ ), -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C (O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -O-R ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a ) S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2) and -R ^b -S(O) _t N(R ^a ) ₂ (where t is 1 or 2); and wherein each R ^b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R ^c is a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0035] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0036] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0037] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0038] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0039] As used herein, the phrase "a subject in need thereof refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0040] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms ““administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0041] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and/or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0042] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0043] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

Compounds [0044] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

A is selected from a 5- to 6-membered heterocycle optionally substituted with one more substituents independently selected from (i), (ii), and (iii):

(i) halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , - OC(O)N(R ¹¹ ) ₂ , -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , - N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ , and -CN;

(ii) C ₁ -io alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , - OC(O)N(R ¹¹ ) ₂ , -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , - N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ ,=O , -CN; and

C _3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, -OR ¹¹ , -

SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , - N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), - S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ ,=O , and -CN; and

(iii) 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , - OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , - N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ ,=O , -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , - OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , - N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ ,=O , and -CN; B is selected from -CH(R ^A )(R ^B ) and C _3-10 carbocycle, wherein the C _3-10 carbocycle is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹² , -SR ¹² , -N(R ¹² ) ₂ , -C(O)R ¹² , -C(O)OR ¹² , -OC(O)R ¹² , -OC(O)N(R ¹² ) _2, -C(O)N(R ¹² ) ₂ , -N(R ¹² )C(O)R ¹² , -N(R ¹² )C(O)OR ¹² , -N(R ¹² )C(O)N(R ¹² ) ₂ , -N(R ¹² )S(O) ₂ (R ¹² ), -S(O)R ¹² , -S(O) ₂ R ¹² , -S(O) ₂ N(R ¹² ) ₂ , -NO ₂ , =,O and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹² , -SR ¹² , -N(R ¹² ) ₂ , -C(O)R ¹² , -C(O)OR ¹² , -OC(O)R ¹² , - OC(O)N(R ¹² ) _2, -C(O)N(R ¹² ) ₂ , -N(R ¹² )C(O)R ¹² , -N(R ¹² )C(O)OR ¹² , -N(R ¹² )C(O)N(R ¹² ) ₂ , - N(R ¹² )S(O) ₂ (R ¹² ), -S(O)R ¹² , -S(O) ₂ R ¹² , -S(O) ₂ N(R ¹² ) ₂ , -NO ₂ , O,,= and -CN;

R ^A and R ^B are each independently selected from: halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , -OC(O)N(R ¹³ ) _2, -C(O)N(R ¹³ ) ₂ , -N(R ¹³ )C(O)R ¹³ , -N(R ¹³ )C(O)OR ¹³ , -N(R ¹³ )C(O)N(R ¹³ ) ₂ , -N(R ¹³ )S(O) ₂ (R ¹³ ), -S(O)R ¹³ , -S(O) ₂ R ¹³ , -S(O) ₂ N(R ¹³ ) ₂ , -NO ₂ , and -CN; C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , - OC(O)N(R ¹³ ) _2, -C(O)N(R ¹³ ) ₂ , -N(R ¹³ )C(O)R ¹³ , -N(R ¹³ )C(O)OR ¹³ , -N(R ¹³ )C(O)N(R ¹³ ) ₂ , - N(R ¹³ ) ₂ S(O) ₂ (R ¹³ ), -S(O)R ¹³ , -S(O) ₂ R ¹³ , -S(O) ₂ N(R ¹³ ) ₂ , -NO ₂ , and -CN; and

C _3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , - OC(O)N(R ¹³ ) _2, -C(O)N(R ¹³ ) ₂ , -N(R ¹³ )C(O)R ¹³ , -N(R ¹³ )C(O)OR ¹³ , -N(R ¹³ )C(O)N(R ¹³ ) ₂ , - N(R ¹³ )S(O) ₂ (R ¹³ ), -S(O)R ¹³ , -S(O) ₂ R ¹³ , -S(O) ₂ N(R ¹³ ) ₂ , -NO ₂ , and -CN;

R ¹ and R ² are each independently selected from (iv), (v), (vi) and (vii):

(iv) hydrogen;

(v) halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , - OC(O)N(R ¹⁴ ) _2, -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , -NO ₂ , and -CN;

(vi) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , - OC(O)N(R ¹⁴ ) _2, -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , - N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , -NO ₂ , and -CN; and

3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^14B , -SR ^14B , -N(R ^14B ) ₂ , - C(O)R ^14B , -C(O)OR ^14B , -OC(O)R ^14B , -OC(O)N(R ^14B ) _2, -C(O)N(R ^14B ) ₂ , - N(R ^14B )C(O)R ^14B , -N(R ^14B )C(O)OR ^14B , -N(R ^14B )C(O)N(R ^14B ) ₂ , -N(R ^14B )S(O) ₂ (R ^14B ), -S(O)R ^14B , -S(O) ₂ R ^14B , -S(O) ₂ N(R ^14B ) ₂ , -NO ₂ , and -CN; and (vii) 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ^14B , -SR ^14B , -N(R ^14B ) ₂ , -C(O)R ^14B , -C(O)OR ^14B , -OC(O)R ^14B , - OC(O)N(R ^14B ) _2, -C(O)N(R ^14B ) ₂ , -N(R ^14B )C(O)R ^14B , -N(R ^14B )C(O)OR ^14B , - N(R ^14B )C(O)N(R ^14B ) ₂ , -N(R ^14B )S(O) ₂ (R ^14B ), -S(O)R ^14B , -S(O) ₂ R ^14B , -S(O) ₂ N(R ^14B ) ₂ , - NO ₂ , and -CN;

R ³ and R ⁴ are each independently selected from (a), (b), (c), and (d):

(a) hydrogen;

(b) C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)NH ₂ , -C(O)-O-C _1-6 -alkyl, - OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , - CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C ₁ -ehaloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , - OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN;

(c) C _2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C ₁ . ₆ .alkyl, -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , - OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; and

(d) C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; or

R ³ and R ⁴ can come together to form a 4- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁶ , -SR ¹⁶ , -N(R ¹⁶ ) ₂ , -C(O)R ¹⁶ , -C(O)OR ¹⁶ , -OC(O)R ¹⁶ , -OC(O)N(R ¹⁶ ) _2, -C(O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ )C(O)R ¹⁶ , -N(R ¹⁶ )C(O)OR ¹⁶ , -N(R ¹⁶ )C(O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ )S(O) ₂ (R ¹⁶ ), -S(O)R ¹⁶ , -S(O) ₂ R ¹⁶ , -S(O) ₂ N(R ¹⁶ ) ₂ , -NO ₂ , =,O and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁶ , -SR ¹⁶ , -N(R ¹⁶ ) ₂ , -C(O)R ¹⁶ , -C(O)OR ¹⁶ , -OC(O)R ¹⁶ , - OC(O)N(R ¹⁶ ) _2, -C(O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ )C(O)R ¹⁶ , -N(R ¹⁶ )C(O)OR ¹⁶ , -N(R ¹⁶ )C(O)N(R ¹⁶ ) ₂ , - N(R ¹⁶ )S(O) ₂ (R ¹⁶ ), -S(O)R ¹⁶ , -S(O) ₂ R ¹⁶ , -S(O) ₂ N(R ¹⁶ ) ₂ , -NO ₂ , ,= aOnd -CN;

R ⁵ is selected from: halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ , -C(O)OR ¹⁷ , -OC(O)R ¹⁷ , -OC(O)N(R ¹⁷ ) _2, -C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )C(O)R ¹⁷ , -N(R ¹⁷ )C(O)OR ¹⁷ , -N(R ¹⁷ )C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁷ , -S(O) ₂ R ¹⁷ , -S(O) ₂ N(R ¹⁷ ) ₂ , -NO ₂ , and -CN; C _1-6 alkyl and C _2-6 alkenyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ , - C(O)OR ¹⁷ , -OC(O)R ¹⁷ , -OC(O)N(R ¹⁷ ) _2, -C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )C(O)R ¹⁷ , -N(R ¹⁷ )C(O)OR ¹⁷ , - N(R ¹⁷ )C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁷ , -S(O) ₂ R ¹⁷ , -S(O) ₂ N(R ¹⁷ ) ₂ , -NO ₂ , , a=nOd - CN; and

C _3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^17B , -SR ^17B , -N(R ^17B ) ₂ , -C(O)R ^17B , -C(O)OR ^17B , -OC(O)R ^17B , - OC(O)N(R ^17B ) _2, -C(O)N(R ^17B ) ₂ , -N(R ^17B )C(O)R ^17B , -N(R ^17B )C(O)OR ^17B , - N(R ^17B )C(O)N(R ^17B ) ₂ , -N(R ^17B )S(O) ₂ (R ^17B ), -S(O)R ^17B , -S(O) ₂ R ^17B , -S(O) ₂ N(R ^17B ) ₂ , -NO ₂ , and -CN;

R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ^14B , R ¹⁵ , R ¹⁶ , R ¹⁷ , and R ^17B are independently selected at each occurrence from

(I), (II) and (III):

(I) hydrogen;

(II) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C _1-6 alkyl, -O-C _1-6 haloalkyl -NH ₂ , -NO ₂ , =O, -CN, C _3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C _3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents selected from: halogen, -OH, C1-C6 haloalkyl, - O-C1-C6 alkyl, -O-C1-C6 haloalkyl -NH ₂ , -NO ₂ , =O, and -CN; and

(III) C _3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-C6 haloalkyl, -O-C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ haloalkyl -NH ₂ , -NO ₂ , =O, and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ haloalkyl -NH ₂ , -NO ₂ , =O, and -CN; and n is selected from 0, 1, 2, 3, and 4, wherein n is selected from 1, 2, 3, and 4; or at least one of R ¹ or R ² is hydrogen.

