Phenylacetamide-Based IL-17A Modulators and Uses Thereof - Patent application

Abstract

The present disclosure herein provides phenylacetamide-based compounds of formula (I), (Ia), (II), and pharmaceutical compositions thereof for the modulation of IL-17A, useful for the treatment of inflammatory diseases (e.g., psoriasis).

Description

[Technical field]

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

[0002] The IL-17 family consists of six cytokines (IL-17A to IL-17F). Interleukin-17A (IL-17A) is a well-established proinflammatory cytokine associated with the induction of IL-6, IL-8, G-CSF, TNF-α, IL-1β, PGE2, and IFN-γ, as well as many 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-17RA and IL-17RC to mediate signal transduction. IL-17A is the main pathogenic cytokine expressed by Th17 cells, which are associated with inflammatory and autoimmune pathologies, as well as CD8+ T cells, γδ cells, NK cells, NKT cells, macrophages, and dendritic cells. Furthermore, IL-17A and Th17 are essential for defense against various microorganisms despite the involvement of inflammation and autoimmune diseases. IL-17A can also act in concert with other inflammatory cytokines, such as TNF-α, IFN-γ, and IL-1β, to mediate pro-inflammatory effects.

[0003] To date, there are several biologics (secukinumab and ixekizumab) approved to modulate IL-17A for the treatment of inflammatory diseases such as psoriasis, ankylosing spondylitis, and psoriatic arthritis. These treatments require injection into patients because they are poorly absorbed by the intestine when taken orally. Furthermore, these approved biologic treatments are expensive to administer to patients, limiting their availability to the patient population in need.

[0004] There are several IL-17A small molecule regulators approved for oral administration. However, although they are convenient for oral administration and low cost for patients, they lack the efficacy of approved biological drugs. Therefore, there is a need for the development of potent small molecule IL-17A regulators for the treatment of inflammatory diseases and other related diseases. Summary of the Invention

[0005] In one embodiment, the present disclosure provides a compound of formula (I): [ka] (I) [In formula: A is selected from a 5- to 6-membered heterocycle optionally substituted with one or 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: 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 A carbocycle and a 3- to 10-membered heterocycle, each of which is selected from the group consisting of 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, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C, which may be optionally substituted with one or more substituents independently selected from 1-10 Alkyl and (iii) a 3- to 10-membered heterocycle: 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 halogens, -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 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-6 a 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from alkyl; B is -CH(R A )(R B ) and C 3-10 Carbocyclic rings, selected from C 3-10 Carbocycles are: 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 R12 , -S(O) 2 N(R 12 ) 2 , -NO 2 , =O, and -CN; and C 1-6 Alkyl, 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 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-6 Alkyl and optionally substituted with one or more substituents independently selected from: R A and R B are, each independently: 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(R13 ) 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, 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 C, optionally substituted with one or more substituents independently selected from -CN. 1-6 Alkyl; and C 3-10 Carbocyclic rings containing halogen, -OR13 , -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 C, optionally substituted with one or more substituents independently selected from -CN. 3-10 Carbocycle Selected from; 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(R14 ) 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 -CN; and (vi) C 1-6 Alkyl: 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 -CN; and A 3- to 10-membered heterocycle, which is 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, C 1-6 Alkyl; and (vii) a 3- to 10-membered heterocycle: 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 2a 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from -CN; R 3 and R 4 are each independently selected from (a), (b), (c), and (d): (a) Hydrogen; (b)C 1 Alkyl: Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)NH 2 , -C(O)-OC 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 Carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is free of 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, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 1 Alkyl; (c)C 2-6 Alkyl: Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 2-6 Alkyl and (d) C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocycles and 3- to 10-membered heterocycles; and C 1-6 Alkyl, 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 2and -CN, 1-6 Alkyl C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; or R 3 and R 4 taken together form a 4- to 12-membered heterocycle: 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, 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(R16 )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; 1-6 Alkyl can form a 4- to 12-membered heterocycle, optionally substituted with one or more substituents independently selected from: R 5 teeth: 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; C1-6 Alkyl and C 2-6 alkenyl, each of which is 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 , ═O, and —CN; 1-6 Alkyl and C 2-6 Alkenyl; and C 3-10 Carbocyclic rings containing 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, 3-10 Carbocycle Selected from; R 11 , R 12 , R 13 , R 14 , R 14B , R 15 , R 16 , R 17 , and R 17B are each independently selected from (I), (II), and (III): (I) hydrogen; (II)C 1-6 Alkyl with halogen, -OH, -OC 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, -NH 2 , -NO 2 , =O, -CN, C 3-10 C which may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; 1-6 Alkyl (C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are free of halogen, -OH, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, -NH 2 , -NO 2 , ═O, and —CN; and (III)C 3-10Carbocycles and 3- to 10-membered heterocycles, each of which is independently selected from halogen, —OH, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, -NH 2 , -NO 2 , =O, and -CN; and C 1-6 Alkyl with halogen, -OH, -OC 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, -NH 2 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-6 C is optionally substituted with one or more substituents independently selected from alkyl; 3-10 Carbocycles and 3- to 10-membered heterocycles; and n is selected from 0, 1, 2, 3, and 4; n is selected from 1, 2, 3, and 4; or R 1 or R 2 at least one of which is hydrogen] or a pharma- ceutically acceptable salt thereof.

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

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

[0008] In some embodiments, the present disclosure provides a method for treating an inflammatory disease or disorder, comprising administering to a subject a compound or salt of Formula (I) or (Ia), or a pharmaceutical composition thereof. In some embodiments, the inflammatory disease or disorder is selected from plaque psoriasis, guttate psoriasis, plaque psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar pustulosis, spondyloarthritis, and non-infectious uveitis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0010] Detailed Description of the Invention While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will 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. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered.

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

[0012] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0013] "Alkyl" refers to an alkyl group that is free of unsaturation and preferably contains 1 to 12 carbon atoms (i.e., C 1 -C 12 "Alkyl" refers to a linear or branched hydrocarbon chain monovalent group consisting solely of carbon and hydrogen atoms having 1 to 12 carbon atoms (i.e., C 1 -C 12 In some embodiments, alkyl includes 1 to 8 carbon atoms (i.e., C 1 -C 8 In other embodiments, alkyl includes 1 to 5 carbon atoms (i.e., C 1 -C 5 In other embodiments, alkyl includes 1 to 4 carbon atoms (i.e., C 1 -C 4 In other embodiments, alkyl includes 1 to 3 carbon atoms (i.e., C 1 -C 3 In other embodiments, alkyl includes 1 to 2 carbon atoms (i.e., C 1 -C 2 In other embodiments, an alkyl group contains one carbon atom (i.e., C 1 In other embodiments, alkyl includes 1 to 15 carbon atoms (i.e., C 5 -C 15 In other embodiments, alkyl includes 5 to 8 carbon atoms (i.e., C 5 -C 8 In other embodiments, alkyl includes 2 to 5 carbon atoms (i.e., C 2 -C 5 In other embodiments, alkyl includes 3 to 5 carbon atoms (i.e., C 3 -C 5For example, an alkyl group may be attached to the remainder of the molecule by a single bond, such as methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), and the like.

[0014] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and preferably having 2 to 12 carbon atoms (i.e., C 2 -C 12 alkenyl) refers to a straight or branched chain hydrocarbon group consisting solely of carbon and hydrogen atoms having from 2 to 8 carbon atoms (i.e., C 2 -C 8 In some embodiments, alkenyl includes 2 to 6 carbon atoms (i.e., C 2 -C 6 In other embodiments, alkenyl includes 2 to 4 carbon atoms (i.e., C 2 -C 4 Alkenyl may be attached to the remainder of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

[0015] "Alkynyl" refers to an alkynyl group containing at least one carbon-carbon triple bond and preferably containing 2 to 12 carbon atoms (i.e., C 2 -C 12 alkynyl refers to a straight or branched chain hydrocarbon group consisting solely of carbon and hydrogen atoms having from 2 to 8 carbon atoms (i.e., C 2 -C 8 In other embodiments, alkynyl includes 2 to 6 carbon atoms (i.e., C 2 -C 6In other embodiments, alkynyl includes 2 to 4 carbon atoms (i.e., C 2 -C 4 Alkynyl may be attached to the remainder of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0016] "Alkylene" means a straight divalent hydrocarbon chain containing no unsaturation, preferably having 1 to 12 carbon atoms, linked through the remainder of the molecule consisting only of carbon and hydrogen, e.g., methylene, ethylene, propylene, butylene, etc. The alkylene chain is attached to the rest of the molecule and to the group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the group are through the terminal carbons, respectively. The alkylene chain may be optionally substituted with one or more substituents, such as those described herein. In certain embodiments, an alkylene is an alkylene having 1 to 10 carbon atoms (i.e., C 1 -C 10 In some embodiments, alkylene includes 1 to 8 carbon atoms (i.e., C 1 -C 8 In other embodiments, alkylene includes 1 to 5 carbon atoms (i.e., C 1 -C 5 In other embodiments, alkylene includes 1 to 4 carbon atoms (i.e., C 1 -C 4 In other embodiments, alkylene includes 1 to 3 carbon atoms (i.e., C 1 -C 3 In other embodiments, the alkylene includes 1 to 2 carbon atoms (i.e., C 1 -C 2 In other embodiments, the alkylene is an alkylene having one carbon atom (i.e., C 1 In other embodiments, the alkylene includes 5 to 8 carbon atoms (i.e., C 5 -C 8In other embodiments, the alkylene includes 2 to 5 carbon atoms (i.e., C 2 -C 5 In other embodiments, the alkylene includes 3 to 5 carbon atoms (i.e., C 3 -C 5 Contains alkylene.

[0017] "Alkenylene" refers to a linear divalent hydrocarbon chain containing at least one carbon-carbon double bond, preferably having from 2 to 12 carbon atoms, linked at the end of the molecule consisting solely of carbon and hydrogen. The alkenylene chain is attached to the rest of the molecule and to groups through single bonds. The points of attachment of the alkenylene chain to the rest of the molecule and to groups are through the terminal carbons, respectively. The alkenylene chain may be optionally substituted with one or more substituents, such as those described herein. In certain embodiments, an alkenylene is an alkyl group having from 2 to 10 carbon atoms (i.e., C 2 -C 10 In some embodiments, alkenylene includes alkyl groups having 2 to 8 carbon atoms (i.e., C 2 -C 8 In other embodiments, alkenylene includes alkyl groups having 2 to 5 carbon atoms (i.e., C 2 -C 5 In other embodiments, alkenylene includes alkyl groups having 2 to 4 carbon atoms (i.e., C 2 -C 4 In other embodiments, alkenylene includes an alkyl group having 2 to 3 carbon atoms (i.e., C 2 -C 3 In other embodiments, alkenylene includes an alkyl group having two carbon atoms (i.e., C 2 In other embodiments, alkenylene includes alkyl groups having 5 to 8 carbon atoms (i.e., C 5 -C 8 In other embodiments, alkenylene includes an alkyl group having 3 to 5 carbon atoms (i.e., C 3 -C 5 Alkenylene).

[0018] "Alkynylene" refers to a linear divalent hydrocarbon chain that contains at least one carbon-carbon triple bond, and preferably has from 2 to 12 carbon atoms, linked through the remainder of the molecule consisting solely of carbon and hydrogen. The alkynylene chain is attached to the rest of the molecule and to the group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the group are through the terminal carbons, respectively. The alkynylene chain may be optionally substituted with one or more substituents, such as those described herein. In certain embodiments, an alkynylene is an alkyl group having from 2 to 10 carbon atoms (i.e., C 2 -C 10 In some embodiments, alkynylene includes alkynylenes having 2 to 8 carbon atoms (i.e., C 2 -C 8 In other embodiments, alkynylene includes alkynylenes having 2 to 5 carbon atoms (i.e., C 2 -C 5 In other embodiments, alkynylene includes alkynylenes having 2 to 4 carbon atoms (i.e., C 2 -C 4 In other embodiments, the alkynylene is an alkynylene having two carbon atoms (i.e., C 2 In other embodiments, alkynylene includes alkynylenes having 5 to 8 carbon atoms (i.e., C 5 -C 8 In other embodiments, alkynylene includes alkynylene having 3 to 5 carbon atoms (i.e., C 3 -C 5 alkynylene).

[0019] The term “C x-y " when used in combination with a chemical moiety such as alkyl, alkenyl, or alkynyl, is meant to include groups containing x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" means a substituted or unsubstituted saturated hydrocarbon group, including straight chain alkyl and branched chain alkyl groups, containing 1 to 6 carbons. The term -C x-yAlkylene- means a substituted or unsubstituted alkylene chain having x to y carbon atoms 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 may be optionally substituted.

[0020] The term “C x-y alkenyl" and "C x-y "Alkynyl" refers to unsaturated aliphatic groups analogous to alkyl, of length and possible substitution, as described above, containing at least one double or triple bond, respectively. x-y Alkenylene- means a substituted or unsubstituted alkenylene chain having 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 may be optionally substituted. The alkenylene chain may have one double bond or two or more double bonds in the alkenylene chain. The term -C x-y Alkynylene- means a substituted or unsubstituted alkynylene chain having x to y carbon atoms in the alkynylene chain. For example, -C 2-6 Alkynylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which may be optionally substituted. The alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0021] The term "carbocycle" as used herein means a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles include 3-10 membered monocyclic rings and 6-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. A bicyclic carbocycle may be a fused, bridged, or spiro ring system. In certain embodiments, a carbocycle is an aryl. In certain embodiments, a carbocycle is a cycloalkyl. In certain embodiments, a carbocycle is a cycloalkenyl. In typical embodiments, 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 is included in the definition of carbocycle, as long as valence allows. Typical carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycles may be optionally substituted with one or more substituents such as those described herein.

[0022] "Cycloalkyl" includes fused or bridged ring groups, preferably containing from 3 to 12 carbon atoms (i.e., C 3-12 Cycloalkyl refers to a stable, fully saturated monocyclic or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms having from 3 to 10 carbon atoms (i.e., C 3-10 In other embodiments, cycloalkyl includes 5 to 7 carbon atoms (i.e., C 5-7Cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Cycloalkyls can be optionally substituted with one or more substituents, such as those described herein.

[0023] "Cycloalkenyl" includes fused or bridged ring groups, preferably having from 3 to 12 carbon atoms and at least one double bond (i.e., C 3-12 Cycloalkenyl refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms. In some embodiments, cycloalkenyl refers to a group having 3 to 10 carbon atoms (i.e., C 3-10 In other embodiments, cycloalkenyl includes 5 to 7 carbon atoms (i.e., C 5-7 Cycloalkenyls include cycloalkenyls, which may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyls may be optionally substituted with one or more substituents, such as those described herein.

[0024] "Aryl" means a group derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring group by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring group contains only hydrogen and carbon, has 5 to 18 carbon atoms, and at least one of the rings in the ring group is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to the Huckel method. Ring groups from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. An aryl may be optionally substituted with one or more substituents, such as those described herein.

[0025] "C x-y "Carbocycle" is intended to include groups containing x to y carbons in the ring. For example, the term "C 3-6 A "carbocycle" can be a saturated, unsaturated, or aromatic ring group containing from 3 to 6 carbon atoms, any of which may be optionally substituted as provided herein.

[0026] The term "heterocycle" as used herein means a saturated, unsaturated, non-aromatic, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3-10 membered monocyclic rings and 6-12 membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. In certain embodiments, the heterocycle contains at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In certain embodiments, the heterocycle contains at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In certain embodiments, the heterocycle contains at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In certain embodiments, the heterocycle contains at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycle may be attached to the remainder of the molecule through any atom of the heterocycle where valence allows, for example, a carbon or nitrogen atom of the heterocycle. In certain 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. The heterocycle may be optionally substituted with one or more substituents, such as those described herein. The bicyclic heterocycle may be a fused, bridged, or spiro ring system. In exemplary embodiments, the heterocycle, such as pyridyl, may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. The heterocycle may be optionally substituted with one or more substituents, such as those described herein.

[0027] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring group containing 2-12 carbon atoms and at least one heteroatom, each of which may be selected from N, O, Si, P, B, and S atoms. In certain embodiments, heterocycloalkyls contain at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In certain embodiments, heterocycloalkyls contain at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In certain embodiments, heterocycloalkyls contain at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In certain embodiments, heterocycloalkyls contain at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. Heterocycloalkyls may be selected from monocyclic or bicyclic, and fused or bridged ring groups. The heteroatoms of a heterocycloalkyl group may be optionally oxidized. One or more nitrogen atoms, if present, may be optionally quaternized. Heterocycloalkyl groups are partially or fully saturated. The heterocycloalkyl is attached to the remainder of the molecule through any atom of the heterocycloalkyl, for example, any carbon or nitrogen atom of the heterocycloalkyl, provided that valence allows. Examples of heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]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. Heterocycloalkyls may be optionally substituted with one or more substituents, such as those described herein.

[0028] The term "heteroaryl" refers to a group derived from a 3-12 membered aromatic ring group containing 1-12 carbon atoms and at least one heteroatom, each of which may be selected from N, O, and S. In certain embodiments, the heteroaryl contains at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In certain embodiments, the heteroaryl contains at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In certain embodiments, the heteroaryl contains at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In certain embodiments, the heteroaryl contains 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 groups, at least one of the rings in said ring groups being aromatic, i.e., containing a cyclic delocalized (4n+2) π-electron system according to the Huckel method. The heteroatoms in the heteroaryl group may be optionally oxidized. One or more nitrogen atoms, if present, may be optionally quaternized. Heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl, e.g., a carbon or nitrogen atom of the heteroaryl, if valence allows. Heteroaryl includes an aromatic monocyclic ring structure, preferably a 5-6 membered ring, said ring structure including at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl may be optionally substituted with one or more substituents, such as those described herein.Heteroaryl also includes polycyclic ring groups having two or more rings, where two or more atoms are shared between two adjacent rings, at least one of which is heteroaromatic, e.g., the other ring may be an aromatic or non-aromatic carbocyclic ring, or a heterocyclic ring. Heteroaryl may be optionally substituted by one or more substituents, such as those described herein.

[0029] An "X-membered heterocycle" refers to the number of ring atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 ring atoms, such as triazole, oxazole, thiophene, and the like.

[0030] "Alkoxy" means a group attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0031] "Halo" or "halogen" means a halogen substituent, such as bromo, chloro, fluoro, and iodo substituents.

[0032] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group, as defined above, that is substituted with one or more halogen groups, such as, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In certain embodiments, the alkyl portion of the fluoroalkyl group may be further optionally substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 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 combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, and I). When an alkyl group is substituted with more than one halogen group, each halogen may be independently selected from, for example, 1-chloro, 2-fluoroethane.

[0033] The term "substituted" means a moiety having a substituent replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH or NH of a compound. 2It is understood that "substituted" or "substituted" includes the implicit proviso that the substitution is permitted for the valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. In some embodiments, "substituted" refers to a moiety having a substituent replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, the term "substituted" is intended to include all permissible substitutions of organic compounds. In a broad embodiment, the permissible substituents include acyclic and cyclic, linear and non-linear, 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 certain embodiments, the substituents may include any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), 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 -OR 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 (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein 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 alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=NH), 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 , -Rb -OR 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 (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2), and -R b -S(O) t N(R a ) 2 where t is 1 or 2; a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl; a is an alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO), where valences permit. 2 ), imino (=NH), 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)Ra , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR 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 (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2), and -R b -S(O) t N(R a ) 2 (wherein t is 1 or 2); each R b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain; c is a straight or branched alkylene, alkenylene, or alkynylene chain. It will be appreciated by those skilled in the art that the substituents themselves may be optionally substituted.

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

[0036] The term "pharmacologically acceptable" is used herein to mean those compounds, substances, compositions, and / or dosage forms that are, within the scope of sound medical judgment, compatible with use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, consistent with a reasonable benefit / risk ratio.

[0037] As used herein, the term "pharmaceutical acceptable excipient" or "pharmaceutical acceptable carrier" means a pharma- ceutically acceptable substance, 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" are used interchangeably and refer to humans, as well as non-human mammals (e.g., non-human primates, dogs, horses, cats, pigs, cows, ungulates, rabbits, etc.). In various embodiments, the subject can be a human (e.g., an adult male, an adult female, an adolescent male, an adolescent female, a boy, a girl) under the care of a physician or other medical practitioner in a hospital, as an outpatient, or in other clinical settings. In some embodiments, the subject may not be under the care or prescription of a physician or other medical practitioner.

[0039] As used herein, the term "subject in need thereof" means a subject as described below suffering from or at risk of a pathology to be treated prophylactically or therapeutically with a compound or salt described herein.

[0040] The terms "administer", "administered", "administers" and "administering" are defined as providing a composition to an individual 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 some embodiments, the oral route of administering the 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 an individual in need thereof.

[0041] As used herein, "treatment" or "treating" refers to a means for obtaining a beneficial or desired outcome with respect to a disease, disorder, or medical condition, including, but not limited to, a therapeutic benefit and / or a preventative benefit. In certain embodiments, treatment or treating refers to administering to a subject a compound or composition disclosed herein. Therapeutic benefit may include eradication or amelioration of the underlying disorder to be treated. Alternatively, therapeutic benefit may be achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in a subject, even though the subject may still suffer from the underlying disorder. In certain embodiments, for preventative benefit, the composition is administered to a subject at risk of developing a particular disease, even if the disease has not been diagnosed, or to a subject who has reported one or more of the physiological symptoms of the disease. Treating may include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of the disease or disorder, or reducing the frequency with which a patient experiences symptoms such as a disease, defect, disorder, or exacerbated condition. Treating can be used herein to mean a method that results in some level of cure or improvement of a disease or disorder, and may include a range of objective results, including, but not limited to, prevention of the overall condition.

[0042] In certain embodiments, the terms "prevent" or "preventing" in relation to a disease or disorder may refer to a compound that, in a statistical sample, reduces the incidence of the disorder or disease in a treated sample compared to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of the disorder or disease compared to an untreated control sample.

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

[0044] compound In one embodiment, the present disclosure provides a compound of formula (I): [ka] (I) [In formula: A is selected from a 5- to 6-membered heterocycle optionally substituted with one or 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 is an alkyl group, 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 A carbocycle and a 3- to 10-membered heterocycle, each of which is selected from the group consisting of 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 R11 , -S(O) 2 N(R 11 ) 2 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 1-10 Alkyl and (iii) a 3- to 10-membered heterocycle, 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, 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; 1-6 Alkyl a 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from B is -CH(R A )(R B ) and C 3-10 carbocyclic ring, wherein said C 3-10 The carbocyclic ring is 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, 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 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-6 Alkyl and optionally substituted with one or more substituents independently selected from: R A and R B are each independently 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, 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 C, optionally substituted with one or more substituents independently selected from -CN. 1-6 Alkyl and C3-10 Carbocyclic rings containing 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 C, optionally substituted with one or more substituents independently selected from -CN. 3-10 Carbocycle Selected from; 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 is an alkyl group, 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 A 3- to 10-membered heterocycle, which is 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, optionally substituted with one or more substituents independently selected from C 1-6 Alkyl and (vii) a 3- to 10-membered heterocycle, 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(R14B ) 2 , -NO 2 a 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from -CN; R 3 and R 4 are each independently selected from (a), (b), (c), and (d): (a) Hydrogen; (b)C 1 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)NH 2 , -C(O)-OC 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 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocycles and 3- to 10-membered heterocycles; (c)C 2-6 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 2-6 Alkyl; and (d) C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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(R15 ) 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; and C 1-6 Alkyl, 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, 1-6 Alkyl C3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; or R 3 and R 4 are taken together to form a 4- to 12-membered heterocycle, 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, 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; 1-6 Alkyl can form a 4- to 12-membered heterocycle, optionally substituted with one or more substituents independently selected from: R 5 teeth, 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 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 , ═O, and —CN; 1-6 Alkyl and C 2-6 Alkenyl and C 3-10 Carbocyclic rings containing 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 R17B , -S(O) 2 N(R 17B ) 2 , -NO 2 and -CN, 3-10 Carbocycle Selected from; R 11 , R 12 , R 13 , R 14 , R 14B , R 15 , R 16 , R 17 , and R 17B are each independently selected from (I), (II), and (III): (I) hydrogen; (II)C 1-6 Alkyl with halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -NH 2 , -NO 2 , =O, -CN, C 3-10 C may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; 1-6 Alkyl (C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are free of halogen, -OH, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, -NH 2 , -NO 2 , ═O, and —CN; and (III)C 3-10 Carbocycles and 3- to 10-membered heterocycles, each of which is independently selected from halogen, —OH, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Alkyl, -OC 1 -C 6Haloalkyl, -NH 2 , -NO 2 , =O, and -CN; and C 1-6 Alkyl with halogen, -OH, -OC 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, -NH 2 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-6 C is optionally substituted with one or more substituents independently selected from alkyl; 3-10 Carbocycles and 3- to 10-membered heterocycles; and n is selected from 0, 1, 2, 3, and 4; n is selected from 1, 2, 3, and 4; or R 1 or R 2 At least one of the groups is hydrogen. or a pharma- ceutically acceptable salt thereof.

[0045] In certain embodiments, for a compound or salt of Formula (I), R 5 is 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)R17B , -S(O) 2 R 17B , -S(O) 2 N(R 17B ) 2 , -NO 2 and C, optionally substituted with one or more substituents independently selected from -CN. 3-10 In one embodiment, R 5 is halogen, -OR 17B , -N(R 17B ) 2 , -C(O)R 17B , -C(O)OR 17B , -NO 2 and C, optionally substituted with one or more substituents independently selected from -CN. 3-6 In one embodiment, R 5 is an optionally substituted saturated C 3-6 In one embodiment, R 5 is optionally substituted C 6 In one embodiment, R 5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any one of which may be optionally substituted. In certain embodiments, R 5 is optionally substituted cyclopropyl. In certain embodiments, R 5 teeth, [ka] It is represented by:

[0046] In certain embodiments, for a compound or salt of Formula (I), R 1 or R 2 One of them is C. 1-6 Alkyl, halogen, -OR 14B , -SR 14B , -N(R 14B ) 2 , -C(O)R 14B , -C(O)OR14B , -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 heterocycles, each of which is 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 2and -CN, optionally substituted with one or more substituents independently selected from a 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from a 3- to 10-membered heterocycle, 1-6 is selected from alkyl.

[0047] In certain embodiments, for a compound or salt of Formula (I), R 1 or R 2 is selected from methyl, ethyl, propyl, and isopropyl, each of which is a 3- to 10-membered heterocycle and is 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 heterocycles, each of which is 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(R14B ) 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; optionally substituted with one or more substituents independently selected from a 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from -CN; optionally substituted with one or more substituents independently selected from a 3- to 10-membered heterocycle.

[0048] In certain embodiments, for a compound or salt of Formula (I), R 1 is hydrogen; and R 2 is C 1-6 Alkyl, 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 (R14B ), -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 heterocycles, each of which is 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, optionally substituted with one or more substituents independently selected from a 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from a 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from C 1-6 is selected from alkyl.

[0049] In certain embodiments, for a compound or salt of Formula (I), R 1 or R 2 One of them is C. 1-6 Alkyl, halogen, -OR 14B , -N(R 14B )2 , -C(O)R 14B , -C(O)OR 14B , -NO 2 and a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from -CN; 1-6 In one embodiment, R 1 or R 2 One of them is C substituted with a 5- to 6-membered saturated heterocycle. 1-6 In one embodiment, R is an alkyl group selected from the group consisting of pyrrolidine, pyrroline, pyrazoline, imidazoline, tetrahydrofuran, dioxolane, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, any one of which may be appropriately substituted. 1 or R 2 One of them is [ka] It is represented by:

[0050] In certain embodiments, for a compound or salt of Formula (I), R 1 is hydrogen; and R 2 is C 1-6 Alkyl, halogen, -OR 14B , -N(R 14B ) 2 , -C(O)R 14B , -C(O)OR 14B , -NO 2 and a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from -CN; 1-6 In one embodiment, R 1 is hydrogen; and R 2 is a C substituted with a 5- to 6-membered saturated heterocycle. 1-6In one embodiment, R is an alkyl group selected from the group consisting of pyrrolidine, pyrroline, pyrazoline, imidazoline, tetrahydrofuran, dioxolane, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, any one of which may be appropriately substituted. 1 is hydrogen; and R 2 teeth, [ka] It is represented by:

[0051] In certain embodiments, for a compound or salt of Formula (I), R 1 or R 2 One of the rings is a 5- to 6-membered heterocycle, and is selected from the group consisting of halogen, -OR 14B , -N(R 14B ) 2 , -C(O)R 14B , -C(O)OR 14B , -NO 2 In one embodiment, R is a 5- to 6-membered heterocycle, optionally substituted with one or more substituents independently selected from - 1 or R 2 is a 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 may be appropriately substituted. 1 or R 2 One of them is [ka] It is represented by:

[0052] In certain embodiments, for a compound or salt of Formula (I), R 1 is hydrogen; and R2 is a 5- to 6-membered heterocycle, 14B , -N(R 14B ) 2 , -C(O)R 14B , -C(O)OR 14B , -NO 2 In one embodiment, R is a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from - 1 is hydrogen; and R 2 is a 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 may be appropriately substituted. 1 is hydrogen; and R 2 teeth, [ka] It is represented by:

[0053] In certain embodiments, for a compound or salt of Formula (I), R 3 and R 4 One of them is C. 1 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)NH 2 , -C(O)-OC 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(R15 )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 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 1 is selected from alkyl.