[0045] In some embodiments, for the compound or salt of Formula (I), R ⁵ is selected from C _3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^17B , -SR ^17B , -N(R ^17B ) ₂ , -C(O)R ^17B , -C(O)OR ^17B , -OC(O)R ^17B , -OC(O)N(R ^17B ) _2, - C(O)N(R ^17B ) ₂ , -N(R ^17B )C(O)R ^17B , -N(R ^17B )C(O)OR ^17B , -N(R ^17B )C(O)N(R ^17B ) ₂ , - N(R ^17B )S(O) ₂ (R ^17B ), -S(O)R ^17B , -S(O) ₂ R ^17B , -S(O) ₂ N(R ^17B ) ₂ , -NO ₂ , and -CN. In some embodiments,

R ⁵ is selected from C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^17B , -N(R ^17B ) ₂ , -C(O)R ^17B , -C(O)OR ^17B , -NO ₂ , and -CN. In some embodiments, R ⁵ is an optionally substituted saturated C3-6 carbocycle. In some embodiments, R ⁵ is an optionally substituted C ₆ aryl. In some embodiments, R ⁵ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any one of which is optionally substituted. In some embodiments, R ⁵ is optionally substituted cyclopropyl. In some embodiments,

R is represented by:

[0046] In some embodiments, for the compound or salt of Formula (I), one of R ¹ or R ² is selected from: C _1-6 alkyl optionally substituted with one or more substituents independently selected from 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^14B , -SR ^14B , -N(R ^14B ) ₂ , -C(O)R ^14B , -C(O)OR ^14B , -OC(O)R ^14B , - OC(O)N(R ^14B ) ₂ -C(O)N(R ^14B ) ₂ , -N(R ^14B )C(O)R ^14B , -N(R ^14B )C(O)OR ^14B , -N(R ^14B )C(O)N(R ^14B ) ₂ , - N(R ^14B )S(O) ₂ (R ^14B ), -S(O)R ^14B , -S(O) ₂ R ^14B , -S(O) ₂ N(R ^14B ) ₂ , -NO ₂ , and -CN; and 3- to 10- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ^14B , -SR ^14B , -N(R ^14B ) ₂ , -C(O)R ^14B , -C(O)OR ^14B , -OC(O)R ^14B , -OC(O)N(R ^14B ) _2, - C(O)N(R ^14B ) ₂ , -N(R ^14B )C(O)R ^14B , -N(R ^14B )C(O)OR ^14B , -N(R ^14B )C(O)N(R ^14B ) ₂ , - N(R ^14B )S(O) ₂ (R ^14B ), -S(O)R ^14B , -S(O) ₂ R ^14B , -S(O) ₂ N(R ^14B ) ₂ , -NO ₂ , and -CN.

[0047] In some embodiments, for the compound or salt of Formula (I), one of R ¹ or R ² is selected from: methyl, ethyl, propyl, and isopropyl, each of which is optionally substituted with one or more substituents independently selected from 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^14B , -SR ^14B , -N(R ^14B ) ₂ , - C(O)R ^14B , -C(O)OR ^14B , -OC(O)R ^14B , -OC(O)N(R ^14B ) _2, -C(O)N(R ^14B ) ₂ , -N(R ^14B )C(O)R ^14B , - N(R ^14B )C(O)OR ^14B , -N(R ^14B )C(O)N(R ^14B ) ₂ , -N(R ^14B )S(O) ₂ (R ^14B ), -S(O)R ^14B , -S(O) ₂ R ^14B , - S(O) ₂ N(R ^14B ) ₂ , -NO ₂ , and -CN; and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ^14B , -SR ^14B , -N(R ^14B ) ₂ , -C(O)R ^14B , - C(O)OR ^14B , -OC(O)R ^14B , -OC(O)N(R ^14B ) _2, -C(O)N(R ^14B ) ₂ , -N(R ^14B )C(O)R ^14B , -N(R ^14B )C(O)OR ^14B , -N(R ^14B )C(O)N(R ^14B ) ₂ , -N(R ^14B )S(O) ₂ (R ^14B ), -S(O)R ^14B , -S(O) ₂ R ^14B , -S(O) ₂ N(R ^14B ) ₂ , -NO ₂ , and - CN.

[0048] In some embodiments, for the compound or salt of Formula (I), R ¹ is hydrogen; and R ² is selected from: C _1-6 alkyl optionally substituted with one or more substituents independently selected from 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^14B , -SR ^14B , -N(R ^14B ) ₂ , -C(O)R ^14B , -C(O)OR ^14B , - OC(O)R ^14B , -OC(O)N(R ^14B ) _2, -C(O)N(R ^14B ) ₂ , -N(R ^14B )C(O)R ^14B , -N(R ^14B )C(O)OR ^14B , - N(R ^14B )C(O)N(R ^14B ) ₂ , -N(R ^14B )S(O) ₂ (R ^14B ), -S(O)R ^14B , -S(O) ₂ R ^14B , -S(O) ₂ N(R ^14B ) ₂ , -NO ₂ , and -CN; and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ^14B , -SR ^14B , -N(R ^14B ) ₂ , -C(O)R ^14B , -C(O)OR ^14B , - OC(O)R ^14B , -OC(O)N(R ^14B ) _2, -C(O)N(R ^14B ) ₂ , -N(R ^14B )C(O)R ^14B , -N(R ^14B )C(O)OR ^14B , - N(R ^14B )C(O)N(R ^14B ) ₂ , -N(R ^14B )S(O) ₂ (R ^14B ), -S(O)R ^14B , -S(O) ₂ R ^14B , -S(O) ₂ N(R ^14B ) ₂ , -NO ₂ , and -CN. [0049] In some embodiments, for the compound or salt of Formula (I), one of R ¹ or R ² is selected from: C _1-6 alkyl optionally substituted with one or more substituents independently selected from 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^14B , -N(R ^14B ) ₂ , -C(O)R ^14B , -C(O)OR ^14B , -NO ₂ , and -CN. In some embodiments, one of R ¹ or R ² is C _1-6 alkyl substituted with a 5- to 6-membered saturated heterocycle wherein the 5- to 6-membered saturated heterocycle selected from pyrrolidine, pyrroline, pyrazoline, imidazoline, tetrahydrofuran, dioxolane, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, any one of which is optionally substituted. In some embodiments, one of R ¹ or R ² is represented by [0050] In some embodiments, for the compound or salt of Formula (I), R ¹ is hydrogen; and R ² is selected from: C _1-6 alkyl optionally substituted with one or more substituents independently selected from 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^14B , -N(R ^14B ) ₂ , -C(O)R ^14B , -C(O)OR ^14B , -NO ₂ , and -CN.

In some embodiments, R ¹ is hydrogen; and R ² is C _1-6 alkyl substituted with a 5- to 6-membered saturated heterocycle wherein the 5- to 6-membered saturated heterocycle selected from pyrrolidine, pyrroline, pyrazoline, imidazoline, tetrahydrofuran, dioxolane, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, any one of which is optionally substituted. In some embodiments, R ¹ is hydrogen; and R ² is represented by

[0051] In some embodiments, for the compound or salt of Formula (I), one of R ¹ or R ² is a 5- to 6- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ^14B , -N(R ^14B ) ₂ , -C(O)R ^14B , -C(O)OR ^14B , -NO ₂ , and -CN. In some embodiments, one of R ¹ or R ² is 5- to 6-membered heterocycle selected from pyrrolidine, pyrroline, pyrazoline, imidazoline, tetrahydrofuran, dioxolane, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, any one of which is optionally substituted. In some embodiments, one of R ¹ or R ² is represented by

[0052] In some embodiments, for the compound or salt of Formula (I), R ¹ is hydrogen; and R ² is a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ^14B , -N(R ^14B ) ₂ , -C(O)R ^14B , -C(O)OR ^14B , -NO ₂ , and -CN. In some embodiments, R ¹ is hydrogen; and R ² is 5- to 6-membered heterocycle selected from pyrrolidine, pyrroline, pyrazoline, imidazoline, tetrahydrofuran, dioxolane, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, any one of which is optionally substituted. In some embodiments, R ¹ is hydrogen; and R ² is represented by

[0053] In some embodiments, for compound or salt of Formula (I), one of R ³ and R ⁴ is selected from C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)NH ₂ , -C(O)-O-C _1-6 -alkyl, - OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN.

[0054] In some embodiments, one of R ³ and R ⁴ is selected from C ₁ alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , - C(O)NH ₂ , -NO ₂ , and -CN. In some embodiments, one of R ³ and R ⁴ is selected from C ₁ alkyl optionally substituted with -C(O)NH ₂ . In some embodiments, one of R ³ and R ⁴ is represented by

[0055] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I-a): or a pharmaceutically acceptable salt thereof, wherein:

A is selected from a 5- to 6-membered heterocycle optionally substituted with one more substituents independently selected from (i), (ii), and (iii):

(i) halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , C(O)OR ¹¹ , -OC(O)R ¹¹ , - OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , - N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ , and -CN;

(ii) C ₁ - ₁₀ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , C(O)OR ¹¹ , -OC(O)R ¹¹ , - OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , - N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ ,=O , -CN; and

C _3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, -OR ¹¹ , - SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , - N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), - S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ ,=O , and -CN; and (iii) 3- to 10 membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , - N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ , =O, -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , - OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , - N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ ,=O , and -CN;

B is selected from -CH(R ^A )(R ^B ) and C _3-10 carbocycle, wherein C _3-10 carbocycle is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹² , -SR ¹² , -N(R ¹² ) ₂ , -C(O)R ¹² , -C(O)OR ¹² , -OC(O)R ¹² , -OC(O)N(R ¹² ) _2, -C(O)N(R ¹² ) ₂ , -N(R ¹² )C(O)R ¹² , -N(R ¹² )C(O)OR ¹² , -N(R ¹² )C(O)N(R ¹² ) ₂ , -N(R ¹² )S(O) ₂ (R ¹² ), -S(O)R ¹² , -S(O) ₂ R ¹² , -S(O) ₂ N(R ¹² ) ₂ , -NO ₂ , =,O and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹² , -SR ¹² , -N(R ¹² ) ₂ , -C(O)R ¹² , -C(O)OR ¹² , -OC(O)R ¹² , - OC(O)N(R ¹² ) _2, -C(O)N(R ¹² ) ₂ , -N(R ¹² )C(O)R ¹² , -N(R ¹² )C(O)OR ¹² , -N(R ¹² )C(O)N(R ¹² ) ₂ , - N(R ¹² )S(O) ₂ (R ¹² ), -S(O)R ¹² , -S(O) ₂ R ¹² , -S(O) ₂ N(R ¹² ) ₂ , -NO ₂ , ,= aOnd -CN;

R ^A and R ^B are each independently selected from: halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , -OC(O)N(R ¹³ ) _2, - C(O)N(R ¹³ ) ₂ , -N(R ¹³ )C(O)R ¹³ , -N(R ¹³ )C(O)OR ¹³ , -N(R ¹³ )C(O)N(R ¹³ ) ₂ , -N(R ¹³ )S(O) ₂ (R ¹³ ), - S(O)R ¹³ , -S(O) ₂ R ¹³ , -S(O) ₂ N(R ¹³ ) ₂ , -NO ₂ , and -CN; C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , - OC(O)N(R ¹³ ) ₂ -C(O)N(R ¹³ ) ₂ , -N(R ¹³ )C(O)R ¹³ , -N(R ¹³ )C(O)OR ¹³ , -N(R ¹³ )C(O)N(R ¹³ ) ₂ , - N(R ¹³ ) ₂ S(O) ₂ (R ¹³ ), -S(O)R ¹³ , -S(O) ₂ R ¹³ , -S(O) ₂ N(R ¹³ ) ₂ , -NO ₂ , and -CN; and

C _3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , - OC(O)N(R ¹³ ) _2, -C(O)N(R ¹³ ) ₂ , -N(R ¹³ )C(O)R ¹³ , -N(R ¹³ )C(O)OR ¹³ , -N(R ¹³ )C(O)N(R ¹³ ) ₂ , - N(R ¹³ )S(O) ₂ (R ¹³ ), -S(O)R ¹³ , -S(O) ₂ R ¹³ , -S(O) ₂ N(R ¹³ ) ₂ , -NO ₂ , and -CN;

R ¹ and R ² are each independently selected from: hydrogen; halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) _2, -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , -NO ₂ , and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , - OC(O)N(R ¹⁴ ) _2, -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , -NO ₂ , and -CN;

R ³ and R ⁴ are each independently selected from (a), (b), (c), and (d):

(a) hydrogen;

(b) C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C ₁ . ₆ .alkyl, -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C ₁ -ehaloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , - OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN;

(c) C _2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C ₁ . ₆ .alkyl, -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C ₁ -ehaloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , - OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) ₂ -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; and

(d) C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; or

R ³ and R ⁴ can come together to form a 4- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁶ , -SR ¹⁶ , -N(R ¹⁶ ) ₂ , -C(O)R ¹⁶ , -C(O)OR ¹⁶ , -OC(O)R ¹⁶ , -OC(O)N(R ¹⁶ ) _2, -C(O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ )C(O)R ¹⁶ , -N(R ¹⁶ )C(O)OR ¹⁶ , -N(R ¹⁶ )C(O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ )S(O) ₂ (R ¹⁶ ), -S(O)R ¹⁶ , -S(O) ₂ R ¹⁶ , -S(O) ₂ N(R ¹⁶ ) ₂ , -NO ₂ , =,O and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁶ , -SR ¹⁶ , -N(R ¹⁶ ) ₂ , -C(O)R ¹⁶ , -C(O)OR ¹⁶ , -OC(O)R ¹⁶ , - OC(O)N(R ¹⁶ ) _2, -C(O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ )C(O)R ¹⁶ , -N(R ¹⁶ )C(O)OR ¹⁶ , -N(R ¹⁶ )C(O)N(R ¹⁶ ) ₂ , - N(R ¹⁶ )S(O) ₂ (R ¹⁶ ), -S(O)R ¹⁶ , -S(O) ₂ R ¹⁶ , -S(O) ₂ N(R ¹⁶ ) ₂ , -NO ₂ , ,= aOnd -CN;

R ⁵ is selected from: halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ , -C(O)OR ¹⁷ , -OC(O)R ¹⁷ , -OC(O)N(R ¹⁷ ) _2, -C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )C(O)R ¹⁷ , -N(R ¹⁷ )C(O)OR ¹⁷ , -N(R ¹⁷ )C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁷ , -S(O) ₂ R ¹⁷ , -S(O) ₂ N(R ¹⁷ ) ₂ , -NO ₂ , and -CN; and C _1-6 alkyl and C _2-6 alkenyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ , - C(O)OR ¹⁷ , -OC(O)R ¹⁷ , -OC(O)N(R ¹⁷ ) _2, -C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )C(O)R ¹⁷ , -N(R ¹⁷ )C(O)OR ¹⁷ , - N(R ¹⁷ )C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁷ , -S(O) ₂ R ¹⁷ , -S(O) ₂ N(R ¹⁷ ) ₂ , -NO ₂ , , a=nOd - CN;

R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , and R ¹⁷ are independently selected at each occurrence from (I), (II) and (III):

(I) hydrogen;

(II) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ haloalkyl -NH ₂ , -NO ₂ , =O, -CN, C _3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C _3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents selected from: halogen, -OH, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C ₁ -C ₆ haloalkyl -NH ₂ , -NO ₂ , =O, and -CN; and

(III) C _3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-C6 haloalkyl, -O-C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ haloalkyl -NH ₂ , -NO ₂ , =O, and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ haloalkyl -NH ₂ , -NO ₂ , =O, and -CN; and n is selected from 0, 1, 2, 3, and 4, wherein n is selected from 1, 2, 3, and 4; or at least one of R ¹ or R ² is hydrogen.