[0054] In one embodiment, R 3 and R 4One of them is C. 1 Alkyl, halogen, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)NH 2 , -NO 2 and -CN, 1 In one embodiment, R 3 and R 4 One of them is -C(O)NH 2 C, which may be optionally substituted with 1 In one embodiment, R 3 and R 4 One of them is [ka] It is represented by:

[0055] In some embodiments, the present disclosure provides a compound of formula (Ia): [ka] (Ia) [In formula: A is selected from a 5- to 6-membered heterocycle optionally substituted with one or 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 is an alkyl group, 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 A carbocycle and a 3- to 10-membered heterocycle, each of which is selected from the group consisting of 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, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 1-10 Alkyl; and (iii) a 3- to 10-membered heterocycle, 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(R11 ) 2 , -NO 2 , =O, -CN; and C 1-6 Alkyl, 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; 1-6 Alkyl a 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from B is -CH(R A )(R B ) and C 3-10 Carbocyclic rings, selected from C 3-10 The carbocycle is 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, 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; 1-6 Alkyl and optionally substituted with one or more substituents independently selected from: R A and R B are each independently 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, 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, 1-6 Alkyl and C 3-10 Carbocyclic rings containing 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, 3-10 Carbocycle Selected from; R 1 and R 2 are each independently hydrogen; Halogen, -OR 14 , -SR 14 , -N(R14 ) 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 -CN; and C 1-6 Alkyl, 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, 1-6 Alkyl Selected from; R 3 and R 4 are each independently selected from (a), (b), (c), and (d): (a) Hydrogen; (b)C 1 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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 Carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is not substituted with 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(R15 ) 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, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 1 Alkyl; (c)C 2-6 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 2-6 Alkyl; and (d) C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)OR 15 , -OC(O)R 15 , -OC(O)N(R15 ) 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 -CN; and C 1-6 Alkyl, 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, 1-6 Alkyl C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings; or R 3 and R 4 are taken together to form a 4- to 12-membered heterocycle, 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, 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(R16 )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; 1-6 Alkyl can form a 4- to 12-membered heterocycle, optionally substituted with one or more substituents independently selected from: R 5 teeth, 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 -CN; and C 1-6 Alkyl and C 2-6 alkenyl, each of which is 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 , ═O, and —CN; 1-6 Alkyl and C 2-6 Alkenyl Selected from; R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are each independently selected from (I), (II), and (III): (I) hydrogen; (II)C 1-6 Alkyl with halogen, -OH, -OC 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, -NH 2 , -NO 2 , =O, -CN, C 3-10 C which may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle;1-6 Alkyl (C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are free of halogen, -OH, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, -NH 2 , -NO 2 , ═O, and —CN; and (III)C 3-10 Carbocycles and 3- to 10-membered heterocycles, each of which is independently selected from halogen, —OH, C 1 -C 6 Haloalkyl, -OC 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, -NH 2 , -NO 2 , =O, and -CN; and C 1-6 Alkyl with halogen, -OH, -OC 1 -C 6 Alkyl, -OC 1 -C 6 Haloalkyl, -NH 2 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and n is selected from 0, 1, 2, 3, and 4; n is selected from 1, 2, 3, and 4; or R 1 or R 2 At least one of the groups is hydrogen. or a pharma- ceutically acceptable salt thereof.

[0056] In certain embodiments, for a compound or salt of formula (I) or (Ia), n is selected from 1, 2, 3, and 4. In certain embodiments, n is selected from 0, 1, 2, and 3. In certain embodiments, n is selected from 0, 1, and 2. In certain embodiments, n is selected from 0 and 1. In certain embodiments, n is selected from 2, 3, and 4. In certain embodiments, n is selected from 3 and 4. In certain embodiments, n is selected from 1 and 2. In certain embodiments, n is 4. In certain embodiments, n is 3. In certain embodiments, n is 2. In certain embodiments, n is 1. In certain embodiments, n is 0.

[0057] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 5 is 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. 5 is halogen, -OR 16 , -SR 16, -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , ═O, and —CN. 5 is C 1-6 Alkyl and C 2-6 alkenyl, each of which 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 In certain embodiments, R 5 is C 1-6 Alkyl and C 2-6 alkenyl, each of which is selected from halogen, -OR 17 , -SR 17 , -N(R 17 ) 2 , -C(O)R 17 , -C(O)OR 17 , -NO 2In certain embodiments, R 5 is halogen, -OR 17 , -SR 17 , -N(R 17 ) 2 , -C(O)R 17 , -C(O)OR 17 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-3 In one embodiment, R 5 is C 2-3 alkenyl, each of which is selected from halogen, -OR 17 , -SR 17 , -N(R 17 ) 2 , -C(O)R 17 , -C(O)OR 17 , -NO 2 In certain embodiments, R 5 is halogen, -OR 17 , -SR 17 , -N(R 17 ) 2 , -C(O)R 17 , -NO 2 , and -CN; and C 1-3 Alkyl and C 2-3 Alkenyl is halogen, -OR 17 , -SR 17 , -N(R 17 ) 2 , -C(O)R 17 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-3 Alkyl and C 2-3 alkenyl.

[0058] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 5is chloro, fluoro, bromo, -OR 17 , -N(R 17 ) 2 , -CN;C 1-3 Alkyl and C 2-3 alkenyl, each of which is selected from chloro, fluoro, -OR 17 , and -N(R 17 ) 2 and optionally substituted with one or more substituents independently selected from 。 In one embodiment, R 5 is chloro, fluoro, bromo, -CN, methyl, ethyl, [ka] In one embodiment, R 5 is chloro, fluoro, bromo, -CN, methyl, ethyl, [ka] In one embodiment, R 5 is selected from chloro, fluoro, bromo, —CN, methyl, and ethyl. 5 teeth, [ka] In one embodiment, R 5 teeth, [ka] In one embodiment, R 5 teeth, [ka] In one embodiment, R 5 teeth, [ka] In one embodiment, R 5 teeth, [ka] It is.

[0059] In certain embodiments, for a compound or salt of Formula (I) or (Ia), 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;C 1-3 Alkyl and C 2-3 alkenyl, each of which is selected from halogen, -OR 17 , and -N(R 17 ) 2 In one embodiment, R 5 is chloro, fluoro, -CN, methyl, ethyl, propyl, isopropyl, -CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , [ka] In one embodiment, R 5 is chloro, fluoro, -CN, methyl, ethyl, [ka] is selected from.

[0060] In certain embodiments, for the compounds or salts of formula (I) or (Ia), A is selected from optionally substituted 5-6 membered heteroaryl. In certain embodiments, A's optionally substituted 5-6 membered heteroaryl contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof. In certain embodiments, A's optionally substituted 5-6 membered heteroaryl contains one or more heteroatoms selected from nitrogen, oxygen, and combinations thereof. In certain embodiments, A's optionally substituted 5-6 membered heteroaryl contains one or more heteroatoms selected from nitrogen, sulfur, and combinations thereof. In certain embodiments, A's optionally substituted 5-6 membered heteroaryl contains one or more heteroatoms selected from oxygen, sulfur, and combinations thereof. In certain embodiments, A's optionally substituted 5-6 membered heteroaryl contains one or more nitrogen heteroatoms. In certain embodiments, A's optionally substituted 5-6 membered heteroaryl contains one or more heteroatoms selected from nitrogen and oxygen.

[0061] In certain embodiments, for a compound or salt of Formula (I) or (Ia), A is (i) halogen, —OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , C(O)OR 11 , -OC(O)R 11 , -NO 2 In some embodiments, A is selected from the group consisting of: (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 certain embodiments, for a compound or salt of Formula (I) or (Ia), A is a 5-6 membered heteroaryl; and (ii) C 1-10 Alkyl, 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(R11 ) 2 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-10 In some embodiments, A is selected from 5-6 membered heteroaryl, optionally substituted with one or more substituents independently selected from alkyl. In some embodiments, A is 5-6 membered heteroaryl, and (ii) C 1-10 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , C(O)OR 11 , -OC(O)R 11 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-10 and 5-6 membered heteroaryl, optionally substituted with one or more substituents independently selected from alkyl.

[0063] In certain embodiments, for a compound or salt of Formula (I) or (Ia), A is a 5-6 membered heteroaryl; and (ii) C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is selected from the group consisting of 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; 3-10 C may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; 1-10 In some embodiments, A is selected from 5-6 membered heteroaryl, optionally substituted with one or more substituents independently selected from alkyl. In some embodiments, A is 5-6 membered heteroaryl, and (ii) C 1-10 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO 2 C, each of which is optionally substituted with one or more substituents independently selected from -O, -CN, 3-10 C may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; 1-10 In some embodiments, A is selected from 5-6 membered heteroaryl, optionally substituted with one or more substituents independently selected from alkyl. In some embodiments, A is 5-6 membered heteroaryl, and (ii) C 1-6 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO 2 C, each of which is optionally substituted with one or more substituents independently selected from -O, -CN, 3-6C may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 6-membered heterocycle; 1-6 In some embodiments, A is selected from 5-6 membered heteroaryl, optionally substituted with one or more substituents independently selected from alkyl. In some embodiments, A is 5-6 membered heteroaryl, and (ii) C 1-6 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO 2 C, each of which is optionally substituted with one or more substituents independently selected from -O, -CN, 3-6 C may be optionally substituted with one or more substituents independently selected from a carbocycle and a 4- to 6-membered saturated heterocycle; 1-6 In some embodiments, A is selected from 5-6 membered heteroaryl, optionally substituted with one or more substituents independently selected from alkyl. In some embodiments, A is 5-6 membered heteroaryl, and (ii) C 1-6 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO 2 C, each of which is optionally substituted with one or more substituents independently selected from -O, -CN, 3-6 C is optionally substituted with one or more substituents independently selected from carbocycle and 5- to 6-membered heteroaryl; 1-6 In some embodiments, A is selected from 5-6 membered heteroaryl, optionally substituted with one or more substituents independently selected from alkyl. In some embodiments, A is 5-6 membered heteroaryl, and (ii) C 1-6 Alkyl, halogen, -OR 11, -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO 2 C, each of which is optionally substituted with one or more substituents independently selected from -O, -CN, 3-6 C, optionally substituted with one or more substituents independently selected from carbocycle, 4- to 6-membered saturated heterocycle, and 5- to 6-membered heteroaryl; 1-6 and 5-6 membered heteroaryl, optionally substituted with one or more substituents independently selected from alkyl.

[0064] In certain embodiments, for a compound or salt of Formula (I) or (Ia), A is a 5-6 membered heteroaryl, and (iii) a 3-10 membered heterocycle that is selected from the group consisting of 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 2In some embodiments, A is selected from (iii) a 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from halogen, -OR, -O, -CN, and (iv) a 5- to 6-membered heteroaryl, optionally substituted with one or more substituents independently selected from halogen, -OR, -O, -CN ... 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO 2 In some embodiments, A is selected from (iii) a 5- to 6-membered heteroaryl, optionally substituted with one or more substituents independently selected from a 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 , -NO 2 , =O, and -CN; optionally substituted with one or more substituents independently selected from 3- to 6-membered heterocycle, optionally substituted with one or more substituents independently selected from -CN, -O, and -CN.

[0065] In certain embodiments, for a compound or salt of Formula (I) or (Ia), A is a 5-6 membered heteroaryl, and (iii) a 3-10 membered heterocycle that is selected from the group consisting of 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 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-6 In some embodiments, A is selected from (iii) a 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 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-6 In some embodiments, A is selected from (iii) a 5- to 6-membered heteroaryl, optionally substituted with one or more substituents independently selected from alkyl, and (iv) a 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 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-6 is selected from 5-6 membered heteroaryl, optionally substituted with one or more substituents independently selected from 3- to 6-membered heterocycle, optionally substituted with alkyl.

[0066] In certain embodiments, for a compound or salt of Formula (I) or (Ia), A is a 5-6 membered heteroaryl, (ii) C 1-10 is an alkyl group, Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , =O, -CN; and halogens, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C, each of which may be optionally substituted with one or more substituents independently selected from: 3-10 C may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; 1-10 Alkyl; and (iii) a 3- to 10-membered heterocycle, Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , =O, -CN; and halogens, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11, -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-6 A 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from alkyl. and optionally substituted with one or more substituents independently selected from:

[0067] In some embodiments, for the compounds or salts of formula (I) or (Ia), A is selected from 5-membered heteroaryl, which may be optionally substituted. In some embodiments, A is selected from pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, triazole, tetrazole, and pyridine, any of which may be optionally substituted. In some embodiments, A is selected from pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which may be optionally substituted. (ii) C 1-10 is an alkyl group, Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , =O, -CN; and halogens, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C, each of which may be optionally substituted with one or more substituents independently selected from: 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 1-10 Alkyl; and (iii) a 3- to 10-membered heterocycle, Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , =O, -CN; and halogens, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-6 Alkyl A 3- to 10-membered heterocycle which may be optionally substituted with one or more substituents independently selected from It may be optionally substituted with one or more substituents independently selected from:

[0068] In certain embodiments, for a compound or salt of Formula (I) or (Ia), A is [ka] any of which is selected from (ii) C 1-10 is an alkyl group, Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , =O, -CN; and halogens, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C, each of which may be optionally substituted with one or more substituents independently selected from: 3-10C may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; 1-10 Alkyl; and (iii) a 3- to 10-membered heterocycle, Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , =O, -CN; and halogens, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 1-6 A 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from alkyl. It may be optionally substituted with one or more substituents independently selected from:

[0069] In certain embodiments, for the compounds or salts of formula (I) or (Ia), A is selected from optionally substituted pyrazole and optionally substituted isoxazole. [ka] each of which may be optionally substituted; [ka] represents a bond to an optional substituent, [ka] indicates the bond of A to the remainder of formula I. In certain embodiments, A is [ka] each of which may be optionally substituted; [ka] indicates the first bond; [ka] represents a second bond, said first bond being from A to an optional substituent, and said second bond representing the bond between A and the structure of formula (I) or formula (Ia).

[0070] In certain embodiments, for a compound or salt of Formula (I) or (Ia), the 5- to 6-membered heterocycle of A is substituted with one or more substituents. In certain 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 is an alkyl group, Halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , =O, -CN; and C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is selected from the group consisting of halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 each optionally substituted with one or more substituents independently selected from -O, -C ... 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 1-6 Alkyl and (iii) a 3- to 10-membered heterocycle, Halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , =O, -CN; and C optionally substituted with halogen 1-6 A 3- to 10-membered heterocycle which may be optionally substituted with one or more substituents independently selected from alkyl.

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

[0072] In certain embodiments, for the compound or salt of Formula (I) or (Ia), the 5- to 6-membered heterocycle of A is substituted with one or more substituents. In certain embodiments, the substituent on the 5- to 6-membered heterocycle of A is selected from the group consisting of (ii) C 1-6 is an alkyl group, Halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , =O, -CN; C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is selected from the group consisting of halogen, -OR 11 , -SR 11 , -N(R 11 )2 , -C(O)R 11 , -NO 2 , ═O, and —CN, optionally substituted with one or more substituents selected from 3-10 C may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; 1-6 In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) C 1-6 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 C, optionally substituted with one or more substituents independently selected from -O, -CN, 3-10 optionally substituted with one or more substituents independently selected from carbocycles, C 1-6 In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) C 1-6 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , ═O, and a 3- to 10-membered heterocycle which may be optionally substituted with one or more substituents independently selected from -CN; 1-6 In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) C 1-6 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2, ═O, and —CN, 1-6 In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) C 1-6 Alkyl, halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , ═O, and a 3- to 6-membered saturated heterocycle which may be optionally substituted with one or more substituents independently selected from -CN; 1-6 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 may be selected from halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , ═O, and —CN; 1-6 alkyl.

[0073] In certain embodiments, for the compound or salt of Formula (I) or (Ia), the 5- to 6-membered heterocycle of A is substituted with one or more substituents. In certain embodiments, the substituents on the 5- to 6-membered heterocycle of A are (iii) halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , =O, -CN, and C1-6 In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , =O, -CN, and C 1-6 In some embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (iii) halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , =O, -CN, and C 1-6 It is independently selected from 3- to 6-membered saturated heterocycles optionally substituted with one or more substituents independently selected from haloalkyl.

[0074] In certain embodiments, for a compound or salt of Formula (I) or (Ia), the 5- to 6-membered heterocycle of A is substituted with one or more substituents. In certain embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) and (iii): (ii) C 1-6 is an alkyl group, Halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , =O, -CN; and C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is selected from the group consisting of halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R11 , -NO 2 C, optionally substituted with one or more substituents selected from -O, -CN, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 1-6 Alkyl; and (iii) a 3- to 10-membered heterocycle, Halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , =O, -CN; and C optionally substituted with halogen 1-6 A 3- to 10-membered heterocycle which may be optionally substituted with one or more substituents independently selected from alkyl.

[0075] In certain embodiments, for a compound or salt of Formula (I) or (Ia), the 5- to 6-membered heterocycle of A is substituted with one or more substituents. In certain embodiments, the substituents on the 5- to 6-membered heterocycle of A are independently selected from (ii) and (iii): (ii) C 1-6 is an alkyl group, Halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , =O, -CN; and C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is selected from the group consisting of halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , ═O, and —CN; 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 1-6 Alkyl; and (iii) a 3- to 6-membered heterocycle, Halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , =O, -CN; and C optionally substituted with halogen 1-6 Alkyl A 3- to 6-membered heterocycle which may be appropriately substituted with one or more substituents independently selected from:

[0076] In certain embodiments, for the compounds or salts of formula (I) or (Ia), the substituents on the 5- to 6-membered heterocycle of A are fluorine, methyl, ethyl, isopropyl, [ka] In some embodiments, the 5-6 membered heteroaryl of A is independently selected from pyrazole, isoxazole, oxadiazole, and pyridine, each of which is independently selected from fluorine, methyl, ethyl, propyl, isopropyl, [ka] In one embodiment, for the compound or salt of formula (I) or (Ia), the substituents on the 5- to 6-membered heterocycle of A are fluorine, methyl, ethyl, isopropyl, [ka] In some embodiments, the 5-6 membered heteroaryl of A is independently selected from pyrazole, isoxazole, and pyridine, each of which is selected from fluorine, methyl, ethyl, propyl, isopropyl, [ka] It may be optionally substituted with a substituent selected from the following:

[0077] In certain embodiments, for a compound or salt of Formula (I) or (Ia), A is [ka] is selected from.

[0078] In certain embodiments, for a compound or salt of Formula (I) or (Ia), A is [ka] is selected from.

[0079] In certain embodiments, for a compound or salt of Formula (I) or (Ia), A is [ka] is selected from.

[0080] In certain embodiments, for compounds or salts of Formula (I) or (Ia), B is -CH(R A )(R B ) and optionally substituted C 3-10 In certain embodiments, B is selected from -CH(R A )(R B ) and R A and R B Each of C 1-6 Alkyl, 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, 1-6 Alkyl and C 3-10 Carbocyclic rings containing 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, 3-10Carbocycle are independently selected from

[0081] In certain embodiments, for compounds or salts of Formula (I) or (Ia), B is -CH(R A )(R B ) and R A and R B Each of C 1-6 Alkyl, 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, 1-6 Alkyl; and C 3-10 Carbocyclic rings containing 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, 3-10 Carbocycle are independently selected from

[0082] In certain embodiments, for compounds or salts of Formula (I) or (Ia), B is -CH(R A )(R B ) and R A and R B Each of C 1-6 Alkyl, halogen, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -NO2 and -CN, 1-6 Alkyl; and C 3-6 Carbocyclic rings containing halogen, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -NO 2 and -CN, 3-6 Carbocycle are independently selected from

[0083] In certain embodiments, for compounds or salts of Formula (I) or (Ia), B is -CH(R A )(R B ) and R A and R B Each of Methyl, ethyl, propyl, and isopropyl, each of which is selected from the group consisting of halogen, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -NO 2 -, and -CN, each optionally substituted with one or more substituents independently selected from methyl, ethyl, propyl, and isopropyl; and C 3-6 A saturated carbocyclic ring containing halogen, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -NO 2 and -CN, 3-6 Saturated carbocyclic rings are independently selected from

[0084] In certain embodiments, for compounds or salts of Formula (I) or (Ia), B is -CH(R A )(R B ) and R A and R B Each of Methyl, ethyl, propyl, and isopropyl, each of which is selected from the group consisting of halogen, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -NO 2 and -CN, optionally substituted with one or more substituents independently selected from methyl, ethyl, propyl, and isopropyl. and C 6 Carbocyclic rings containing halogen, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -NO 2 and -CN, 6 Carbocycle are independently selected from

[0085] In certain embodiments, for compounds or salts of Formula (I) or (Ia), B is -CH(R A )(R B ) and R A and R B Each of Methyl, ethyl, propyl, and isopropyl, each of which is selected from the group consisting of halogen, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -NO 2 and -CN, optionally substituted with one or more substituents independently selected from methyl, ethyl, propyl, and isopropyl. and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, each of which is selected from the group consisting of halogen, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -NO 2 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, optionally substituted with one or more substituents independently selected from -CN; are independently selected from

[0086] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R A and R B is independently selected from ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and phenyl, any of which may be optionally substituted. [ka] is selected from.

[0087] In certain embodiments, for compounds or salts of formula (I) or (Ia), B is optionally substituted C 3-10 In some embodiments, B is an optionally substituted saturated C 3-10 In some embodiments, B is an optionally substituted unsaturated ring. 3-10 In some embodiments, B is a carbocyclic ring. 3 carbocycle, C 4 carbocycle, C 5 carbocycle, C 6 carbocycle, C 7 carbocycle, C 8 carbocycle, C 9 carbocycle, C 10 In certain embodiments, B is selected from C 4-10 carbocycle, C5-10 carbocycle, C 6-10 carbocycle, C 7-10 carbocycle, C 8-10 Carbocyclic, and C 9-10 carbocycles, any of which may be optionally substituted.

[0088] In certain embodiments, for compounds or salts of formula (I) or (Ia), B is optionally substituted C 5-8 Cycloalkyl or optionally substituted C 7-10 In some embodiments, B is a bicyclic carbocycle. 5-8 Cycloalkyl and C 7-10 bicyclic carbocycles, 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 1-6 Haloalkyl, and -C 1-6 In some embodiments, B is optionally substituted with one or more substituents independently selected from optionally substituted cyclohexyl, cycloheptyl, cyclooctyl, spiro[2.5]octanyl, and indanyl. 6-10 In certain embodiments, B is an optionally substituted C 6-10 Carbocyclic rings containing 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 1-6 Haloalkyl, and -C 1-6cyclohexyl, cycloheptyl, cyclooctyl, spiro[2.5]octanyl, and indanyl, each of which may be optionally substituted with one or more substituents independently selected from alkoxy; 6-10 In some embodiments, B is [ka] is selected from.

[0089] In certain embodiments, for a compound or salt of Formula (I) or (Ia), B is [ka] is selected from.

[0090] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 1 and R 2 Each independently represents a 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 2In one embodiment, R 1 and R 2 Each independently represents a 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.

[0091] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 1 and R 2 are 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 C, optionally substituted with one or more substituents independently selected from -CN. 1-6 In one embodiment, R 1 and R 2 are halogen, -OR 14 , -SR 14 , -N(R14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -NO 2 and C, optionally substituted with one or more substituents independently selected from -CN. 1-6 In one embodiment, R 1 and R 2 Each independently represents a halogen, -OR 14 , -SR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -NO 2 C, optionally substituted with substituents independently selected from -CN; 1-3 It is an alkyl.

[0092] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 1 and R 2 Each is hydrogen. In certain embodiments, R 1 and R 2 are each independently Hydrogen, halogen, -OR 14 , -NO 2 -CN; and C 1-6 Alkyl, 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, 1-6 Alkyl is selected from.

[0093] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 1 and R 2 Each is hydrogen. In certain embodiments, R 1 and R 2 are each independently Hydrogen, halogen, -OR 14 , -NO 2 -CN; and C 1-6 Alkyl, 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, 1-6 Alkyl is selected from.

[0094] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 1 and R 2 are each independently hydrogen, [ka] In one embodiment, R 1 and R 2 are each independently hydrogen, [ka] In one embodiment, R 1 and R 2 are each independently [ka] In one embodiment, R 1 and R 2 are each independently hydrogen and [ka] In one embodiment, R 1 and R 2 are hydrogen, [ka] In one embodiment, R 1 and R 2 are each independently hydrogen, [ka] In one embodiment, R1 and R 2 are each independently hydrogen, [ka] In one embodiment, R 1 and R 2 are selected from different substituents. In some embodiments, R 1 and R 2 In certain embodiments, one of R 1 and R 2 One of them is C. 1-3 In one embodiment, R 1 and R 2 In certain embodiments, one of R 1 and R 2 In certain embodiments, one of R 1 is hydrogen; and R 2 is selected from methyl, ethyl, propyl, isopropyl, and butyl, each of which is selected from chloro, fluoro, bromo, and -OR 14 In one embodiment, R 1 is hydrogen; and R 2 is selected from methyl, ethyl, propyl, and butyl, each of which is selected from chloro, fluoro, bromo, and -OR 14 In one embodiment, R 1 and R 2 are each independently hydrogen, and [ka] In one embodiment, R 1 and R 2 are each independently hydrogen, and [ka] is selected from.

[0095] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from hydrogen. 3 and R 4 In certain embodiments, one of R 3 and R 4 In some embodiments, one of R 3 and R 4 In some embodiments, one of R 3 and R 4 In some embodiments, one of R 3 and R 4 one of is selected from (d).

[0096] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 Each of R is selected from (c). 3 and R 4 Each of the groups is a halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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 C, optionally substituted with one or more substituents independently selected from -CN. 2-6 In one embodiment, R 3 and R 4 Each of the 3-10 C, which may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; 2-6 alkyl, any of which may be 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 In one embodiment, R 3 and R 4Each of the groups is a 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 C, optionally substituted with one or more substituents independently selected from -CN. 2-6 In one embodiment, R 3 and R 4 Each of the optionally substituted C 2-6 alkyl, [ka] teeth, [ka] It is represented by:

[0097] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (b): (a) Hydrogen; (b)C 1 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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, optionally substituted with one or more substituents independently selected from 1 Alkyl; C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocycles and 3- to 10-membered heterocycles.

[0098] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R3 and R 4 are each independently selected from (a) and (b): (a) Hydrogen; (b)C 1 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 C, optionally substituted with one or more substituents independently selected from -CN; 1 Alkyl; C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocycles and 3- to 10-membered heterocycles.

[0099] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (b): (a) Hydrogen; (b)C 1 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 , -CN, optionally substituted with one or more substituents independently selected from 1 Alkyl; C 3-6Carbocyclic rings and 3- to 6-membered heterocyclic rings, each of which is 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, 3-6 Carbocycles and 3- to 6-membered heterocycles.

[0100] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 One of the groups is hydrogen, and R 3 and R 4 The other is C 1 is an alkyl group, Halogen, -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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 3-10A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 1 is selected from alkyl.

[0101] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 One of the groups is hydrogen, and R 3 and R 4 is C 1 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R15 , -NO 2 , -CN; C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings, each of which is 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, 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings C 1 In one embodiment, [ka] teeth, [ka] In one embodiment, R 3 and R 4 One of the is hydrogen, [ka] teeth, [ka] It is represented by:

[0102] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (c): (a) hydrogen; and (c)C 2-6 is an alkyl group, Halogen, -OR 15 , -SR15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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, 2-6 Alkyl; C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocycles and 3- to 10-membered heterocycles.