[0056] In some embodiments, for a compound or salt of Formula (I) or (I-a), n is selected from 1,

2, 3, and 4. In some embodiments, n is selected form 0, 1, 2, and 3. In some embodiments, n is selected from 0, 1, and 2. In some embodiments, n is selected from 0 and 1. In some embodiments, n is selected from 2, 3, and 4. In some embodiments, n is selected from 3 and 4. In some embodiments, n is selected from 1 and 2. In some embodiments, n is 4. In some embodiments, n is

3. In some embodiments, n is 2, In some embodiments, n is 1. In some embodiments, n is 0.

[0057] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ⁵ is selected from halogen, -OR ¹⁶ , -SR ¹⁶ , -N(R ¹⁶ ) ₂ , -C(O)R ¹⁶ , -C(O)OR ¹⁶ , -OC(O)R ¹⁶ , -OC(O)N(R ¹⁶ ) _2, -C(O)N(R ¹⁶ ) ₂ , - N(R ¹⁶ )C(O)R ¹⁶ , -N(R ¹⁶ )C(O)OR ¹⁶ , -N(R ¹⁶ )C(O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ )S(O) ₂ (R ¹⁶ ), -S(O)R ¹⁶ , -S(O) ₂ R ¹⁶ , - S(O) ₂ N(R ¹⁶ ) ₂ , -NO ₂ , =O, and -CN. In some embodiments, R ⁵ is selected from halogen, -OR ¹⁶ , - SR ¹⁶ , -N(R ¹⁶ ) ₂ , -C(O)R ¹⁶ , -C(O)OR ¹⁶ , -NO ₂ , =O, and -CN. In some embodiments, R ⁵ is selected from C _1-6 alkyl and C _2-6 alkenyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ , -C(O)OR ¹⁷ , - OC(O)R ¹⁷ , -OC(O)N(R ¹⁷ ) _2, -C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )C(O)R ¹⁷ , -N(R ¹⁷ )C(O)OR ¹⁷ , -N(R ¹⁷ )C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁷ , -S(O) ₂ R ¹⁷ , -S(O) ₂ N(R ¹⁷ ) ₂ , -NO ₂ , ,= aOnd -CN. In some embodiments, R ⁵ is selected from C _1-6 alkyl and C _2-6 alkenyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ )2, -C(O)R ¹⁷ , - C(O)OR ¹⁷ , -NO2, =O, and -CN. In some embodiments, R ⁵ is selected from C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁷ , -SR ¹⁷ , - N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ , -C(O)OR ¹⁷ , -NO2, =O, and -CN. In some embodiments, R ⁵ is selected from C ₂ -3 alkenyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ )2, -C(O)R ¹⁷ , -C(O)OR ¹⁷ , -NO2, =, O and -CN. In some embodiments, R ⁵ is selected from halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ )2, -C(O)R ¹⁷ , -NO2, and -CN; and C ₁ - ₃ alkyl and C ₂ -3 alkenyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ )2, -C(O)R ¹⁷ , -NO2, ,= aOnd -CN.

[0058] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ⁵ is selected from chloro, fluoro, bromo, -OR ¹⁷ , -N(R ¹⁷ )2, -CN; C1-3 alkyl and C ₂ -3 alkenyl each of which is optionally substituted with one or more substituents independently selected from chloro, fluoro, -OR ¹⁷ , and - N(R ¹⁷ ) _2. In some embodiments, R ⁵ is selected from chloro, fluoro, bromo, -CN, methyl, ethyl, . In some embodiments, R ⁵ is selected from chloro, fluoro, bromo, -CN, methyl, ethyl, j _{n some} embodiments, R ⁵ is selected from chloro, fluoro, bromo, -CN, methyl, and ethyl. In some embodiments, R ⁵ is selected from . In some embodiments, R ⁵ is . In some embodiments, R ⁵ is ^nh 2 . In some embodiments, R ⁵ is CF 3 . In some embodiments, R ⁵ is

[0059] In some embodiments, for the compound or salt of Formula (I) or (I-a), R ⁵ is selected from halogen, -OR ¹⁷ , -N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ , -C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )C(O)R ¹⁷ , -N(R ¹⁷ )C(O)OR ¹⁷ , -CN; C1.3 alkyl and C _2-3 alkenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁷ , and -N(R ¹⁷ ) _2. . In some embodiments, R ⁵ is selected from chloro, fluoro, -CN, methyl, ethyl, propyl, isopropyl, -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -OCF ₃ , , and In some embodiments, R ⁵ is selected from chloro, fluoro, -CN, methyl, ethyl,

[0060] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from optionally substituted 5- to 6-membered heteroaryl. In some embodiments, the optionally substituted 5- to 6-membered heteroaryl of A comprises one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combination thereof. In some embodiments, the optionally substituted 5- to 6-membered heteroaryl of A comprises one or more heteroatoms selected from nitrogen, oxygen, and combination thereof. In some embodiments, the optionally substituted 5- to 6- membered heteroaryl of A comprises one or more heteroatoms selected from nitrogen, sulfur, and combination thereof. In some embodiments, the optionally substituted 5- to 6-membered heteroaryl of A comprises one or more heteroatoms selected from oxygen, sulfur, and combination thereof. In some embodiments, the optionally substituted 5- to 6-membered heteroaryl of A comprises one or more nitrogen heteroatoms. In some embodiments, the optionally substituted 5- to 6-membered heteroaryl of A comprises one or more heteroatoms selected from nitrogen and oxygen.

[0061] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (i) halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , C(O)OR ¹¹ , -OC(O)R ¹¹ , -NO ₂ , and - CN. In some embodiments, A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (i) halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , - C(O)R ¹¹ , C(O)OR ¹¹ , -OC(O)R ¹¹ , -OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , - N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , - NO ₂ ,=O , and -CN.

[0062] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (ii) C ₁ -io alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , C(O)OR ¹¹ , -OC(O)R ¹¹ , -OC(O)N(R ¹¹ ) _2, - C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), - S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , -NO ₂ , =O, and -CN. In some embodiments, A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (ii) C ₁ -io alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , C(O)OR ¹¹ , -OC(O)R ¹¹ , -NO ₂ ,=O , and - CN.

[0063] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (ii) C ₁ -io alkyl optionally substituted with one or more substituents independently selected from C _3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , - N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , - N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )S(O) ₂ (R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ ) ₂ , - NO ₂ ,=O , and -CN. In some embodiments, A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (ii) C ₁ -10 alkyl optionally substituted with one or more substituents independently selected from C _3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , - OC(O)R ¹¹ , -NO ₂ ,=O , and -CN. In some embodiments, A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from C3-6 carbocycle and 3- to 6-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , - C(O)OR ¹¹ , -OC(O)R ¹¹ , -NO ₂ ,=O , and -CN. In some embodiments, A is selected from 5- to 6- memebred heteroaryl optionally substituted with one or more substituents independently selected from (ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from C3-6 carbocycle and 4- to 6-membered saturated heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , - C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -NO ₂ ,=O , and -CN. In some embodiments, A is selected from 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently selected from (ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from C3-6 carbocycle and 5- to 6-membered heteroaryl each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , - N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , -NO ₂ ,=O , and -CN. In some embodiments, A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from C3-6 carbocycle, 4- to 6-membered saturated heterocycle, and 5- to 6- membered heteroaryl each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , - NO2,=O, and -CN.

[0064] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (iii) 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , -C(O)OR ¹¹ , - OC(O)R ¹¹ , -OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ )2, -N(R ¹¹ )S(O)2(R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ )2, -NO2, =O, -CN. In some embodiments, A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (iii) 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , - C(O)OR ¹¹ , -OC(O)R ¹¹ , -NO2,=O, and -CN. In some embodiments, A is selected from 5- to 6- memebred heteroaryl optionally substituted with one or more substituents independently selected from (iii) 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , -C(O)OR ¹¹ , -OC(O)R ¹¹ , - NO2,=O, and -CN.

[0065] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (iii) 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , -C(O)OR ¹¹ , - OC(O)R ¹¹ , -OC(O)N(R ¹¹ ) _2, -C(O)N(R ¹¹ ) ₂ , -N(R ¹¹ )C(O)R ¹¹ , -N(R ¹¹ )C(O)OR ¹¹ , -N(R ¹¹ )C(O)N(R ¹¹ )2, -N(R ¹¹ )S(O)2(R ¹¹ ), -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -S(O) ₂ N(R ¹¹ )2, -NO2, =O, and -CN. In some embodiments, A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (iii) 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , -C(O)OR ¹¹ , - OC(O)R ¹¹ , -NO2, =O, and -CN. In some embodiments, A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (iii) 3- to 6-membered heterocycle optionally substituted with C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , - C(O)OR ¹¹ , -OC(O)R ¹¹ , -NO2, =O, and -CN. [0066] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from 5- to 6- membered heteroaryl optionally substituted with one or more substituents independently selected from:

(ii) C ₁ -io alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -NO ₂ ,=O , -CN; and C _3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, - OR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -NO ₂ ,=O , -CN; and

(iii) 3- to 10 membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -NO ₂ ,=O , -CN; and C ₁ -e alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -NO ₂ ,=O , and -CN.

[0067] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from an optionally substituted 5- membered heteroaryl. In some embodiments, A is selected from pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, triazole, tetrazole, and pyridine, any of which is optionally substituted. In some embodiments, A is selected from pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from:

(ii) C ₁ -10 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -NO ₂ ,=O , -CN; and C _3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, - OR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -NO ₂ ,=O , -CN; and

(iii) 3- to 10 membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -NO ₂ ,=O , -CN; and C ₁ -e alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -NO ₂ ,=O , and -CN. [0068] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from: any of which are optionally substituted with one or more substituents independently selected from:

(ii) C ₁ -io alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -NO ₂ ,=O , -CN; and C _3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, - OR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -NO ₂ ,=O , -CN; and

(iii) 3- to 10 membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -NO ₂ ,=O , -CN; and C ₁ -e alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -NO ₂ ,=O , and -CN.