[0103] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (c): (a) hydrogen; and (c)C 2-6 Alkyl, halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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, 2-6In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (c): (a) hydrogen; and (c)C 2-6 Alkyl, 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, 2-6 Alkyl.

[0104] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 One of the groups is hydrogen, and R 3 and R 4 The other is 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 C, optionally substituted with one or more substituents independently selected from -CN. 2-6 In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] It is represented by:

[0105] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 One of the is hydrogen, [ka] teeth, [ka] In one embodiment, R 3 and R 4 One of the is hydrogen, [ka] teeth, [ka] In one embodiment, R 3 and R 4One of the is hydrogen, [ka] teeth, [ka] In one embodiment, R 3 and R 4 One of the is hydrogen, [ka] teeth, [ka] It is represented by:

[0106] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (c): (a) Hydrogen; (c)C 2-6 Alkyl, C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 C may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; 2-6 Alkyl.

[0107] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (c): (a) Hydrogen; (c)C 2-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles, each of which is 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 , -NO 2 and C, optionally substituted with one or more substituents independently selected from -CN. 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings C 2-6 Alkyl.

[0108] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (c): (a) Hydrogen; (c)C 2-6 Alkyl and halogen; 3-6 Carbocycles and 3- to 6-membered heterocycles, each of which is independently selected from halogen, C 1-6 Haloalkyl, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 and C, optionally substituted with one or more substituents independently selected from -CN. 3-6 C may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 6-membered heterocycle; 2-6 In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] It is represented by:

[0109] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 One of the groups is hydrogen, and R 3 and R 4 The other is C 2-6 Alkyl and halogen; 3-6 Carbocycles and 3- to 6-membered heterocycles, each of which is independently selected from halogen, C 1-6 Haloalkyl, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2and C, optionally substituted with one or more substituents independently selected from -CN. 3-6 C may be optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 6-membered heterocycle; 2-6 In one embodiment, R 3 and R 4 One of the is hydrogen, [ka] teeth, [ka] In one embodiment, R 3 and R 4 One of the is hydrogen, [ka] teeth, [ka] It is represented by:

[0110] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (d): (a) hydrogen; and (d) C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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)R15 , -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, 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, 1-6 Alkyl C 3-10 Carbocycles and 3- to 10-membered heterocycles.

[0111] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (d): (a) hydrogen; and (d) C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocycles and 3- to 10-membered heterocycles.

[0112] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (d): (a) hydrogen; and (d) C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings, each of which is independently selected from halogen, -OR15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)OR 15 , -OC(O)R 15 , -NO 2 and -CN, 3-6 Carbocycles and 3- to 6-membered heterocycles.

[0113] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (d): (a) hydrogen; and (d) C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is 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 C, optionally substituted with one or more substituents independently selected from -CN. 1-6C is optionally substituted with one or more substituents independently selected from alkyl; 3-10 Carbocycles and 3- to 10-membered heterocycles.

[0114] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a) and (d): (a) hydrogen; and (d) C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings, each of which is independently selected from halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)OR 13 , -OC(O)R 15 , -NO 2 and C, optionally substituted with one or more substituents independently selected from -CN. 1-3 optionally substituted with alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles.

[0115] In certain embodiments, for a compound or salt of Formula (I) or (Ia): [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] In certain embodiments, for a compound or salt of formula (I) or (Ia), R 3 and R 4 One of the is hydrogen, [ka] teeth, [ka] In one embodiment, R 3 and R 4 One of the is hydrogen, [ka] teeth, [ka] In one embodiment, R 3 and R 4 One of the is hydrogen, [ka] teeth, [ka] In one embodiment, R 3 and R 4 One of the is hydrogen, [ka] teeth, [ka] In one embodiment, R 3 and R 4 One of the is hydrogen, [ka] teeth, [ka] It is represented by:

[0116] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (b) and (c): (b)C 1 It is an alkyl Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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 R15 , -S(O) 2 N(R 15 ) 2 , -NO 2 , -CN; C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 1 Alkyl; (c)C 2-6 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 2-6 Alkyl.

[0117] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (b) and (c): (b)C 1 is an alkyl group, 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; C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings, each of which is 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, 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings C 1 Alkyl; (c)C 2-6 is an alkyl group, 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; C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings, each of which is 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, 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings C 2-6 Alkyl.

[0118] In certain embodiments, for a compound or salt of Formula (I) or (Ia): [ka] teeth, [ka] In one embodiment, R 3 and R 4 One of the groups is methyl, [ka] teeth, [ka] In one embodiment, R 3 and R 4 is optionally substituted methyl; [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] It is.

[0119] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (b) and (d): (b)C 1 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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 A carbocycle and a 3- to 10-membered heterocycle, each of which is independently selected from halogen, C1-6 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, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 1 Alkyl; and (d) C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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 -CN; and C 1-6 Alkyl, 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, 1-6 Alkyl C 3-10 Carbocycles and 3- to 10-membered heterocycles.

[0120] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R3 and R 4 are each independently selected from (b) and (d): (b)C 1 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -OC(O)R 15 , -NO 2 , -CN; C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings, each of which is 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, 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings C 1 Alkyl; and (d) C 3-6 A carbocycle and a 3- to 6-membered heterocycle, each of which is 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, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R15 , -C(O)OR 13 , -OC(O)R 15 , -NO 2 and -CN, 1-6 Alkyl C 3-6 Carbocycles and 3- to 6-membered heterocycles.

[0121] In certain embodiments, for a compound or salt of Formula (I) or (Ia): [ka] teeth, [ka] In one embodiment, R 3 and R 4 One of the groups is methyl, [ka] teeth, [ka] It is represented by:

[0122] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a), (b), and (c): (a) Hydrogen; (b)C 1 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 1-6- Alkyl, -OC(O)R 15 , -OC(O)N(R15 ) 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 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10Carbocyclic and 3- to 10-membered heterocyclic rings C 1 Alkyl; and (c)C 2-6 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-OC 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 -CN; and C 3-10 A carbocycle and a 3- to 10-membered heterocycle, each of which is 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, 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings C 2-6 Alkyl.

[0123] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a), (b), and (c): (a) Hydrogen; (b)C 1 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -OC(O)R 15 , -NO 2 , -CN; C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings, each of which is 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 2and -CN, 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings C 1 Alkyl; and (c)C 2-6 is an alkyl group, Halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -OC(O)R 15 , -NO 2 , and -CN and C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings, each of which is 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, 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings C 2-6 Alkyl.

[0124] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are each independently selected from (a), (b), (c), and (d): (a) Hydrogen; (b)C 1 Alkyl, halogen, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO2 , -CN; and halogens, C 1-6 Haloalkyl, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 and C, optionally substituted with one or more substituents independently selected from -CN. 3-6 Carbocycle C 1 Alkyl; (c)C 2-6 Alkyl, -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;C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings, each of which is independently selected from halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 and -CN, 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings C 2-6 Alkyl; and (d) C 3-6 Carbocyclic rings and 3- to 6-membered heterocyclic rings, each of which is independently selected from halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 , -CN; and halogens, -OR15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 and C, optionally substituted with one or more substituents independently selected from -CN. 1-3 Alkyl C 1-3 Alkyl.

[0125] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 or R 4 is C 1 Alkyl, halogen, -C(O)N(R 15 ) 2 , -OR 15 and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, each of which is selected from the group consisting of halogen, C 1-3 Haloalkyl and / or -OR 15 optionally substituted with one or more substituents independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl; 1 is selected from alkyl.

[0126] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 or R 4 is methyl, [ka] , and [ka] is selected from.

[0127] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R3 or R 4 is C 2-6 Alkyl, 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 Carbocyclic rings and 3- to 6-membered heterocyclic rings, each of which is independently selected from halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 and -CN, 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings C 2-6 is selected from alkyl.

[0128] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 or R 4 is selected from ethyl, propyl, isopropyl, isobutyl, and butyl, each of which is 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 It may be optionally substituted with one or more substituents independently selected from:

[0129] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 or R 4 teeth, [ka] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 or R 4 teeth, [ka] is selected from.

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

[0131] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 or R 4 teeth, [ka] In one embodiment, R 3 or R 4 teeth, [ka] is selected from.

[0132] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 or R 4 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxetanyl, azetidine, pyrrolidinyl, and pyridinyl, each of which is selected from chloro, fluoro, bromo, -OR 15 , -NO 2 , -CN; and chloro, fluoro, bromo, -OR 15 , -NO 2 and C, optionally substituted with one or more substituents independently selected from -CN. 1-3 It may be optionally substituted with one or more substituents independently selected from alkyl.

[0133] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 or R 4 teeth, [ka] is selected from.

[0134] In certain embodiments, for a compound or salt of Formula (I) or (Ia): [ka] R 3 and R 4 are taken together to form a 4- to 12-membered heterocycle, any one of which is 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)R16 , -N(R 16 )C(O)OR 16 , -N(R 16 )C(O)N(R 16 ) 2 , -NO 2 , =O, and -CN; and C 1-6 Alkyl, halogen, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)R 16 , -NO 2 and -CN, 1-6 Alkyl and forming a 4- to 12-membered heterocycle which may be appropriately substituted with one or more substituents independently selected from:

[0135] In certain embodiments, for a compound or salt of Formula (I) or (Ia): [ka] R 3 and R 4 taken together form an optionally substituted 4-12 membered heterocycle containing one or more heteroatoms selected from oxygen, nitrogen, sulfur, and any combination thereof.

[0136] In certain embodiments, the optionally substituted 4-12 membered heterocycle optionally contains more than one heteroatom selected from oxygen, nitrogen, and any combination thereof. In certain embodiments, the optionally substituted 4-12 membered heterocycle optionally contains more than one heteroatom selected from oxygen, sulfur, and any combination thereof. In certain embodiments, the optionally substituted 4-12 membered heterocycle optionally contains more than one heteroatom selected from nitrogen and sulfur, and any combination thereof. In certain embodiments, the optionally substituted 4-12 membered heterocycle optionally contains more than one heteroatom selected from oxygen and nitrogen. In certain embodiments, the optionally substituted 4-12 membered heterocycle optionally contains more than one heteroatom selected from oxygen and sulfur. In certain embodiments, the optionally substituted 4-12 membered heterocycle optionally contains more than one heteroatom selected from nitrogen and sulfur. In certain embodiments, the optionally substituted 4-12 membered heterocycle optionally contains at least one additional heteroatom selected from oxygen, nitrogen, sulfur, and any combination thereof. In certain embodiments, the optionally substituted 4- to 12-membered heterocycle contains one nitrogen heteroatom. In certain embodiments, for the compound or salt of formula (I) or (Ia), the 4- to 12-membered heterocycle is selected from a saturated 4- to 8-membered heterocycle and a 6- to 12-membered unsaturated heterocycle, any one of which may be optionally substituted. In certain embodiments, [ka] R 3 and R 4 are taken together to form a saturated 4- to 8-membered heterocycle, any one of which may be appropriately substituted.

[0137] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4are taken together to form a saturated 4-8 membered heterocycle, the saturated 4-8 membered heterocycle being selected from azetidine, oxetane, pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, morpholine, oxazepane, and azaspiro[3.3]heptane, any one of which may be 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 , -NO 2 , and -CN; and C 1-3 Alkyl, chloro, fluoro, OR 16 , -NO 2 and C, optionally substituted with one or more substituents independently selected from -CN. 1-3 It may be optionally substituted with one or more substituents independently selected from alkyl.

[0138] In certain embodiments, for a compound or salt of Formula (I) or (Ia): [ka] R 3 and R 4 are taken together to form a saturated 4- to 8-membered heterocycle, and the 4- to 8-membered heterocycle is [ka] is selected from.

[0139] In certain embodiments, for a compound or salt of Formula (I) or (Ia): [ka] R 3 and R 4are taken together to form a saturated 4- to 8-membered heterocycle, and the 4- to 8-membered heterocycle is [ka] is selected from.

[0140] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are taken together to form a saturated 4-8 membered heterocycle, the saturated 4-8 membered heterocycle being selected from azetidine, oxetane, pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, morpholine, oxazepane, and azaspiro[3.3]heptane, any one of which may be chloro, fluoro, -OR 16 , -NO 2 , and -CN; and C 1-3 Alkyl, chloro, fluoro, OR 16 , -NO 2 and C, optionally substituted with one or more substituents independently selected from -CN. 1-3 It may be optionally substituted with one or more substituents independently selected from alkyl.

[0141] In certain embodiments, for a compound or salt of Formula (I) or (Ia), R 3 and R 4 are taken together to form a saturated 4-8 membered heterocycle, the saturated 4-8 membered heterocycle being selected from azetidine, oxetane, pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, morpholine, oxazepane, and azaspiro[3.3]heptane, any one of which may be chloro, fluoro, -OR 16 , -NO 2 , -C(O)N(R 16 ) 2 , and -CN; and C1-3 Alkyl, chloro, fluoro, OR 16 , -NO 2 and C, optionally substituted with one or more substituents independently selected from -CN. 1-3 It may be optionally substituted with one or more substituents independently selected from alkyl.

[0142] In certain embodiments, for a compound or salt of Formula (I) or (Ia): [ka] R 3 and R 4 taken together form a saturated 4- to 8-membered heterocycle, [ka] teeth, [ka] is selected from.

[0143] In certain embodiments, for a compound or salt of Formula (I) or (Ia): [ka] R 3 and R 4 taken together form a saturated 4- to 8-membered heterocycle, [ka] teeth, [ka] is selected from.

[0144] In certain embodiments, for the compound or salt of Formula (I) or (Ia), the 4- to 12-membered heterocycle is an unsaturated 4- to 12-membered heterocycle, any one of which may be optionally substituted.

[0145] In certain embodiments, for a compound or salt of Formula (I) or (Ia): [ka] R 3 and R 4 taken together form an unsaturated 4- to 12-membered heterocycle, [ka] teeth, [ka] It is represented by:

[0146] In certain embodiments, for a compound or salt of Formula (I) or (Ia): [ka] teeth, [ka] [ka] is selected from.

[0147] In certain embodiments, for a compound or salt of Formula (I) or (Ia): [ka] teeth, [ka] [ka] is selected from.

[0148] In another aspect, the present disclosure provides a compound of formula (II): [ka] (II); [In the formula, A, B, R 1 , R 2 , R 3 , R 4 and n is as defined in formula (I) or formula (Ia), and R 5 teeth, 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 halogen, -OR 17 , -SR 17 , -N(R 17 ) 2 , -C(O)R 17 , -S(=O)(=NR 17 )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 , ═O, and —CN; 1-6 Alkyl and C 2-6 Alkenyl and C 3-10 Carbocycles and 3- to 10-membered heterocycles, including 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; 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings Select from or a pharma- ceutically acceptable salt thereof.

[0149] In certain embodiments, for a compound or salt of Formula (II), R 5 teeth, 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 -CN; and C 3-10 Carbocycles and 3- to 10-membered heterocycles, including 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; 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is selected from.

[0150] In certain embodiments, for a compound or salt of Formula (II), R 5 teeth, C 1-6 Alkyl and C 2-6 alkenyl, each of which is halogen, -OR 17 , -SR 17 , -N(R 17 ) 2 , -C(O)R 17 , -S(=O)(=NR 17 )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 , ═O, and —CN; 1-6 Alkyl and C 2-6 Alkenyl and C 3-10 Carbocycles and 3- to 10-membered heterocycles, including 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; 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is selected from.

[0151] In certain embodiments, for a compound or salt of Formula (II), R 5 is C 3-10 Carbocycles and 3- to 10-membered heterocycles, including halogen, -OR 17B , -SR17B , -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; 3-10 It is selected from a carbocycle and a 3- to 10-membered heterocycle.

[0152] In one embodiment, R 5 is a 3- to 10-membered heterocycle, 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 In one embodiment, R is a 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from -, ... 5 is a 3- to 10-membered saturated heterocycle, 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 In one embodiment, R is a 3- to 10-membered saturated heterocycle, optionally substituted with one or more substituents independently selected from , ═O, and —CN. 5 teeth, [ka] In one embodiment, R 5 teeth, [ka] In one embodiment, R 5 teeth, [ka] In one embodiment, R 5 teeth, [ka] It is.

[0153] In certain embodiments, the compound or salt of formula (I), (Ia), or (II) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a salt thereof.

[0154] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will 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. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered.

[0155] Compounds with carbon-carbon or carbon-nitrogen double bonds can exist in Z- or E-forms (or cis or trans forms). Additionally, certain compounds can exist in various tautomeric forms. Unless otherwise specified, the compounds or salts of formula (I), (Ia), or (II) are intended to include all Z-, E- and tautomeric forms. "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 one another. 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. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. Compounds to be resolved, whose absolute configuration is unknown, can be designated (+) or (-) according to the direction of rotation of plane polarized light at the wavelength of the sodium D line (dextrorotatory or levorotatory). Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)-. The compounds, pharmaceutical compositions, and methods of the invention are intended to include all such possible stereoisomers (including racemic mixtures, and may also include pure forms as appropriate), mixtures of diastereomers, and mixtures of intermediates. Optically active (R)- and (S)-isomers can be prepared using chiral synthon methods or chiral reagents, or resolved using conventional techniques. The optical activity of the compounds can be analyzed by any suitable method, including, but not limited to, chiral chromatography and polarimetry, to determine the degree of dominance of one stereoisomer over the other.

[0156] Compounds or salts of formula (I), (Ia), or (II) may, in some cases, exist as diastereomeric, enantiomeric, or other stereoisomeric forms. The compounds provided herein include all diastereomeric, enantiomeric, and epimeric forms, as well as racemic, diastereomeric, and other mixtures thereof, to the extent that they can be prepared by one skilled in the art by conventional experimental methods. Separation of stereoisomers can be accomplished by forming diastereomers and separating them 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 can also be obtained by stereoselective synthesis. Additionally, a mixture of the two enantiomers enriched in one of the two can be purified by recrystallization and / or trituration to provide a more optically enriched form of the major enantiomer.

[0157] In some embodiments, the compound or salt of formula (I), (Ia) or (II) may comprise two or more enantiomers or diastereomers of the compound, where a single enantiomer or diastereomer is 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 for producing substantially pure enantiomers are well known to those skilled in the art. For example, a single stereoisomer, e.g., an enantiomer that is substantially free of its stereoisomer, may be obtained by resolving racemic mixtures using methods such as the formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by EL 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 pure stereoisomers, and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. Another method for separating enantiomers uses Dicel Chiral columns with organic mobile phases and eluents, for example, by Chiral Technologies (www.chiraltech.com) on a pay-per-service basis.

[0158] "Tautomer" refers to a molecule capable of proton shift from one atom of the molecule to another atom of the same molecule. In certain embodiments, the compounds or salts of formula (I), (Ia), or (II) exist as tautomers. When tautomers are possible, chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Non-limiting examples of tautomer equilibration include: [ka] Includes:

[0159] The compounds of formula (I), (Ia) or (II) may be present in different isotopically enriched forms, e.g. 2 H, 3 H, 11 C. 13 C, and / or 14 The compound can be used in which the C content is rich.In certain embodiments, the compound is deuterated at at least one position.Such deuterated forms can be prepared by the method described in U.S. Patent No. 5,846,514 and U.S. Patent No. 6,334,997.As described in U.S. Patent No. 5,846,514 and U.S. Patent No. 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of action of the drug.

[0160] In certain embodiments, a compound of Formula (I), (Ia), or (II) is 1 Some or all of the H atoms have been replaced 2 H atoms. Methods for the synthesis of compounds containing deuterium are known in the art and include, by way of non-limiting example only, the following synthetic methods:

[0161] Deuterium substituted compounds are synthesized using a variety of methods such as those 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.

[0162] Deuterated starting materials are readily available and can be subjected to the synthetic methods described herein to provide for the synthesis of compounds containing deuterium. Many of the deuterium-containing reagents and building blocks are commercially available from chemical manufacturers such as Aldrich Chemical Co.

[0163] Unless otherwise indicated, compounds of formula (I), (Ia), or (II) are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon with a C-rich carbon are within the scope of this disclosure.

[0164] The compounds of formula (I), (Ia), or (II) may optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain isotopes such as deuterium (2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 All isotopic substitutions with I are encompassed within the scope of the present invention. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0165] Salts (particularly pharma- ceutically acceptable salts) of compounds of formula (I), (Ia), or (II) are included in the present disclosure. Compounds of the present disclosure may have sufficiently acidic, sufficiently basic, or both functional groups, and can react with any of many inorganic bases, as well as inorganic and organic acids, to form salts. Alternatively, compounds that are inherently charged (such as those with quaternized nitrogen) can form salts with suitable counterions, such as halides (such as bromide, chloride, or fluoride).

[0166] In some embodiments, the compound or salt of formula (I), (Ia), or (II) may be a prodrug. The term "prodrug" is intended to include compounds that are converted to pharmaceutical agents of the present disclosure under physiological conditions. One method for preparing a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to expose the desired molecule. In other embodiments, the prodrug is converted by the enzyme activity of the host animal (e.g., specific target cells) in the host animal.

[0167] In certain embodiments, the prodrug design increases the hydrophobicity of the pharmaceutical agent, hi certain embodiments, the prodrug design increases the effective aqueous solubility. For example, Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; and Edward B. Roche, See Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein by reference in their entirety. According to another embodiment, the present disclosure provides a method for preparing the compounds defined above. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are synthesized by conventional techniques from readily available starting materials.

[0168] Synthetic chemistry transformations and methods useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0169] Pharmaceutical preparations In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), (Ia), or (II) and at least one pharma- ceutical acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound or salt of Formula (I), (Ia), or (II) and a pharma- ceutical acceptable excipient.

[0170] Pharmaceutical compositions can be formulated with one or more physiologically acceptable carriers, including excipients and adjuvants. Formulations can be modified according to the route of administration selected. Pharmaceutical compositions containing compounds, salts or complexes can be prepared, for example, by lyophilizing the compounds, salts or complexes, mixing, dissolving, emulsifying, encapsulating or entrapping the complexes. Pharmaceutical compositions can also contain compounds, salts or complexes in free base form or in pharma-ceutically acceptable salt form.

[0171] Pharmaceutical compositions may often contain more than one active compound (e.g., compounds, salts or complexes, and other drugs) depending on the needs of the particular application to be treated. Active compounds may have complementary activities that do not adversely affect each other. Such molecules may be included in combination in amounts that are useful for the intended purpose.

[0172] The compounds or salts of any one of formulas (I), (Ia), or (II) may be formulated into any suitable pharmaceutical formulation. The pharmaceutical formulations of the present disclosure typically contain an active ingredient (e.g., a compound or salt of any one of formula I) and one or more pharma- ceutically acceptable excipients or carriers, including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, antioxidants, solubilizers, and adjuvants.

[0173] In certain embodiments, the compound or salt of Formula (I), (Ia), or (II) is formulated with a chelating agent or other substance capable of binding to metal ions, for example, ethylenediaminetetraacetic acid (EDTA) and its salts, which can increase the stability of the compound or salt of Formula (I), (Ia), or (II).

[0174] The pharmaceutical formulation may be provided in any suitable form, which will depend on the route of administration.

[0175] In some embodiments, the present disclosure provides a pharmaceutical composition for oral administration, comprising at least one of the compounds or salts of formula (I), (Ia) or (II) and pharmaceutical excipients for oral administration.The composition may be in the form of solid, liquid, gel, semi-liquid or semi-solid.In some embodiments, the composition further comprises a second agent.

[0176] The pharmaceutical compositions of the present disclosure suitable for oral administration can be present as separate dosage forms such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids or aerosol sprays, each containing a predetermined amount of active ingredient as a powder, or in granules, solutions, or suspensions in aqueous or non-aqueous liquids, water-in-oil emulsions, or water-in-oil liquid emulsions, or in dispersible powders or granules, or in syrups or elixirs. Such dosage forms can be prepared by any method in the pharmaceutical art, typically including the step of combining the active ingredient with a carrier. In general, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product into the desired presentation form. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, mixed with excipients including, but not limited to, binders, lubricants, inert diluents, and / or surface active or dispersing agents. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound or salt of any one of formulas (I), (Ia), or (II) moistened with a liquid diluent.

[0177] Pharmaceutical compositions may also be prepared from a compound or salt of any one of Formulas (I), (Ia), or (II) and one or more pharma- ceutically acceptable excipients. Preparation of such pharmaceutical compositions is well known in the art. For example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0178] Treatment method In certain aspects, the disclosure provides a method of modulating IL-17A in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (I), (Ia), or (II) or a pharmaceutical composition thereof.

[0179] In some embodiments, the present disclosure provides a method for treating an inflammatory disease or disorder in a subject in need thereof, comprising administering to said subject a compound or salt of formula (I), (Ia) or (II), or a pharmaceutical composition thereof.In some embodiments, the inflammatory disease or disorder is selected from plaque psoriasis, guttate psoriasis, plaque psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar pustulosis, spondyloarthritis, and non-infectious uveitis.

[0180] In some embodiments, the compounds or salts of formula (I), (Ia) or (II) can be used to treat or prevent diseases or disorders mediated directly or indirectly by IL-17A. Such diseases include inflammatory diseases or conditions, proliferative diseases (e.g., cancer), autoimmune diseases, and other diseases described herein. The methods generally involve administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition thereof.

[0181] Elevated levels of IL-17A are associated with several diseases, including airway inflammation, rheumatoid arthritis (RA), osteoarthritis, bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disease (IBD), allograft rejection, psoriasis, psoriatic arthritis, ankylosing spondylitis, certain types of cancer, angiogenesis, atherosclerosis, and multiple sclerosis (MS). Both IL-17A and IL-17R are upstream regulated in the synovial tissue of RA patients. IL-17A plays its role in RA pathogenesis through IL-1-β and TNF-α-dependent and -independent pathways. IL-17A stimulates the secretion of other cytokines and chemokines, such as TNF-α, IL-1β, IL-6, IL-8, and Gro-α. IL-17A directly contributes to the pathological progression of RA. Injection of IL-17A into mouse knees promotes joint destruction independent of IL-Iβ activity (Ann Rheum Dis 2000, 59: 529-32). Anti-IL-1β antibodies have no effect on IL-17A-induced inflammation and joint damage (J. Immunol 2001, 167: 1004-1013). In a streptococcal cell wall (SCW)-induced mouse arthritis model, IL-17A induced inflammatory cell infiltration and proteoglycan depletion in wild-type, IL-1β knockout, and TNF-α knockout mice. IL-17A knockout mice are phenotypically normal without antigen challenge but show significantly reduced arthritis after type II collagen immunization (J. Immunol 2003, 171: 6173-6177). Increased levels of IL-17A-secreting cells were also observed in the facet joints of patients with ankylosing spondylitis (H Appel et al., Arthritis Res Therap. 2011, 13:R95).

[0182] Multiple sclerosis is an autoimmune disease characterized by central nervous system (CNS) inflammation due to damage to the myelin sheath around axons. A hallmark of MS is T cell infiltration into the CNS. Increases in peripheral blood mononuclear cells (MNCs) expressing IL-17A mRNA are detected during MS clinical exacerbations compared to remissions (Multiple Sclerosis, 5:101-104, 1999). Furthermore, experimental autoimmune encephalomyelitis ("EAE"), a preclinical animal model of MS, is significantly suppressed in IL-17A knockout mice.

[0183] In certain embodiments, the disclosure provides a method of regulating IL-17A in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (I), (Ia), or (II). In certain embodiments, the compound or salt of Formula (I), (Ia), or (II) inhibits the activity of IL-17A in a subject in need thereof.

[0184] In some embodiments, the compound or salt of formula (I), (Ia) or (II) is used to treat or prevent inflammatory disease or disorder.In some embodiments, the compound or salt of formula (I), (Ia) or (II) is administered to a subject in need thereof to treat inflammatory disease or disorder, such as psoriasis.