[0069] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from optionally substituted pyrazole and optionally substituted isoxazole. In some embodiments, A is selected from: each of which is optionally substituted; and wherein denotes the connection to the optional substituent and denotes the connection of A to the remainder of Formula I. In some embodiments, A is selected from: each of which is optionally substituted; denotes a first connection; and A \ denotes a second connection, wherein the first connection is from A to the optional substituents and the second connection represents the bond between A and the structure of Formula (I) or Formula (I-a).

[0070] In some embodiments, for a compound or salt of Formula (I) or (I-a), the 5- to 6-membered heterocycle of A is substituted with one or more substituents. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (i), (ii), and (iii):

(i) halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ , =O, and -CN;

(ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ , =O, -CN; and C _3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ , =O, and -CN; and

(iii) 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ , =O, -CN; and C _1-6 alkyl optionally substituted with halogen.

[0071] In some embodiments, for a compound or salt of Formula (I) or (I-a), the 5- to 6-membered heterocycle of A is substituted with one or more substituents. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (i) halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ , =O, and -CN.

[0072] In some embodiments, for a compound or salt of Formula (I) or (I-a), the 5- to 6-membered heterocycle of A is substituted with one or more substituents. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ , =O, -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ , =O, and -CN. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: C _3-10 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ , =O, and -CN. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , -NO2, =O, and -CN. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: 3- to 10-membered saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , -NO2, =O, and -CN. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: 3- to 6-membered saturated heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , - NO2,=O, and -CN. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from azetidine, piperidine, piperazine, morpholine, and thiomorpholine, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , -NO2, =O, and -CN.

[0073] In some embodiments, for a compound or salt of Formula (I) or (I-a), the 5- to 6-membered heterocycle of A is substituted with one or more substituents. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (iii) 3- to-10 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , -NO2, =O, -CN and C _1-6 haloalkyl. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (iii) 3- to-10 membered saturated heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ )2, -C(O)R ¹¹ , -NO2, =O, - CN and C _1-6 haloalkyl. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (iii) 3- to-6 membered saturated heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ¹¹ , -SR ¹¹ , - N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO2,=O, -CN and C ₁ ^ haloalkyl.

[0074] In some embodiments, for a compound or salt of Formula (I) or (I-a), the 5- to 6-membered heterocycle of A is substituted with one or more substituents. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) and (iii): (ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO2, =O, -CN; and C _3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, -OR ¹¹ , - SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ ,=O , and -CN; and (iii) 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ , =O, -CN; and C _1-6 alkyl optionally substituted with halogen.

[0075] In some embodiments, for a compound or salt of Formula (I) or (I-a), the 5- to 6-membered heterocycle of A is substituted with one or more substituents. In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) and (iii): (ii) C _1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ , =O, -CN; and C _3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, -OR ¹¹ , - SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ ,=O , and -CN; and (iii) 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR ¹¹ , -SR ¹¹ , -N(R ¹¹ ) ₂ , -C(O)R ¹¹ , -NO ₂ , =O, -CN; and C _1-6 alkyl optionally substituted with halogen.

[0076] In some embodiments, for a compound or salt of Formula (I) or (I-a), the substituents on the 5- to 6-membered heterocycle of A are independently selected from: fluorine, methyl, ethyl, isopropyl,

In some embodiments, the 5- to 6-membered heteroaryl of A is independently selected from pyrazole, isoxazole, oxadiazole, and pyridine, each of which is optionally substituted with substituents selected from: fluorine, methyl, ethyl, propyl, isopropyl, [0077] In some embodiments, for a compound or salt of Formula (I) or (I-a), the substituents on the 5- to 6-membered heterocycle of A are independently selected from: fluorine, methyl, ethyl, isopropyl, and . In some embodiments, the 5- to 6-membered heteroaryl of A is independently selected from pyrazole, isoxazole, and pyridine, each of which is optionally substituted with substituents selected from: fluorine, methyl, ethyl, propyl, isopropyl,

[0078] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from:

[0079] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from: [0080] In some embodiments, for a compound or salt of Formula (I) or (I-a), A is selected from:

[0081] In some embodiments, for a compound or salt of Formula (I) or (I-a), B is selected from - CH(R ^A )(R ^b ) and optionally substituted C _3-10 carbocycle. In some embodiments, B is -CH(R ^A )(R ^B ) and each of R ^A and R ^B are independently selected from: C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , -OC(O)N(R ¹³ ) _2, -C(O)N(R ¹³ ) ₂ , - N(R ¹³ )C(O)R ¹³ , -N(R ¹³ )C(O)OR ¹³ , -N(R ¹³ )C(O)N(R ¹³ ) ₂ , -N(R ¹³ ) ₂ S(O) ₂ (R ¹³ ), -S(O)R ¹³ , -S(O) ₂ R ¹³ , - S(O) ₂ N(R ¹³ ) ₂ , -NO ₂ , and -CN; and

C _3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , -OC(O)N(R ¹³ ) _2, - C(O)N(R ¹³ ) ₂ , -N(R ¹³ )C(O)R ¹³ , -N(R ¹³ )C(O)OR ¹³ , -N(R ¹³ )C(O)N(R ¹³ ) ₂ , -N(R ¹³ )S(O) ₂ (R ¹³ ), - S(O)R ¹³ , -S(O) ₂ R ¹³ , -S(O) ₂ N(R ¹³ ) ₂ , -NO ₂ , and -CN.

[0082] In some embodiments, for a compound or salt of Formula (I) or (I-a), B is -CH(R ^A )(R ^B ) and each of R ^A and R ^B are independently selected from: C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , -NO ₂ , and -CN; and

C _3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -C(O)OR ¹³ , -OC(O)R ¹³ , -NO ₂ , and -CN.

[0083] In some embodiments, for a compound or salt of Formula (I) or (I-a), B is selected from - CH(R ^A )(R ^b ) and each of R ^A and R ^B are independently selected from: C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -NO ₂ , and -CN; and

C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -NO ₂ , and -CN.

[0084] In some embodiments, for a compound or salt of Formula (I) or (I-a), B is selected from - CH(R ^A )(R ^b ) and each of R ^A and R ^B are independently selected from: methyl, ethyl, propyl, and isopropyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ )2, -C(O)R ¹³ , -NO2, and -CN; and

C3-6 saturated carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ )2, -C(O)R ¹³ , -NO2, and -CN.

[0085] In some embodiments, for a compound or salt of Formula (I) or (I-a), B is selected from - CH(R ^A )(R ^b ) and each of R ^A and R ^B are independently selected from: methyl, ethyl, propyl, and isopropyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ )2, -C(O)R ¹³ , -NO2, and -CN; and

C ₆ carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ ) ₂ , -C(O)R ¹³ , -NO2, and -CN.

[0086] In some embodiments, for a compound or salt of Formula (I) or (I-a), B is selected from - CH(R ^A )(R ^b ) and each of R ^A and R ^B are independently selected from: methyl, ethyl, propyl, and isopropyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , -N(R ¹³ )2, -C(O)R ¹³ , -NO2, and -CN; and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹³ , -SR ¹³ , - N(R ¹³ ) ₂ , -C(O)R ¹³ , -NO2, and -CN.

[0087] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ^A and R ^B are each independently selected from: ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and phenyl, any of which is optionally substituted. In some embodiments, B is selected from:

[0088] In some embodiments, for a compound or salt of Formula (I) or (I-a), B is optionally substituted C _3-10 carbocycle. In some embodiments, B is an optionally substituted saturated C _3-10 carbocycle. In some embodiments, B is an optionally substituted unsaturated C _3-10 carbocycle. In some embodiments, B is selected from C3 carbocycle, C4 carbocycle, C5 carbocycle, C ₆ carbocycle, C7 carbocycle, Cx carbocycle, C9 carbocycle, C10 carbocycle, any of which is optionally substituted. In some embodiments, B is selected from C4-10 carbocycle, C5-10 carbocycle, C6-10 carbocycle, C7-10 carbocycle, Cs-io carbocycle, and C9-10 carbocycle, any of which is optionally substituted. [0089] In some embodiments, for a compound or salt of Formula (I) or (I-a), B is an optionally substituted C _5-8 cycloalkyl or optionally substituted C _7-10 bicyclic carbocycle. In some embodiments, B is selected from C _5-8 cycloalkyl and C _7-10 bicyclic carbocycle and of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹² , - SR ¹² , -N(R ¹² ) ₂ , -C(O)R ¹² , -C(O)OR ¹² , -OC(O)R ¹² , -NO2, =,O -CN, -C _1-6 haloalkyl, and -C _1-6 alkoxy. In some embodiments, B is an optionally substituted C _6-10 carbocycle selected from cyclohexyl, cycloheptyl, cyclooctyl, spiro [2.5] octanyl, and indanyl any of which are optionally substituted. In some embodiments, B is an optionally substituted C _6-10 carbocycle selected from cyclohexyl, cycloheptyl, cyclooctyl, spiro [2.5] octanyl, and indanyl any of which are optionally substituted with one or more substituents independently selected from halogen, -OR ¹² , -SR ¹² , -N(R ¹² ) ₂ , - C(O)R ¹² , -C(O)OR ¹² , -OC(O)R ¹² , -NO ₂ , =O, -CN, -C ₁ -ehaloalkyl, and -C _1-6 alkoxy. In some embodiments, B is selected from [0090] In some embodiments, for a compound or salt of Formula (I) or (I-a), B is selected from:

[0091] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ¹ and R ² are each independently selected from halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , - OC(O)N(R ¹⁴ ) _2, -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , -NO _! , and -CN. In some embodiments, R ¹ and R ² are each independently selected from halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , - C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -NO _¾ and -CN.

[0092] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ¹ and R ² are each C ₁ - ₆ alkyl optionally substituted with one or more substituents independently selected from halogen, - OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) _2, -C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , - S(O) ₂ N(R ¹⁴ ) ₂ , -NO _! , and -CN. In some embodiments, R ¹ and R ² are each C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁴ , -SR ¹⁴ , - N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -NO ₂ , and -CN. In some embodiments, R ¹ and R ² are each independently C1-3 alkyl optionally substituted with a substituent independently selected from halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -NO2, and -CN.

[0093] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ¹ and R ² are each hydrogen. In some embodiments, R ¹ and R ² are each independently selected from: hydrogen, halogen, -OR ¹⁴ , -NO2, and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) _2, -C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , - S(O) ₂ N(R ¹⁴ ) ₂ , -NO2, and -CN.

[0094] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ¹ and R ² are each hydrogen. In some embodiments, R ¹ and R ² are each independently selected from: hydrogen, halogen, -OR ¹⁴ , -NO2, and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) _2, -C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , - S(O) ₂ N(R ¹⁴ ) ₂ , -NO2, and -CN.

[0095] In some embodiments, for the compound or salt of Formula (I) or (I-a), R ¹ and R ² are each independently selected from: hydrogen, and In some embodiments, R ¹ and R ² are each independently selected from: hydrogen, , and . In some embodiments, R ¹ and R ² are each independently selected from: and

. In some embodiments, R ¹ and R ² are each independently selected from: hydrogen and In some embodiments, R ¹ and R ² are each selected from hydrogen, and . In some embodiments, R ¹ and R ² are each independently selected from: hydrogen, In \ and some embodiments, R ¹ and R ² are each independently selected from: hydrogen, . In some embodiments, R ¹ and R ² are selected from different substituents. In some embodiments, one of R ¹ and R ² , is hydrogen. In some embodiments, one of R ¹ and R ² , is C1-3 alkyl. In some embodiments, one of R ¹ and R ² is selected from methyl, ethyl, and propyl. In some embodiments, one of R ¹ and R ² is methyl. In some embodiments, R ¹ is hydrogen; and R ² is selected from: methyl, ethyl, propyl, isopropyl and butyl, each of which is optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, and -OR ¹⁴ . In some embodiments, R ¹ is hydrogen; and R ² is selected from: methyl, ethyl, propyl, and butyl, each of which is optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, and -OR ¹⁴ . In some embodiments, R ¹ and R ² are each independently selected from: hydrogen, and In some embodiments, R ¹ and R ² are each independently selected from: hydrogen, and

[0096] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from hydrogen. In some embodiments, one of R ³ and R ⁴ is selected from hydrogen. In some embodiments, one of R ³ and R ⁴ is selected from (a). In some embodiments, one of R ³ and R ⁴ is selected from (b). In some embodiments, one of R ³ and R ⁴ is selected from (c). In some embodiments, one of R ³ and R ⁴ is selected from (d).

[0097] In some embodiments, for a compound or salt of Formula (I) or (I-a), each of R ³ and R ⁴ is selected from (c). In some embodiments, each of R ³ and R ⁴ is selected from C ₂ -6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , - N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C 1-6-alkyl, -OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) ₂ -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , - NO ₂ , and -CN. In some embodiments, each of R ³ and R ⁴ is selected from C _2-6 alkyl optionally substituted with one or more substituents independently selected from: C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN. In some embodiments, each of R ³ and R ⁴ is selected from C _2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , - OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -NO ₂ , and -CN. In some embodiments, each of R ³ and R ⁴ is selected from optionally substituted C _2-6 alkyl and is represented by:

[0098] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (b): (a) hydrogen;

(b) C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C ₁ . ₆ .alkyl, -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) ₂ -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -N0 _¾ and -CN.

[0099] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (b):

(a) hydrogen;

(b) C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -NO _¾ -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , -NO ₂ , and -CN.

[0100] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (b):

(a) hydrogen;

(b) C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -NO _¾ -CN;

C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , -NO ₂ , and -CN.

[0101] In some embodiments, for a compound or salt of Formula (I) or (I-a), one of R ³ and R ⁴ is hydrogen, and the other of R ³ and R ⁴ is selected from C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C ₁ . ₆ .alkyl, -OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), - S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, - OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , - S(O) ₂ N(R ¹⁵ ) ₂ , -N0 _¾ and -CN.

[0102] In some embodiments, for a compound or salt of Formula (I) or (I-a), one of R ³ and R ⁴ is hydrogen, and the other of R ³ and R ⁴ is selected from C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -NO _¾ -CN;

C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, -OR ¹⁵ , -SR ¹⁵ , -

N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , -NO ₂ , and -CN. In some embodiments, represented by . In some embodiments, one of R ³ and R ⁴ is hydrogen and

[0103] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (c):

(a) hydrogen; and

(c) C _2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C ₁ . ₆ .alkyl, -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -

N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -N0 _¾ and -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN.

[0104] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (c):

(a) hydrogen; and

(c) C _2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C _1-6 -alkyl, -OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, - C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), - S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN.

[0105] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (c):

(a) hydrogen; and

(c) C _2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -NO ₂ , and -CN.

[0106] In some embodiments, for a compound or salt of Formula (I) or (I-a), one of R ³ and R ⁴ is hydrogen, and the other of R ³ and R ⁴ is C _2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)N(R ¹⁵ ) ₂ , -

N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -NO ₂ , and -CN. In some embodiments, is represented . In some embodiments, is represented by: and 3 . In some embodiments, is represented by

[0107] In some embodiments, for a compound or salt of Formula (I) or (I-a), one of R ³ and R ⁴ is 3 hydrogen, and is represented by: , and r r . In some 3 embodiments, one of R ³ and R ⁴ is hydrogen and is represented by: and . In some 3 embodiments, one of R ³ and R ⁴ is hydrogen and is represented by: , and . In some embodiments, one of R ³ and R ⁴ is hydrogen ^ and is represented by

[0108] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (c):

(a) hydrogen;

(c) C ₂ -6 alkyl optionally substituted with one or more substituents independently selected from: C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, - OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , - S(O) ₂ N(R ¹⁵ ) ₂ , -NO2, and -CN.

[0109] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (c):

(a) hydrogen;

(c) C ₂ -6 alkyl optionally substituted with one or more substituents independently selected from: C3-6 carbocycle and 3- to 6-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, - OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , -NO2, and -CN.

[0110] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (c):

(a) hydrogen;

(c) C ₂ -6 alkyl optionally substituted with one or more substituents independently selected from: halogen; C3-6 carbocycle and 3- to 6-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, -

[0111] In some embodiments, for a compound or salt of Formula (I) or (I-a), one of R ³ and R ⁴ is hydrogen and the other of R ³ and R ⁴ is C ₂ -6 alkyl optionally substituted with one or more substituents independently selected from: halogen; C3-6 carbocycle and 3- to 6-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, -OR ¹⁵ , -N(R ¹⁵ )2, -C(O)R ¹⁵ , -NO2, and -CN. In some embodiments, one of R ³ and R ⁴ is hydrogen, and is represented by: some embodiments, one of R ³ and R ⁴ is hydrogen, and R ⁴ is represented by:

[0112] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (d):

(a) hydrogen; and

(d) C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) ₂ -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN.

[0113] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (d):

(a) hydrogen; and

(d) C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , - N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , - N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , - NO ₂ , and -CN.

[0114] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (d):

(a) hydrogen; and (d) C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ )2, - C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , -NO2, and -CN.

[0115] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (d):

(a) hydrogen; and

(d) C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , - N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2J -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , - N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -

NO2, and -CN.

[0116] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a) and (d):

(a) hydrogen; and

(d) C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with C ₁ - ₃ alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , -NO2, and -CN.

[0117] In some embodiments, for a compound or salt of Formula (I) or (I-a), represented by: , , . , S represented by: . In some embodiments, In

[0118] In some embodiments, for a compound or salt of Formula (I) or (I-a), one of R ³ and R ⁴ is

A„- ^r3 NH pfe hydrogen, and R ⁴ is represented by: o V- some embodiments, one of R ³ and R ⁴ is

A _n - ^r3 hydrogen, and R ⁴ is represented by: Ί Ί _Ί , , , and . In some embodiments, one of R ³ and R ⁴ is hydrogen, and [0119] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (b) and (c):

(b) C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C ₁ . ₆ .alkyl, -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) ₂ -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -N0 _¾ and -CN;

(c) C _2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C ₁ . ₆ .alkyl, -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -N0 _¾ and -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -N0 _¾ and -CN.