[0185] In some embodiments, the compound or salt of formula (I), (Ia) or (II) is used to treat or prevent inflammatory diseases or disorders selected from plaque psoriasis, guttate psoriasis, plaque psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar pustulosis, spondyloarthritis and non-infectious uveitis.In some embodiments, the compound or salt of formula (I), (Ia) or (II) is used to treat or prevent psoriasis.In some embodiments, the compound or salt of formula (I), (Ia) or (II) is used to treat or prevent conditions, including but not limited to airway inflammation, ankylosing spondylitis, asthma, RA (including juvenile RA) and other inflammatory disorders, conditions or diseases. EXAMPLES

[0186] The present invention has now been generally described and will be more readily understood by reference to the following examples, which are included merely to illustrate certain aspects and embodiments of the invention and are not intended to limit the invention in any manner.

[0187] The following synthesis scheme is provided for illustrative purposes and is not limiting. The following examples illustrate various methods for preparing the compounds described herein. It is understood that those skilled in the art can prepare these compounds by combining similar methods or other methods known to those skilled in the art. It is also understood that those skilled in the art can prepare the compounds in a similar manner to the methods described below by using suitable starting materials and modifying the synthetic route as necessary. In general, starting materials and reagents can be obtained from commercial suppliers, synthesized according to sources known to those skilled in the art, or prepared as described herein.

[0188] General Methods and Examples 1-176 provide general and exemplary procedures for the preparation of IL-17A modulators of the invention. Example 177 provides IL-17A / A bioassay inhibition data.

[0189] General method General method A To a solution of Boc-amine (1 eq) in DCM (0.1-0.5 M) was added trifluoroacetic acid (equal to the amount of DCM or ~20 eq). The reaction mixture was stirred until the Boc-amine starting material disappeared. The reaction mixture was then concentrated and purified by prep-HPLC or silica gel column chromatography to give the corresponding amine.

[0190] [ka] General method B: To a solution of carboxylic acid (1.0 eq) in DCM (0.1-0.5 M) cooled to 0° C., DIPEA (15 eq) is added, followed by the dropwise addition of a solution of T3P in EtOAc or ACN (2-10 eq). The reaction is warmed to RT and stirred for 30 min to 16 h until the carboxylic acid starting material has disappeared. The reaction mixture is then immersed in H 2 The mixture was diluted with O and extracted with EtOAc. The combined organic layers were washed with brine and 2 SO 4 Drying at rt, filtration and concentration under reduced pressure gave a crude residue that was purified by silica gel chromatography or prep-HPLC to give the corresponding amide.

[0191] [ka] General method C: To a solution of tert-butyl carbamate (1 eq) in DCM (0.2 M) cooled in an ice bath, 4N HCl in 1,4-dioxane was added dropwise. The reaction was allowed to warm to room temperature and stirred until the starting material disappeared. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (ACN in buffered water) to give the amine compound.

[0192] [ka] General method D:To a solution of carboxylic acid (1 eq) and amine (1.5 eq) in pyridine (0.1 M) was added EDCl (3 eq). The reaction mixture was stirred at room temperature for 1-18 hours. The reaction mixture was diluted with H 2 Dilute with O, extract with EtOAc, and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC or silica gel chromatography to give the desired amide compound.

[0193] Example 1: General Scheme C - Synthesis of Compounds 1-67 [ka] Compounds synthesized according to general Scheme C are used as the aniline and amino acid in step 1, followed by the carboxylic acid in step 3 and the amine in step 5. Starting materials are listed in the order of use. [ka]

[0194] Example 2: Synthesis of (S)-N-(1-cycloheptyl-2-((2-fluoro-4-(2-(methyl(2,2,2-trifluoroethyl)amino)-2-oxoethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (1) [ka] Step 1 - Synthesis of methyl 2-(4-amino-3-fluorophenyl)acetate: A solution of 2-(4-amino-3-fluorophenyl)acetic acid (300 mg, 1.77 mmol, 1.00 eq) in MeOH (4.00 mL) was added with SOCl 2 (253mg, 2.13mmol, 154uL, 1.20eq) was added dropwise. The mixture was stirred at 60°C for 3h. The reaction mixture was concentrated under reduced pressure to give methyl 2-(4-amino-3-fluorophenyl)acetate (300mg, 1.6mmol, 92% yield) as a yellow solid. LCMS [M+H] + = 184.2 m / z

[0195] [ka] Step 2 - Synthesis of methyl (S)-2-(4-(2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetamido)-3-fluorophenyl)acetate: To a solution of methyl 2-(4-amino-3-fluorophenyl)acetate (300 mg, 1.64 mmol, 1.00 eq) and (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid (533 mg, 1.97 mmol, 1.20 eq) in Py (5.00 mL) was added EDCI (941 mg, 4.91 mmol, 3.00 eq). The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and H 2 The mixture was diluted with O and extracted with EtOAc. The organic layers were combined and washed with Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure afforded methyl (S)-2-(4-(2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetamido)-3-fluorophenyl)acetate (600 mg, 1.4 mmol, 84% yield) as a yellow solid. LCMS [M+H] + = 437.3 m / z. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.65 - 9.08 (m, 1H), 7.81 - 7.68 (m, 1H), 7.17 (dd, J 1 = 1.6 Hz, J 2 = 11.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.11 (t, J = 8.0 Hz, 1H), 3.68 - 3.62 (m, 5H), 1.93 - 1.87 (m, 1H), 1.70 - 1.50 (m, 8H), 1.41 - 1.36 (m, 13H).

[0196] [ka] Step 3 - Synthesis of methyl (S)-2-(4-(2-amino-2-cycloheptylacetamido)-3-fluorophenyl)acetate: To a solution of methyl (S)-2-(4-(2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetamido)-3-fluorophenyl)acetate (600 mg, 1.37 mmol, 1.00 eq) in DCM (5.00 mL) was added HCl / dioxane (4.00 M, 3.44 mL, 10.0 eq) at 0° C. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give methyl (S)-2-(4-(2-amino-2-cycloheptylacetamido)-3-fluorophenyl)acetate (450 mg, 1.2 mmol, 88% yield, HCl) as a yellow solid. LCMS [M+H] + = 337.3 m / z.

[0197] [ka] Step 4 - Synthesis of methyl (S)-2-(4-(2-cycloheptyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)acetate: To a solution of methyl (S)-2-(4-(2-amino-2-cycloheptylacetamido)-3-fluorophenyl)acetate (450 mg, 1.21 mmol, 1.00 eq, HCl) and 1-ethyl-1H-pyrazole-5-carboxylic acid (253 mg, 1.81 mmol, 1.50 eq) in Py (10 mL) was added EDCI (694 mg, 3.62 mmol, 3.00 eq). The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and H 2 The mixture was diluted with O and extracted with EtOAc. The organic layers were combined and washed with saturated NH 4 Wash with Cl solution and Na 2 SO 4 The residue was purified by silica gel chromatography (SiO 2, petroleum ether:EtoAc=100:1 to 1:1) to give methyl (S)-2-(4-(2-cycloheptyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)acetate (420 mg, 920 umol, 76% yield) as a white solid. LCMS [M+H] + = 459.4 m / z. 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.91 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 8.4 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.18 (dd, J 1 = 1.6 Hz, J 2 = 11.6 Hz, 1H), 7.06 (dd, J 1 = 1.2 Hz, J 2 = 8.4 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 4.62 (t, J = 8.4 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 3.69 (s, 2H), 3.62 (s, 3H), 2.12 - 2.09 (m, 1H), 1.74 - 1.38 (m, 12H), 1.28 (t, J = 7.2 Hz, 3H).

[0198] [ka] Step 5 - Synthesis of (S)-2-(4-(2-cycloheptyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)acetic acid: A solution of methyl (S)-2-(4-(2-cycloheptyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)acetate (100 mg, 218 umol, 1.00 eq) in MeOH (4.00 mL) was added to H 2 LiOH H in O (1.00 mL) 2 A solution of 20O (10.9 mg, 261 umol, 1.20 eq) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H2 Dilute with O, extract with EtOAc, and 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave (S)-2-(4-(2-cycloheptyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)acetic acid (95 mg, 210 umol, 98% yield) as a white solid. LCMS [M+H] + = 445.3 m / z. 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.39 (s, 1H), 9.89 (s, 1H), 8.45 (d, J = 8.8 Hz, 1H), 7.67 (t, J = 8.4 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.16 (dd, J 1 = 1.6 Hz, J 2 = 11.6 Hz, 1H), 7.04 (dd, J 1 = 1.2 Hz, J 2 = 8.4 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 4.61 (t, J = 8.4 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 3.57 (s, 2H), 2.12 - 2.09 (m, 1H), 1.73 - 1.35 (m, 12H), 1.28 (t, J = 7.2 Hz, 3H).

[0199] [ka] Step 6 - Synthesis of (S)-N-(1-cycloheptyl-2-((2-fluoro-4-(2-(methyl(2,2,2-trifluoroethyl)amino)-2-oxoethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (1) To a solution of (S)-2-(4-(2-cycloheptyl-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)acetic acid (95.0 mg, 213 umol, 1.00 eq) and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride (63.9 mg, 427 umol, 2.00 eq, HCl) in Py (5.00 mL) was added EDCI (122 mg, 641 umol, 3.00 eq). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with H 2 The mixture was diluted with O and extracted with DCM. The organic layers were combined and washed with saturated NaHCO 3 Wash with solution of Na 2 SO 4 The residue was analyzed by Prep-TLC (SiO 2 , DCM:MeOH=10:1, TLC, Plate 1, DCM:MeOH=10:1, R f =0.5) and prep-HPLC (basic condition, column: Phenomenex Gemini-NX C18 75x30mmx3um; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 28%-58%, 7 min). (S)-N-(1-cycloheptyl-2-((2-fluoro-4-(2-(methyl(2,2,2-trifluoroethyl)amino)-2-oxoethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (44mg, 80umol, 37% yield) was obtained as a white solid. LCMS [M+H] + = 540.4 m / z.

[0200] Example 3: Synthesis of Compound 2 [ka] (S)-N-(1-cycloheptyl-2-((2-fluoro-4-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (2) Prepared according to general scheme C using ethyl 2-(4-amino-3-fluorophenyl)acetate and (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and 2,2,2-trifluoroethan-1-amine hydrochloride. LCMS [M+H] + = 526.4 m / z.

[0201] Example 4: Synthesis of Compound 3 [ka] Ethyl 2-(4-amino-3-fluorophenyl)propanoate To a solution of ethyl 2-(3-fluoro-4-nitrophenyl)propanoate (1.00 g, 4.15 mmol, 1.00 eq) in EtOH (10.0 mL), 2 Pd / C (100 mg, 10% purity) was added under reduced pressure. The suspension was degassed under reduced pressure and H 2 The mixture was stirred at 15° C. under 15 PSI of hydrogen gas for 15 hours. The reaction mixture was filtered and the filtrate was concentrated to give ethyl 2-(4-amino-3-fluorophenyl)propanoate (0.85 g, 4.0 mmol, 97% yield) as a brown oil. LCMS [M+H] + = 212.0 m / z. 1 H NMR (400 MHz, CDCl 3 ): δ 6.98 (dd, J 1 = 2.0 Hz, J 2 = 12.0 Hz, 1H), 6.89 (dd, J 1 = 2.0 Hz, J 2 = 8.4 Hz, 1H), 6.80 - 6.73 (m, 1H), 4.21 - 4.05 (m, 2H), 3.64 - 3.52 (m, 1H), 1.45 (d, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H).

[0202] [ka] N-[(1S)-1-cycloheptyl-2-[2-fluoro-4-[(1R)-1-methyl-2-[methyl(2,2,2-trifluoroethyl)amino]-2-oxo-ethyl]anilino]-2-oxo-ethyl]-2-ethyl-pyrazole-3-carboxamide (3) The title compound was prepared according to general scheme C using ethyl 2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride. The title compound was purified using chiral SFC (column: DAICEL CHIRALPAK AD-H (250mmx30mm, 5um); mobile phase: 0.1% NH in 30% [IPA]. 3 H 2 0]) as the first eluting single stereoisomer. LCMS [M+H] + = 554.3 m / z. The absolute stereochemistry of the benzylic center was assigned by comparison with the small molecule x-ray of Example 4.

[0203] Example 5: Synthesis of Compound 4 [ka] N-((S)-1-cycloheptyl-2-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (4) The title compound was prepared according to general scheme C using ethyl 2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride. The title compound was purified using chiral SFC (column: DAICEL CHIRALPAK AD-H (250mmx30mm, 5um); mobile phase: 0.1% NH in 30% [IPA]. 3H 2 0]) as a single stereoisomer eluting second. LCMS [M+H] + = 554.3 m / z. The absolute stereochemistry was determined by small molecule x-ray of a single crystal obtained by slow evaporation with 1:3 EtOAc / ACN.

[0204] Example 6: Synthesis of Compound 5 [ka] (S)-N-(1-cycloheptyl-2-((2-fluoro-4-(2-(methyl(1-(trifluoromethyl)cyclopropyl)amino)-2-oxoethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (5) Prepared according to general scheme C using ethyl 2-(4-amino-3-fluorophenyl)acetate and (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and N-methyl-1-(trifluoromethyl)cyclopropan-1-amine hydrochloride. LCMS [M+H] + = 566.3 m / z.

[0205] Example 7: Synthesis of Compound 6 [ka] Benzyl (1,1,1-trifluoro-3-(methylamino)-3-oxopropan-2-yl)carbamate 2-(((benzyloxy)carbonyl)amino)-3,3,3-trifluoropropanoic acid (100 mg, 360 umol, 1.00 eq) in DCM (2.00 mL), MeNH 2 (2.00M, 3.61mL, 20.0eq) was added to a solution of T in DIEA (233mg, 1.80mmol, 314uL, 5.00eq) and EtOAc (459mg, 721umol, 429uL, 50% purity, 2.00eq). 3P was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H 2 The mixture was diluted with O and extracted with EtOAc. The combined organic layers were washed with brine and 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave crude benzyl (1,1,1-trifluoro-3-(methylamino)-3-oxopropan-2-yl)carbamate (40.0 mg) as a yellow solid. LCMS [M+H] + = 313.2 m / z.

[0206] [ka] 2-Amino-3,3,3-trifluoro-N-methylpropanamide To a solution of 1,1,1-trifluoro-3-(methylamino)-3-oxopropan-2-yl)carbamate (40.0 mg, 137 umol, 1.00 eq) in DCM (2.00 mL) and THF (2.00 mL), N 2 Pd / C (0.050 g, 137 umol, 10% purity, 1.00 eq) was added under atmospheric pressure. 2 (15 Psi) at 15° C. for 2 hours. TLC (Plate 1, petroleum ether:ethyl acetate=1:1, R f (R1)=0.40) indicated that 1,1,1-trifluoro-3-(methylamino)-3-oxopropan-2-yl)carbamate was completely consumed and a new spot was detected. The mixture was filtered to obtain crude 2-amino-3,3,3-trifluoro-N-methylpropanamide (20 mg) as a pale yellow solid, which was used directly in the next reaction.

[0207] [ka] N-((1S)-1-cycloheptyl-2-((2-fluoro-4-(2-oxo-2-((1,1,1-trifluoro-3-(methylamino)-3-oxopropan-2-yl)amino)ethyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (6) Prepared according to general scheme C using ethyl 2-(4-amino-3-fluorophenyl)acetate and (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and 2-amino-3,3,3-trifluoro-N-methylpropanamide. LCMS [M+H] + = 583.5 m / z.

[0208] Example 8: Synthesis of Compound 7 [ka] Ethyl 2-(3-fluoro-4-nitrophenyl)-2-methylpropanoate To a solution of ethyl 2-(3-fluoro-4-nitrophenyl)propanoate (1.00 g, 4.15 mmol, 1.00 eq) in DMF (3.00 mL) was added NaH (249 mg, 6.22 mmol, 60% purity, 1.50 eq) at 0° C., followed by iodomethane (706 mg, 4.97 mmol, 309 uL, 1.20 eq). The reaction mixture was stirred at 0° C. for 10 min. Hydrochloric acid (1 M, 20.0 mL) was added to the reaction mixture at 0° C. Then the reaction mixture was diluted with H 2 The mixture was diluted with O and extracted with EtOAc. The organic layers were combined and washed with Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure afforded ethyl 2-(3-fluoro-4-nitrophenyl)-2-methylpropanoate (1.0 g, 4.1 mmol, 99% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3): δ 8.06 - 8.02 (m, 1H), 7.30 - 7.25 (m, 2H), 4.18 - 4.13 (m, 2H), 1.60 (s, 6H), 1.23 (t, J = 3.2 Hz, 3H).

[0209] [ka] Ethyl 2-(4-amino-3-fluorophenyl)-2-methylpropanoate A mixture of ethyl 2-(3-fluoro-4-nitrophenyl)-2-methylpropanoate (1.05 g, 4.11 mmol, 1.00 eq), Pd / C (0.100 g, 10% purity) in EtOH (15.0 mL) was stirred at room temperature under 15 Psi of hydrogen gas for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to give ethyl 2-(4-amino-3-fluorophenyl)-2-methylpropanoate (0.92 g, 4.1 mmol, 99% yield) as a yellow oil. LCMS [M+H] + = 226.0 m / z.

[0210] [ka] Synthesis of methyl (S)-2-(3-fluoro-4-nitrophenyl)propanoate To a solution of (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid (0.500 g, 2.35 mmol, 1.00 eq) in MeOH (5.00 mL), DMF (0.500 mL), was added SOCl 2 (837 mg, 7.04 mmol, 510 uL, 3.00 eq) was added. The mixture was stirred at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was then purified by H 2 Dilute with O, extract with ethyl acetate, and 2 SO 4 The mixture was evaporated in vacuo, dried at 40° C., filtered and concentrated under reduced pressure to give methyl (S)-2-(3-fluoro-4-nitrophenyl)propanoate (0.50 g, 2.2 mmol, 94% yield) as a yellow oil.

[0211] [ka] Synthesis of methyl (S)-2-(4-amino-3-fluorophenyl)propanoate To a solution of methyl (S)-2-(3-fluoro-4-nitrophenyl)propanoate (0.500 g, 2.20 mmol, 1.00 eq) in THF (5.00 mL), 2 Pd / C (10%, 0.10 g) was added under atmospheric pressure. The mixture was heated under 15 PSI of H 2 The mixture was stirred at room temperature for 2 hours under reduced pressure. The reaction mixture was concentrated under reduced pressure to give crude methyl (S)-2-(4-amino-3-fluorophenyl)propanoate (0.40 g) as a yellow oil. LCMS [M+H] + = 198.0 m / z.

[0212] [ka] (S)-N-(1-cycloheptyl-2-((2-fluoro-4-(2-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (7) Prepared according to general scheme C using ethyl 2-(4-amino-3-fluorophenyl)-2-methylpropanoate and (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and 2,2,2-trifluoroethan-1-amine hydrochloride. LCMS [M+H] + = 554.4 m / z.

[0213] Example 9: Synthesis of Compound 8 [ka] N-((S)-1-cycloheptyl-2-((4-((S)-1-((cyclopropylmethyl)(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (8) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and N-(cyclopropylmethyl)-2,2,2-trifluoroethan-1-amine hydrochloride. LCMS [M+H] + = 594.3 m / z.

[0214] Example 10: Synthesis of Compound 9 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (9) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and (R)-2-(trifluoromethyl)pyrrolidine. LCMS [M+H] + = 578.2 m / z.

[0215] Example 11: Synthesis of Compound 10 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-((2-hydroxyethyl)(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (10) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and 2-((2,2,2-trifluoroethyl)amino)ethan-1-ol. LCMS [M+H] + = 582.1 m / z.

[0216] Example 12: Synthesis of Compound 11 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (11) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and (S)-2-(trifluoromethyl)pyrrolidine. LCMS [M+H] + = 578.2 m / z.

[0217] Example 13: Synthesis of Compound 12 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-((1,1,1-trifluoro-4-hydroxybutan-2-yl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (12) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and 2-(trifluoromethyl)azetidine to give N-((2S)-1-((4-((2S)-1-((4-chloro-1,1,1-trifluorobutan-2-yl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide, followed by Converted to the title compound by the following method: N-((2S)-1-((4-((2S)-1-((4-chloro-1,1,1-trifluorobutan-2-yl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (20.0 mg, 33.3 umol, 1.00 eq), DIEA (8.62 mg, 66.6 umol, 11.6 uL, 2.00 eq), and NaI (499 ug, 3.33 umol, 0.100 eq) were added to a microwave tube and diluted with i-PrOH (1.00 mL). The sealed tube was heated to 120° C. in the microwave for 60 minutes. The reaction mixture was filtered, concentrated under reduced pressure, and purified by prep-HPLC (0-100% ACN in water (with 0.225% formic acid)) to give N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-((1,1,1-trifluoro-4-hydroxybutan-2-yl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (6.2 mg, 10 umol, 31% yield) as a white solid. LCMS [M+H] + = 582.4 m / z.

[0218] Example 14: Synthesis of Compound 13 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (13) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and 3-(trifluoromethyl)azetidine hydrochloride. LCMS [M+H] + = 564.3 m / z.

[0219] Example 15: Synthesis of Compound 14 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-(3-(trifluoromethyl)azetidin-1-yl)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (14) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and 2,2,2-trifluoroethan-1-amine hydrochloride. LCMS [M+H] + = 538.3 m / z.

[0220] Example 16: Synthesis of Compound 15 [ka] N-((S)-1,1-dicyclopropyl-3-((4-((S)-1-(3,3-difluoroazetidin-1-yl)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (15) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-ethyl-1H-pyrazole-5-carboxylic acid and 3,3-difluoroazetidine hydrochloride. LCMS [M+H] + = 532.1 m / z.

[0221] Example 17: Synthesis of Compound 16 [ka] N-((S)-1,1-dicyclopropyl-3-((4-((S)-1-(cyclopropylamino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (16) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and cyclopropanamine. LCMS [M+H] + = 510.2 m / z.

[0222] Example 18: Synthesis of Compound 17 [ka] N-((S)-1,1-dicyclopropyl-3-((4-((S)-1-((2,2-difluoroethyl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (17) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2,2-difluoroethan-1-amine. LCMS [M+H] + = 534.3 m / z.

[0223] Example 19: Synthesis of Compound 18 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-(3-(trifluoromethyl)morpholino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (18) The title compound was prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoate followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 3-(trifluoromethyl)morpholine hydrochloride. The title compound was purified by two tandem chiral SFC purifications (first: column: Phenomenex-cellulose-2 (250mmx30mm, 10um); mobile phase: 30% [0.1% NH in methanol], 3 H 2 2nd: Column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); Mobile phase: 25% [0.1% NH 3 H 2O]) as the first eluting single stereoisomer. LCMS [M+H] + = 608.3 m / z.

[0224] Example 20: Synthesis of Compound 19 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-(3-(trifluoromethyl)morpholino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (19) The title compound was prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoate followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 3-(trifluoromethyl)morpholine hydrochloride. The title compound was purified by two tandem chiral SFC purifications (first: column: Phenomenex-cellulose-2 (250mmx30mm, 10um); mobile phase: 30% [0.1% NH in methanol], 3 H 2 2nd: Column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); Mobile phase: 25% [0.1% NH 3 H 2 O]) was isolated as the second eluting single stereoisomer. LCMS [M+H] + = 608.3 m / z.

[0225] Example 21: Synthesis of Compound 20 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-(2-(trifluoromethyl)piperidin-1-yl)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (20) The title compound was prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoate followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2-(trifluoromethyl)piperidine. The title compound was purified using chiral SFC (column: DAICEL CHIRALPAK AD (250mmx30mm, 10um); mobile phase: 0.1% NH in 20% [IPA]. 3 H 2 O]) as a single stereoisomer which eluted first. LCMS [M+H] + = 606.4 m / z.

[0226] Example 22: Synthesis of Compound 21 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-(2-(trifluoromethyl)piperidin-1-yl)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (21) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoate followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and (2-(trifluoromethyl)piperidine). The title compound was purified using chiral SFC (column: DAICEL CHIRALPAK AD (250mmx30mm,10um); mobile phase: 0.1% NH in 20% [IPA]. 3H 2 O]) as a single stereoisomer eluting second. LCMS [M+H] + = 606.3 m / z.

[0227] Example 23: Synthesis of Compound 22 [ka] Tert-Butyl methyl(2-((2,2,2-trifluoroethyl)amino)ethyl)carbamate To a solution of tert-butyl (2-aminoethyl)(methyl)carbamate (1.00 g, 5.74 mmol, 1.03 mL, 1.00 eq) in dioxane (10.0 mL) was added DIEA (1.11 g, 8.61 mmol, 1.50 mL, 1.50 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.63 g, 6.89 mmol, 1.20 eq). The mixture was stirred at 100° C. for 12 h. The residue was purified by H 2 The mixture was diluted with O and extracted with EtOAc. The combined organic layers were washed with brine and 2 SO 4 Drying at 40° C., filtering, concentrating under reduced pressure, and column chromatography (SiO 2 , petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain tert-butyl methyl (2-((2,2,2-trifluoroethyl)amino)ethyl)carbamate (830 mg, 3.24 mmol, 56.4% yield) as a white solid. LCMS [M+H] + = 257.1 m / z.

[0228] [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-((2-(methylamino)ethyl)(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (22) tert-Butyl (2-((S)-2-(4-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-3-fluorophenyl)-N-(2,2,2-trifluoroethyl)propanamido)ethyl)(methyl)carbamate was prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and tert-butyl methyl(2-((2,2,2-trifluoroethyl)amino)ethyl)carbamate. The title compound was prepared according to general method C using tert-butyl (2-((S)-2-(4-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-3-fluorophenyl)-N-(2,2,2-trifluoroethyl)propanamido)ethyl)(methyl)carbamate. LCMS [M+H] + = 609.3 m / z.

[0229] Example 24: Synthesis of Compound 23 [ka] Tert-Butyl (methyl-d3)(2,2,2-trifluoroethyl)carbamate To a solution of tert-butyl (2,2,2-trifluoroethyl)carbamate (500 mg, 2.51 mmol, 1.00 eq) in DMF (3.00 mL) was added NaH (150 mg, 3.75 mmol, 60% purity, 1.49 eq) at 0° C. The mixture was stirred at 0° C. for 0.2 h. CD 3 I (500 mg, 3.52 mmol, 215 uL, 1.40 eq) was added to the reaction mixture and the mixture was stirred at room temperature for 2 hours. 2 The organic layers were combined and diluted with H2O and extracted with DCM. 2 O, followed by saline washing, and Na 2SO 4 Dry, filter, and concentrate under reduced pressure to obtain tert-butyl (methyl-d 3 ) (2,2,2-trifluoroethyl)carbamate (300 mg, 1.39 mmol, 55.3% yield) was obtained as a yellow oil. LCMS [M+H] + = 161.1 m / z.

[0230] [ka] 2,2,2-trifluoro-N-(methyl-d3)ethan-1-amine To a solution of tert-butyl (methyl-d3)(2,2,2-trifluoroethyl)carbamate (300 mg, 1.39 mmol, 1.00 eq) in DCM (2.00 mL) was added HCl / dioxane (4 M, 2.00 mL, 5.77 eq) at 0° C. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give 2,2,2-trifluoro-N-(methyl-d 3 ) ethan-1-amine (200 mg, 1.31 mmol, 94.4% yield, HCl) was obtained as a yellow oil.

[0231] [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-((methyl-d3)(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (23) According to general scheme C, methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoate are prepared, followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2,2,2-trifluoro-N-(methyl-d 3 ) Prepared using ethan-1-amine. LCMS [M+H]+ = 569.3 m / z.

[0232] Example 25: Synthesis of Compound 24 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (24) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 1-(2,2,2-trifluoroethyl)piperazine. LCMS [M+H] + = 621.2 m / z.

[0233] Example 26: Synthesis of Compound 25 [ka] N-((2S)-1,1-dicyclopropyl-3-((4-((2S)-1-((2-(difluoromethyl)cyclopropyl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (25) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2-(difluoromethyl)cyclopropan-1-amine hydrochloride. LCMS [M+H] + = 560.2 m / z.

[0234] Example 27: Synthesis of Compound 26 [ka] N-((2S)-1,1-dicyclopropyl-3-((4-((2S)-1-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (26) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 1-cyclopropyl-2,2,2-trifluoroethan-1-amine. LCMS [M+H] + = 592.2 m / z.

[0235] Example 28: Synthesis of Compound 27 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-((1,1,1-trifluoro-3-(pyridin-2-yl)propan-2-yl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (27) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 1,1,1-trifluoro-3-(pyridin-2-yl)propan-2-amine. LCMS [M+H] += 643.2m / z.