[0120] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (b) and (c):

(b) C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -NO ₂ , -CN;

C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , -NO ₂ , and -CN.

(c) C _2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -NO ₂ , -CN;

C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , -NO ₂ , and -CN. [0121] In some embodiments, for a compound or salt of Formula (I) or (I-a), is represented by: some embodiments, one of R ³ and

' 4

R ⁴ is methyl, and R is represented by . In some embodiments, one of R ³ and R ⁴

A _N ' ^R3

' 4 is optionally substituted methyl, and R is represented by , ,

[0122] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (b) and (d):

(b) C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C _1-6 -alkyl, -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) ₂ -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; and

(d) C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN. [0123] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (b) and (d):

(b) C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -OC(O)R ¹⁵ , -NO ₂ , -CN;

C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , -NO ₂ , and -CN; and

(d) C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -OC(O)R ¹⁵ , -NO ₂ , -CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , - C(O)OR ¹³ , -OC(O)R ¹⁵ , -NO ₂ , and -CN.

[0124] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ⁴ is represented . , 4 some embodiments, one of R and R is methyl, and R is represented by

[0125] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a), (b), and (c):

(a) hydrogen;

(b) C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C ₁ . ₆ .alkyl, -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) ₂ -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , -N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , - N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , -CN;

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , - OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; and

(c) C _2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)-O-C ₁ . ₆ .alkyl, -OC(O)R ¹⁵ , - OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN; and

C _3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, C _1-6 alkoxy, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , - OC(O)R ¹⁵ , -OC(O)N(R ¹⁵ ) _2, -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , -N(R ¹⁵ )C(O)OR ¹⁵ , - N(R ¹⁵ )C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )S(O) ₂ (R ¹⁵ ), -S(O)R ¹⁵ , -S(O) ₂ R ¹⁵ , -S(O) ₂ N(R ¹⁵ ) ₂ , -NO ₂ , and -CN.

[0126] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a), (b), and (c):

(a) hydrogen;

(b) C ₁ alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -OC(O)R ¹⁵ , -NO _¾ -CN;

C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹³ , -OC(O)R ¹⁵ , -NO ₂ , and - CN; and

(c) C _2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -OC(O)R ¹⁵ , -NO ₂ , and -CN; and

C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)OR ¹⁵ , -OC(O)R ¹⁵ , -NO ₂ , and - CN.

[0127] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ are each independently selected from (a), (b), (c), and (d):

(a) hydrogen; (b) C ₁ alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -NO ₂ , -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, C _1-6 haloalkyl, -OR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -NO ₂ , and -CN;

(c) C _2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)R ¹⁵ , - N(R ¹⁵ )C(O)OR ¹⁵ , -NO ₂ , -CN; C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -NO ₂ , and -CN; and

(d) C3-6 carbocycle and 3- to 6-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , - SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -NO ₂ , -CN; and C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -NO ₂ , and -CN.

[0128] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ or R ⁴ is selected from C ₁ alkyl optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R ¹⁵ ) ₂ , -OR ¹⁵ ; and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 haloalkyl and -OR ¹⁵ .

[0129] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ or R ⁴ is selected

[0130] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ or R ⁴ is selected from C ₂ -6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -C(O)N(R ¹⁵ ) ₂ , -N(R ¹⁵ )C(O)OR ¹⁵ , -NO ₂ , -CN; C _3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -NO ₂ , and -CN.

[0131] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ or R ⁴ is selected from ethyl, propyl, isopropyl, isobutyl, and butyl, each of which is optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, -OR ¹⁵ , -N(R ¹⁵ ) ₂ , - C(O)N(R ¹⁵ ) ₂ and -N(R ¹⁵ )C(O)OR ¹⁵ . [0132] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ or R ⁴ is selected some embodiments, for a compound or salt of

Formula (I) or (I-a), R ³ or R ⁴ is selected from

[0133] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ or R ⁴ is selected from C ₂ -6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , -N(R ¹⁵ )2, C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁵ , - SR ¹⁵ , -N(R ¹⁵ ) ₂ , -C(O)R ¹⁵ , -NO2, and -CN.

[0134] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ or R ⁴ is selected embodiments, R ³ or R ⁴ is selected from

[0135] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ or R ⁴ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxetanyl, azetidine, pyrrolidinyl, and pyridinyl, each of which is optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, -OR ¹⁵ , -NO ₂ , -CN; and C1-3 alkyl optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, -OR ¹⁵ , -NO ₂ , and -CN. [0136] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ or R ⁴ is selected from

[0137] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ of R ⁴ come together to form a 4- to 12-membered heterocycle any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR ¹⁶ , -SR ¹⁶ , -N(R ¹⁶ ) ₂ , -C(O)R ¹⁶ , -C(O)OR ¹⁶ , -OC(O)R ¹⁶ , -OC(O)N(R ¹⁶ ) _2, -C(O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ )C(O)R ¹⁶ , -N(R ¹⁶ )C(O)OR ¹⁶ , -N(R ¹⁶ )C(O)N(R ¹⁶ ) ₂ , -NO ₂ , ,= aOnd - CN; and C _1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁶ , -SR ¹⁶ , -N(R ¹⁶ ) ₂ , -C(O)R ¹⁶ , -NO ₂ , and -CN.

[0138] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ of R ⁴ come together to form an optionally substituted 4- to 12-membered heterocycle comprising more than one heteroatom selected from oxygen, nitrogen, sulfur, and any combination thereof. In some embodiments, the optionally substituted 4- to 12-membered heterocycle optionally comprises more than one heteroatom selected from oxygen, nitrogen, and any combination thereof. In some embodiments, the optionally substituted 4- to 12-membered heterocycle optionally comprises more than one heteroatom selected from oxygen, sulfur, and any combination thereof. In some embodiments, the optionally substituted 4- to 12-membered heterocycle optionally comprises more than one heteroatom selected from nitrogen and sulfur and any combination thereof. In some embodiments, the optionally substituted 4- to 12-membered heterocycle optionally comprises more than one heteroatom selected from oxygen and nitrogen. In some embodiments, the optionally substituted 4- to 12-membered heterocycle optionally comprises more than one heteroatom selected from oxygen and sulfur. In some embodiments, the optionally substituted 4- to 12-membered heterocycle comprises more than one heteroatom selected from nitrogen and sulfur. In some embodiments, the optionally substituted 4- to 12-membered heterocycle optionally comprises at least one additional heteroatom selected from oxygen, nitrogen, sulfur, and any combination thereof. In some embodiments, the optionally substituted 4- to 12-membered heterocycle comprises one nitrogen heteroatom. In some embodiments, for a compound or salt of Formula (I) or (I-a), the 4- to 12-membered heterocycle is selected from a saturated 4- to 8-membered heterocycle and 6- to 12-membered unsaturated heterocycle, any one of one which is optionally substituted. In some embodiments, the R ³ and R ⁴ of R ⁴ come together to form a saturated 4- to 8-membered heterocycle any one of which is optionally substituted.

[0139] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ come together to form a saturated 4- to 8-membered heterocycle and the saturated 4- to 8-membered heterocycle is selected from azetidine, oxetane, pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, morpholine, oxazepane, and azaspiro[3.3]heptane, any one of which is optionally substituted with one substituents independently selected from chloro, fluoro, -OR ¹⁶ , -N(R ¹⁶ )2, -C(O)OR ¹⁶ , - C(O)N(R ¹⁶ ) ₂ , -N(R ¹⁶ )C(O)R ¹⁶ , -NO2, and -CN; and C1-3 alkyl optionally substituted with one or more substituents independently selected from chloro, fluoro, OR ¹⁶ , -NO2, and -CN.

[0140] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ of R ⁴ come together to form the saturated 4- to 8-membered heterocycle and the 4- to 8-membered

[0141] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ of ^r4 come together to form the saturated 4- to 8-membered heterocycle and the 4- to 8-membered heterocycle is selected from:

[0142] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ come together to form a saturated 4- to 8-membered heterocycle and the saturated 4- to 8-membered heterocycle is selected from azetidine, oxetane, pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, morpholine, oxazepane, and azaspiro[3.3]heptane, any one of which is optionally substituted with one substituents independently selected from chloro, fluoro, -OR ¹⁶ , -NO ₂ , and -CN; and C _1-3 alkyl optionally substituted with one or more substituents independently selected from chloro, fluoro, OR ¹⁶ , -NO2, and -CN.

[0143] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ come together to form a saturated 4- to 8-membered heterocycle and the saturated 4- to 8-membered heterocycle is selected from azetidine, oxetane, pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, morpholine, oxazepane, and azaspiro[3.3]heptane, any one of which is optionally substituted with one substituents independently selected from chloro, fluoro, -OR ¹⁶ , -NO2, -C(O)N(R ¹⁶ ) ₂ , and -CN; and C ₁ - ₃ alkyl optionally substituted with one or more substituents independently selected from chloro, fluoro, OR ¹⁶ , -NO2, and -CN.