[0236] Example 29: Synthesis of Compound 28 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (28) The title compound was prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoate followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2-amino-3,3,3-trifluoropropan-1-ol hydrochloride. The title compound was purified by chiral SFC purification (column: Regis Whelk-01 (250mmx30mm, 10um); mobile phase: 25% [0.1% NH in MeOH] 3 H 2 O]) as a single stereoisomer which eluted first. LCMS [M+H] + = 582.3 m / z.

[0237] Example 30: Synthesis of Compound 29 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (29) The title compound was prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoate followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2-amino-3,3,3-trifluoropropan-1-ol hydrochloride. The title compound was purified by chiral SFC purification (column: Regis Whelk-01 (250mmx30mm, 10um); mobile phase: 25% [0.1% NH in MeOH] 3 H 2 O]) as a single stereoisomer eluting second. LCMS [M+H] + = 582.3 m / z.

[0238] Example 31: Synthesis of Compound 30 [ka] N-((S)-1,1-dicyclopropyl-3-((4-((S)-1-(3,3-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (30) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 3,3-difluoropyrrolidine. LCMS [M+H] + = 560.2 m / z.

[0239] Example 32: Synthesis of Compound 31 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-((3S,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (31) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and (3R,4S)-4-fluoropyrrolidin-3-ol hydrochloride. LCMS [M+H] + = 558.2 m / z.

[0240] Example 33: Synthesis of Compound 32 [ka] N-((2S)-1,1-dicyclopropyl-3-((4-((2S)-1-((2-(dimethylamino)-3,3,3-trifluoropropyl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (32) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 3,3,3-trifluoro-N2,N2-dimethyl-propane-1,2-diamine dihydrochloride. LCMS [M+H] + = 609.2 m / z.

[0241] Example 34: Synthesis of Compound 33 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (33) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and (3-fluoroazetidin-3-yl)methanol. LCMS [M+H] + = 558.2 m / z.

[0242] Example 35: Synthesis of Compound 34 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-((2-fluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (34) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2-fluoroethanamine hydrochloride. LCMS [M+H] + = 516.2 m / z.

[0243] Example 36: Synthesis of Compound 35 [ka] tert-Butyl (3-((S)-2-(4-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-3-fluorophenyl)propanamido)-2,2-difluoropropyl)carbamate (35) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and tert-butyl N-(3-amino-2,2-difluoro-propyl)carbamate. LCMS [M+H] + = 628.2 m / z.

[0244] Example 37: Synthesis of Compound 36 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2-(trifluoromethyl)benzyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (36) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and [2-(trifluoromethyl)phenyl]methanamine. LCMS [M+H] + = 663.3 m / z.

[0245] Example 38: Synthesis of Compound 37 [ka] N-((S)-1,1-dicyclopropyl-3-((4-((S)-1-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (37) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 6,6-difluoro-2-azaspiro[3.3]heptane hydrochloride. LCMS [M+H] + = 586.2 m / z.

[0246] Example 39: Synthesis of Compound 38 [ka] N-((S)-1,1-dicyclopropyl-3-((4-((S)-1-((3S,4S)-3,4-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (38) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and (3S,4S)-3,4-difluoropyrrolidine hydrochloride. LCMS [M+H] + = 560.2 m / z.

[0247] Example 40: Synthesis of Compound 39 [ka] tert-Butyl 4-((S)-2-(4-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-3-fluorophenyl)propanoyl)-3-(trifluoromethyl)piperazine-1-carboxylate (39) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate. LCMS [M+H] + = 707.2 m / z.

[0248] Example 41: Synthesis of Compound 40 [ka] N-((S)-1,1-dicyclopropyl-3-((4-((S)-1-((3S,4R)-3,4-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (40) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and (3S,4R)-3,4-difluoropyrrolidine hydrochloride. LCMS [M+H] + = 560.2 m / z.

[0249] Example 42: Synthesis of Compound 41 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-((2,2,2-trifluoro-1-(pyridin-2-yl)ethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (41) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2,2,2-trifluoro-1-(2-pyridyl)ethanamine dihydrochloride. LCMS [M+H] + = 629.2 m / z.

[0250] Example 43: Synthesis of Compound 42 [ka] N-((S)-1-((4-((S)-1-(bis(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (42) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2,2,2-trifluoro-N-(2,2,2-trifluoroethyl)ethanamine. LCMS [M+H] + = 634.2 m / z.

[0251] Example 44: Synthesis of Compound 43 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((3-(trifluoromethyl)oxetan-3-yl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (43) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 3-(trifluoromethyl)oxetan-3-amine hydrochloride. LCMS [M+H] + = 594.2 m / z.

[0252] Example 45: Synthesis of Compound 44 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,3,3,3-pentafluoropropyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (44) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2,2,3,3,3-pentafluoropropan-1-amine hydrochloride. LCMS [M+H] + = 602.2 m / z.

[0253] Example 46: Synthesis of Compound 45 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-(5-(trifluoromethyl)-1,4-oxazepin-4-yl)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (45). Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 5-(trifluoromethyl)-1,4-oxazepane hydrochloride. LCMS [M+H] + = 622.2 m / z.

[0254] Example 47: Synthesis of Compound 46 [ka] tert-Butyl 3-((S)-2-(4-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-3-fluorophenyl)propanamido)-3-(trifluoromethyl)azetidine-1-carboxylate (46). Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and name. LCMS [M+H] + = 693.2 m / z.

[0255] Example 48: Synthesis of Compound 47 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-(4-fluoro-2-(trifluoromethyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (47) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. LCMS [M+H] + = 610.1 m / z.

[0256] Example 49: Synthesis of Compound 48 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-(2-(trifluoromethyl)oxazolidin-3-yl)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (48) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2-(trifluoromethyl)oxazolidine. The title compound was isolated as the first eluting isomer by silica gel chromatography (eluting with 0-100% EtOAc in hexanes). LCMS [M+H] + = 594.1 m / z.

[0257] Example 50: Synthesis of Compound 49 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-(2-(trifluoromethyl)oxazolidin-3-yl)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (49) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoate followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2-(trifluoromethyl)oxazolidine. The title compound was isolated as the second eluting isomer by silica gel chromatography (eluting with 0-100% EtOAc in hexanes). LCMS [M+H] + = 594.1 m / z.

[0258] Example 51: Synthesis of Compound 50 [ka] N-((S)-1-(4,4-difluorocyclohexyl)-2-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (50) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and ((S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2,2,2-trifluoroethan-1-amine hydrochloride. LCMS [M+H] + = 590.1 m / z.

[0259] Example 52: Synthesis of Compound 51 [ka] N-((S)-1-(4,4-difluorocyclohexyl)-2-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (51) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and ((S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride. LCMS [M+H] + = 576.1 m / z.

[0260] Example 53: Synthesis of Compound 52 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((3-(trifluoromethyl)azetidin-3-yl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (52) As exemplified in general method C, compound 52 was prepared from tert-butyl 3-((S)-2-(4-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-3-fluorophenyl)propanamido)-3-(trifluoromethyl)azetidine-1-carboxylate. LCMS [M+H] + = 593.1 m / z.

[0261] Example 54: Synthesis of Compound 53 [ka] N-((S)-1-((4-((S)-1-(bis(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (53) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and bis(2,2,2-trifluoroethyl)amine hydrochloride. LCMS [M+H] + = 620.1 m / z.

[0262] Example 55: Synthesis of Compound 54 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-(((R)-1,1,1-trifluoropropan-2-yl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (54) Methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and (R)-1,1,1-trifluoropropan-2-amine hydrochloride were prepared according to general scheme C. LCMS [M+H] + = 566.1 m / z.

[0263] Example 56: Synthesis of Compound 55 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-(((S)-1,1,1-trifluoropropan-2-yl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (55) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and (S)-1,1,1-trifluoropropan-2-amine hydrochloride. LCMS [M+H] + = 566.1 m / z.

[0264] Example 57: Synthesis of Compound 56 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-(5-(trifluoromethyl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (56) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 5-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine. LCMS [M+H] + = 670.1 m / z.

[0265] Example 58: Synthesis of Compound 57 [ka] N-((S)-1,1-dicyclopropyl-3-((4-((S)-1-((2,2-difluoropropyl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (57) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2,2-difluoropropan-1-amine hydrochloride. LCMS [M+H] + = 548.2 m / z. Example 59: Synthesis of Compound 58 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-((2S,4R)-4-fluoro-2-(trifluoromethyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (58) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and (2S,4R)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. LCMS [M+H] + = 610.1 m / z.

[0266] Example 60: Synthesis of Compound 59 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-((2R,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (59) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and (2R,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. LCMS [M+H] + = 610.1 m / z.

[0267] Example 61: Synthesis of Compound 60 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-((2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (60) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride in the procedure exemplified for T3P. LCMS [M+H] + = 610.1 m / z.

[0268] Example 62: Synthesis of Compound 61 [ka] Ethyl 3-((S)-2-(4-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-3-fluorophenyl)propanamido)-4,4,4-trifluorobutanoate (61) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoate followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and ethyl 3-amino-4,4,4-trifluoro-butanoate. LCMS [M+H] + = 638.2 m / z.

[0269] Example 63: Synthesis of Compound 62 [ka] Methyl 2-[[(2S)-2-[4-[[(2S)-3,3-dicyclopropyl-2-[(2-isopropylpyrazole-3-carbonyl)amino]propanoyl]amino]-3-fluoro-phenyl]propanoyl]amino]-3,3,3-trifluoro-propanoate (62) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and methyl 2-amino-3,3,3-trifluoro-propanoate hydrochloride. LCMS [M+H] + = 610.1 m / z.

[0270] Example 64: Synthesis of Compound 63 [ka] N-((2S)-1-((4-((2S)-1-((3-amino-1,1,1-trifluoro-3-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (63) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2-amino-3,3,3-trifluoro-propanamide hydrochloride. LCMS [M+H] + = 595.1 m / z.

[0271] Example 65: Synthesis of Compound 64 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((S)-2-(trifluoromethyl)azetidin-1-yl)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (64) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and (S)-2-(trifluoromethyl)azetidine tosylate. LCMS [M+H] + = 578.1 m / z.

[0272] Example 66: Synthesis of Compound 65 [ka] N-((S)-1,1-dicyclopropyl-3-((4-((S)-1-((2,2-difluoro-3-hydroxypropyl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (65) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 3-amino-2,2-difluoro-propan-1-ol. LCMS [M+H] + = 564.2 m / z.

[0273] Example 67: Synthesis of Compound 66 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-((2,2,2-trifluoro-1-phenylethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (66) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2,2,2-trifluoro-1-phenyl-ethanamine hydrochloride. LCMS [M+H] + = 628.1 m / z.

[0274] Example 68: Synthesis of Compound 67 [ka] N-[(1S)-1-(dicyclopropylmethyl)-2-[2-fluoro-4-[(1S)-1-methyl-2-oxo-2-[(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)amino]ethyl]anilino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide (67) Prepared according to general scheme C using methyl (S)-2-(4-amino-3-fluorophenyl)propanoate and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid followed by 1-isopropyl-1H-pyrazole-5-carboxylic acid and 2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethanamine. LCMS [M+H] + = 622.2 m / z.

[0275] Example 69: General Scheme A - Synthesis of Compounds 68-101 [ka] Examples synthesized according to general Scheme A utilize a carboxylic acid and an amine in the first step, followed by an amino acid in step 3 and a carboxylic acid in step 5. Starting materials are listed in the order of use.

[0276] Example 70: Synthesis of Compound 68 [ka] (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid THF (50.0 mL) and H 2 To a solution of ethyl 2-(3-fluoro-4-nitrophenyl)propanoate (5.00 g, 20.7 mmol, 1.00 eq) in 20H2O (20.0 mL) was added LiOH (1.99 g, 82.2 mmol, 4.00 eq). The reaction mixture was stirred at 10 °C for 3 h and concentrated under reduced pressure. The residue was purified by H2O chromatography (HCl). 2 The mixture was diluted with 200 mL of HO (50.0 mL), adjusted to pH = 4 with HCl (1.00 M), and extracted with ethyl acetate. The organic layers were combined and washed with Na2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by prep-SFC (column: DAICEL CHIRALPAK AD-H (250 mm×30 mm, 5 um), mobile phase: 15% [1:1 heptane:EtOH]) to give (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid (2.50 g, 11.7 mmol, 56.6% yield) as the second eluting isomer and a yellow oil.

[0277] [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (68) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 1-ethyl-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 552.2 m / z.

[0278] Example 71: Synthesis of Compound 69 [ka] N-((1S)-1-cycloheptyl-2-((4-(1-(ethyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (69) The title compound was prepared according to general scheme A using 2-(3-fluoro-4-nitrophenyl)propanoic acid and N-ethyl-2,2,2-trifluoroethan-1-amine hydrochloride, followed by (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid and 1-ethyl-1H-pyrazole-5-carboxylic acid. The title compound was purified using chiral SFC (column: DAICEL CHIRALPAK AD (250mmx30mm, 10um); mobile phase: 20% [0.1% NH in IPA] 3 H 2 O]) was isolated as a single isomer eluting first. LCMS [M+H] + = 568.2 m / z.

[0279] Example 72: Synthesis of Compound 70 [ka] N-((1S)-1-cycloheptyl-2-((4-(1-(ethyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (70) The title compound was prepared according to general scheme A using 2-(3-fluoro-4-nitrophenyl)propanoic acid and N-ethyl-2,2,2-trifluoroethan-1-amine hydrochloride, followed by (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid and 1-ethyl-1H-pyrazole-5-carboxylic acid. The title compound was purified using chiral SFC (column: DAICEL CHIRALPAK AD (250mmx30mm, 10um); mobile phase: 20% [0.1% NH in IPA] 3 H 2 O]) as a single stereoisomer eluting second. LCMS [M+H] + = 568.2 m / z.

[0280] Example 73: Synthesis of Compound 71 [ka] 1-Ethyl-N-((S)-2-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-((1r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1H-pyrazole-5-carboxamide (71) Prepared according to general scheme A using 2-(3-fluoro-4-nitrophenyl)propanoic acid and N-methyl-2,2,2-trifluoroethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-2-((1r,4S)-4-methylcyclohexyl)acetic acid and 1-ethyl-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 554.3 m / z.

[0281] Example 74: Synthesis of Compound 72 [ka] N-((2S,3S)-3-(4-chlorophenyl)-1-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-1-oxopentan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (72) Prepared according to general scheme A using 2-(3-fluoro-4-nitrophenyl)propanoic acid and N-methyl-2,2,2-trifluoroethan-1-amine hydrochloride followed by (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(4-chlorophenyl)pentanoic acid and 1-ethyl-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 610.3 m / z.

[0282] Example 75: Synthesis of Compound 73 [ka] (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(2-chlorophenyl)-4-methylpentanoic acid Prepared according to WO2019 / 223718. Absolute configuration was analyzed by single crystal x-ray diffraction of the diastereomer (S)-phenylethylamine, related as a tight ion pair with (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(2-chlorophenyl)-4-methylpentanoic acid, crystals grown by slow evaporation of 15 mg of the title compound with 5.4 mg of (S)-phenylethylamine in 0.9 mL of 1:2 ACN / water at 45 °C [parameters: (CuKα), space group = I2, a = 12.6111(4), b = 6.5141(3), c = 30.7194(10), and alpha = 90°, beta = 90.390(3)°, gamma = 90°].

[0283] [ka] N-((2S,3S)-3-(2-chlorophenyl)-1-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (73) Prepared according to general scheme A using 2-(3-fluoro-4-nitrophenyl)propanoic acid and N-methyl-2,2,2-trifluoroethan-1-amine hydrochloride followed by (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(2-chlorophenyl)-4-methylpentanoic acid and 1-ethyl-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 624.2 m / z.

[0284] Example 76: Synthesis of Example 74 Compound [ka] N-((S)-1-(4,4-difluorocyclohexyl)-2-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (74) Prepared according to general scheme A using 2-(3-fluoro-4-nitrophenyl)propanoic acid and N-methyl-2,2,2-trifluoroethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid and 1-ethyl-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 576.3 m / z.

[0285] Example 77: Synthesis of Compound 75 [ka] 1-Ethyl-N-((S)-2-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxo-1-(spiro[2.5]octan-6-yl)ethyl)-1H-pyrazole-5-carboxamide (75) Prepared according to general scheme A using 2-(3-fluoro-4-nitrophenyl)propanoic acid and N-methyl-2,2,2-trifluoroethan-1-amine hydrochloride followed by (S)-2-(((benzyloxy)carbonyl)amino)-2-(spiro[2.5]octan-6-yl)acetic acid and 1-ethyl-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 566.4 m / z.

[0286] Example 78: Synthesis of Compound 76 [ka] Synthesis of methyl 2-(5-fluoro-2-methylphenyl)acetate A mixture of 2-(5-fluoro-2-methylphenyl)acetonitrile (4.00 g, 26.8 mmol, 1.00 eq) in HCl / MeOH (4.00 M, 70.0 mL, 10.4 eq) was dissolved in N 2 The mixture was stirred at 80° C. for 16 hours under atmospheric pressure. 2 The aqueous layer was diluted with saturated NaHCO 3 The pH was adjusted to 8 with aqueous sodium hydroxide, followed by extraction with EtOAc. The combined organic layers were washed with anhydrous Na 2 SO 4 The extract was dried at 40° C., filtered and concentrated under reduced pressure to give methyl 2-(5-fluoro-2-methylphenyl)acetate (4.3 g, 24 mmol, 88% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.15 - 7.11 (m, 1H), 6.95 - 6.88 (m, 2H), 3.71 (s, 3H), 3.62 (s, 2H), 2.27 (s, 3H).

[0287] [ka] Methyl 2-(5-fluoro-2-methylphenyl)propanoate To a solution of methyl 2-(5-fluoro-2-methylphenyl)acetate (3.90 g, 21.4 mmol, 1.00 eq) in DMF (50.0 mL) was added NaH (980 mg, 24.5 mmol, 60.0% purity, 1.14 eq) at 0° C. The mixture was stirred at 0° C. for 0.2 h, then iodomethane (2.73 g, 19.2 mmol, 1.20 mL, 0.900 eq) was added. The mixture was stirred at 10° C. for 1.5 h. The reaction mixture was quenched with 1.00 M HCl at 0° C. and extracted with EtOAc. The organic layers were combined and washed with Na 2 SO 4 The residue was concentrated, extracted with EtOAc, and the organic layer was washed with anhydrous NaCl. 2 SO 4The extract was dried at 40° C., filtered, and concentrated under reduced pressure to give methyl 2-(5-fluoro-2-methylphenyl)propanoate (2.80 g, 14.2 mmol, 66.6% yield) as a yellow oil. 1 H NMR: (400 MHz, CDCl 3 ) δ 7.14 - 7.10 (m, 1H), 6.99 (dd, J 1 = 2.8 Hz, J 2 = 10.4 Hz, 1H), 6.88 - 6.83 (m, 1H), 3.96 - 3.90 (m, 1H), 3.68 (s, 3H), 2.32 (s, 3H), 1.47 (d, J = 8.0 Hz, 3H).

[0288] [ka] 2-(5-fluoro-2-methylphenyl)propanoic acid A solution of methyl 2-(5-fluoro-2-methylphenyl)propanoate (2.80 g, 14.2 mmol, 1.00 eq) in MeOH (35.0 mL) was heated at 0 °C with H 2 A solution of NaOH (1.14 g, 28.5 mmol, 2.00 eq) in 2O (8.00 mL) was added. The mixture was stirred at 30° C. for 3 h. The reaction mixture was concentrated and diluted with H 2 The aqueous layer was adjusted to pH=3 with 1.00M HCl and extracted with EtOAc. The organic layers were combined and washed with anhydrous Na 2 SO 4 The mixture was dried at rt, filtered, and concentrated under reduced pressure to give 2-(5-fluoro-2-methylphenyl)propanoic acid (2.45 g, 13.4 mmol, 94.2% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 11.4 (s, 1H), 7.15 - 7.11 (m, 1H), 7.03 (dd, J 1 = 2.8 Hz, J 2= 12.8 Hz, 1H), 6.90 - 6.85 (m, 1H), 3.99 - 3.93 (m, 1H), 2.34 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H).

[0289] [ka] 2-(5-fluoro-2-methyl-4-nitrophenyl)propanoic acid H 2 SO 4 A solution of 2-(5-fluoro-2-methylphenyl)propanoic acid (2.45 g, 13.4 mmol, 1.00 eq) in 20.0 mL of 1000 sulphuric acid was added to the flask at 0 °C with HNO 3 (1.82 g, 20.2 mmol, 1.30 mL, 70.0% purity, 1.50 eq) was slowly added and the mixture was stirred at 0° C. for 2 h. The mixture was quenched with ice water and extracted with EtOAc, the combined organic layers were washed with brine and added with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give crude 2-(5-fluoro-2-methyl-4-nitrophenyl)propanoic acid (3.60 g) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 2.8 Hz, 1H), 4.16 - 4.12 (m, 1H), 2.43 (s, 3H), 1.57 - 1.56 (m, 3H).

[0290] [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-5-methyl-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (76) The title compound was prepared according to general scheme A using 2-(5-fluoro-2-methyl-4-nitrophenyl)propanoic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride, followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 1-ethyl-1H-pyrazole-5-carboxamide. The title compound was purified using chiral SFC purification (column: DAICEL CHIRALPAK IC (250mmx30mm, 5um); mobile phase: 0.1% NH in 30% [methanol]). 3 H 2 O]) as a single stereoisomer eluting first. LCMS [M+H] + = 566.3 m / z.

[0291] Example 79: Synthesis of Compound 77 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-5-methyl-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (77) The title compound was prepared according to general scheme A using 2-(5-fluoro-2-methyl-4-nitrophenyl)propanoic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride, followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 1-ethyl-1H-pyrazole-5-carboxamide. The title compound was purified using chiral SFC purification (column: DAICEL CHIRALPAK IC (250mmx30mm, 5um); mobile phase: 0.1% NH in 30% [methanol]). 3 H 2 O]) as the second eluting single stereoisomer. LCMS [M+H] + = 566.3 m / z.

[0292] Example 80: Synthesis of Compound 78 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (78) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 1-isopropyl-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 566.2 m / z.

[0293] Example 81: Synthesis of Compound 79 [ka] 1-Ethyl-4-fluoro-1H-pyrazole-5-carboxylic acid 1-Ethyl-1H-pyrazole-5-carboxylic acid (0.500 g, 3.57 mmol, 1.00 eq) and Select F (2.53 g, 7.14 mmol, 2.00 eq) were added to a microwave reaction vial and diluted with MeCN (8.00 mL) and AcOH (3 mL). The sealed tube was heated in the microwave at 110° C. for 6 h. The reaction mixture was then cooled to 100° C. for 2 h. 2 The mixture was diluted with O and extracted with EtOAc. The organic layers were combined and washed with Na 2 SO 4 Drying at 40° C., filtration, and concentration under reduced pressure gave a residue that was purified by prep-HPLC (eluted with 7-37% ACN (containing 0.225% formic acid) in water) to give 1-ethyl-4-fluoro-1H-pyrazole-5-carboxylic acid (160 mg, 1.01 mmol, 28.3% yield) as a yellow solid. 1H NMR (400 MHz, CDCl 3 ) δ 7.43 (d, J = 4.4 Hz, 1H), 4.57 - 4.52 (m, 2H), 1.44 (t, J = 7.2 Hz, 3H).

[0294] [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-4-fluoro-1H-pyrazole-5-carboxamide (79) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 1-ethyl-4-fluoro-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 570.3 m / z.

[0295] Example 82: Synthesis of Compound 80 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-3-ethylisoxazole-4-carboxamide (80) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 3-ethylisoxazole-4-carboxylic acid. LCMS [M+H] + = 553.2 m / z.

[0296] Example 83: Synthesis of Compound 81 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-2-ethylnicotinamide (81) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 2-ethylnicotinic acid. LCMS [M+H] + = 563.2 m / z.

[0297] Example 84: Synthesis of Compound 82 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (82) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 1-isopropyl-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 552.2 m / z.

[0298] Example 85: Synthesis of Compound 83 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-4-fluoro-1H-pyrazole-5-carboxamide (83) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 1-ethyl-4-fluoro-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 556.3.

[0299] Example 86: Synthesis of Compound 84 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-3-ethylisoxazole-4-carboxamide (84) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 3-ethylisoxazole-4-carboxylic acid. LCMS [M+H] + = 539.1.

[0300] Example 87: Synthesis of Compound 85 [ka] 1-Fluoro-4-(1-methoxybut-1-en-2-yl)benzene To a solution of 1-(4-fluorophenyl)propan-1-one (400 g, 2.63 mol, 363 mL, 1.00 eq) in THF (2000 mL) was added t-BuOK (442 g, 3.94 mol, 1.50 eq) and (methoxymethyl)triphenylphosphonium chloride (1.17 kg, 3.42 mol, 1.30 eq). The mixture was stirred at 0-5° C. for 2 h. The reaction mixture was treated with water (2000 mL), diluted with EtOAc (2000 mL) and extracted with EtOAc (3×2000 mL). The combined organic layers were washed with brine (800 mL) and concentrated with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to obtain 480 g of a pale yellow residue, which was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=10:1) to give the title compound (320 g, 1.78 mol, 67.5% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.46 - 7.44 (m, 1H), 7.28 - 7.23 (m, 1H), 7.04 - 6.98 (m, 2H), 6.14 (d, J = 48.0 Hz, 1H), 3.67 (d, J = 23.2 Hz, 3H), 2.53 - 2.47 (m, 1H), 2.35 - 2.30 (m, 1H), 1.02 - 0.97 (m, 3H).

[0301] [ka] 2-(4-fluorophenyl)butanal Dioxane (4000 mL) and H 2To a solution of 1-fluoro-4-(1-methoxybut-1-en-2-yl)benzene (420 g, 2.33 mol, 1.00 eq) in 2H2O (400 mL) was added TsOH (1.61 kg, 9.32 mol, 4.00 eq). The mixture was stirred at 100-105° C. for 2 h. The reaction mixture was treated with water (4000 mL) and then diluted with EtOAc (4000 mL) and extracted with EtOAc (3×3000 mL). The organic layers were combined and washed with saturated NaHCO 3 Wash with aqueous solution (2000 mL) and brine (1000 mL) and add Na 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure to give the title compound (400 g, crude) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ 9.65 (s, 1H), 7.18 - 7.15 (m, 2H), 7.10 - 7.04 (m, 2H), 3.43 - 3.38 (m, 1H), 2.12 - 2.04 (m, 1H), 1.77 - 1.70 (m, 1H), 0.92 - 0.87 (m, 3H).

[0302] [ka] (S)-N-((E)-2-(4-fluorophenyl)butylidene)-2-methylpropane-2-sulfinamide A solution of 2-(4-fluorophenyl)butanal (400 g, 2.41 mol, 1.00 eq) in THF (3000 mL) was diluted with (S)-2-methylpropane-2-sulfinamide (350 g, 2.89 mol, 1.20 eq) and Ti(i-PrO). 4 (1.37 kg, 4.81 mol, 2.00 eq) was added. The mixture was stirred at 70-80° C. for 2 hours. The reaction mixture was diluted with H 2 The mixture was treated with 200 mL of 2H2O (5000 mL), filtered, and the filtrate was extracted with EtOAc (3x5000 mL). The combined organic layers were washed with brine (3000 mL) and sodium 2 SO 4The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50:1 to 10:1) to give the title compound (450 g, 1.67 mol, 69.4% yield) as a pale yellow oil. 1 H NMR (400MHz, CDCl 3 ): δ 8.06 - 8.04 (m, 1H), 7.19 - 7.15 (m, 2H), 7.04 - 7.01 (m, 2H), 3.64 - 3.60 (m, 1H), 2.08 - 2.03 (m, 1H), 1.86 - 1.76 (m, 1H),1.17 (d, J = 24.0 Hz, 9H), 0.93 - 0.89 (m ,3H).

[0303] [ka] (S)-N-((1S)-1-cyano-2-(4-fluorophenyl)butyl)-2-methylpropane-2-sulfinamide To a solution of (S)-N-((E)-2-(4-fluorophenyl)butylidene)-2-methylpropane-2-sulfinamide. To a solution of 2-(4-fluorophenyl)butanal (220 g, 817 mmol, 1.00 eq) in DCM (2000 mL), TMSCN (162 g, 1.63 mol, 204 mL, 2.00 eq), CsF (37.2 g, 245 mmol, 9.03 mL, 0.30 eq) and H 2 O (2.94 g, 163 mmol, 2.94 mL, 0.20 eq) was added. The mixture was stirred at 10-25° C. for 12 h. The reaction mixture was treated with water (2000 mL), then diluted with DCM (2000 mL) and extracted with DCM (3×2000 mL). The combined organic layers were washed with brine (800 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2, petroleum ether:EtOAc=20:1 to 5:1) to afford the title compound (200 g, 674 mmol, 82.6% yield) as an off-white solid. 1 H NMR (400MHz, CDCl 3 ): δ 7.25 - 7.22 (m, 1H), 7.18 - 7.13 (m, 1H), 7.03 - 7.00 (m, 2H), 4.35 - 4.19 (m, 1H), 3.63 - 3.46 (m, 1H), 2.92 - 2.81 (m, 1H), 1.98 - 1.73 (m, 2H), 1.11 (d, J = 20.0 Hz, 9H), 0.85 - 0.77 (m, 3H).

[0304] [ka] (2S)-2-Amino-3-(4-fluorophenyl)pentanoic acid hydrochloride To a solution of (S)-N-((1S)-1-cyano-2-(4-fluorophenyl)butyl)-2-methylpropane-2-sulfinamide (200 g, 674 mmol, 1.00 eq) in AcOH (400 mL) was added HCl (8 M, 2000 mL, 23.7 eq). The mixture was stirred at 100-105° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue (200 g, crude) as a brown oil. The residue was used in the next step without further purification.

[0305] [ka] (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(4-fluorophenyl)pentanoic acid THF (1200 mL) and H 2 To a solution of (2S)-2-amino-3-(4-fluorophenyl)pentanoic acid hydrochloride (200 g, crude) in 20O (1200 mL) was added Boc 2 O (413 g, 1.89 mol, 435 mL) and K 2 CO 3(523 g, 3.79 mol) was added. The mixture was stirred at 15-25° C. for 3 h. The reaction mixture was adjusted to pH=3-4 with 1M HCl, diluted with EtOAc (2000 mL) and extracted with EtOAc (3×2000 mL). The combined organic layers were washed with brine (800 mL) and extracted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 The extract was purified by reverse phase HPLC (column: Welch Ultimate XB-SiOH) using a mixture of petroleum ether / ethyl acetate = 20 / 1 to 5 / 1. 2 50x50, 10um; Mobile phase: [Hexane-EtOH, 0.1% NH 3 .H 2 HO]; B%: 10%-40%) and SFC (column: DAICEL CHIRALPAK AD (250 mm x 50 mm, 10 um); mobile phase: [0.1% NH 3 H 2 Further purification by 100% ethanol (HO IPA); B%: 25%) gave a mixture of isomers (60.0 g, 186 mmol, 19.7% yield, 96.8% purity) as a pale yellow oil. The title compound was obtained by chiral SFC purification of 25.0 g of the mixture (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); 0.1% NH in ethanol). 3 H 2 The title compound (12.0 g, 38.5 mmol, 48.0% yield) was obtained as the first eluting isomer and as an off-white solid. LCMS: [M+Na] + = 334.1; 1 H NMR (400 MHz, MeOD): δ 7.23 - 7.19 (m, 2H), 7.02 - 6.98 (m, 2H), 4.37 - 4.34 (m, 1H), 3.00 - 2.95 (m, 1H), 1.83 - 1.67 (m, 2H), 1.42 (s, 9H), 0.88 - 0.76 (m, 3H). The absolute configuration was determined by single crystal x-ray diffraction of crystals grown by slow evaporation of 17 mg of the title compound and 6.5 mg of (R)-phenylethylamine in 1 mL of 1:1 ACN / MeOH [parameters: (CuKα), space group = P2 1 , a = 11.0606(3), b = 5.51880(10), c = 19.8399(5), and alpha = 90°, beta = 102.312(2)°, gamma = 90°].

[0306] [ka] 1-Ethyl-N-((2S,3S)-1-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-3-(4-fluorophenyl)-1-oxopentan-2-yl)-1H-pyrazole-5-carboxamide (85) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride followed by (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(4-fluorophenyl)pentanoic acid and 1-ethyl-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 594.1 m / z.

[0307] [ka] N-Methoxy-N-methylcyclobutanecarboxamide To a solution of cyclobutanecarboxylic acid (75.0 g, 749 mmol, 71.4 mL, 1.00 eq) in DCM (350 mL) was added N,O-dimethylhydroxylamine hydrochloride (87.7 g, 899 mmol, 1.20 eq), EDCI (215 g, 1.12 mol, 1.50 eq), and TEA (114 g, 1.12 mol, 156 mL, 1.50 eq) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with saturated NaHCO 3 The combined organic layers were washed with 1N HCl and brine, and then extracted with DCM. 2 SO 4 The extract was dried at rt, filtered, and concentrated under reduced pressure to give N-methoxy-N-methylcyclobutanecarboxamide (98.0 g, 684 mmol, 91.3% yield) as a pale yellow liquid. 1 H NMR (400 MHz, CDCl 3 ): δ: 3.64 (s, 3H), 3.46 (d, J = 6.8 Hz, 1H), 3.16 (s, 3H), 2.35 - 2.29 (m, 2H), 2.14 - 2.10 (m, 2H), 1.96 - 1.81 (m, 2H).

[0308] [ka] 1-Cyclobutylpropan-1-one To a solution of N-methoxy-N-methylcyclobutanecarboxamide (20.0 g, 140 mmol, 1.00 eq) in THF (100 mL) was added EtMgBr (3.00 M, 55.9 mL, 1.20 eq) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction was treated with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic layers were washed with water and brine, and then extracted with Na 2 SO 4 The extract was dried at 40° C., filtered and concentrated under reduced pressure to give 1-cyclobutylpropan-1-one (13.0 g, crude) as a pale yellow liquid. 1 H NMR (400 MHz, CDCl 3): δ: 3.29 - 3.22 (m, 1H), 2.40 - 2.33 (m, 2H), 2.22 - 2.11 (m, 4H), 2.04 - 1.94 (m, 2H), 1.04 (t, J = 7.6 Hz, 3H).

[0309] [ka] (E)-(1-Methoxypent-1-en-3-yl)cyclobutene A solution of (methoxymethyl)triphenylphosphonium chloride (49.5 g, 144 mmol, 1.20 eq) in THF (60.0 mL) was added to 2 t-BuOK (16.2 g, 144 mmol, 1.20 eq) in THF (60.0 mL) was added dropwise at 0° C. under reduced pressure. After addition, the mixture was stirred at 5° C. for 1 h, and then 1-cyclobutylpropan-1-one (13.5 g, 120 mmol, 1.00 eq) was added dropwise. The resulting mixture was stirred at 30° C. for 12 h. The reaction was then cooled to 30° C. for 1 h. 2 The organic layers were combined, washed with brine, and then extracted with DCM. 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=50:1) to give (E)-(1-methoxypent-1-en-3-yl)cyclobutane (10.0 g, 71.3 mmol, 59.2% yield) as a pale yellow liquid. 1 H NMR (400 MHz, CDCl 3 ): δ: 5.67 (d, J = 11.2 Hz, 1H), 3.54 (d, J = 13.2 Hz, 3H), 2.91 - 2.86 (m, 1H), 2.05 - 2.01 (m, 4H), 2.00 - 1.85 (m, 2H), 1.84 - 1.83 (m, 2H), 1.00 - 0.93 (m, 3H).

[0310] [ka] 2-Cyclobutylbutanal Dioxane (50.0 mL) and H 2 A solution of (E)-(1-methoxypent-1-en-3-yl)cyclobutane (10.0 g, 71.3 mmol, 1.00 eq) in 2H2O (5.00 mL) was added to the reaction mixture with TsOH H 2 O (54.3 g, 285 mmol, 4.00 eq) was added. The mixture was stirred at 110° C. for 3 h. The reaction mixture was diluted with saturated NaHCO 3 The combined organic layers were washed with brine and extracted with Na 2 SO 4 The extract was dried at 40° C., filtered and concentrated under reduced pressure to give 2-cyclobutylbutanal (10.0 g, crude) as a pale yellow liquid. 1 H NMR (400 MHz, CDCl 3 ): δ: 9.53 (d, J = 3.2 Hz, 1H), 2.49 - 2.47 (m, 1H), 2.19 - 2.06 (m, 1H), 1.91 - 1.82 (m, 2H), 1.82 - 1.79 (m, 4H), 1.55 - 1.51 (m, 2H), 0.88 (d, J = 7.2 Hz, 3H).

[0311] [ka] (S)-N-((E)-2-cyclobutylbutylidene)-2-methylpropane-2-sulfinamide A solution of 2-cyclobutylbutanal (10.0 g, 79.2 mmol, 1.00 eq) in dioxane (60.0 mL) was added to 2 (S)-2-Methylpropane-2-sulfinamide (11.5 g, 95.1 mmol, 1.20 eq) was added at 15° C. under reduced pressure. After the addition, the mixture was stirred for 0.5 h, and then CuSO 4 (25.3 g, 158 mmol, 24.3 mL, 2.00 eq) was added dropwise. The resulting mixture was stirred at 60° C. for 12 h. The reaction mixture was filtered and the filter cake was washed with DCM. The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2, petroleum ether:ethyl acetate=5:1) to give (S)-N-((E)-2-cyclobutylbutylidene)-2-methylpropane-2-sulfinamide (8.70 g, crude) as a pale yellow oil.

[0312] [ka] (S)-N-((1S)-1-cyano-2-cyclobutylbutyl)-2-methylpropane-2-sulfinamide A solution of (S)-N-((E)-2-cyclobutylbutylidene)-2-methylpropane-2-sulfinamide (8.70 g, 37.9 mmol, 1.00 eq) in DCM (80.0 mL) was heated at 0 °C with H 2 CsF (1.15 g, 7.59 mmol, 280 uL, 0.20 eq) in 2O (1.37 g, 75.9 mmol, 1.37 mL, 2.00 eq) and TMSCN (7.53 g, 75.9 mmol, 9.49 mL, 2.00 eq) were added. The reaction mixture was stirred at 30 °C for 12 h. The reaction mixture was diluted with H 2 The organic layers were combined, washed with brine, and then extracted with DCM. 2 SO 4 The residue was purified by column chromatography (SiO 2 The residue was purified by chiral SFC purification (column: (S,S)Whelk-O1 (250mmx30mm, 5um); mobile phase: 5%-40% [0.05% diethylamine in MeOH]) to give the first eluting isomer of (S)-N-((1S)-1-cyano-2-cyclobutylbutyl)-2-methylpropane-2-sulfinamide (3.20g, 12.5mmol, 32.8% yield, 99.7% purity) as a pale yellow oil and the second eluting isomer of (S)-N-((1S)-1-cyano-2-cyclobutylbutyl)-2-methylpropane-2-sulfinamide (3.00g, 11.7mmol, 30.8% yield, 100% purity) as a pale yellow oil. First eluting isomer: LCMS [M+H] += 257.0 m / z; 1 H NMR (400 MHz, CDCl 3 ): δ: 4.18 (dd, J = 3.6 Hz, 8.0 Hz, 1H), 3.55 (d, J = 8.4 Hz, 1H), 2.39 - 2.37 (m, 1H), 2.12 - 2.08 (m, 2H), 1.90 - 1.62 (m, 5H), 1.50 - 1.47 (m, 2H), 1.25 (s, 9H), 0.97 (t, J = 7.6 Hz, 3H). Second eluting isomer: LCMS [M+H] + = 257.0 m / z; 1 H NMR (400 MHz, CDCl 3 ): δ: 4.16 (dd, J = 4.0 Hz, 9.6 Hz, 1H), 3.55 (d, J = 9.6 Hz, 1H), 2.46 - 2.41 (m, 1H), 2.09 - 2.07 (m, 2H), 1.84 - 1.75 (m, 5H), 1.41 - 1.39 (m, 2H), 1.24 (s, 9H), 0.97 (t, J = 7.4 Hz, 3H).

[0313] [ka] (2S)-2-((tert-butoxycarbonyl)amino)-3-cyclobutylpentanoic acid To a solution of the first eluting isomer of (S)-N-((1S)-1-cyano-2-cyclobutylbutyl)-2-methylpropane-2-sulfinamide (3.20 g, 12.5 mmol, 99.7% purity, 1.00 eq) in AcOH (6.70 g, 112 mmol, 6.38 mL, 8.97 eq) was added HCl (12.0 M, 37.2 mL, 35.9 eq) at room temperature. The mixture was stirred at 120° C. for 12 h. The reaction mixture was cooled to 15° C. and concentrated under reduced pressure to give a residue. The residue was purified by hexane distillation at room temperature with H 2 K in O (100 mL) 2 CO 3 (2.58 g, 18.7 mmol, 1.50 eq), followed by Boc in THF (50.0 mL). 2The reaction mixture was treated with 2.72 g, 12.5 mmol, 2.86 mL, 1.00 eq) and stirred for 12 h. The reaction mixture was extracted with DCM. The aqueous layers were combined, adjusted to pH 4-5 with saturated aqueous citric acid, extracted with DCM, and 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue that was purified by prep-HPLC eluting with ACN in water (containing 0.1% TFA) to give (2S)-2-((tert-butoxycarbonyl)amino)-3-cyclobutylpentanoic acid (668 mg, 2.44 mmol, 19.6% yield, 99.2% purity) as a single stereoisomer of unknown absolute configuration at the cyclobutyl center and as a white solid. LCMS [M+H-Boc] + = 172.2 m / z; 1 H NMR (400 MHz, DMSO-d6): δ 6.21 (d, J = 6.0 Hz, 1H), 3.86 - 3.84 (m, 1H), 2.38 - 2.36 (m, 1H), 1.89 - 1.72 (m, 2H), 1.68 - 1.58 (m, 5H), 1.37 (s, 9H), 1.15 - 1.09 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H).

[0314] [ka] (2S)-2-((tert-butoxycarbonyl)amino)-3-cyclobutylpentanoic acid To a solution of the second eluting isomer of (S)-N-((1S)-1-cyano-2-cyclobutylbutyl)-2-methylpropane-2-sulfinamide (3.00 g, 11.7 mmol, 100% purity, 1.00 eq) in AcOH (6.30 g, 105 mmol, 6.00 mL, 8.97 eq) was added HCl (12.0 M, 35.0 mL, 35.9 eq) at room temperature. The mixture was stirred at 120° C. for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. 2 The residue and K in O (100 mL) 2 CO 3A solution of (2.43 g, 17.6 mmol, 1.50 eq) of Boc in THF (50.0 mL) at room temperature was 2 O (2.55 g, 11.7 mmol, 2.69 mL, 1.00 eq) was added. The mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with DCM. The aqueous layers were combined, adjusted to pH=4-5 with saturated aqueous citric acid, extracted with DCM, and then washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue that was purified by prep-HPLC eluting with ACN in water (containing 0.1% TFA) to give (2S)-2-((tert-butoxycarbonyl)amino)-3-cyclobutylpentanoic acid (1.26 g, 4.46 mmol, 38.1% yield, 96.1% purity) as a single stereoisomer of unknown absolute configuration at the cyclobutyl center and as a white solid. LCMS [M+H-Boc] + = 172.2 m / z; 1 H NMR (400 MHz, DMSO-d6): δ 6.02 (d, J = 6.8 Hz, 1H), 3.74 - 3.72 (m, 1H), 2.22 - 2.08 (m, 1H), 1.95 - 1.92 (m, 2H), 1.71 - 1.62 (m, 5H), 1.23 (s, 9H), 1.22 - 1.15 (m, 2H), 0.79 (t, J = 7.2 Hz, 3H).

[0315] Example 88: Synthesis of Compound 86 [ka] N-((2S)-3-cyclobutyl-1-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-1-oxopentan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (86) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethan-1-amine hydrochloride, followed by (2S)-2-((tert-butoxycarbonyl)amino)-3-cyclobutylpentanoic acid (first eluting isomer as (S)-N-((1S)-1-cyano-2-cyclobutylbutyl)-2-methylpropane-2-sulfinamide and a single stereoisomer with unknown absolute stereochemistry at the cyclobutyl) and 1-ethyl-1H-pyrazole-5-carboxylic acid. The title compound is a single stereoisomer of unknown absolute stereochemistry at the cyclobutyl center. LCMS [M+H] + = 540.1 m / z.

[0316] Example 89: Synthesis of Compound 87 [ka] N-((2S)-3-cyclobutyl-1-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-1-oxopentan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (87) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethan-1-amine hydrochloride, followed by (2S)-2-((tert-butoxycarbonyl)amino)-3-cyclobutylpentanoic acid ((S)-N-((1S)-1-cyano-2-cyclobutylbutyl)-2-methylpropane-2-sulfinamide as the first second isomer and a single stereoisomer with unknown absolute stereochemistry at the cyclobutyl) and 1-ethyl-1H-pyrazole-5-carboxylic acid. The title compound is a single stereoisomer with unknown absolute stereochemistry at the cyclobutyl center. LCMS [M+H] + = 540.1 m / z. Example 90: Synthesis of Compound 88 [ka] N-((S)-1,1-dicyclobutyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-ethyl-1H-pyrazole-5-carboxamide (88) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclobutylpropanoic acid (prepared according to WO2020127685) and 1-ethyl-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 566.1 m / z.

[0317] Example 91: Synthesis of Compound 89 [ka] Methyl 1-(2-morpholinoethyl)-1H-pyrazole-5-carboxylate Methyl-1H-pyrazole-5-carboxylate (500 mg, 3.96 mmol, 1.00 eq), 2-morpholinoethan-1-ol (624 mg, 4.76 mmol, 583 uL, 1.20 eq) and PPh in THF (5.00 mL). 3 (1.56 g, 5.95 mmol, 1.50 eq) was added dropwise to a solution of DIAD (1.20 g, 5.95 mmol, 1.16 mL, 1.50 eq) at 0° C., and the mixture was then stirred at room temperature for 4 h. The residue was 2 The mixture was diluted with O and extracted with EtOAc. The combined organic layers were washed with brine and 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether (containing 0–100% EtOAc) followed by prep-HPLC (12–42% ACN (0.05% NH 4Purification by elution with hexanes (containing OH) afforded methyl 1-(2-morpholinoethyl)-1H-pyrazole-5-carboxylate (0.600 g, 2.51 mmol, 63.3% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.49 (s, 1H), 6.82 (t, J = 2.0 Hz, 1H), 4.75 (t, J = 6.4 Hz, 2H), 3.89 (d, J = 2.0 Hz, 3H), 3.70 (s, 4H), 2.83 (t, J = 6.4 Hz, 2H), 2.57 (s, 4H).

[0318] [ka] 1-(2-morpholinoethyl)-1H-pyrazole-5-carboxylic acid A solution of methyl 1-(2-morpholinoethyl)-1H-pyrazole-5-carboxylate (0.600 g, 2.51 mmol, 1.00 eq) in THF (10.0 mL) was heated at 0 °C with H 2 LiOH H in O (5.00 mL) 2 A solution of 2H2O (158 mg, 3.76 mmol, 1.50 eq) was added dropwise and then the mixture was allowed to warm to room temperature and stirred for 2 h. The pH of the mixture was adjusted to 6 with 1M HCl. The mixture was concentrated under reduced pressure to give 1-(2-morpholinoethyl)-1H-pyrazole-5-carboxylic acid (0.500 g, 2.22 mmol, 88.5% yield) as a yellow oil. LCMS [M+H] + = 226.2 m / z.

[0319] [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-(2-morpholinoethyl)-1H-pyrazole-5-carboxamide (89) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 1-(2-morpholinoethyl)-1H-pyrazole-5-carboxylic acid. LCMS [M+H] + = 623.4 m / z.

[0320] Example 92: Synthesis of Compound 90 [ka] (S)-2-((S)-6-Bromo-2,3-dihydro-1H-inden-1-yl)-2-((tert-butoxycarbonyl)amino)acetic acid It was prepared according to the procedure as reported in WO2020127685. The absolute configuration was determined by comparison with single crystal x-ray diffraction of the following diastereomeric pair:

[0321] [ka] (S)-2-((R)-6-Bromo-2,3-dihydro-1H-inden-1-yl)-2-((tert-butoxycarbonyl)amino)acetic acid It was prepared according to the procedure reported in WO2020127685. The absolute configuration was determined by single crystal x-ray diffraction of crystals grown by slow evaporation of 15 mg of the title compound in 1 mL of 1:1 methanol / MTBE [parameters: (CuKα), space group = P2 1 , a = 9.62160(10), b = 6.02750(10), c = 14.06420(10), and alpha = 90°, beta = 97.9340(10)°, gamma = 90°].

[0322] [ka] N-((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)-2-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (90) Prepared according to general scheme A using 2-(5-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride followed by (S)-2-((S)-6-bromo-2,3-dihydro-1H-inden-1-yl)-2-((tert-butoxycarbonyl)amino)acetic acid and 1-ethyl-1H-pyrazole-5-carboxylic acid. The title compound was synthesized by the following procedure: To a solution of N-((S)-1-((S)-6-bromo-2,3-dihydro-1H-inden-1-yl)-2-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (15.5 mg, 23.0 umol, 1.00 eq) in MeOH (1.00 mL) was added Pd / C (3.0 mg, 10% purity). The mixture was heated at 15 psi with H 2 The mixture was stirred at room temperature for 2 hours under reduced pressure. The reaction mixture was diluted with MeOH, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (eluted with 10:1 DCM:MeO) to give N-((S)-1-((S)-2,3-dihydro-1H-inden-1-yl)-2-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (7.62 mg, 12.5 umol, 54.4% yield) as a yellow solid. LCMS [M+H] + = 574.3 m / z.

[0323] Example 93: Synthesis of Compound 91 [ka] N-((S)-1-((R)-2,3-dihydro-1H-inden-1-yl)-2-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (91) N-((S)-1-((R)-6-bromo-2,3-dihydro-1H-inden-1-yl)-2-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide was prepared according to general scheme A using 2-(5-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride, followed by (S)-2-((R)-6-bromo-2,3-dihydro-1H-inden-1-yl)-2-((tert-butoxycarbonyl)amino)acetic acid and 1-ethyl-1H-pyrazole-5-carboxylic acid. The title compound was synthesized in the following manner: To a solution of N-((S)-1-((R)-6-bromo-2,3-dihydro-1H-inden-1-yl)-2-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (8.00 mg, 11.9 umol, 1.00 eq) in MeOH (1.00 mL) was added N 2 Pd / C (10%, 0.010 g) was added under atmospheric pressure. The mixture was heated at 10° C. 2 The mixture was stirred at (15 Psi) for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give N-((S)-1-((R)-2,3-dihydro-1H-inden-1-yl)-2-((2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (6.39 mg, 10.7 umol, 89.56% yield) as a yellow solid. LCMS [M+H] + = 574.4 m / z.

[0324] Example 94: Synthesis of Compound 92 [ka] Methyl 1-(1-morpholinopropan-2-yl)-1H-pyrazole-5-carboxylate A solution of methyl-1H-pyrazole-5-carboxylate (500 mg, 3.44 mmol, 1.00 eq) and 1-morpholinopropan-2-ol (480 mg, 3.81 mmol, 1.11 eq) in THF (10.0 mL) was added at 0 °C with DIAD (1.39 g, 6.89 mmol, 1.34 mL, 2.00 eq), and PPh 3 (1.81 g, 6.89 mmol, 2.00 eq) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO 2 , petroleum ether:EtOAc = 10:1 to 8:1), followed by prep-HPLC (eluting with 15-45% ACN in water (containing 0.05% ammonium hydroxide)) to give methyl 1-(1-morpholinopropan-2-yl)-1H-pyrazole-5-carboxylate (300 mg, 1.18 mmol, 34.4% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.52 (d, J = 1.6 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 5.64 - 5.59 (m, 1H), 3.87 (s, 3H), 3.60 - 3.55 (m, 4H), 2.78 - 2.60 (m, 1H), 2.59 - 2.50 (m, 1H), 2.49 - 2.30 (m, 2H), 2.29 - 2.25 (m, 2H), 1.52 (d, J = 6.8 Hz, 3H). LCMS [M+H] + = 254.0 m / z.

[0325] [ka] 1-(1-morpholinopropan-2-yl)-1H-pyrazole-5-carboxylic acid To a solution of methyl 1-(1-morpholinopropan-2-yl)-1H-pyrazole-5-carboxylate (300 mg, 1.18 mmol, 1.00 eq) in THF (5.00 mL) was added NaOH (1.00 M, 2.37 mL, 2.00 eq). The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give 1-(1-morpholinopropan-2-yl)-1H-pyrazole-5-carboxylic acid (280 mg, 1.17 mmol, 98.8% yield, sodium salt) as a colorless oil.

[0326] [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-(1-morpholinopropan-2-yl)-1H-pyrazole-5-carboxamide (92) The title compound was prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethane-1-amine hydrochloride, followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 1-(1-morpholinopropan-2-yl)-1H-pyrazole-5-carboxylic acid. The title compound was the first to elute as a single stereoisomer by chiral SFC purification (column: DAICEL CHIRALPAK AD (250mmx30mm,10um); mobile phase: 0.1% NH in 15% [IPA]). 3 H 2 O]). LCMS [M+H] + = 637.4 m / z.

[0327] Example 95: Synthesis of Compound 93 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-(1-morpholinopropan-2-yl)-1H-pyrazole-5-carboxamide (93) The title compound was prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethane-1-amine hydrochloride, followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 1-(1-morpholinopropan-2-yl)-1H-pyrazole-5-carboxylic acid. The title compound was purified by chiral SFC (column: DAICEL CHIRALPAK AD (250mmx30mm10um); mobile phase: 15% [0.1% NH in IPA] 3 H 2 O]) as the second eluting single stereoisomer. LCMS [M+H] + = 637.4 m / z.

[0328] Example 96: Synthesis of Compound 94 [ka] Methyl 1-(2-bromoethyl)-1H-pyrazole-5-carboxylate Methyl-1H-pyrazole-5-carboxylate (1.00 g, 7.93 mmol, 1.00 eq), 2-bromoethan-1-ol (1.49 g, 11.9 mmol, 845 uL, 1.50 eq), and PPh in THF (20 mL) 3 (3.12 g, 11.9 mmol, 1.50 eq) was added dropwise to a solution of DIAD (2.41 g, 11.9 mmol, 2.31 mL, 1.50 eq) at 0° C., and the mixture was then stirred at room temperature for 2 h. 2 The mixture was diluted with O and extracted with ethyl acetate. The combined organic layers were washed with brine and2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether:EtOAc=100:1 to 1:1) to give methyl 1-(2-bromoethyl)-1H-pyrazole-5-carboxylate (1.30 g, 5.58 mmol, 70.3% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.54 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 4.97 (t, J = 6.8 Hz, 2H), 3.90 (s, 3H), 3.72 (t, J = 6.8 Hz, 2H). LCMS [M+H] + = 234.9 m / z.

[0329] [ka] Methyl 1-(2-(3,3-difluoroazetidin-1-yl)ethyl)-1H-pyrazole-5-carboxylate Methyl 1-(2-bromoethyl)-1H-pyrazole-5-carboxylate (100 mg, 429 umol, 1.00 eq), 3,3-difluoroazetidine hydrochloride (111 mg, 858 umol, 2.00 eq), and DIEA (277 mg, 2.15 mmol, 374 uL, 5.00 eq) were placed in a microwave reaction vial in IPA (3.00 mL). The sealed tube was heated in a microwave at 100° C. for 8 hours. The mixture was concentrated under reduced pressure to give a residue, which was analyzed by prep-TLC (SiO 2 , Plate 1, petroleum ether:EtOAc=3:1) to give methyl 1-(2-(3,3-difluoroazetidin-1-yl)ethyl)-1H-pyrazole-5-carboxylate (90.0 mg, 367 umol, 85.5% yield) as a colorless oil. LCMS [M+H] + = 246.0 m / z.

[0330] [ka] Sodium 1-(2-(1H-imidazol-1-yl)ethyl)-1H-pyrazole-5-carboxylate A solution of methyl 1-(2-(3,3-difluoroazetidin-1-yl)ethyl)-1H-pyrazole-5-carboxylate (90.0 mg, 367 umol, 1.00 eq) in MeOH (2.00 mL) was added to H 2 A solution of NaOH (17.6 mg, 440 umol, 1.20 eq) in O (1.00 mL) was added dropwise, and the mixture was then stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give sodium 1-(2-(1H-imidazol-1-yl)ethyl)-1H-pyrazole-5-carboxylate (90.0 mg, 354 umol, 96.5% yield, sodium salt) as a white solid.

[0331] [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-(2-(3,3-difluoroazetidin-1-yl)ethyl)-1H-pyrazole-5-carboxamide (94) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and sodium 1-(2-(1H-imidazol-1-yl)ethyl)-1H-pyrazole-5-carboxylate. LCMS [M+H] + = 629.3 m / z.

[0332] Example 97: Synthesis of Compound 95 [ka] Methyl 1-(2-(1H-imidazol-1-yl)ethyl)-1H-pyrazole-5-carboxylate Methyl 1-(2-bromoethyl)-1H-pyrazole-5-carboxylate (300 mg, 1.29 mmol, 1.00 eq), imidazole (175 mg, 2.57 mmol, 2.00 eq), and K 2 CO 3 (534 mg, 3.86 mmol, 3.00 eq) was diluted with 3.0 mL of ACN in a microwave reaction vial. The sealed tube was heated at 100° C. for 4 h under microwave heating. The reaction mixture was filtered, concentrated under reduced pressure, and purified by prep-HPLC (eluted with 10-40% ACN in water (containing 10 mM ammonium carbonate)) to give methyl 1-(2-(1H-imidazol-1-yl)ethyl)-1H-pyrazole-5-carboxylate (120 mg, 545 umol, 42.3% yield) as a colorless oil. LCMS [M+H] + = 221.1 m / z.

[0333] [ka] Sodium 1-(2-(1H-imidazol-1-yl)ethyl)-1H-pyrazole-5-carboxylate A solution of methyl 1-(2-(1H-imidazol-1-yl)ethyl)-1H-pyrazole-5-carboxylate (100 mg, 454 umol, 1.00 eq) in MeOH (2.00 mL) was added to H 2 A solution of NaOH (18.2 mg, 454 umol, 1.0) in O (1 mL) was added dropwise and then the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give a residue of crude sodium 1-(2-(1H-imidazol-1-yl)ethyl)-1H-pyrazole-5-carboxylate (0.100 g, 436 umol, 96.1% yield, sodium salt) as a white solid.

[0334] [ka] 1-(2-(1H-imidazol-1-yl)ethyl)-N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1H-pyrazole-5-carboxamide (95) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and sodium 1-(2-(1H-imidazol-1-yl)ethyl)-1H-pyrazole-5-carboxylate. LCMS [M+H] + = 604.3 m / z.

[0335] Example 98: Synthesis of Compound 96 [ka] Tert-Butyl 3-(5-(methoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate tert-Butyl 3-hydroxypiperidine-1-carboxylate (760 mg, 3.78 mmol, 1.5 eq), methyl-1H-pyrazole-5-carboxylate (317 mg, 2.51 mmol, 1 eq), and PPh in THF (10 mL) 3 (988.0 mg, 3.77 mmol, 1.5 eq) was added dropwise to a solution of DIAD (763 mg, 3.77 mmol, 733.65 uL, 1.5 eq) at 0° C., and the mixture was then stirred at room temperature for 3 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO 2, eluted with 0-10% EtOAc in petroleum ether) to afford tert-butyl 3-(5-(methoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (718 mg, 2.32 mmol, 92.43% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.51 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 5.19 - 5.12 (m, 1H), 4.26 (brs, 1H), 4.13 - 4.07 (m, 1H), 3.89 (s, 3H), 3.23 (t, J = 11.2 Hz, 1H), 2.78 (t, J = 12.4 Hz, 1H), 2.15 - 2.06 (m, 2H), 1.86 - 1.83 (m, 1H), 1.67 - 1.64 (m, 1H), 1.46 (s, 9H).

[0336] [ka] Lithium 1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-1H-pyrazole-5-carboxylate. THF (10 mL), MeOH (6 mL) and H 2 A solution of tert-butyl 3-(5-(methoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (718 mg, 2.32 mmol, 1 eq) in 2 mL of H2O was added with LiOH H 2 O (292.18 mg, 6.96 mmol, 3 eq) was added. The mixture was stirred at 60° C. for 6 h. The reaction mixture was concentrated under reduced pressure to give crude lithium 1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-1H-pyrazole-5-carboxylate (518 mg, 1.71 mmol, 73.84% yield, lithium salt) as a white foam.

[0337] [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-(piperidin-3-yl)-1H-pyrazole-5-carboxamide (96) Prepared according to general scheme A using (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethan-1-amine hydrochloride followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and sodium 1-(piperidin-3-yl)-1H-pyrazole-5-carboxylate. The title compound was isolated after SFC separation and Boc removal with hydrochloric acid as follows: tert-butyl 3-(5-(((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate was purified by chiral SFC (column: DAICEL CHIRALPAK AC (250mmx30mm, 5um); mobile phase: 0.1% NH in 20% [IPA]. 3 H 2 O]) to give single stereoisomers. The first eluted single stereoisomer (28 mg, 40 umol, 1.0 eq) was diluted in 0.5 mL of DCM and treated with 4M HCl in dioxane (100 uL, 10 eq). The mixture was stirred at room temperature for 0.5 h. The reaction was treated with saturated sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-(piperidin-3-yl)-1H-pyrazole-5-carboxamide (20 mg, 33 umol, 81% yield) as a white solid. LCMS [M+H]+ = 593.3 m / z.

[0338] Example 99: Synthesis of Compound 97 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-(piperidin-3-yl)-1H-pyrazole-5-carboxamide (97) The title compound was prepared from the second eluting single stereoisomer of tert-butyl 3-(5-(((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (29 mg, 41.86 umol, 1 eq), diluted with 0.5 mL of DCM and treated with 4M HCl in dioxane (100 uL, 10 eq). The mixture was stirred at room temperature for 0.5 h. The reaction was treated with saturated sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give N-((S)-1,1-dicyclopropyl-3-((2-fluoro-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-(piperidin-3-yl)-1H-pyrazole-5-carboxamide (18 mg, 29 umol, 69% yield) as a white solid. LCMS [M+H] + = 593.3 m / z.

[0339] Example 100: Synthesis of Compound 98 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-5-methyl-4-((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (98) The title compound was prepared according to general scheme A using 2-(5-fluoro-2-methyl-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethan-1-amine followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 1-isopropyl-1H-pyrazole-5-carboxylic acid. The title compound was purified by chiral SFC (column: DAICEL CHIRALPAK OD-H (250mmx30mm, 5um); mobile phase: 20% [0.1% NH in MeOH] 3 H 2 O]) was isolated as the first eluting single stereoisomer. LCMS [M+H] + = 566.3 m / z. The absolute stereochemistry was confirmed by resynthesis starting from optically pure (S)-2-(5-fluoro-2-methyl-4-nitrophenyl)propanoic acid.

[0340] Example 101: Synthesis of Compound 99 [ka] N-((S)-1,1-dicyclopropyl-3-((2-fluoro-5-methyl-4-((R)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (99) The title compound was prepared according to general scheme A using 2-(5-fluoro-2-methyl-4-nitrophenyl)propanoic acid and 2,2,2-trifluoroethan-1-amine followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 1-isopropyl-1H-pyrazole-5-carboxylic acid. The title compound was purified by chiral SFC (column: DAICEL CHIRALPAK OD-H (250mmx30mm, 5um); mobile phase: 20% [0.1% NH in MeOH] 3 H 2 O]) was isolated as a single stereoisomer eluting second. LCMS [M+H] + = 566.3 m / z. The absolute configuration was confirmed by comparison with Example 17252, which was resynthesized starting from optically pure (S)-2-(5-fluoro-2-methyl-4-nitrophenyl)propanoic acid.

[0341] Example 102: Synthesis of Compound 100 [ka] N-((S)-1-((4-((S)-1-((3-amino-2,2-difluoropropyl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (100) Prepared using general method A using tert-butyl N-[3-[[(2S)-2-[4-[[(2S)-3,3-dicyclopropyl-2-[(2-isopropylpyrazole-3-carbonyl)amino]propanoyl]amino]-3-fluoro-phenyl]propanoyl]amino]-2,2-difluoro-propyl]carbamate. LCMS [M+H] + = 563.2 m / z.

[0342] Example 103: Synthesis of Compound 101 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-((2S)-1-oxo-1-(2-(trifluoromethyl)piperazin-1-yl)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (101) Prepared using general method A using tert-butyl 4-[(2S)-2-[4-[[(2S)-3,3-dicyclopropyl-2-[(2-isopropylpyrazole-3-carbonyl)amino]propanoyl]amino]-3-fluoro-phenyl]propanoyl]-3-(trifluoromethyl)piperazine-1-carboxylate. LCMS [M+H] + = 607.2 m / z.

[0343] Example 104: General Scheme B - Synthesis of Compounds 102-105 [ka] Examples synthesized according to general Scheme B utilize an aryl halide in step 1, an amino acid in step 3, and a carboxylic acid in step 5. Starting materials are listed in the order of use.

[0344] Example 105: Synthesis of Compound 102 [ka] Synthesis of 2-(4-bromo-3-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide Prepared according to general method B using 2-(4-bromo-3-fluorophenyl)acetic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride.

[0345] [ka] Synthesis of 2-(4-bromo-3-fluorophenyl)-3-methoxy-N-methyl-N-(2,2,2-trifluoroethyl)propanamide To a solution of 2-(4-bromo-3-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (1.00 g, 3.05 mmol, 1.00 eq) in THF (13.0 mL) was added LiHMDS (1.00 M, 3.05 mL, 1.00 eq) and bromo(methoxy)methane (380 mg, 3.05 mmol, 248 uL, 1.00 eq) at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with H 2 Dilute with O, extract with EtOAc, and 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue which was purified by reverse-phase prep-HPLC (41-71% CAN (10 mM N 4 HCO 3 Purification by HPLC (containing ethyl acetate) afforded 2-(4-bromo-3-fluorophenyl)-3-methoxy-N-methyl-N-(2,2,2-trifluoroethyl)propanamide (600 mg, 1.6 mmol, 53% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.56 - 7.48 (m, 1H), 7.1, 9 - 7.09 (m, 1H), 7.02 - 6.96 (m, 1H), 4.29 - 4.17 (m, 1H), 4.09 - 4.02 (m, 1H), 4.00 - 3.94 (m, 1H), 3.93 - 3.83 (m, 1H), 3.57 - 3.49 (m, 1H), 3.35 - 3.31 (m, 3H), 3.08 - 3.03 (m, 3H). LCMS [M+H] + = 372.0 m / z.

[0346] [ka] Synthesis of tert-butyl (2-fluoro-4-(3-methoxy-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)carbamate 2-(4-bromo-3-fluorophenyl)-3-methoxy-N-methyl-N-(2,2,2-trifluoroethyl)propanamide (560 mg, 1.50 mmol, 1.00 eq), tert-butyl carbamate (264 mg, 2.26 mmol, 1.50 eq), Pd 2 (dba) 3 (68.9mg, 75.2umol, 0.05eq), Cs 2 CO 3 A mixture of (1.23 g, 3.76 mmol, 2.5 eq), and Xphos (71.7 mg, 150 umol, 0.100 eq) was degassed and then diluted with N 2 The mixture was heated at 80° C. for 2 hours under reduced pressure. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (PE:EtOAc=100:1 to 3:1) to obtain tert-butyl (2-fluoro-4-(3-methoxy-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)carbamate (400 mg, 980 umol, 65% yield) as a yellow oil. LCMS [M+H] + = 409.1 m / z.

[0347] [ka] Synthesis of 2-(4-amino-3-fluorophenyl)-3-methoxy-N-methyl-N-(2,2,2-trifluoroethyl)propanamide Prepared according to general procedure A using tert-butyl (2-fluoro-4-(3-methoxy-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)carbamate. 1 H NMR (400 MHz, CDCl 3): δ 7.01 - 6.91 (m, 1H), 6.89 - 6.83 (m, 1H), 6.79 - 6.71 (m, 1H), 4.30 - 4.17 (m, 1H), 3.98 - 3.81 (m, 3H), 3.50 - 3.45 (m, 1H), 3.35 - 3.32 (m, 3H), 3.06 - 3.03 (m, 3H).

[0348] [ka] Synthesis of N-((1S)-1-cycloheptyl-2-((2-fluoro-4-(3-methoxy-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (102). The title compound was prepared according to general scheme B using 2-(4-amino-3-fluorophenyl)-3-methoxy-N-methyl-N-(2,2,2-trifluoroethyl)propanamide, (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid, and 1-ethyl-1H-pyrazole-5-carboxylic acid. The title compound was purified using chiral SFC (column: DAICEL CHIRALPAK AD (250mmx30mm, 10um); mobile phase: 0.1% NH in 25% [IPA]. 3 H 2 O]) as a single stereoisomer as a white solid and the first eluting single stereoisomer. LCMS [M+H] + = 584.3 m / z.

[0349] Example 106: Synthesis of Compound 103 [ka] Synthesis of N-((1S)-1-cycloheptyl-2-((2-fluoro-4-(3-methoxy-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (103) The title compound was prepared according to general scheme B using 2-(4-amino-3-fluorophenyl)-3-methoxy-N-methyl-N-(2,2,2-trifluoroethyl)propanamide, (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid, and 1-ethyl-1H-pyrazole-5-carboxylic acid. The title compound was purified by chiral SFC (column: DAICEL CHIRALPAK AD (250mmx30mm10um); mobile phase: 25% [0.1% NH in IPA] 3 H 2 O]) as a white solid, a single stereoisomer, and the second eluting single stereoisomer. LCMS [M+H] + = 584.3 m / z.

[0350] Example 107: Synthesis of Compound 104 [ka] Methyl 2-(4-bromo-3-fluorophenyl)acetate A solution of 2-(4-bromo-3-fluorophenyl)acetic acid (3.00 g, 12.8 mmol, 1.00 eq) in MeOH (30.0 mL) was added to the flask at 0 °C with SOCl 2 (3.06 g, 25.8 mmol, 1.87 mL, 2.00 eq) and DMF (94.1 mg, 1.29 mmol, 99.1 uL, 0.100 eq) were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue which was then purified by H 2 The mixture was diluted with saturated NaHCO 3 Basify to pH=8 with aqueous solution of 100% NaCl, extract with EtOAc, and 2 SO 4 Drying at 40° C., filtering and concentrating in vacuo gave methyl 2-(4-bromo-3-fluorophenyl)acetate (3.10 g, 12.6 mmol, 97.4% yield) as a yellow oil.

[0351] [ka] Methyl 2-(4-bromo-3-fluorophenyl)-3-methoxypropanoate To a solution of methyl 2-(4-bromo-3-fluorophenyl)acetate (3.10 g, 12.5 mmol, 1.00 eq) in THF (50.0 mL) was added LiHMDS (12.5 mL, 1.00 eq) and bromo(methoxy)methane (1.57 g, 12.6 mmol, 1.02 mL, 1.00 eq) at −15° C. The mixture was stirred at −15° C. for 1 h. The mixture was diluted with H 2 Dilute with 202.0, acidify with 1M HCl to pH = 8.0, extract with EtOAc, and 2 SO 4 The resulting residue was purified by column chromatography (SiO 2 , petroleum ether:EtOAc=1:0-100:3) to give methyl 2-(4-bromo-3-fluorophenyl)-3-methoxypropanoate (3.30 g, 11.3 mmol, 90.3% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.52 - 7.48 (m, 1H), 7.20 - 7.11 (m, 1H), 7.05 - 6.95 (m, 1H), 3.95 - 3.75 (m, 2H), 3.71 (s, 3H), 3.68 - 3.57 (m, 1H), 3.36 (s, 3H).

[0352] [ka] 2-(4-bromo-3-fluorophenyl)-3-methoxypropanoic acid A solution of methyl 2-(4-bromo-3-fluorophenyl)-3-methoxypropanoate (1.00 g, 3.44 mmol, 1.00 eq) in toluene (20.0 mL) was added at room temperature to (Bu 3 Sn) 22H2O (9.36 g, 15.7 mmol, 8.00 mL, 4.57 eq) was added. The mixture was stirred at 120° C. for 60 h. The mixture was filtered, concentrated under reduced pressure and washed with 10 mL of saturated aqueous KF and 30.0 mL of H2O. 2 The mixture was diluted with 200 mL of 1.0 M HCl and stirred at room temperature for 2 h. The mixture was acidified to pH=5.0 with 1.0 M HCl, filtered, extracted with DCM, and diluted with Na 2 SO 4 The resulting residue was purified by prep-HPLC (eluted with 1-30% EtOH (containing 0.1% formic acid) in hexanes) to give 2-(4-bromo-3-fluorophenyl)-3-methoxypropanoic acid (800 mg, 2.89 mmol, 84.1% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.51 (t, J = 3.8 Hz, 1H), 7.24 - 7.13 (m, 1H), 7.08 - 6.95 (m, 1H), 3.95 - 3.80 (m, 2H), 3.70 - 3.60 (m, 1H), 3.45 - 3.30 (m, 3H). LCMS [2M+H] + = 552.9 m / z.

[0353] [ka] 2-(4-bromo-3-fluorophenyl)-3-methoxy-N-(2,2,2-trifluoroethyl)propanamide To a solution of 2-(4-bromo-3-fluorophenyl)-3-methoxypropanoic acid (400 mg, 1.44 mmol, 1.00 eq) and 2,2,2-trifluoroethan-1-amine (214 mg, 2.17 mmol, 170 uL, 1.50 eq) in DCM (10.0 mL) was added T3P (1.38 g, 2.17 mmol, 1.29 mL, 50% purity, 1.50 eq) and DIEA (1.87 g, 14.4 mmol, 2.51 mL, 10.0 eq). The mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with H 2 The mixture was diluted with O and extracted with EtOAc. The combined organic layers were washed with saturated NaCl and2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give crude 2-(4-bromo-3-fluorophenyl)-3-methoxy-N-(2,2,2-trifluoroethyl)propanamide (500 mg, 1.40 mmol, 96.7% yield) as a yellow solid. LCMS [M+H] + = 357.9 m / z.

[0354] [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-(3-methoxy-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (104) The title compound was prepared according to general scheme B using 2-(4-bromo-3-fluorophenyl)-3-methoxy-N-(2,2,2-trifluoroethyl)propanamide, (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid, and 1-isopropyl-1H-pyrazole-5-carboxylic acid. The title compound was purified by chiral SFC (column: DAICEL CHIRALPAK OD-H (250mmx30mm, 5um); mobile phase: 20% [0.1% NH in MeOH] 3 H 2 O]) was isolated as the first eluting single stereoisomer. LCMS [M+H] + = 582.3 m / z.

[0355] Example 108: Synthesis of Compound 105 [ka] N-((2S)-1,1-dicyclopropyl-3-((2-fluoro-4-(3-methoxy-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (105) The title compound was prepared according to general scheme B using 2-(4-bromo-3-fluorophenyl)-3-methoxy-N-(2,2,2-trifluoroethyl)propanamide, (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid, and 1-isopropyl-1H-pyrazole-5-carboxylic acid. The title compound was purified by chiral SFC (column: DAICEL CHIRALPAK OD-H (250mmx30mm, 5um); mobile phase: 20% [0.1% NH in MeOH] 3 H 2 O]) was isolated as a single stereoisomer, the second elution. LCMS [M+H] + = 582.3 m / z.

[0356] Example 109: General Scheme E - Synthesis of Compound 106 [ka]

[0357] Example 110: Synthesis of Compound 106 [ka] (S)-3,3-Dicyclopropyl-N-(2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)-2-(pyrazolo[1,5-a]pyrazin-4-ylamino)propenamide (106) According to general scheme E, (S)-2-(3-fluoro-4-nitrophenyl)propanoic acid and 2,2,2-trifluoro-N-methylethan-1-amine hydrochloride were used, followed by (S)-2-((tert-butoxycarbonyl)amino)-3,3-dicyclopropylpropanoic acid and 4-chloropyrazolo[1,5-a]pyrazine, as shown in the procedure below: Amino-3,3-dicyclopropyl-N-(2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)propanamide (35.0 mg, 81.5 umol, 1.00 eq), 4-chloropyrazolo[1,5-a]pyrazine (15.0 mg, 97.8 umol, 1.20 eq), BINAP (5.07 mg, 8.15 umol, 0.100 eq), Pd 2 (dba) 3 A mixture of (7.46 mg, 8.15 umol, 0.100 eq) and t-BuONa (11.7 mg, 122 umol, 1.50 eq) was stirred at 100° C. for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was analyzed by prep-TLC (SiO 2 , petroleum ether:EtOAc 1:1), followed by prep-HPLC eluting with 46-76% ACN in water (containing 0.225% formic acid) to give (S)-3,3-dicyclopropyl-N-(2-fluoro-4-((S)-1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)-2-(pyrazolo[1,5-a]pyrazin-4-ylamino)propanamide (15.0 mg, 27.3 umol, 33.5% yield) as a white solid. LCMS [M+H] + = 547.3.

[0358] Example 111: General Scheme F - Synthesis of Compound 107 [ka] Examples synthesized according to general Scheme F utilize an aniline and an amino acid in step 1, followed by an amine in step 3 and a carboxylic acid in step 5. Starting materials are listed in the order of use.

[0359] Example 112: Synthesis of Compound 107 [ka] (S)-N-(1,1-dicyclopropyl-3-((2-fluoro-4-(2-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-o...

Claims

1. Formula I: 【Chemical 1】 (I) [Formula: A is selected from one or more substituents independently selected from (i), (ii), and (iii), and may be optionally substituted with a 5- to 6-membered heterocycle: (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 is alkyl and: 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 A carbon ring and a 3- to 10-membered heterocyclic ring, each of which is independently selected from halogen, -OR １１ , -SR １１ , -N(R １１ ), -C(O)R ２ , -C(O)OR １１ , -OC(O)R １１ , -OC(O)N(R １１ ), -C(O)N(R １１ ), -N(R ２ ), -N(R １１ ), -N(R ２ ), -N(R １１ ), -N(R １１ ), -N(R １１ ), -N(R １１ ), -N(R １１ ), -N(R １１ ), -N(R ２ ), -N(R １１ ), -S(O) ２ (R １１ ), -S(O)R １１ , -S(O) ２ R １１ , -S(O) ２ , -S(O) １１ N(R ２ ), -NO ２ , =O, and -CN, and may be optionally substituted with one or more substituents independently selected therefrom, a C ３－１０ carbon ring and a 3- to 10-membered heterocyclic ring Optionally substituted with one or more substituents independently selected from, C １－１０ alkyl; and (iii) A 3- to 10-membered heterocycle: 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 ), -C(O)R ２ , -C(O)OR １１ , -OC(O)R １１ , -OC(O)N(R １１ ), -C(O)N(R １１ ), -N(R ２ ), -N(R １１ ), -N(R ２ ), -N(R １１ )C(O)R １１ ), -N(R １１ )C(O)OR １１ ), -N(R １１ )C(O)N(R １１ ), -N(R ２ ), -N(R １１ )S(O) ２ (R １１ ), -S(O)R １１ ), -S(O) ２ R １１ ), -S(O) ２ N(R １１ ), -NO ２ , =O, and -CN, and is optionally substituted with one or more substituents independently selected therefrom, C ２ alkyl １－６ alkyl Optionally substituted with one or more substituents independently selected from: A 3- to 10-membered heterocycle; B is -CH(R Ａ )(R Ｂ ) and C ３－１０ selected from a carbocyclic ring, and the C ３－１０ carbocyclic ring is 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, 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; １－６ Alkyl Optionally substituted with one or more substituents independently selected from: R Ａ and R Ｂ each independently 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 ), -C(O)R ２ , -C(O)OR １３ , -OC(O)R １３ , -OC(O)N(R １３ ), -C(O)N(R １３ ), -N(R ２ ), -N(R １３ ), -N(R ２ ), -N(R １３ ), -N(R １３ ), -N(R １３ ), -N(R １３ ), -N(R １３ ), -N(R １３ ), -N(R ２ ), -N(R １３ ), -N(R ２ ), -S(O) ２ (R １３ ), -S(O)R １３ ), -S(O) ２ R １３ ), -S(O) ２ N(R １３ ), -NO ２ ), and -CN; and optionally substituted C ２ alkyl; and １－６ and C ３－１０ A carbon ring, 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 optionally substituted with one or more substituents independently selected from -CN, a C ３－１０ carbon ring Selected from: 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 which is alkyl 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 C １－６ alkyl optionally substituted with one or more substituents independently selected from -CN; and A 3- to 10-membered heterocycle, 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 a 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from -CN; and (vii) A 3- to 10-membered heterocycle, 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 a 3- to 10-membered heterocycle which may be optionally substituted with one or more substituents independently selected from halogen, -OR, -SR, -N(R), -C(O)R, -C(O)OR, -OC(O)R, -OC(O)N(R), -C(O)N(R), -N(R),C(O)R, -N(R),C(O)OR, -N(R),C(O)N(R), -N(R),S(O)(R), -S(O)R, -S(O)R, -S(O)N(R), -NO, and -CN; R ３ and R ４ each independently selected from (a), (b), (c), and (d): (a) Hydrogen; (b) C １ which is alkyl, 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 Carbocycles and 3- to 10-membered heterocycles, any of which may be 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, ３－１０ Carbocycles and 3- to 10-membered heterocycles; (c) C ２－６ alkyl, 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)-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 is optionally substituted with one or more substituents independently selected therefrom, C ２－６ alkyl; C ３－１０ A carbon ring and a 3- to 10-membered heterocycle, which are 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 ), -C(O)R ２ , -C(O)OR １５ , -OC(O)R １３ , -OC(O)N(R １５ ), -C(O)N(R １５ ), -N(R ２ ), -C(O)N(R １５ ), -N(R ２ ), -N(R １５ ), -N(R １５ ), -N(R １５ ), -N(R １５ ), -N(R １５ ), -N(R １５ ), -N(R ２ ), -N(R １５ ), -N(R ２ ), -S(O) １５ ), -S(O)R １５ ), -S(O) ２ R １５ ), -S(O) ２ ), -S(O) １５ ), -NO ２ ), and -CN, and are optionally substituted with one or more substituents independently selected from halogen, C ２ haloalkyl, C ３－１０ A carbon ring and a 3- to 10-membered heterocycle Optionally substituted with one or more substituents independently selected from, C １ alkyl; and (d) C ３－１０ A carbon ring and a 3- to 10-membered hetero ring, any of which 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 ), -C(O)R ２ , -C(O)OR １５ , -OC(O)R １３ , -OC(O)N(R １５ ), -C(O)N(R １５ ), -N(R ２ ), -N(R １５ ), -N(R ２ ), -N(R １５ )C(O)R １５ ), -N(R １５ )C(O)OR １５ ), -N(R １５ )C(O)N(R １５ ), -N(R ２ ), -N(R １５ )S(O) ２ (R １５ ), -S(O)R １５ ), -S(O) ２ R １５ ), -S(O) ２ N(R １５ ), -NO ２ , and -CN, and optionally substituted with one or more substituents independently selected from the above, C ２ alkyl １－６ alkyl Optionally substituted with one or more substituents independently selected from, C ３－１０ carbocyclic ring and 3- to 10-membered heterocyclic ring; or R ３ and R ４ together form a 4- to 12-membered heterocycle, 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 ), -C(O)R ２ , -C(O)OR １６ , -OC(O)R １６ , -OC(O)N(R １６ ), -C(O)N(R １６ ), -N(R ２ ), -C(O)N(R １６ ), -N(R ２ ), -N(R １６ ), -N(R １６ ), -N(R １６ ), -N(R １６ ), -N(R １６ ), -N(R １６ ), -N(R ２ ), -N(R １６ ), -S(O) ２ (R １６ ), -S(O)R １６ ), -S(O) ２ R １６ ), -S(O) ２ N(R １６ ), -NO ２ , =O, and -CN, and is optionally substituted with one or more substituents independently selected therefrom, C ２ alkyl １－６ alkyl Can form a 4- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: R ５ is 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, any of which may be optionally substituted with one or more substituents independently selected from halogen, -OR １７ , -SR １７ , -N(R １７ ), -C(O)R ２ , -C(O)OR １７ , -OC(O)R １７ , -OC(O)N(R １７ ), -C(O)N(R １７ ), -N(R ２ ), -C(O)N(R １７ ), -N(R ２ ), -N(R １７ ), -C(O)R １７ , -N(R １７ ), -C(O)OR １７ , -N(R １７ ), -C(O)N(R １７ ), -N(R ２ ), -N(R １７ ), -S(O) ２ (R １７ ), -S(O)R １７ , -S(O) ２ R １７ , -S(O) ２ , -S(O) １７ (R ２ ), -NO ２ , =O, and -CN, and may be optionally substituted with one or more substituents independently selected therefrom, C １－６ alkyl and C ２－６ alkenyl; and C ３－１０ A carbon ring, 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, and may be optionally substituted with one or more substituents independently selected from, C ３－１０ carbon ring Selected from: R １１ 、 R １２ 、 R １３ 、 R １４ 、 R １４Ｂ 、 R １５ 、 R １６ 、 R １７ 、 and R １７Ｂ are each independently selected 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 alkyl optionally substituted with one or more substituents independently selected from carbocyclic rings and 3- to 10-membered heterocyclic rings (wherein the carbocyclic rings and 3- to 10-membered heterocyclic rings are optionally substituted with one or more substituents selected from halogen, -OH, C １－６ alkyl, -O-C ３－１０ alkyl, -O-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 A carbon ring and a 3- to 10-membered heterocyclic ring, each of which is 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; C １－６ alkyl which may be 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; a C １－６ carbon ring and a 3- to 10-membered heterocyclic ring which may be optionally substituted with one or more substituents independently selected from C ３－１０ alkyl; and n is selected from 0, 1, 2, 3, and 4, n is selected from 1, 2, 3, and 4; or R １ or R ２ at least one of which is hydrogen] A compound represented by the structure or a pharmaceutically acceptable salt thereof.

2. R ５ is a C ３－１０ carbocyclic ring, optionally substituted with one or more substituents independently selected from halogen, -OR １７Ｂ , -SR １７Ｂ , -N(R １７Ｂ ), -C(O)R ２ , -C(O)OR １７Ｂ , -OC(O)R １７Ｂ , -OC(O)N(R １７Ｂ ), -C(O)N(R １７Ｂ ), -N(R ２ ), -C(O)N(R １７Ｂ ), -N(R ２ ), -N(R １７Ｂ ), -C(O)R １７Ｂ ), -N(R １７Ｂ ), -C(O)OR １７Ｂ ), -N(R １７Ｂ ), -C(O)N(R １７Ｂ ), -N(R ２ ), -N(R １７Ｂ ), -S(O) ２ (R １７Ｂ ), -S(O)R １７Ｂ ), -S(O) ２ R １７Ｂ ), -S(O) ２ N(R １７Ｂ ), -NO ２ ), and -CN, and is optionally substituted with one or more substituents independently selected therefrom, a compound or salt according to claim 1, selected from a C ２ carbocyclic ring. ３－１０ ​

3. R ５ is a C ３－６ carbocyclic ring optionally substituted with one or more substituents independently selected from halogen, -OR １７Ｂ , -N(R １７Ｂ ), -C(O)R ２ , -C(O)OR １７Ｂ , -NO １７Ｂ , and -CN, and is selected from C ２ carbocyclic rings, the compound or salt according to claim 2. ３－６ ​

4. R ５ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any of which may be optionally substituted, the compound or salt according to claim 3.

5. R ５ is 【Chemical 2】 The compound or salt according to Claim 4, represented by:

6. R １ or R ２ One of them is C １－６ alkyl, which is independently selected from halogen, -OR １４Ｂ , -SR １４Ｂ , -N(R １４Ｂ ), -C(O)R ２ , -C(O)OR １４Ｂ , -OC(O)R １４Ｂ , -OC(O)N(R １４Ｂ ), -C(O)N(R １４Ｂ ), -N(R ２ ), -C(O)N(R １４Ｂ ), -N(R ２ ), -N(R １４Ｂ )C(O)R １４Ｂ ), -N(R １４Ｂ )C(O)OR １４Ｂ ), -N(R １４Ｂ ), -C(O)N(R １４Ｂ ), -N(R ２ ), -N(R １４Ｂ ), -S(O) ２ (R １４Ｂ ), -S(O)R １４Ｂ ), -S(O) ２ R １４Ｂ ), -S(O) ２ N(R １４Ｂ ), -NO ２ , and -CN, and is optionally substituted with one or more substituents independently selected from 3- to 10-membered heterocycles that are optionally substituted with one or more substituents independently selected from halogen, -OR ２ , -SR １－６ alkyl; and A 3- to 10-membered heterocycle, 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, The compound or salt according to Claim 1, selected from:

7. R １ Or R ２ One of them is C. １－６ Alkyl, halogen, -OR １４Ｂ , -N(R １４Ｂ ) ２ , -C(O)R １４Ｂ , -C(O)OR １４Ｂ , -NO ２ and a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from -CN; １－６ 7. The compound or salt of claim 6, wherein the aryl group is selected from alkyl.

8. R １ or R ２ in which one of them is C １－６ alkyl substituted with a 5- or 6-membered saturated heterocycle, wherein the 5- or 6-membered saturated heterocycle is selected from pyrrolidine, pyrroline, pyrazoline, imidazoline, tetrahydrofuran, dioxolane, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, and any one of them may be optionally substituted, the compound or salt according to claim 7.

9. R １ or R ２ One of them is 【Chemical 3】 The compound or salt according to Claim 8, represented by:

10. R １ Or R ２ is a 5- to 6-membered heterocycle, and one of the １４Ｂ , -N(R １４Ｂ ) ２ , -C(O)R １４Ｂ , -C(O)OR １４Ｂ , -NO ２ 7. The compound or salt of claim 6, optionally substituted with one or more substituents independently selected from:

11. R １ or R ２ wherein the 5- or 6-membered heterocyclic ring is a 5- or 6-membered saturated heterocyclic ring selected from pyrrolidine, pyrroline, pyrazoline, imidazoline, tetrahydrofuran, dioxolane, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, and any one of these may be optionally substituted, the compound or salt according to claim 10.

12. R １ or R ２ wherein the 5- or 6-membered saturated heterocyclic ring is 【Chemical 4】 The compound or salt according to Claim 11, represented by:

13. R ３ and R ４ One of them is C １ alkyl, and 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 A carbon ring and a 3- to 10-membered heterocyclic ring, each of which is independently selected from halogen, C １－６ haloalkyl, C １－６ alkoxy, -OR １５ , -SR １５ , -N(R １５ ), -C(O)R ２ , -C(O)OR １５ , -OC(O)R １５ , -OC(O)N(R １５ ), -C(O)N(R １５ ), -N(R ２ ), -C(O)N(R １５ ), -N(R ２ ), -N(R １５ ), -C(O)R １５ , -N(R １５ ), -C(O)OR １５ , -N(R １５ ), -C(O)N(R １５ ), -N(R ２ ), -N(R １５ ), -S(O) ２ (R １５ ), -S(O)R １５ , -S(O) ２ R １５ , -S(O) ２ , -S(O) １５ N(R ２ ), -NO ２ , and -CN, and may be optionally substituted with one or more substituents independently selected therefrom, a C ３－１０ carbon ring and a 3- to 10-membered heterocyclic ring Optionally substituted with one or more substituents independently selected from, C １ The compound or salt according to claim 1, selected from alkyl.

14. R ３ and R ４ One of which is 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, and is optionally substituted with one or more substituents independently selected from halogen, -OR １ alkyl, the compound or salt according to claim 13

15. R ３ and R ４ One of them is [Chemical Formula 5] The compound or salt according to Claim 14, represented by:

16. The compound of Formula I is of Formula (I-a): 【Chemical Formula 6】 (I-a) [Wherein: A is selected from one or more substituents independently selected from (i), (ii), and (iii), and may be optionally substituted with a 5- to 6-membered heterocycle: (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 is alkyl, 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 Carbocycles and 3- to 10-membered heterocycles, each of which is selected from the group consisting of 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; ３－１０ Carbocycles and 3- to 10-membered heterocycles Optionally substituted with one or more substituents independently selected from, C １－１０ alkyl; and (iii) A 3- to 10-membered heterocycle, 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 ), -C(O)R ２ , -C(O)OR １１ , -OC(O)R １１ , -OC(O)N(R １１ ), -C(O)N(R １１ ), -N(R ２ ), -N(R １１ ), -N(R ２ ), -N(R １１ )C(O)R １１ ), -N(R １１ )C(O)OR １１ ), -N(R １１ )C(O)N(R １１ ), -N(R ２ ), -N(R １１ ), -S(O) ２ (R １１ ), -S(O)R １１ ), -S(O) ２ R １１ ), -S(O) ２ N(R １１ ), -NO ２ ), =O, and -CN, and is optionally substituted with one or more substituents independently selected therefrom, C ２ alkyl １－６ alkyl Optionally substituted with one or more substituents independently selected from: B is -CH(R Ａ )(R Ｂ ) and C ３－１０ selected from a carbocyclic ring, and the C ３－１０ carbocyclic ring is 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 ), -C(O)R ２ , -C(O)OR １２ , -OC(O)R １２ , -OC(O)N(R １２ ), -C(O)N(R １２ ), -N(R ２ ), -N(R １２ ), -N(R ２ ), -N(R １２ ), -N(R １２ ), -N(R １２ ), -N(R １２ ), -N(R １２ ), -N(R １２ ), -N(R ２ ), -N(R １２ ), -NO ２ ), =O, and -CN, and is optionally substituted with one or more substituents independently selected from halogen, -OR １２ ), -SR １２ ), -S(O)R ２ ), -S(O) １２ R ２ ), -S(O) １２ N(R ２ ), -NO ２ ), =O, and -CN, and is optionally substituted with one or more substituents independently selected from halogen, -OR １－６ alkyl A 3- to 10-membered heterocycle; R Ａ and R Ｂ each independently 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, 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, １－６ Alkyl; and C ３－１０ A carbon ring, halogen, -OR １３ , -SR １３ , -N(R １３ ), -C(O)R ２ , -C(O)OR １３ , -OC(O)R １３ , -OC(O)N(R １３ ), -C(O)N(R １３ ), -N(R ２ ), -N(R １３ ), -N(R ２ ), -N(R １３ ), -N(R １３ ), -N(R １３ ), -N(R １３ ), -N(R １３ ), -N(R １３ ), -N(R ２ ), -N(R １３ ), -S(O) ２ (R １３ ), -S(O)R １３ , -S(O) ２ R １３ , -S(O) ２ , -S(O) １３ N(R ２ ), -NO ２ , and -CN, and may be optionally substituted with one or more substituents independently selected from, C ３－１０ carbon ring Optionally substituted with one or more substituents independently selected from: R １ and R ２ each independently is 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 ), -C(O)R ２ , -C(O)OR １４ , -OC(O)R １４ , -OC(O)N(R １４ ), -C(O)N(R １４ ), -N(R ２ ), -C(O)N(R １４ ), -N(R ２ ), -N(R １４ ), -C(O)R １４ ), -N(R １４ ), -C(O)OR １４ ), -N(R １４ ), -C(O)N(R １４ ), -N(R ２ ), -N(R １４ ), -S(O) ２ (R １４ ), -S(O)R １４ ), -S(O) ２ R １４ ), -S(O) ２ N(R １４ ), -NO ２ , and -CN, and optionally substituted with one or more substituents independently selected therefrom, C ２ alkyl １－６ alkyl Selected from: R ３ and R ４ each independently selected from (a), (b), (c), and (d): (a) Hydrogen; (b) C １ which is alkyl, 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 Carbocycles and 3- to 10-membered heterocycles, any of which may be 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, ３－１０ Carbocycles and 3- to 10-membered heterocycles Optionally substituted with one or more substituents independently selected from, C １ alkyl; (c) C ２－６ is alkyl, 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 A carbon ring and a 3- to 10-membered heterocyclic ring, any of which may be 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 ), -C(O)R ２ , -C(O)OR １５ , -OC(O)R １３ , -OC(O)N(R １５ ), -C(O)N(R １５ ), -N(R ２ ), -C(O)N(R １５ ), -N(R ２ ), -N(R １５ ), -N(R １５ ), -N(R １５ ), -N(R １５ ), -N(R １５ ), -N(R １５ ), -N(R ２ ), -N(R １５ ), -N(R ２ ), -S(O) １５ ), -S(O)R １５ ), -S(O) ２ R １５ ), -S(O) ２ N(R １５ ), -NO ２ ), and -CN, and may be optionally substituted with one or more substituents independently selected from halogen, C ２ haloalkyl, C ３－１０ a carbon ring and a 3- to 10-membered heterocyclic ring Optionally substituted with one or more substituents independently selected from, C ２－６ alkyl; and (d) C ３－１０ A carbon ring and a 3- to 10-membered hetero ring, any of which 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, 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, １－６ Alkyl Optionally substituted with one or more substituents independently selected from, C ３－１０ carbocyclic ring and 3- to 10-membered heterocyclic ring; or R ３ and R ４ together form a 4- to 12-membered heterocycle, 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 ), -C(O)R ２ , -C(O)OR １６ , -OC(O)R １６ , -OC(O)N(R １６ ), -C(O)N(R １６ ), -N(R ２ ), -N(R １６ ), -N(R ２ ), -N(R １６ ), -N(R １６ ), -N(R １６ ), -N(R １６ ), -N(R １６ ), -N(R １６ ), -N(R ２ ), -N(R １６ ), -NO ２ ), -S(O) １６ ), -S(O)R １６ ), -S(O) ２ R １６ ), -S(O) ２ ), -S(O) １６ ), -NO ２ ), =O, and -CN, and is optionally substituted with one or more substituents independently selected therefrom, C ２ alkyl １－６ alkyl Can form a 4- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: R ５ is 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 independently selected from halogen, -OR １７ , -SR １７ , -N(R １７ ), -C(O)R ２ , -C(O)OR １７ , -OC(O)R １７ , -OC(O)N(R １７ ), -C(O)N(R １７ ), -N(R ２ ), -C(O)N(R １７ ), -N(R ２ ), -N(R １７ ), -N(R １７ ), -N(R １７ ), -N(R １７ ), -N(R １７ ), -N(R １７ ), -N(R ２ ), -N(R １７ ), -S(O) ２ (R １７ ), -S(O)R １７ , -S(O) ２ R １７ , -S(O) ２ , -S(O) １７ , -NO ２ , =O, and -CN, and may be optionally substituted with one or more substituents independently selected from these, C ２ alkyl and C １－６ alkenyl ２－６ alkenyl Selected from: R １１ 、R １２ 、R １３ 、R １４ 、R １５ 、R １６ 、and R １７ are each independently selected 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 alkyl optionally substituted with one or more substituents independently selected from carbocyclic rings and 3- to 10-membered heterocyclic rings (the carbocyclic rings and 3- to 10-membered heterocyclic rings are optionally substituted with one or more substituents selected from halogen, -OH, C １－６ alkyl, the C ３－１０ carbocyclic rings and 3- to 10-membered heterocyclic rings 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 A carbon ring and a 3- to 10-membered heterocyclic ring, each of which is 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 C １－６ alkyl which may be 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 a C １－６ carbon ring and a 3- to 10-membered heterocyclic ring which may be optionally substituted with one or more substituents independently selected from C ３－１０ alkyl; and n is selected from 0, 1, 2, 3, and 4, n is selected from 1, 2, 3, and 4; or R １ or R ２ at least one of which is hydrogen]] The compound or salt according to Claim 1, represented by:

17. The compound or salt according to claim 16, wherein n is selected from 1, 2, 3, and 4.

18. The compound or salt according to claim 16, wherein n is selected from 1 and 2.

19. The compound or salt according to claim 16, wherein n is 1.

20. R ５ is halogen, -OR １７ -SR １７ -N(R １７ ) ２ -C(O)R １７ -NO ２ 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 , -NO ２ , =O, and -CN, and is optionally substituted with C １－３ alkyl and C ２－３ alkenyl The compound or salt according to claim 16, selected from

21. R ５ is chloro, fluoro, bromo, -OR １７ , -N(R １７ ), ２ , -CN; C １－３ 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 and is optionally substituted with one or more substituents independently selected from chloro, fluoro, -OR １－３ alkyl and C ２－３ alkenyl The compound or salt according to claim 16, selected from

22. R ５ is chloro, fluoro, bromo, -CN, methyl, ethyl, 【Chemical Formula 7】 The compound or salt according to claim 21, selected from

23. R ５ is chloro, fluoro, bromo, -CN, methyl, ethyl, 【Chemical 8】 The compound or salt according to claim 21, selected from

24. A is a 5- to 6-membered heteroaryl, C １－１０ Alkyl, halogen, -OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ , =O, -CN; and C ３－１０ Carbocycles and 3- to 10-membered heterocycles, each of which is selected from the group consisting of halogen, —OR １１ , -N(R １１ ) ２ , -C(O)R １１ , -C(O)OR １１ , -NO ２ , ═O, —CN, ３－１０ C is optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; １－１０ Alkyl; and A 3- to 10-membered heterocycle, halogen, -OR １１ , -N(R １１ ), -C(O)R ２ , -C(O)OR １１ , -NO １１ , =O, -CN; and C ２ alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR １－６ , -N(R １１ ), -C(O)R １１ , -C(O)OR ２ , -NO １１ , =O, and -CN, and a 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from C １１ alkyl optionally substituted with one or more substituents independently selected from the above ２ １－６ ​​ which may be optionally substituted with one or more substituents selected from The compound or salt according to claim 16, selected from

25. The compound or salt according to claim 16, wherein A is selected from optionally substituted 5-membered heteroaryl.

26. The compound or salt according to claim 25, wherein A is selected from pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, triazole, tetrazole, and pyridine, any of which may be optionally substituted.

27. The compound or salt according to claim 26, wherein A is selected from optionally substituted pyrazole and optionally substituted isoxazole.

28. A is [Chemical Formula 9] selected from, each of which may be optionally substituted; wherein 【Chemical Formula 10】 represents a bond to any substituent, 【Chemical 11】 represents a bond to the remainder of formula I of A, The compound or salt according to claim 27.

29. The compound or salt according to claim 25, wherein the 5- to 6-membered heterocycle of A is substituted with one or more substituents.

30. The substituents on the 5- to 6-membered heterocycle of A are independently (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 which is alkyl, halogen, -OR １１ , -SR １１ , -N(R １１ ), ２ , -C(O)R １１ , -NO ２ , =O, -CN; and C ３－１０ A carbon ring and a 3- to 10-membered heterocyclic ring, 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 a C ３－１０ carbon ring and a 3- to 10-membered heterocyclic ring which may be optionally substituted optionally substituted with one or more substituents selected from, C １－６ alkyl; and (iii) a 3- to 10-membered heterocycle, halogen, -OR １１ , -SR １１ , -N(R １１ ), ２ , -C(O)R １１ , -NO ２ , =O, -CN; and a 3- to 10-membered heterocycle optionally substituted with one or more substituents selected from halogen, -OR １－６ , -SR, -N(R), -C(O)R, -NO, =O, -CN; and optionally substituted with one or more substituents selected from C The compound or salt according to claim 29, selected from

31. The substituents on the 5- to 6-membered heterocycle of A are independently fluorine, methyl, ethyl, isopropyl, 【Chemical Formula 12】 The compound or salt according to claim 29, selected from

32. A is 【Chemical 13】 The compound or salt according to claim 29, selected from

33. B is -CH(R Ａ )(R Ｂ ) and optionally substituted C ６－１０ The compound or salt according to claim 16, selected from a carbon ring.

34. B is -CH(R Ａ )(R Ｂ ), and R Ａ and R Ｂ are independently C １－６ alkyl optionally substituted with one or more substituents independently selected from halogen, -OR １３ , -SR １３ , -N(R １３ ), -C(O)R ２ , -NO １３ , and -CN; and ２ alkyl optionally substituted with one or more substituents independently selected from halogen, -OR １－６ , -SR, -N(R), -C(O)R, -NO, and -CN; and C ３－６ a carbon ring 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 ３－６ a carbon ring The compound or salt according to claim 33, selected from

35. R Ａ and R Ｂ is independently selected from ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and phenyl, any of which may be optionally substituted, the compound or salt according to claim 16.

36. B is C which may be appropriately substituted ５－８ Cycloalkyl or C which may be appropriately substituted ７－１０ The compound or salt according to claim 33, which is a bicyclic carbocyclic ring

37. B is an optionally substituted C selected from cyclohexyl, cycloheptyl, cyclooctyl, spiro[2.5]octanyl, and indanyl, which may be optionally substituted ６－１０ The compound or salt according to claim 36, which is a carbocyclic ring.

38. wherein B is 【Chemical 14】 The compound or salt according to claim 37, represented by

39. R １ and R ２ are each independently Hydrogen, halogen, -OR １４ , -NO ２ , and -CN; and C １－６ Alkyl, 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, １－６ Alkyl The compound or salt according to claim 16, selected from

40. R １ is hydrogen; R ２ is selected from methyl, ethyl, propyl, isopropyl, and butyl, each of which may be optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, and -OR １４ The compound or salt according to claim 39, which may be optionally substituted.

41. R １ and R ２ each independently is hydrogen, 【Chemical Formula 15】 The compound or salt according to claim 40, selected from

42. R １ is hydrogen; 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 The compound or salt according to claim 39, which may be optionally substituted.

43. R １ and R ２ each independently represents hydrogen, 【Chemical 16】 The compound or salt according to claim 39, selected from

44. R ３ and R ４ are each independently (a) hydrogen; (b) C １ is alkyl, halogen, -OR １５ , -N(R １５ ), -C(O)R ２ , -NO １５ , -CN; and C ２ is a carbocyclic ring optionally substituted with one or more substituents independently selected from halogen, C ３－６ haloalkyl, -OR １－６ , -N(R １５ ), -C(O)R １５ ), -NO ２ , and -CN; and C １５ alkyl optionally substituted with one or more substituents independently selected from a C ２ carbocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, C ３－６ haloalkyl, -OR １ ), -N(R (c) C ２－６ alkyl, 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; C ３－６ carbocyclic ring and 3- to 6-membered heterocyclic ring, 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 , and -CN, and is optionally substituted with one or more substituents independently selected from C ３－６ carbocyclic ring and 3- to 6-membered heterocyclic ring, and is optionally substituted with one or more substituents independently selected from C ２－６ alkyl; and (d) C ３－６ A carbon ring and a 3- to 6-membered heterocycle, each of which is halogen, -OR １５ , -SR １５ , -N(R １５ ) ２ , -C(O)R １５ , -NO ２ , -CN; and C １－３ alkyl, which may be 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 may be optionally substituted with one or more substituents independently selected from C １－３ alkyl, and a C ３－６ carbon ring and a 3- to 6-membered heterocycle The compound or salt according to claim 16, selected from

45. R ３ or R ４ is optionally substituted with one or more substituents independently selected from halogen, -OR １５ alkyl; and cyclo-propyl, cyclo-butyl, cyclo-pentyl, cyclo-hexyl, and phenyl each optionally substituted with one or more substituents independently selected from halogen, C １ haloalkyl, and -OR １－３ The compound or salt according to claim 44, selected from １５ those optionally substituted with one or more substituents independently selected from halogen, C​

46. R ３ or R ４ is methyl, 【Chemical 17】 Selected from, the compound or salt according to claim 45.

47. R ３ or R ４ is C ２－６ alkyl, 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 carbocyclic ring and 3- to 6-membered heterocyclic ring, 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 , and -CN, and is optionally substituted with one or more substituents independently selected from C ３－６ carbocyclic ring and 3- to 6-membered heterocyclic ring, and is optionally substituted with one or more substituents independently selected from C ２－６ alkyl, the compound or salt according to claim 44.

48. R ３ or R ４ is selected from ethyl, propyl, isopropyl, isobutyl, and butyl, any of which is optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, -OR １５ , -N(R １５ ), -C(O)N(R ２ ), and -N(R １５ ), and -N(R ２ ), and -N(R １５ ), and -N(R １５ ), and the compound or salt according to claim 47, which may be optionally substituted with one or more substituents independently selected from

49. R ３ or R ４ is 【Chemical 18】 The compound or salt according to claim 47, selected from

50. R ３ or R ４ is 【Chemical 19】 The compound or salt according to claim 47, selected from

51. R ３ or R ４ is 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 , -NO ２ , and -CN, and optionally substituted with one or more substituents independently selected from halogen, -OR １５ , -N(R １５ ), ２ , C ３－６ carbocyclic ring, and optionally substituted with one or more substituents independently selected from 3- to 6-membered heterocyclic rings, C ２－６ alkyl, the compound or salt according to claim 44.

52. R ３ or R ４ is 【Chemical 20】 The compound or salt according to claim 51, selected from

53. R ３ or R ４ is 【Chemical 21】 The compound or salt according to claim 51, selected from

54. R ３ or R ４ is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxetanyl, azetidine, pyrrolidinyl, and pyridinyl, each of which is chloro, fluoro, bromo, -OR １５ , -NO ２ , -CN; and chloro, fluoro, bromo, -OR １５ , -NO ２ , and -CN, and is optionally substituted with one or more substituents independently selected from C １－３ alkyl optionally substituted with one or more substituents independently selected from, the compound or salt according to claim 44.

55. R ３ or R ４ is 【Chemical 22】 The compound or salt according to claim 54, selected from

56. 【Fig. 23】 of R ３ and R ４ together form a 4- to 12-membered heterocyclic ring, 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 , =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 , -NO ２ , and -CN, and optionally substituted with one or more substituents independently selected from halogen, -OR １－６ alkyl The compound or salt according to claim 16, which may be optionally substituted with one or more substituents independently selected from, and forms a 4- to 12-membered heterocycle.

57. The compound or salt according to claim 56, wherein the optionally substituted 4- to 12-membered heterocycle may optionally contain more than one heteroatom selected from oxygen, nitrogen, sulfur, and any combination thereof.

58. 【Fig. 24】 R of ３ and R ４ The compound or salt according to claim 57, wherein R and R together form a saturated 4- to 8-membered heterocyclic ring in which any one of them may be appropriately substituted.

59. R ３ and R ４ together 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, and any one of these is 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 , -NO ２ , and -CN; and optionally substituted with one or more substituents independently selected from chloro, fluoro, OR １６ , -NO ２ , and -CN, and the compound or salt according to claim 58, optionally substituted with one or more substituents independently selected from C １－３ alkyl optionally substituted with one or more substituents independently selected from the above.

60. 【Fig. 25】 of R ３ and R ４ together form a saturated 4- to 8-membered heterocycle, and the 4- to 8-membered heterocycle is 【Chemical 26】 The compound or salt according to claim 59, selected from

61. 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, and any one of these is chloro, fluoro, -OR １６ , -NO ２ , -C(O)N(R １６ ), ２ , and -CN; and optionally substituted with one or more substituents independently selected from chloro, fluoro, OR １６ , -NO ２ , and -CN, and optionally substituted with one or more substituents independently selected from C １－３ alkyl, the compound or salt according to claim 58.

62. 【Fig. 27】 of R ３ and R ４ together form a saturated 4- to 8-membered heterocyclic ring, and the 4- to 8-membered heterocyclic ring is 【Chemical 28】 The compound or salt according to claim 61, selected from

63. The compound or salt according to claim 56, wherein the 4- to 12-membered heterocycle is an unsaturated 4- to 12-membered heterocycle, and any one of them may be optionally substituted.

64. wherein the unsaturated 4- to 12-membered heterocycle is 【Chemical 29】 The compound or salt according to claim 63, represented by

65. 【Fig. 30】 【Chemical 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical 39】 【Chemical 40】 【Chemical 41】 【Chemical Formula 42】 【Chemical 43】 【Chemical 44】 【Chemical 45】 【Chemical Formula 46】 【Chemical 47】 【Chemical 48】 【Chemical 49】 【Chemical Formula 50】 A compound selected from or a salt of any one of them.

66. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound or salt according to any one of claims 1 to 65.

67. A medicament for regulating IL-17A, comprising the compound or salt according to any one of claims 1 to 65.

68. A therapeutic agent for treating an inflammatory disease or disorder, the therapeutic agent comprising the compound or salt according to any one of claims 1 to 65.

69. The therapeutic agent according to claim 68, wherein the inflammatory disease or disorder is selected from plaque psoriasis, guttate psoriasis, psoriasis vulgaris, pustular psoriasis, psoriatic erythroderma, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar pustulosis, spondyloarthritis, and non-infectious uveitis.

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