[0144] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ of R ⁴ come together to form the saturated 4- to 8-membered heterocycle and R ⁴ is selected from:

[0145] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ of R ⁴ come together to form the saturated 4- to 8-membered heterocycle and R ⁴ is selected from: F C CN

F ₃ C.

A® , a _a n _n d _d KX>:

[0146] In some embodiments, for a compound or salt of Formula (I) or (I-a), the 4- to 12- membered heterocycle is an unsaturated 4- to 12-membered heterocycle any one of which is optionally substituted.

X ^r3

[0147] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ³ and R ⁴ of R come together to form an unsaturated 4- to 12-membered heterocycle and R is represented

F ₃ C

V N by

3

N _I

[0148] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ^' is selected

F

[0149] In some embodiments, for a compound or salt of Formula (I) or (I-a), R ⁴ is selected

[0150] In another aspect, the present disclosure provides a compound represented by the structure of Formula (II): or a pharmaceutically acceptable salt thereof, wherein A, B, R ¹ , R ² , R ³ , R ⁴ , and n are as defined in

Formula (I) or Formula (I-a), and

R ⁵ is selected from: halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ , -C(O)OR ¹⁷ , -OC(O)R ¹⁷ , -OC(O)N(R ¹⁷ ) _2, -C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )C(O)R ¹⁷ , -N(R ¹⁷ )C(O)OR ¹⁷ , -N(R ¹⁷ )C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁷ , -S(O) ₂ R ¹⁷ , -S(O) ₂ N(R ¹⁷ ) ₂ , -NO ₂ , and -CN; C _1-6 alkyl and C _2-6 alkenyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ ,

C _3-10 carbocycle and 3- to 10 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^17B , -SR ^17B , -N(R ^17B ) ₂ , - C(O)R ^17B , -C(O)OR ^17B , -OC(O)R ^17B , -OC(O)N(R ^17B ) _2, -C(O)N(R ^17B ) ₂ , -N(R ^17B )C(O)R ^17B , - N(R ^17B )C(O)OR ^17B , -N(R ^17B )C(O)N(R ^17B ) ₂ , -N(R ^17B )S(O) ₂ (R ^17B ), -S(O)R ^17B , -S(O) ₂ R ^17B , - S(O) ₂ N(R ^17B ) ₂ , -NO ₂ , =O, and -CN.

[0151] In some embodiments, for the compound or salt of Formula (II), R ⁵ is selected from: halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ , -C(O)OR ¹⁷ , -OC(O)R ¹⁷ , -OC(O)N(R ¹⁷ ) _2, -C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )C(O)R ¹⁷ , -N(R ¹⁷ )C(O)OR ¹⁷ , -N(R ¹⁷ )C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁷ , -S(O) ₂ R ¹⁷ , -S(O) ₂ N(R ¹⁷ ) ₂ , -NO ₂ , and -CN; and

C _3-10 carbocycle and 3- to 10 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^17B , -SR ^17B , -N(R ^17B ) ₂ , - C(O)R ^17B , -C(O)OR ^17B , -OC(O)R ^17B , -OC(O)N(R ^17B ) _2, -C(O)N(R ^17B ) ₂ , -N(R ^17B )C(O)R ^17B , - N(R ^17B )C(O)OR ^17B , -N(R ^17B )C(O)N(R ^17B ) ₂ , -N(R ^17B )S(O) ₂ (R ^17B ), -S(O)R ^17B , -S(O) ₂ R ^17B , - S(O) ₂ N(R ^17B ) ₂ , -NO ₂ , =O, and -CN.

[0152] In some embodiments, for the compound or salt of Formula (II), R ⁵ is selected from: C _1-6 alkyl and C _2-6 alkenyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR ¹⁷ , -SR ¹⁷ , -N(R ¹⁷ ) ₂ , -C(O)R ¹⁷ , -N(R ¹⁷ )C(O)OR ¹⁷ , -N(R ¹⁷ )C(O)N(R ¹⁷ ) ₂ , -N(R ¹⁷ )S(O) ₂ (R ¹⁷ ), -S(O)R ¹⁷ , -S(O) ₂ R ¹⁷ , - S(O) ₂ N(R ¹⁷ ) ₂ , -NO ₂ , =O, and -CN; and C _3-10 carbocycle and 3- to 10 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^17B , -SR ^17B , -N(R ^17B ) ₂ , - C(O)R ^17B , -C(O)OR ^17B , -OC(O)R ^17B , -OC(O)N(R ^17B ) _2, -C(O)N(R ^17B ) ₂ , -N(R ^17B )C(O)R ^17B , - N(R ^17B )C(O)OR ^17B , -N(R ^17B )C(O)N(R ^17B ) ₂ , -N(R ^17B )S(O) ₂ (R ^17B ), -S(O)R ^17B , -S(O) ₂ R ^17B , - S(O) ₂ N(R ^17B ) ₂ , -NO ₂ , =O, and -CN.

[0153] In some embodiments, for the compound or salt of Formula (II), R ⁵ is selected from C _3-10 carbocycle and 3- to 10 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^17B , -SR ^17B , -N(R ^17B )2, -C(O)R ^17B , -C(O)OR ^17B , - OC(O)R ^17B , -OC(O)N(R ^17B ) _2, -C(O)N(R ^17B ) ₂ , -N(R ^17B )C(O)R ^17B , -N(R ^17B )C(O)OR ^17B , - N(R ^17B )C(O)N(R ^17B ) ₂ , -N(R ^17B )S(O) ₂ (R ^17B ), -S(O)R ^17B , -S(O) ₂ R ^17B , -S(O) ₂ N(R ^17B ) ₂ , -NO ₂ , , and =O -CN. In some embodiments, R ⁵ is 3- to 10 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^17B , -SR ^17B , -N(R ^17B ) ₂ , -C(O)R ^17B , - C(O)OR ^17B , -OC(O)R ^17B , -OC(O)N(R ^17B ) _2, -C(O)N(R ^17B ) ₂ , -N(R ^17B )C(O)R ^17B , -N(R ^17B )C(O)OR ^17B , -N(R ^17B )C(O)N(R ^17B ) ₂ , -N(R ^17B )S(O) ₂ (R ^17B ), -S(O)R ^17B , -S(O) ₂ R ^17B , -S(O) ₂ N(R ^17B ) ₂ , -NO ₂ , , and =O -CN. In some embodiments, R ⁵ is a 3- to 10 membered saturated heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR ^17B , -SR ^17B , -N(R ^17B ) ₂ , - C(O)R ^17B , -C(O)OR ^17B , -OC(O)R ^17B , -OC(O)N(R ^17B ) _2, -C(O)N(R ^17B ) ₂ , -N(R ^17B )C(O)R ^17B , - N(R ^17B )C(O)OR ^17B , -N(R ^17B )C(O)N(R ^17B ) ₂ , -N(R ^17B )S(O) ₂ (R ^17B ), -S(O)R ^17B , -S(O) ₂ R ^17B , -

S(O) ₂ N(R ^i7B ) ₂ , -NO ₂ , =O, and -CN. In some embodiments, R ⁵ is selected from and . In some embodiments, R ⁵ is .In some embodiments, R ⁵ is . In some embodiments,

[0154] In some aspects, the compound or salt of Formula (I), (I-a), or (II), is selected from:

[0155] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0156] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salts of Formula (I), (I-a), or (II), are intended to include all Z-, E- and tautomeric forms as well.

[0157] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0158] The compounds or salts for Formula (I), (I-a), or (II), may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration.

[0159] In certain embodiments, compounds or salts for Formula (I), (I-a), or (II), may comprise two or more enantiomers or diastereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those of skill in the art. For example, a single stereoisomer, e.g ., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283- 302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.

[0160] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds or salts for Formula (I), (I-a), or (II), exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non-limiting examples of tautomeric equilibrium include:

[0161] The compounds of Formula (I), (I-a), or (II), can be used in different enriched isotopic forms, e.g., enriched in the content of ² H, ¾, ^U C, ¹³ C and/or ¹⁴ C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0162] In certain embodiments, the compounds of Formula (I), (I-a), or (II), have some or all of the ¾ atoms replaced with ² H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0163] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron , 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem ., 1981, 64(1-2), 9-32.

[0164] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0165] Unless otherwise stated, compounds of Formula (I), (I-a), or (II), are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the present disclosure.

[0166] The compounds of Formula (I), (I-a), or (II), optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). Isotopic substitution with ² H, ^U C, ¹³ C, ¹⁴ C, ¹⁵ C, ¹² N, ¹³ N, ¹⁵ N, ¹⁶ N, ¹⁶ 0, ¹⁷ 0, ¹⁴ F, ¹⁵ F, ¹⁶ F, ¹⁷ F, ¹⁸ F, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ³⁵ C1, ³⁷ C1, ⁷⁹ Br, ⁸¹ Br, and ¹²⁵ I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0167] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds of Formula (I), (I-a), or (II). The compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride.