Heteroarylindole inhibitors of apol-1

Abstract

The present disclosure relates to heteroarylindole compounds and pharmaceutically acceptable salts thereof, to processes for the preparation of, intermediates used in the preparation of, and compositions containing such compounds and the uses of such compounds as inhibitors of APOL1 and in the treatment of non-diabetic kidney disease or focal segmental glomerulosclerosis.

Description

HETEROARYLINDOLE INHIB(TORS OF APOL-1 CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 463,854 filed May 3, 2023, which is incorporated herein by reference in its entirety. BACKGROUND Field

[0002] The present disclosure relates to novel 3-heteroarylindole compounds including their pharmaceutically acceptable salts. The disclosure also relates processes for the preparation of, intermediates used in the preparation of, pharmaceutical compositions containing and the uses of such compounds in treating human diseases in which Apol1 inhibition is beneficial, for example, kidney disease, including non-diabetic kidney disease and focal segmental glomerulosclerosis. Description of the Related Art

[0003] Apolipoprotein L1 (APOL1) genetic coding variants were identified in 2010 and incidence studies since then have demonstrated that such dysfunctional alleles are relatively common among individuals of sub-Saharan African descent. Combined allele frequency of the two common variants G1 and G2 occurs in about 34% of African Americans and have clinically been identified as a frequent cause of kidney disease (termed APOL1 nephropathy) that typically manifests as focal segmental glomerulosclerosis and clinically manifests as hypertension and arterionephrosclerosis. Additional cell culture studies have suggested that APOL1 variants cause cell dysfunction through several processes, including alterations in cation channel activity, inflammasome activation, increased endoplasmic reticulum stress, activation of protein kinase R, mitochondrial dysfunction and disruption of APOL1 ubiquitinylation. Although risk of APOL1 nephropathy is mostly confined to individuals with two APOL1 risk variants, evidence has accumulated that secondary factors elevate the clinical risk for even one allele. The most common secondary factor responsible for clinically relevant kidney disease is a chronic viral infection, particularly HIV-1, resulting in interferon-mediated activation of the APOL1 promoter. See for example, Avi Z. Rosenberg et. al., "The evolving story of apolipoprotein L1 nephropathy: the end of the beginning," Nature Reviews Nephrology, 18, 307–320 (2022).

[0004] The clinical pathophysiology of APOL1 has been described by numerous investigators including: David J. Friedman and Martin R. Pollak, "APOL1 Nephropathy: From Genetics to Clinical Applications," CJASN February 2021, 16 (2) 294-303; DOI: https: / / doi.org / 10.2215 / CJN.15161219. See also Barry Freedman et al., "APOL1 at ten years: Progress and next steps," Kidney Int.2021 Jun; 99(6): 1296–1302. SUMMARY

[0005] The compounds of the present disclosure are inhibitors of apolipoprotein L1 (APOL1) and as such the present disclosure includes methods of using these compounds to treat APOL1-mediated diseases, such as non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), pancreatic cancer, arterionephrosclerosis and in treating or ameliorating comorbidities such as hypertension, atherosclerosis, sepsis, sickle cell disease and Covid-19 infection. In some embodiments, the FSGS and / or NDKD is associated with at least one of the 2 common APOL1 genetic variants (G1: S342G:I384M and G2: N388del:Y389del). In some embodiments, pancreatic cancer is associated with elevated levels of APOL1 (such as, e.g., elevated levels of APOL1 in pancreatic cancer tissues).

[0006] Some embodiments disclosed herein include a compound having the structure of Formula (I): (I)of, wherein: ring A is C6-10aryl or 5-10-membered heteroaryl; X is a 5- to 10-membered heteroaryl optionally substituted with R8or a 5-10 membered heterocyclyl optionally substituted with one or more R8; each R1is independently selected from the group consisting of: H, halo, -CN, -NO2, - C(O)R4, -C(O)OR4, –(C1-C6)haloalkyl, –O(C1-C6)haloalkyl, -OC(O)R4, -OR4, - OC(O)OR4, -OC(O)N(R4)2,-N(R4)2, -NR4C(O)R4, -NR4C(O)OR4, -NR4C(O)N(R4)2,-C(O)N( R4)2, -SR4, -(O)R4, -SO2R4, -SO2N(R4)2, -N(R4)SO2R4, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)(C1-C9)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl,(C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, - NO2, (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1- C6)alkyl, -OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH((C1-C6)alkyl), -OC(O)N((C1- C6)alkyl)2, NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1- C6)alkyl)-C(O)(C1-C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1- C6)alkyl),-N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl),-N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, - NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1- C6)alkyl), -C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1- C6)alkyl, -SO2NH2, -SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and - N((C1-C6)alkyl)SO2(C1-C6)alkyl; and m is an integer from zero to four; each R2is independently selected from the group consisting of: H, halo, perfluoro(C1- C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OR5, - OC(O)OR5, -OC(O)N(R5)2, -N(R5)2, -NR5C(O)R5, -NR5C(O)OR5, -NR5C(O)N(R5)2, - C(O)N(R5)2, -SR5, -S(O)R5, -SO2R5, -SO2N(R5)2, -N(R5)SO2R5, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6- C10)aryl, and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1- C6)alkyl, -OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH((C1-C6)alkyl), -OC(O)N((C1- C6)alkyl)2, NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1- C6)alkyl)C(O)(C1-C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2,- NHC(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1- C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1- C6)alkyl,-C(O)NH2, -C(O)NH((C1-C6)alkyl), -C(O)N((C1-C6)alkyl)2, -S(C1- C6)alkyl, -S(O)(C1-C6)alkyl -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1- C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1-C6)alkyl)SO2(C1- C6)alkyl; and n is an integer from zero to four; R3is selected from the group consisting of: -C(O)R6, -C(O)OR6, -OC(O)R6, -OR6, oxo(=O), -OC(O)OR6, -OC(O)N(R6)2, -N(R6)2, -NR6C(O)R6, -NR6C(O)N(R6)2, - NR6C(O)OR6, -C(O)N(R6)2, -SR6, -S(O)R6, -SO2R6, -SO2N(R6)2, -N(R6)SO2R6, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -halo, - OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1- C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, - OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1-C6)alkyl)2, NH2, NH(C1- C6)alkyl, -N((C1-C6)alkyl)2, -NH(C1-C6)alkyl-C(O)-NH-(C1-C6)alkyl-O-(C1- C6)alkyl, -NH(C1-C6)alkyl-C(O)-NH2, -NH(C1-C6)alkyl-C(O)NH-(C1-C6)alkyl, -NHC(O)(C1- C6)alkyl, -NHC(O)(C1-C6)alkyl-O-(C1-C6)alkyl, -NHC(O)(C3-C10)cycloalkyl, -NHC(O) (3-13 membered)heterocycloalkyl, -NH(3-13 membered)heterocycloalkyl, -N((C1- C6)alkyl)C(O)(C1-C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1- C6)alkyl), -N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1- C6)alkyl)2, -NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, - C(O)NH((C1-C6)alkyl), -C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1- C6)alkyl and -N((C1-C6)alkyl)SO2(C1-C6)alkyl; wherein each of said (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, and (3-13 membered)heterocycloalkyl may additionally be optionally substituted with =O; each R4is independently selected from the group consisting of: H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6- C10)aryl and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -halo, -OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1- C6)alkyl, -OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1- C6)alkyl)2, NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1- C6)alkyl)C(O)(C1-C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2,-NHC(O)NH((C1- C6)alkyl), -N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, - NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl,-C(O)NH2, -C(O)NH((C1- C6)alkyl), -C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1- C6)alkyl)SO2(C1-C6)alkyl; each R5is independently selected from the group consisting of: H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6- C10)aryl and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -halo, OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1- C6)alkyl, -OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1- C6)alkyl)2, NH2, NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1- C6)alkyl)C(O)(C1-C6)alkyl, NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1- C6)alkyl), -N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, - NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1- C6)alkyl), -C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, - SO2NH2, -SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1- C6)alkyl)SO2(C1-C6)alkyl; each R6is independently selected from the group consisting of: H, -(C1-C6)alkyl-(R7)p, -(C2-C6)alkenyl- (R7)p, -(C2-C6)alkynyl-(R7)p, -C(O)(C1-C6)alkyl-(R7)p, -C(O)O(C1-C6)alkyl-(R7)p, -C(O)NH2, -C(O)NH((C1-C6)alkyl)-(R7)p, -C(O)N((C1-C6)alkyl-(R7)p)2, (C3-C10)cycloalkyl-(R7)p, (3-13 membered)heterocycloalkyl-(R7)p, (C6-C10)aryl-(R7)p and (5-12 membered)heteroaryl-(R7)p, wherein p is an integer from 1-3; each R7is independently selected from hydrogen, halo, OH, oxo(=O), perfluoro(C1- C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, (C1-C6)alkoxy, -C(O)(C1- C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl, -OC(O)O(C1- C6)alkyl, -OC(O)NH2, -OC(O)NH((C1-C6)alkyl), -OC(O)N((C1-C6)alkyl)2, NH2, -NH(C1- C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)-C(O)(C1- C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1-C6)alkyl), -N((C1- C6)alkyl)C(O)NH((C1-C6)alkyl),-N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1- C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1-C6)alkyl), - C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, - SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl, -N((C1-C6)alkyl)SO2(C1- C6)alkyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12membered)heteroaryl and wherein each of said (C1-C6)alkyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl moieties is optionally substituted with one to three substituents independently selected from the group consisting of: -halo, OH, oxo, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, - (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl , -O-C(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1-C6)alkyl)2, NH2, NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)(C1- C6)alkyl, NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2,-NHC(O)NH((C1-C6)alkyl),-N((C1- C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1- C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl,-C(O)NH2, -C(O)NH((C1-C6)alkyl), - C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, - SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1- C6)alkyl)SO2(C1-C6)alkyl; R8is independently selected from the group consisting of: H, OH, -halo, perfluoro(C1- C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, -(C1-C6)alkyl-R9, -C(O)R9, -C(O)OR9, - OC(O)R9, -OR9, -OC(O)OR9, -OC(O)N(R9)2, -N(R9)2, -NR9C(O)R9, -NR9C(O)OR9, - NR9C(O)N(R9)2,-C(O)N(R9)2, -SR9, -S(O)R9, -SO2R9, -SO2N(R9)2, -N(R9)SO2R9and -(C1- C6)alkyl-R9; R9is selected from the group consisting of: H, -C(O)R10, -C(O)OR10, -OC(O)R10, - OR10, -OC(O)OR10, -OC(O)N(R10)2, -N(R10)2, -NR10C(O)OR10, -NR10C(O)R10, - NR10C(O)N(R10)2,-C(O)N(R10)2, -SR10, -S(O)R10, -SO2R10, -SO2N(R10)2, -N(R10)SO2R10, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -halo, OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1- C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1-C6)alkyl)2, NH2, NH(C1-C6)alkyl, - N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)(C1-C6)alkyl, NHC(O)NH2, - N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)NH((C1- C6)alkyl),-N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1-C6)alkyl, -N((C1- C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1-C6)alkyl), -C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1-C6)alkyl), - SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1-C6)alkyl)SO2(C1-C6)alkyl; and R10is H or (C1-C6)alkyl.

[0007] In some embodiments, the composition comprises a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.

[0008] Another embodiment of the disclosure is directed to a method for treating non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), pancreatic cancer, arterio-nephrosclerosis and in treating or ameliorating comorbidities such as hypertension, atherosclerosis, sepsis, sickle cell disease and Covid-19 infection in a mammal, preferably a human, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof.

[0009] The compounds of Formula I and the pharmaceutically acceptable salts thereof are useful for the treatment of non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), pancreatic cancer, arterio-nephrosclerosis and in treating or ameliorating comorbidities such as hypertension, atherosclerosis, sepsis, sickle cell disease and Covid-19 infection. Accordingly, in one embodiment, the disclosure provides a method for treating a condition in a mammal, such as a human, selected from the conditions above, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to the mammal. The mammal is preferably a mammal in need of such treatment or prevention.

[0010] In some embodiments, the compounds of the disclosure are useful for treatment and / or prophylaxis of chronic kidney disease including the treatment of renal disorders, including renal insufficiency and kidney failure. Renal insufficiency and kidney failure comprise both acute and chronic manifestations (chronic kidney disease; CKD) thereof, as well as underlying or related kidney diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney graft rejection and immunocomplex-induced kidney diseases, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, diabetic kidney diseases (DKD), pyelonephritis, renal cysts and polycystic kidney disease, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which can be characterized diagnostically for example by abnormally reduced creatinine and / or water excretion, abnormally raised blood concentrations of urea, nitrogen, potassium and / orcreatinine, altered activity of renal enzymes such as, for example, glutamyl synthetase, altered urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, lesions on glomerulae and arterioles, tubular dilation, hyperphosphataemia and / or need for dialysis. The present disclosure also encompasses the use of the compounds according to the disclosure for treatment and / or prophylaxis of sequelae of renal insufficiency, for example hypertension, pulmonary oedema, heart failure, uremia, anemia, electrolyte disturbances (for example hyperkalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.

[0011] In further embodiments, the compounds of the disclosure are suitable for treatment and / or prevention of urological disorders, for example benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), prostatitis, neurogenic overactive bladder (OAB), incontinence, for example mixed, urge, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, interstitial cystitis (IC) and also erectile dysfunction and female sexual dysfunction. DETAILED DESCRIPTION Definitions

[0012] “Subject” as used herein, means a human or a non-human mammal including but not limited to a dog, cat, horse, donkey, mule, cow, domestic buffalo, camel, llama, alpaca, bison, yak, goat, sheep, pig, elk, deer, domestic antelope, or a non-human primate selected for treatment or therapy.

[0013] “Subject in need thereof” means a subject identified as in need of a therapy or treatment.

[0014] A therapeutic effect relieves, to some extent, one or more of the symptoms of a disease or disorder, and includes curing the disease or disorder. “Curing” means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after a cure is obtained (such as extensive tissue damage).

[0015] The phrase "therapeutically effective amount" means an amount of a compound or a combination of compounds that ameliorates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition.

[0016] “Treat,” “treatment,” or “treating,” as used herein refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term“prophylactic treatment” refers to treating a patient who does not yet have the relevant disease or disorder, but who is susceptible to, or otherwise at risk of, a particular disease or disorder, whereby the treatment reduces the likelihood that the patient will develop the disease or disorder. The term “therapeutic treatment” refers to administering treatment to a patient already having a disease or disorder.

[0017] “Preventing” or “prevention” refers to delaying or forestalling the onset, development or progression of a condition or disease for a period of time, including weeks, months, or years.

[0018] “Amelioration” means a lessening of severity of at least one indicator of a condition or disease. In certain embodiments, amelioration includes a delay or slowing in the progression of one or more indicators of a condition or disease. The severity of indicators may be determined by subjective or objective measures which are known to those skilled in the art.

[0019] “Modulation" or “modulate” means a perturbation of function or activity. In certain embodiments, modulation means an increase in gene expression. In certain embodiments, modulation means a decrease in gene expression. In certain embodiments, modulation means an increase or decrease in total serum levels of a specific protein. In certain embodiments, modulation means an increase or decrease in free serum levels of a specific protein. In certain embodiments, modulation means an increase or decrease in total serum levels of a specific non-protein factor. In certain embodiments, modulation means an increase or decrease in free serum levels of a specific non-protein factor. In certain embodiments, modulation means an increase or decrease in total bioavailability of a specific protein. In certain embodiments, modulation means an increase or decrease in total bioavailability of a specific non-protein factor.

[0020] “Administering” means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self- administering.

[0021] Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof, or other agents disclosed herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.

[0022] “Parenteral administration,” means administration through injection or infusion. Parenteral administration includes, but is not limited to, subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, and intracranial administration.

[0023] “Subcutaneous administration” means administration just below the skin.

[0024] “Intravenous administration” means administration into a vein.

[0025] “Intraarterial administration” means administration into an artery.

[0026] The term “agent” includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to, e.g., protein, polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances.

[0027] “Pharmaceutical agent” means a substance that provides a therapeutic effect when administered to a subject.

[0028] “Pharmaceutical composition” means a mixture of substances suitable for administering to an individual that includes a pharmaceutical agent.

[0029] The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds with which they are associated and, which are not biologically or otherwise undesirable. In many cases, the compounds herein are capable of forming acid and / or base salts by virtue of the presence of phenol and / or phosphonate groups or groups similar thereto. One of ordinary skill in the art will be aware that the protonation state of any or all of these compounds may vary with pH and ionic character of the surrounding solution, and thus the present disclosure contemplates multiple charge states of each compound. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calciumand magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).

[0030] “Solvate” refers to the compound formed by the interaction of a solvent and an EPI, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.

[0031] As used herein, the term "alkyl" is defined to include saturated aliphatic hydrocarbons including straight chains and branched chains and 1 to 6 carbon atoms. For example, as used herein, the term "(C1-C6)alkyl,” as well as the alkyl moieties of other groups referred to herein (e.g., (C1-C6)alkoxy), refers to linear or branched radicals of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary- butyl), optionally substituted by 1 to 5 suitable substituents.

[0032] Whenever a numerical range is used in this application, for example when 1 to 6 is used in the definition of “alkyl” means that the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 6 carbon atoms.

[0033] As used herein, the term "alkenyl" is defined to include aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight chains and branched chains having at least one carbon-carbon double bond and 2 to 6 carbon atoms. For example, as used herein, the term "(C2-C6)alkenyl" means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionally substituted by 1 to 5 suitable substituents. When the compounds of Formula I contain an alkenyl group, the alkenyl group may exist as the pure E (entgegen) form, the pure Z (zusammen) form, or any mixture thereof.

[0034] As used herein, the term "alkynyl" is defined to include aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight chains and branched chains having at least one carbon-carbon triple bond and 2 to 6 carbon atoms. For example, as used herein, the term "(C2-C6)alkynyl” is used herein to mean straight or branched hydrocarbon chain alkynyl radical as defined above having 2 to 6 carbon atoms and one triple bond; optionally substituted by 1 to 5 suitable substituents.

[0035] As used herein, the term "cycloalkyl” is defined to include saturated or unsaturated (non aromatic) monocyclic or bicyclic hydrocarbon rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl); optionally substituted by 1 to 5 suitable substituents. The cycloalkyl group has 3 to 12 carbon atoms. One group of monocyclic cycloalkyl rings have 3 to 6 carbon atoms. In another embodiment the cycloalkyl may optionally contain one, two or more non-cumulative non aromatic double or triple bonds.

[0036] As used herein, the term “bicycloalkyl” is defined to include a cycloalkyl as defined above which is bridged to a second carbocyclic ring (e.g., bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.). Preferably, the bicycloalkyl group has 6 to 20 carbon atoms. More preferably, the bicycloalkyl group has 6 to 15 carbon atoms. Most preferably, the bicycloalkyl group has 6 to 12 carbon atoms. The bicycloalkyl is optionally substituted by 1 to 5 suitable substituents. In one embodiment the bicycloalkyl may optionally contain one, two or more non-cumulative non aromatic double or triple bonds

[0037] As used herein, the term "aryl" is defined to include all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. The aryl group has 6, 8, 9, 10 or 12 carbon atoms in the ring(s). In one embodiment the aryl group has 6 or 10 carbon atoms in the ring(s). One aryl group of particular interest is the 6 carbon atom phenyl ring. For example, as used herein, the term “(C6-C10)aryl” means aromatic radicals containing from 6 to 10 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, indanyl and the like. The aryl group is optionally substituted by 1 to 5 suitable substituents.

[0038] As used herein, the term “heteroaryl” is defined to include monocyclic or fused-ring polycyclic aromatic heterocyclic groups with one or more heteroatoms selected from O, S and N in the ring. The heteroaryl group has 5 to 12 ring atoms including one to five heteroatoms selected from O, S, and N. For example, as used herein, the term “5 to 12 membered heteroaryl” means aromatic radicals containing at least one ring heteroatom selected from O, S and N and from 1 to 11 carbon atoms such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like. The heteroaryl group is optionally substituted by 1 to 5 suitable substituents.

[0039] As used herein, the term “heterocycloalkyl” is defined to include a monocyclic, bridged, polycyclic or fused polycyclic saturated or unsaturated non-aromatic 3 to13 membered ring including 1 or more heteroatoms selected from O, S and N. Examples of such heterocycloalkyl rings include azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, and the like. Further examples of said heterocycloalkyl rings are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin- 4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin- 3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidine, 1,3- thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2- yl, 1,2,5-oxathiazin-4-yl and the like. The heterocycloalkyl ring is optionally substituted by 1 to 5 suitable substituents.

[0040] An "aldehyde" group refers to a carbonyl group where R is hydrogen.

[0041] An "alkoxy" group refers to both an –O-alkyl and an –O-cycloalkyl group, as defined herein.

[0042] An "alkoxycarbonyl" refers to a -C(O)OR.

[0043] An "alkylaminoalkyl" group refers to an -alkyl-NR-alkyl group.

[0044] An "alkylsulfonyl" group refer to a -SO2alkyl.

[0045] An "amino" group refers to an -NH2 or an -NRR'group.

[0046] An "aminoalkyl" group refers to an –alky-NRR' group.

[0047] An "aminocarbonyl" refers to a -C(O)NRR'.

[0048] An "arylalkyl" group refers to -alkylaryl, where alkyl and aryl are defined herein.

[0049] An "aryloxy" group refers to both an –O-aryl and an –O-heteroaryl group, as defined herein.

[0050] An "aryloxycarbonyl" refers to -C(O)Oaryl.

[0051] An "arylsulfonyl" group refers to a -SO2aryl.

[0052] A "C-amido" group refers to a -C(O)NRR' group.

[0053] A "carbonyl" group refers to a -C(O)R.

[0054] A "C-carboxyl" group refers to a -C(O)OR groups.

[0055] A "carboxylic acid" group refers to a C-carboxyl group in which R is hydrogen.

[0056] A "cyano" group refers to a -CN group.

[0057] A "dialkylamionalkyl" group refers to an –(alkyl)N(alkyl)2group.

[0058] A "halo" or "halogen" group refers to fluorine, chlorine, bromine or iodine.

[0059] A "heteroaryloxyl" group refers to a heteroaryl-O group with heteroaryl as defined herein.

[0060] A "hydroxy" group refers to an -OH group.

[0061] An "N-amido" group refers to a -R'C(O)NR group.

[0062] An "N-carbamyl" group refers to a -ROC(O)NR-group.

[0063] A "nitro" group refers to a -NO2group.

[0064] An "N-Sulfonamido" group refers to a -NR-SO2R group.

[0065] An "O-carbamyl" group refers to a -OC(O)NRR' group.

[0066] An "O-carboxyl" group refers to a RC(O)O group.

[0067] An “oxo” group refers to a carbonyl moiety such that alkyl substituted by oxo refers to a ketone group.

[0068] A "perfluoroalkyl group" refers to an alkyl group where all of the hydrogen atoms have been replaced with fluorine atoms.

[0069] An "S-sulfonamido" group refers to a -SO2NR-group.

[0070] A "sulfinyl" group refers to a -S(O)R group.

[0071] A "sulfonyl" group refers to a -SO2R group.

[0072] A "C-carboxyl" group refers to a -C(O)OR groups.

[0073] A “BOC”, “Boc” or “boc” means N-tert-butoxycarbonyl, “DCM” (CH2Cl2) means methylene chloride or dichloromethane, “DIPEA” or “DIEA” means diisopropyl ethyl amine, “DMA” means N,N-dimethylacetamide, "DMF" means N-N-dimethyl formamide, “DMSO" means dimethylsulfoxide, “DPPP” means 1,3-bis(diphenylphosphino)propane, “HOAc” or “AcOH” means acetic acid, “IPA” means isopropyl alcohol. "MTBE" means methyl t-butyl ether, “NMP” means 1-methyl 2-pyrrolidinone, “TEA” or “Et3N” means triethyl amine, “TFA” or “TFAA” means trifluoroacetic acid, “EtOAc” , “EA”, or “AcOEt” means ethyl acetate, “MgSO4” means magnesium sulphate, “Na2SO4” means sodium sulphate, “MeOH” means methanol, “EtOH” means ethanol, “H2O” means water, “HCl” means hydrochloric acid, “POCl3” means phosphorus oxychloride, “DMSO” means dimethyl sulfoxide, “K2CO3” means potassium carbonate, “t-BuOK” means potassium tert-butoxide, “NIS” means N-iodosuccinimide, “THF” means tetrahydrofuran, “CuI” means copper(I) iodide, “MeI” means iodomethane, “ACN or MeCN” means acetonitrile, “N2H4•H2O” means hydrazine hydrate, “CDI” means carbonyldiimidazole, “BnNH2” means benzylamine, “BOP” means beznotrazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, “TCFH”means chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate, “m-CPBA” means meta-chloroperoxybenzoic acid, “NH4HCO3” means ammonium bicarbonate, “MnO2” means manganese dioxide, “NaH” means sodium hydride, “NaN3” means sodium azide, “STAB” means sodium triacetoxyborohydride, “NaBH3CN” means sodium cyanoborohydride, “NMI” means 1-methylimidazole, “TsCl” means 4-toluenesulfonyl chloride, “DIEA” means N-N,- diisopropylethylamine, “LiOH” means lithium hydroxide, “NaIO4” means sodium periodate “TLC” means thin-layer chromatography; “PE” means petroleum ether, “Cs2CO3” means cesium carbonate, “Pd(dppf)Cl2” means (1,1’bis(diphenylphosphino)ferrocene) palladium(II) dichloride, “PdCl2(PPh3)2” means palladium(II)bis(triphenylphosphine) dichloride, “Pd(OH)2 / C” means Pearlman’s catalyst or palladium(II) hydroxide on activated carbon, “RuO2” means ruthenium(iv) oxide, “Zn(CN)2” means zinc(II) cyanide, “LCMS” means liquid chromatography-mass spectrometry, “ESI” means electrospray ionization “1H-NMR” means proton nuclear magnetic resonance, “FA” means formic acid, “N” means Normal, “M” means molar, “g” means gram or grams, “mg” means milligram, “mL” means millilitre, “mmol” means millimoles, “μmol” means micromoles, “eq.” or “equiv.” means equivalent, “h” means hour or hours, “nm” means nanometer, “RT” or “rt” means room temperature “°C” means degrees Celsius, “Pa” means pascals.

[0074] The compounds of Formula I are useful for modulating or inhibiting APOL 1 activity. Accordingly, these compounds are useful for the prevention and / or treatment of disease states associated with APOL1 disfunction. The term "APOL1," as used herein, means apolipoprotein L1 protein and the term "APOL1" means apolipoprotein L1 gene.

[0075] The term "APOL1 mediated disease" refers to a disease or condition associated with aberrant APOL1 (e.g., certain APOL1 genetic variants; elevated levels of APOL1). In some embodiments, an APOL1 mediated disease is an APOL1 mediated kidney disease. In some embodiments, an APOL1 mediated disease is associated with patients having two APOL1 risk alleles, e.g., patients who are homozygous or compound heterozygous for the G1 or G2 alleles. In some embodiments, an APOL1 mediated disease is associated with patients having one APOL1 risk allele.

[0076] The term "APOL1 mediated kidney disease" refers to a disease or condition that impairs kidney function and can be attributed to APOL1. In some embodiments, APOL1 mediated kidney disease is associated with patients having two APOL1 risk alleles, e.g., patients who are homozygous or compound heterozygous for the G1 or G2 alleles. In some embodiments, the APOL1 mediated kidney disease is chosen from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterio-nephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1 mediated kidney disease is chronic kidney disease or proteinuria.

[0077] The term "FSGS," as used herein, means focal segmental glomerulosclerosis, which is a disease of the podocyte (glomerular visceral epithelial cells) responsible for proteinuria and progressive decline in kidney function, and associated with 2 common APOL1 genetic variants (G1: S342G:I384M and G2: N388del:Y389del).

[0078] The term "NDKD," as used herein, means non-diabetic kidney disease, which is characterized by severe hypertension and progressive decline in kidney function, and associated with 2 common APOL1 genetic variants (G1: S342G:I384M and G2: N388del:Y389del).

[0079] The terms "ESKD" and "ESRD" are used interchangeably herein to refer to end stage kidney disease or end stage renal disease. ESKD / ESRD is the last stage of kidney disease, i.e., kidney failure, and means that the kidneys have stopped working well enough for the patient to survive without dialysis or a kidney transplant. In some embodiments, ESKD / ESRD is associated with two APOL1 risk alleles.

[0080] As used herein the terms “Formula I” or “Formula I or pharmaceutically acceptable salts thereof” including Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id) and Formula (Ie), are defined to include all forms of the compound of Formula I, including stereoisomers, hydrates, solvates, crystalline and non-crystalline forms, isomorphs, and polymorphs thereof.

[0081] The compounds of the disclosure may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point’).

[0082] The compounds of the disclosure may also exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the disclosure and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water.

[0083] A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

[0084] When the solvent or water is tightly bound, the complex will have a well- defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0085] Also included within the scope of the disclosure are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non- covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

[0086] The compounds of the disclosure may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as -COO- Na+, -COO-K+, or -SO3-Na+) or non-ionic (such as -N-N+(CH3)3) polar head group. For moreinformation, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970).

[0087] Hereinafter all references to compounds of formula I include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi- component complexes and liquid crystals of salts thereof.

[0088] The compounds of the disclosure include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, stereoisomers thereof (including optical and geometric isomers), and tautomers thereof, as hereinafter defined and isotopically-labeled compounds of formula I.

[0089] The disclosure also relates to prodrugs of the compounds of Formula I. Thus certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as “prodrugs”. Further information on the use of prodrugs may be found in Pro- drugs as Novel Delivery Systems, Vol.14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

[0090] Prodrugs in accordance with the disclosure can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

[0091] Some non-limiting examples of prodrugs in accordance with the disclosure include: (i) where the compound of Formula I contains a carboxylic acid functionality which is functionalized into a suitably metabolically labile group (esters, carbamates, etc.) compound of Formula I (ii) where the compound of Formula I contains an alcohol functionality which is functionalized into a suitably metabolically labile group (ethers, esters, carbamates, acetals, ketals, etc.)compound of Formula I ; and (iii) where the compound of Formula I contains a primary or secondary amino functionality, or an amide which are functionalized into a suitably metabolically labile group, e.g., a hydrolysable group (amides, carbamates, ureas, phosphonates, sulfonates, etc.).compound of Formula I.

[0092] Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

[0093] Moreover, certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.

[0094] Also included within the scope of the disclosure are metabolites of compounds of Formula I, that is, compounds formed in vivo upon administration of the drug.

[0095] The compounds of Formula I may have asymmetric carbon atoms and may exist as two or more stereoisomers. The carbon-carbon bonds of the compounds of Formula I may be depicted herein using a solid line ( ), a solid wedge ( ), or a dotted wedge ( ). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of Formula I may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds of Formula I can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of Formula I and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.

[0096] Stereoisomers of Formula I include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of Formula I, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid addition or base addition salts wherein the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl- tartrate or dl-arginine.

[0097] When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

[0098] The compounds of the Formula I may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds of Formula I may exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of compounds of Formula I. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present disclosure includes all tautomers of the compounds of Formula I.

[0099] The present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

[0100] Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulphur, such as35S.

[0101] Certain isotopically labelled compounds of formula I, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0102] Substitution with heavier isotopes such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0103] Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0104] Isotopically labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed.

[0105] Provided herein are compounds that are inhibitors of apolipoprotein L1 (APOL1). In some embodiments the compounds provided herein have the structure of Formula (I):(I) of, wherein:ring A is C6-10 aryl or 5-10-membered heteroaryl; X is a 5- to 10-membered heteroaryl optionally substituted with R8or a 5-10 membered heterocyclyl optionally substituted with one or more R8; each R1is independently selected from the group consisting of: H, halo, -CN, -NO2, - C(O)R4, -C(O)OR4, –(C1-C6)haloalkyl –(C1-C6)haloalkyl, -OC(O)R4, -OR4, - OC(O)OR4, -OC(O)N(R4)2,-N(R4)2, -NR4C(O)R4, -NR4C(O)OR4, -NR4C(O)N(R4)2,-C(O)N( R4)2, -SR4, -(O)R4, -SO2R4, -SO2N(R4)2, -N(R4)SO2R4, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, - NO2, (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1- C6)alkyl, -OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH((C1-C6)alkyl), -OC(O)N((C1- C6)alkyl)2, NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1- C6)alkyl)-C(O)(C1-C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1- C6)alkyl),-N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl),-N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, - NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1- C6)alkyl), -C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1- C6)alkyl, -SO2NH2, -SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and - N((C1-C6)alkyl)SO2(C1-C6)alkyl; and m is an integer from zero to four; each R2is independently selected from the group consisting of: H, halo, perfluoro(C1- C6)alkyl, perfluoro(C1-C6)alkoxy,-CN, -NO2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OR5, - OC(O)OR5, -OC(O)N(R5)2, -N(R5)2, -NR5C(O)R5, -NR5C(O)OR5, -NR5C(O)N(R5)2,-C(O)N(R5)2, -SR5, -S(O)R5, -SO2R5, -SO2N(R5)2, -N(R5)SO2R5, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6- C10)aryl, and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl,(C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1- C6)alkyl, -OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH((C1-C6)alkyl), -OC(O)N((C1- C6)alkyl)2, NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1- C6)alkyl)C(O)(C1-C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1- C6)alkyl),-N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl),-N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, - NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1- C6)alkyl), -C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1- C6)alkyl)SO2(C1-C6)alkyl; and n is an integer from zero to four; R3is selected from the group consisting of: -C(O)R6, -C(O)OR6, -OC(O)R6, -OR6, oxo(=O), -OC(O)OR6, -OC(O)N(R6)2, -N(R6)2, -NR6C(O)R6, -NR6C(O)N(R6)2, - NR6C(O)OR6, -C(O)N(R6)2, -SR6, -S(O)R6, -SO2R6, -SO2N(R6)2, -N(R6)SO2R6, (C1- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -halo, - OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1- C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, - OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1-C6)alkyl)2, NH2, NH(C1- C6)alkyl, -N((C1-C6)alkyl)2, -NH(C1-C6)alkyl-C(O)-NH-(C1-C6)alkyl-O-(C1- C6)alkyl, -NH(C1-C6)alkyl-C(O)-NH2, -NH(C1-C6)alkyl-C(O)NH-(C1-C6)alkyl, -NHC(O)(C1- C6)alkyl, -NHC(O)(C1-C6)alkyl-O-(C1-C6)alkyl, -NHC(O)(C3-C10)cycloalkyl, -NHC(O)(3-13 membered)heterocycloalkyl, -NH(3-13 membered)heterocycloalkyl, -N((C1- C6)alkyl)C(O)(C1-C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2,-NHC(O)NH((C1- C6)alkyl), -N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1- C6)alkyl)2, -NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl,-C(O)NH2, - C(O)NH((C1-C6)alkyl), -C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, - SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1- C6)alkyl and -N((C1-C6)alkyl)SO2(C1-C6)alkyl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, and (3-13 membered)heterocycloalkyl may additionally be optionally substituted with =O; each R4is independently selected from the group consisting of: H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6- C10)aryl and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -halo, -OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1- C6)alkyl, -OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1- C6)alkyl)2, NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1- C6)alkyl)C(O)(C1-C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1- C6)alkyl), -N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, - NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1- C6)alkyl), -C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, - SO2NH2, -SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1- C6)alkyl)SO2(C1-C6)alkyl; each R5is independently selected from the group consisting of: H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6- C10)aryl and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -halo, OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1- C6)alkyl, -OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1- C6)alkyl)2, NH2, NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1- C6)alkyl)C(O)(C1-C6)alkyl, NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1- C6)alkyl),-N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl),-N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, - NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1- C6)alkyl), -C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, - SO2NH2, -SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1- C6)alkyl)SO2(C1-C6)alkyl; each R6is independently selected from the group consisting of: H, –(C1-C6)alkyl-(R7)p, -(C2-C6)alkenyl-(R7)p,-(C2-C6)alkynyl-(R7)p, -C(O)(C1-C6)alkyl-(R7)p, -C(O)O(C1-C6)alkyl-(R7)p, -C(O)NH2, -C(O )NH((C1-C6)alkyl)-(R7)p, -C(O)N((C1-C6)alkyl-(R7)p)2, (C3-C10)cycloalkyl-(R7)p, (3-13 membered)heterocycloalkyl-(R7)p, (C6-C10)aryl-(R7)p and (5-12 membered)heteroaryl-(R7)p, wherein p is an integer from 1-3; each R7is independently selected from hydrogen, halo, OH, oxo(=O), perfluoro(C1- C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, (C1-C6)alkoxy, -C(O)(C1- C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl, -OC(O)O(C1- C6)alkyl, -OC(O)NH2, -OC(O)NH((C1-C6)alkyl), -OC(O)N((C1-C6)alkyl)2, NH2, -NH(C1- C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)-C(O)(C1- C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2,-NHC(O)NH((C1-C6)alkyl),-N((C1- C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1- C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1-C6)alkyl), - C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, - SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl, -N((C1-C6)alkyl)SO2(C1- C6)alkyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl and wherein each of said (C1-C6)alkyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl moieties is optionally substituted with one to three substituents independently selected from the group consisting of: -halo, OH, oxo, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, - (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl , -O-C(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1-C6)alkyl)2, NH2, NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)(C1- C6)alkyl, NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2,-NHC(O)NH((C1-C6)alkyl),-N((C1- C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1- C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl,-C(O)NH2, -C(O)NH((C1-C6)alkyl), - C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, - SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1- C6)alkyl)SO2(C1-C6)alkyl; R8is independently selected from the group consisting of: H, OH, -halo, perfluoro(C1- C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, -(C1-C6)alkyl-R9, -C(O)R9, -C(O)OR9, - OC(O)R9, -OR9, -OC(O)OR9, -OC(O)N(R9)2, -N(R9)2, -NR9C(O)R9, -NR9C(O)OR9, - NR9C(O)N(R9)2,-C(O)N(R9)2, -SR9, -S(O)R9, -SO2R9, -SO2N(R9)2, -N(R9)SO2R9and - (C1-C6)alkyl-R9;R9is selected from the group consisting of: H, -C(O)R10, -C(O)OR10, -OC(O)R10, - OR10, -OC(O)OR10, -OC(O)N(R10)2, -N(R10)2, -NR10C(O)OR10, -NR10C(O)R10, - NR10C(O)N(R10)2, -C(O)N(R10)2, -SR10, -S(O)R10, -SO2R10, -SO2N(R10)2, -N(R10)SO2R10, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -halo, OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1- C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1-C6)alkyl)2, NH2, NH(C1-C6)alkyl, - N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)(C1-C6)alkyl, NHC(O)NH2, - N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)NH((C1- C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1-C6)alkyl, -N((C1- C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1-C6)alkyl), -C(O)N((C1-C6)alkyl)2, - S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1-C6)alkyl), - SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1-C6)alkyl)SO2(C1-C6)alkyl; and R10is H or (C1-C6)alkyl.

[0106] In some embodiments of Formula (I), the compound of Formula (I) is a compound of Formula (Ia):, or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments of Formula (I), the compound of Formula (I) is a compound of Formula (Ib):or a pharmaceutically acceptable salt thereof

[0108] In some embodiments of Formula (I), the compound of Formula (I) is a compound of Formula (Ic) , or a pharmaceutically acceptable salt thereo.

[0109] In some embodiments of Formula (I), the compound of Formula (I) is a compound of Formula (Id) , or a pharmaceutically acceptable saltthereof.

[0110] In some embodiments of Formula (I), the compound of Formula (I) is a compound of Formula (Ie) , or a pharmaceutically acceptable salt thereof

[0111] In some embodiments of Formula (I), each R1is independently selected from the group consisting of: halo, -CN, (C1-C6)alkyl, -O(C1-C6)alkyl, (C1-C6)haloalkyl, - O(C1-C6)haloalkyl, or (C3-C10)cycloalkyl; and m is an integer from zero to four In some embodiments, m is 2 and each R1is fluoro. In other embodiments, m is 1 and R1is fluoro. In other embodiments, m is 1 and R1is chloro. In still yet other embodiments, m is 2 and each R1is independently fluoro, chloro, -CN or (C1-C6)alkyl. In other embodiments, R1is –O(C1- C6)haloalkyl. In still other embodiments, R1is –(C1-C6)haloalkyl. In some embodiments, R1is (C3-C10)cycloalkyl. In some embodiments, R1is cyclopropyl.

[0112] In some embodiments of Formula (I), ring A is a C6-10aryl. In some such embodiments, ring A is phenyl. In some embodiments, ring A is a 5-10 membered heteroaryl. Ub sine such embodiments, ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl, pyrazolyl, tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothienyl, benzofuryl and indolyl. In some embodiments, ring A is pyridyl.

[0113] In some embodiments, ring A is substituted with (R2)n. In some such embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, each R2is independently is -F, - CN, -Br, -OH, -O(C1-C6)alkyl, (C1-C6)haloalkyl, -O(C1-C6)haloalkyl, or -SO2R5; and n is an integer from zero to four. In some embodiments, n is 1 and R2is fluoro. In other embodiments, n is 1 and R2is cyano. In yet other embodiments, n is 1 and R2is bromo. In still yet other embodiments, n is 2 and each R2is independently selected from -OH and fluoro.

[0114] In some embodiments, X is 5-membered heteroaryl optionally substituted with R8. In other embodiments, X is oxadiazolyl, oxazolyl, isoxazolyl, or triazolyl, each ofwhich is optionally substituted with R8. In some embodiments X is selected from the group consisting of: . In some emboIn yet other embodiments, X isIn some other embodiments, X isIn other embodiments, X is a 5-10more R8. In yet other embodiments, X is tetrahydrofuanyl optionally substituted with one or more R8. In still yet other embodiments, each R8is independently –OH or –CH2OH.

[0115] In some embodiments, R3is selected from the group consisting of: -OH, oxo(=O), optionally substituted (C1-C6)alkyl, optionally substituted -O-(C1-C6)alkyl. optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (3-13 membered)heterocycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (5-12 membered)heteroaryl, -SR6, -S(O)R6, -SO2R6, -SO2N(R6)2, -N(R6)SO2R6, -N(R6)2NR6C(O)N(R6)2, -NR6C(O)OR6, –C(O)R6, –C(O)O(R6), or -C(O)N(R6)2. In other embodiments, R3is -OH. In yet other embodiments, R3is -O-(C1-C6)alkyl. In other embodiments, R3is oxo(=O).

[0116] In some embodiments, R3is NH2. In other embodiments, R3is -N(R6)2. In some such embodiments, one of said R6is H or (C1-C6)alkyl; and the other of said R6is (3-13 membered)heterocycloalkyl-(R7)p; p is 1 or 2; and each R7is independently selected from hydrogen, -OH, -(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, or oxo. In other such embodiments, one of said R6is H or (C1-C6)alkyl; and the other of said R6is. In yet other such embodiments, one of id R6is (C3-C10)cycloalkyl-(R7)p; p is 1 or 2;and each R7is independently selected from hydrogen, -OH, -(C1-C6)alkyl, halo, or oxo.

[0117] In yet other embodiments, R3is -N(R6)2, wherein one of said R6is H or (C1- C6)alkyl; and the other of said R6is -(C1-C6)alkyl-(R7)p; p is 1; and R7is -SO2(C1-C6)alkyl, - SO2NH2, -SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl, or -N((C1- C6)alkyl)SO2(C1-C6)alkyl. In other embodiments, R3is -N(R6)2, wherein one of said R6is H or (C1-C6)alkyl; and the other of said R6is -(C1-C6)alkyl-(R7)p; p is 1; and R7is optionally substituted (C3-C10)cycloalkyl, optionally substituted (3-13 membered)heterocycloalkyl, optionally substituted (C6-C10)aryl, or optionally substituted (5-12 membered)heteroaryl. In still yet other embodiments, R3is -N(R6)2, wherein one of said R6is H or (C1-C6)alkyl; and the other of said R6is -(C1-C6)alkyl-(R7)p; p is 1; and R7is –OH, oxo, or (C1-C6)alkoxy. In some embodiments, one of said R6is H and the other of said R6is -CH2CH2OH.

[0118] In some embodiments, R3is -N(R6)2, wherein one of said R6is H or (C1- C6)alkyl; and the other of said R6is -(C1-C6)alkyl-(R7)p; p is 1; and R7is –O(C1-C6)alkyl, NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)-C(O)(C1- C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1-C6)alkyl), -N((C1- C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1- C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1-C6)alkyl), - C(O)NH((C3-C10)cycloalkyl)(C1-C6)alkyl))-OH, or -C(O)N((C1-C6)alkyl)2. In some embodiments, R7is -N((C1-C6)alkyl)2, -C(O)NH2,-C(O)NH((C1-C6)alkyl) or -C(O)N((C1- C6)alkyl)2.

[0119] In some embodiments, R3is –C(O)N(R6)2and one of said R6is H or (C1- C6)alkyl; and the other of said R6is (3-13 membered)heterocycloalkyl-(R7)p; p is 1 or 2; and each R7is independently selected from hydrogen, -OH, CH2OH, or oxo. In other embodiments, R3is –C(O)N(R6)2 and one of said R6is H or (C1-C6)alkyl; and the other of said R6is (C3- C10)cycloalkyl-(R7)p; p is 1 or 2; and each R7is independently selected from hydrogen, -OH, - CH2OH, -CH2OCH3, or oxo. In yet other embodiments, R3is –C(O)N(R6)2 and one of said R6is H or (C1-C6)alkyl; and the other of said R6is -(C1-C6)alkyl-(R7)p; p is 1; and R7is -OH or - C(O)NH2. In some embodiments, R3is –C(O)O(R6). In some embodiments, R3is –C(O)OCH3.

[0120] In some embodiments, R3is optionally substituted (C1-C6)alkyl. In other embodiments, R3is (C1-C6)alkyl substituted with -NHC(O)(C1-C6)alkyl, -NHC(O)(C1- C6)alkyl-O-(C1-C6)alkyl, -NHC(O)(C3-C10)cycloalkyl, -NHC(O) (3-13 membered)heterocycloalkyl, -N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl), N((C1- C6)alkyl)C(O)NH2 or -NH(3-13 membered)heterocycloalkyl. In some embodiments, R3is (C1- C6)alkyl substituted with -NHC(O)CH3. In other embodiments, R3is (C1-C6)alkyl substituted with -NHC(O)CH2OCH3.

[0121] In some embodiments R3is –C(O)R6and R6is (3-13 membered)heterocycloalkyl-(R7)p; p is 1 or 2; and each R7is independently selected from -OH, CH2OH or oxo.

[0122] In some embodiments, the compound of Formula (I) is selected from the , ,, , , ,,

[0123] In some embodiments, the compound is selected from the group consisting O O H Handon, comprising a compound or salt of one or more compounds disclosed herein.

[0125] Another embodiment of the disclosure is directed to a method for treating non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), pancreatic cancer, arterio-nephrosclerosis and in treating or ameliorating comorbidities such as hypertension, atherosclerosis, sepsis, sickle cell disease and Covid-19 infection in a mammal, preferably a human, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof. Pharmaceutical Compositions

[0126] The disclosure also relates to compositions comprising a compound of Formula (I), and Formulae (Ia), (Ib), (Ic), (Id) and (Ie) wherein or an acceptable salt thereof (e.g., pharmaceutical compositions). Accordingly, in one embodiment, the invention relates to a pharmaceutical composition comprising a compound of Formula I, a pharmaceutically acceptable carrier and, optionally, at least one additional medicinal or pharmaceutical agent. In one embodiment, the at least one additional medicinal or pharmaceutical agent is an anti- Alzheimer agent as described below.

[0127] The pharmaceutical acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates). The pharmaceuticalcompositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0128] The compounds of formula I should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication.

[0129] Compounds of the disclosure intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

[0130] They may be administered alone or in combination with one or more other compounds of the disclosure or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term ’excipient’ is used herein to describe any ingredient other than the compound(s) of the disclosure. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0131] Pharmaceutical compositions suitable for the delivery of compounds of the present disclosure and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

[0132] The compounds of the disclosure may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract,and / or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.

[0133] Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal / mucoadhesive patches.

[0134] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

[0135] The compounds of the disclosure may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).

[0136] For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.

[0137] Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[0138] Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.

[0139] Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.

[0140] Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.

[0141] Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.

[0142] Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

[0143] The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol.1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0144] Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.

[0145] The compound of formula I may be water-soluble or insoluble. A water- soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, the compound of formula I may be in the form of multiparticulate beads.

[0146] The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.

[0147] Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.

[0148] Films in accordance with the disclosure are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.

[0149] Solid formulations for oral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained- , pulsed-, controlled-, targeted and programmed release.

[0150] Suitable modified release formulations for the purposes of the disclosure are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00 / 35298.

[0151] The compounds of the disclosure may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle- free injectors and infusion techniques.

[0152] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

[0153] The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0154] The solubility of compounds of formula I used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

[0155] Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained- , pulsed-, controlled-, targeted and programmed release. Thus, compounds of the disclosure may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(dl-lactic-coglycolic)acid (PGLA) microspheres.

[0156] The compounds of the disclosure may also be administered topically, (intra)dermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).

[0157] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

[0158] Formulations for topical administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[0159] The compounds of the disclosure can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

[0160] The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the disclosure comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

[0161] Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bedjet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

[0162] Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the disclosure, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0163] A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1μg to 20mg of the compound of the disclosure per actuation and the actuation volume may vary from 1μl to 100μl. A typical formulation may comprise a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

[0164] Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the disclosure intended for inhaled / intranasal administration.

[0165] Formulations for inhaled / intranasal administration may be formulated to be immediate and / or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[0166] The compounds of the disclosure may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

[0167] Formulations for rectal / vaginal administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained- , pulsed-, controlled-, targeted and programmed release.

[0168] The compounds of the disclosure may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable (e.g. absorbable gel sponges, collagen) and non- biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[0169] Formulations for ocular / aural administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained- , pulsed-, controlled-, targeted, or programmed release.

[0170] The compounds of the disclosure may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste- masking, bioavailability and / or stability for use in any of the aforementioned modes of administration.

[0171] Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91 / 11172, WO 94 / 02518 and WO 98 / 55148.

[0172] Since the present disclosure has an aspect that relates to the treatment of the disease / conditions described herein with a combination of active ingredients which may be administered separately, the disclosure also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula I a prodrug thereof or a salt of such compound or prodrug and a second compound as described above. The kit comprises means for containing the separate compositions such as a container, a divided bottle or a divided foil packet. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0173] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparentplastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0174] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday,etc.... Second Week, Monday, Tuesday,..." etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of Formula I compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.

[0175] In another specific embodiment of the disclosure, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and / or reminds one when the next dose is to be taken.

[0176] The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.

[0177] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.

[0178] The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.

[0179] In one preferred embodiment the composition comprises a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.

[0180] Another embodiment of the disclosure is directed to a method for treating non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), pancreatic cancer, arterio-nephrosclerosis and in treating or ameliorating comorbidities such as hypertension, atherosclerosis, sepsis, sickle cell disease and Covid-19 infection in a mammal, preferably a human, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof.

[0181] The compounds of Formula I and the pharmaceutically acceptable salts thereof are useful for the treatment of non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), pancreatic cancer, arterio-nephrosclerosis and in treating or ameliorating comorbidities such as hypertension, atherosclerosis, sepsis, sickle cell disease and Covid-19 infection. Accordingly, in one embodiment, the disclosure provides a method for treating a condition in a mammal, such as a human, selected from the conditions above, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to the mammal. The mammal is preferably a mammal in need of such treatment or prevention.

[0182] Administration of the compounds of Formula I may be affected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.

[0183] Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0184] Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present disclosure.

[0185] It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present disclosure encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the active agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

[0186] The amount of the compound of Formula (I), and Formulae (I'), (I"), (la’), (lb’), (Ic) and (Id), wherein administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g / day, preferably about 0.1 to about 2.5 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

[0187] As used herein, the term “combination therapy” refers to the administration of a compound of Formula I together with an at least one additional pharmaceutical or medicinal agent, either sequentially or simultaneously.

[0188] The present disclosure includes the use of a combination of a compound as provided in Formula I and one or more additional pharmaceutically active agent(s). If a combination of active agents is administered, then they may be administered sequentially orsimultaneously, in separate dosage forms or combined in a single dosage form. Accordingly, the present disclosure also includes pharmaceutical compositions comprising an amount of: (a) a first agent comprising a compound of Formula (I) or a pharmaceutically acceptable salt of the compound; (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, vehicle or diluent.

[0189] Various pharmaceutically active agents may be selected for use in conjunction with the compounds of Formula I, depending on the disease, disorder, or condition to be treated. Pharmaceutically active agents that may be used in combination with the compositions of the present disclosure include, without limitation:

[0190] As used herein, the term “another active agent” refers to any therapeutic agent, other than the compound of Formula I, or salt thereof, that is useful for the treatment of a subject disorder.

[0191] The compounds of the disclosure are useful for treatment and / or prophylaxis of chronic kidney disease including the treatment of renal disorders, including renal insufficiency and kidney failure. Renal insufficiency and kidney failure comprise both acute and chronic manifestations (chronic kidney disease; CKD) thereof, as well as underlying or related kidney diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney graft rejection and immunocomplex-induced kidney diseases, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, diabetic kidney diseases (DKD), pyelonephritis, renal cysts and polycystic kidney disease, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which can be characterized diagnostically for example by abnormally reduced creatinine and / or water excretion, abnormally raised blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such as, for example, glutamyl synthetase, altered urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, lesions on glomerulae and arterioles, tubular dilation, hyperphosphataemia and / or need for dialysis. The present disclosure also encompasses the use of the compounds according to the disclosure for treatment and / or prophylaxis of sequelae of renal insufficiency, for example hypertension, pulmonary oedema, heart failure, uremia, anemia, electrolyte disturbances (for example hyperkalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.

[0192] In addition, the compounds of the disclosure are suitable for treatment and / or prevention of urological disorders, for example benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), prostatitis, neurogenic overactive bladder (OAB), incontinence, for example mixed, urge, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, interstitial cystitis (IC) and also erectile dysfunction and female sexual dysfunction.

[0193] Examples of additional active agents which may he employed include but are not limited to antiretroviral therapeutics (ART) including Nucleoside Reverse Transcriptase Inhibitors (NRTIs) such as Abacavir, Emtricitabine, Lamivudine, Tenofovir disoproxil fumarate, and Zidovudine; Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) such as Doravirine, Efavirenz, Etravirine, Nevirapine, Rilpivirine; Protease Inhibitors (Pls) such as Atazanavir, Darunavir, Fosamprenavir, Tipranavir; Fusion Inhibitors such as Enfuvirtide; CCR5 Antagonists such as Maraviroc; Integrase Strand Transfer Inhibitors (INSTIs) such As Cabotegravir, Dolutegravir, Raltegravir; Attachment Inhibitors such as Fostemsavir; PostAttachment Inhibitors such as Ibalizumab-uiyk; Pharmacokinetic Enhancers such as Cobicistat; and combinations of the aforesaid HIV therapeutics; Angiotensin Converting Enzyme Inhibitors (e.g., Alacepril, Benazepril, Captopril, Ceronapril, Cilazapril, Delapril, Enalapril, Enalaprilat, Fosinopril, Imidapril, Lisinopril, Moveltipril, Perindopril, Quinapril, Ramipril, Spirapril, Temocapril, Or Trandolapril), Angiotensin II Receptor Antagonists (e.g., Losartan i.e., COZAAR®, Valsartan, Candesartan, Olmesartan, Telmesartan and any of these drugs used in combination with Hydrochlorothiazide such as HYZAAR®); Neutral Endopeptidase Inhibitors (E.G., Thiorphan And Phosphoramidon), Aldosterone Antagonists, Aldosterone Synthase Inhibitors, Renin Inhibitors (e.g. urea derivatives of di- and tri-peptides, amino acids and derivatives, amino acid chains linked by non-peptidic bonds, di- and tripeptide derivatives, peptidyl amino diols and peptidyl beta- aminoacyl aminodiol carbamates; also, and small molecule renin inhibitors including diol sulfonamides and, N-morpholino derivatives, N-heterocyclic alcohols and pyrolimidazolones; also, pepstatin derivatives and fluoro- and chloro-derivatives of statone-containing peptides, enalkrein, RO 42-5892, A 65317, CP 80794, ES 1005, ES 8891 , SQ 34017, aliskiren (2(S),4(S),5(S),7(S)— N-(2-carbamoyl-2- methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)- phenyl]-octanamid hemifumarate) SPP600, SPP630 and SPP635), endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g. Sildenafil, Tadalfil And Vardenafil), vasodilators, calcium channel blockers (e.g., Amlodipine, Nifedipine, Veraparmil, Diltiazem,Gallopamil, Niludipine, Nimodipins, Nicardipine), potassium channel activators (e.g., Nicorandil, Pinacidil, Cromakalim, Minoxidil, Aprilkalim, Loprazolam), diuretics (e.g., Hydrochlorothiazide), sympatholitics, beta-adrenergic blocking drugs (e.g., Propranolol, Atenolol, Bisoprolol, Carvedilol, Metoprolol, Or Metoprolol Tartate), alpha adrenergic blocking drugs (e.g., Doxazosin, Prazosin Or Alpha Methyldopa) central alpha adrenergic agonists, peripheral vasodilators (e.g. hydralazine); lipid lowering agents e.g., HMG-CoA reductase inhibitors such as Simvastatin And Lovastatin which are marketed as ZOCOR® and MEV ACOR® in lactone pro-drug form and function as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoA reductase inhibitors such as Atorvastatin (particularly the calcium salt sold in LIPITOR®), rosuvastatin (particularly the calcium salt sold in CRESTOR®), pravastatin (particularly the sodium salt sold in PRAVACHOL®), fluvastatin (particularly the sodium salt sold in LESCOL®), cerivastatin, and pitavastatin; a cholesterol absorption inhibitor such as ezetimibe (ZETIA®) and ezetimibe in combination with any other lipid lowering agents such as the HMG-CoA reductase inhibitors noted above and particularly with simvastatin (VYTORIN®) or with atorvastatin calcium; niacin in immediate-release or controlled release forms, and / or with an HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists; anti-cholesterol agents such as PCSK9 inhibitors (alirocumab, evolocumab), Nexletol™ (bempedoic acid, ACL inhibitor), and Vascepa® (Icosapent ethyl); metabolic altering agents including insulin and insulin mimetics (e.g., insulin degludec, insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin, omarigliptin, linagliptin, vildagliptin); insulin sensitizers, including (i) P-klotho / FGFRT activating monoclonal antibody (e.g. MK-3655), pan FGFR1-4 / KLB modulators, FGF19 analogue (e.g. Aldafermin) (ii) PPARy agonists, such as the glitazones (e.g. pioglitazone, AMG 131, CHS 131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, rosiglitazone, and balaglitazone), and other PPAR ligands, including (1) PPARa / y dual agonists (e.g. ZYH2, ZYH1, GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, and naveglitazar); (2) PPARU agonists such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), (3) selective PPARy modulators (SPPARyM's), (e.g., such as those disclosed in WO 02 / 060388, WO 02 / 08188, WO 2004 / 019869, WO 2004 / 020409, WO 2004 / 020408, and WO 2004 / 066963); (4) PPARy partial agonists, (5) PPAR a / 5 dual agonists (e.g. Elafibranor); (iii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended- release formulations thereof, such as Glumetza™, Fortamet™, and GlucophageXR™; and (iv)protein tyrosine phosphatase- IB (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, insulin degludec, insulin glargine, insulin lispro and inhalable formulations of each); leptin and leptin derivatives and agonists; amylin and amylin analogs (e.g., pramlintide); sulfonylurea and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, meglitinides, nateglinide and repaglinide); a-glucosidase inhibitors (e.g., acarbose, voglibose and miglitol); glucagon receptor antagonists (e.g., MK-3577, MK-0893, LY-240902I and KT6-971); incretin mimetics, such as GLP-1 , GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof), bile acid sequestering agents (e.g., colestilan, colestimide, colesevalam hydrochloride, colestipol, cholestyramine, and dialkylaminoalkyl derivatives of a cross-linked dextran), acyl Co A: cholesterol acyltransferase inhibitors, (e.g., avasimibe); antiobesity compounds; agents intended for use in inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX- 2 inhibitors such as Celocoxib; glucokinase activators (GKAs) (e.g., AZD6370); inhibitors of 1 ip-hydroxy steroid dehydrogenase type 1 (e.g., such as those disclosed in U.S. Pat. No. 6,730,690, andLY-2523199); CETP inhibitors (e.g., anacetrapib, torcetrapib, and evacetrapib): inhibitors of fructose 1 ,6-bisphosphatase, (e.g., such as those disclosed in U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476); inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC 1 or ACC2); AMP-activated Protein Kinase (AMPK) activators; other agonists of the G-protein-coupled receptors: (i) GPR-109, (ii) GPR-119 (e.g., MBX2982 and PSN821), and (iii) GPR-40 (e.g., TAK875); SSTR3 antagonists (e.g., such as those disclosed in WO 2009 / 001836); neuromedin U receptor agonists (e.g., such as those disclosed in WO 2009 / 042053, including, but not limited to, neuromedin S (NMS)); SCD modulators (e.g. Aramchol); GPR-105 antagonists (e.g., such as those disclosed in WO 2009 / 000087); SGLT inhibitors (e.g., ASP1941, SGLT-3, SGLT-2 such as empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin, BI-10773, remogloflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211); inhibitors of acyl coenzyme A carboxylase (ACC, MK-4074); inhibitors of diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2); inhibitors of fatty acid synthase; inhibitors of acyl coenzyme A: monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2); agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR); ileal bile acid transporter inhibitors; bile acid modulators; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; IL-lb antibodies, (e.g., XOMA052 andcanakinumab), anti-fibrotic and / or anti-inflammatory agents (CCR2 / CCR5 dual receptor antagonist (e.g. cenicriviroc); galectin 3 inhibitor (e.g. belapectin, GB-1107, GB-1211), siRNA against HSP 47 (e.g. BMS-986263); NSAID derived from pirfenidone (e.g. hydronidone), A3AR agonist (e.g. namodenoson, FM101); TGFTX4 (e.g. nitazoxanide); 5 -lipoxygenase inhibitor (e.g. tipelukast), Bifunctional urate inhibitor (e.g. ACQT1127), adiponectin receptor agonist (e.g. ALY688), TNF receptor antagonist (e.g. atrosimab), Autotaxin inhibitor (e.g. BLD-0409, TJC 0265, TJC 0316), CCL24 blocking monoclonal antibody (e.g. CM101), IL-11 inhibitor (e.g. ENx 108A), LPA1 receptor antagonist (e.g. EPGN 696), Dual JAK1 / 2 inhibitor (e.g. EX 76545), GPR antagonist (e.g. GPR91 antagonist), Integrin avpi, avP3 and avP6 inhibitor (e.g. IDL 2965), NLRP3 antagonist (e.g. IFM-514), inflammasome inhibitors (e.g. JT194, JT349), Cell membrane permeability inhibitor (e.g. Larazotide), CCR5 antagonist (e.g. leronlimab), TNF inhibitor (e.g. LIVNate), integrin avP6 inhibitor (e.g. MORF beta6), NLRP inflammasome antagonists, siRNA (e.g. OLX 701), dual TFGp / Hedgehog inhibitor (e.g. Oxy 200), GPR40 agonist / GPR84 antagonist (e.g. PBI-4547), neutrophil elastase inhibitor (e.g. PHP-303), integrin inhibitor (e.g. PLN-1474), TGFpi modulator (e.g.PRM-151), CCK receptor antagonist (e.g. proglumide), LOXL2 inhibitor (e.g. PXS-5338K, PXS-5382A), IL-11 inhibitors, MPYS protein inhibitor (e.g. cGAS / STING antagonists), kinase inhibiting RNase, membrane protein mAbs, tumor necrosis factor inhibitor, NRF2 activator (e.g. SCO 116), SSAO inhibitor (e.g. TERN 201), TRAIL2 agonist (e.g. TLY012), IL-6 receptor antagonist (e.g. TZLS 501), AOC3 inhibitor (e.g. UD-014), SSAO / VAP-1 inhibitor, TREM2); antioxidant (e.g. vitamin E); anti-inflammatory agents (e.g. norfloxacin, ciprofloxacin, ceftriaxone); coagulation modifiers (e.g. anti-coagulants, anti-platelet agents, pentoxifylline, vitamin K, DDAVP); dual GIP and GLP-1 receptor agonist (e.g. tirzepetide); dual GLP-l / GRA (e.g. cotadutide, ALT-801, DD 01, G49, PB-718); dual GLP-1 (e.g. CT 868); GLP-l / GRA / GIP triple agonist (e.g. HM15211); GRP120 stimulant / inflammasome modulator / PPARy dual agonist (e.g. KDT501); GLP-1 / FGF21 (e.g. YH25724); GLP-1 agonist (e.g. Ozempic (semaglutide sc), XW 003); selective thyroid hormone receptor-P agonist (e.g. resmetirom); apoptosis modulators (JNK-1 inhibitor (e.g. CC-90001), Peroxidase inhibitor (e.g. AZM198), ASK-1 inhibitor (e.g. CS-17919, SRT 015)); erythropoietin- stimulating agents (erythropoietin receptor agonist (e.g. cibinetide)); glucose pathway modulators (SGLT-2 inhibitor (e.g. Forxiga, Farxiga (dapagliflozin)); dual SGLT-1 / 2 inhibitor (e.g. licogliflozin), Glucose-6-P dehydrogenase inhibitor (e.g. fluasterone) LAPS glucagon combo (e.g. HM14320), SGLT-1 inhibitor (e.g. SGL5213)); immune modulators (TLR4 inhibitor (e.g. GBK-233), immunomodulatory polyclonal antibody (e.g. IMM-124E), TLR4 antagonist (e.g. JKB-122),CD3 monoclonal antibody (e.g.foralumab), TLR4 antagonist (e.g. JKB 133), TLR4 inhibitor (e.g. mosedipimod), Macrophage inhibitor via CD206 targeting (e.g. MT2002), TLR2 / 4 antagonist (e.g. VB-201, VB-703), immunomodulatory polyclonal antibody (e.g. IMM-124E)); incretin-based therapies (GLP-1 agonist (e.g. Ozempic (semaglutide sc), XW 003), GLP- 1 / glucagon dual receptor agonist (e.g. H1M12525A), prandial insulin (e.g. ORMD 0801)); lipid modulators (AMPK Activator / Glutathione transferase (e.g. oltipraz), THR-beta agonist (e.g. resmetirom, VK2809, MGL-3745, ALG-009, ASC41, CNPT-101101, TERN 501), IBAT inhibitor (e.g. elobixibat, CJ 14199), omega-6-fatty acid (e.g. epeleuton), FASN inhibitor (e.g. TVB2640, FT 4101, FT 8225), ANGPTL3 inhibitor (e.g. vupanorsen), PNPLA3 inhibitor (e.g. AZD2693), RAS domain kinase inhibitor (e.g. BioEl l 15), NTCP inhibitor (e.g. bulevirtide), P2Y13 receptor agonist (e.g. CER-209), omega-3 fatty acid, HSD1713 inhibitor; metabolism modulators (FXR agonist (e.g. Ocaliva (obeticholic acid), IOT022), recombinant variant of FGF19 (e.g. aldafermin), bi-specific FGFR1 / KLB antibody (e.g. BFKB8488A), mTOT modulator (e.g. MSDC-0602K), pegylated analog of FGF21 (e.g. pegbelfermin, BMS- 986171), non-bile FXR agonist (e.g. cilofexor, EDP-305, EYP 001, tropifexor, MET409, AGN-242256, AGN-242266, EDP 297, HPG 1860, MET642, RDX023, TERN 101), ACC inhibitor (e.g. firsocostat, PF-05221304), ketohexokinase inhibitor (e.g. PF-06835919), AMPK activator (e.g. PXL770, MSTM 101, 0304), bile acid modulator (e.g. Albiero), FGF21 analog (e.g. BI089-100), MOTSc analog (e.g. CB4211), cyclophilin inhibitor (e.g. CRV 431), FGF19 (e.g. DEL 30), mitochondrial uncoupler (e.g. GEN 3026), FXR / GPCR dual agonist (e.g. INT- 767), Cysteamine derivative (e.g. KB-GE-001), dual amylin and calcitonin receptor agonist (e.g. KBP-089), transient FXR agonist (e.g. M 1217), anti-beta-klotho (KLB)-FGFRlc receptor complex mAh (e.g. MK3655), GDF15 analog (e.g. NGM395), cyclophilin inhibitor (e.g. NV556), LXR modulator (e.g. PX 329, PX 655, PX 788), LXR inverse agonist (e.g. PX016), deuterated obeticholic acid (e.g. ZG 5216)); PPAR modulators (dual PPARot / y agonist (e.g. elafibranor), PPAR pan agonist (e.g. lanifibranor), PPARa agonists (e.g. Parmodia), PPARy agonist (e.g. CHS 131), MPC inhibitor (e.g. PXL065), PPAR5 / y agonist (e.g.T3D 959)); RAAS mIMModulators (mineralocorticoid receptor antagonist (e.g. apararenone, eplerenone, spironolactone), angiotensin receptor blocker (e.g. losartan potassium)); neurotransmitter modulators (cannabinoid receptor modulator, CBT receptor antagonist (e.g. CRB-4001, IM-102, nimacimab), TPH1 inhibitor (e.g. CU 02), GPR120 agonist (e.g. KBR2001), combination of cannabinoid and botanical anti-inflammatory compound (e.g. SCN 002)); PDE Modulator (PDE4 inhibitor (e.g. ART 648)); CYP2E1 inhibitor (e.g. SNP-610); cell therapies (e.g. HepaStem) and bromocriptine mesylate and rapid-release formulationsthereof; or with other drugs beneficial for the prevention or the treatment of the above- mentioned diseases including nitroprusside and diazoxide the free-acid, free-base, and pharmaceutically acceptable salt forms of the above active agents where chemically possible. In another embodiment, the present disclosure provides methods of treating kidney disease and other human disease where ApoLl inhibition is beneficial, comprising administering to a mammal, preferably a mammal in need thereof, an amount of a compound of Formula I or a pharmaceutically acceptable salt thereof effective in treating such disorders.

[0194] It will be understood that the intermediate compounds of Formula I depicted above are not limited to the particular enantiomer shown, but also include all stereoisomers and mixtures thereof.Combinations With Additional Pharmaceutical Agents

[0195] The compounds of Formula (I) presented herein may be administered in combination with one or more additional pharmaceutical agents. In some embodiments, the compounds described above may be administered in combination with one additional pharmaceutical agent. In some embodiments, the compounds described above may be administered in combination with two additional pharmaceutical agents. In some embodiments, the compounds described above may be administered in combination with three or more additional pharmaceutical agents.

[0196] In some embodiments, the compounds of Formula (I) presented herein may be administered simultaneously with one or more additional pharmaceutical agents. In other embodiments, the compounds of the present disclosure may be administered sequentially with one or more additional pharmaceutical agents.Methods of Treatment

[0197] Another embodiment of the disclosure is directed to a method for treating non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), pancreatic cancer, arterio-nephrosclerosis and in treating or ameliorating comorbidities such as hypertension, atherosclerosis, sepsis, sickle cell disease and Covid- 19 infection in a mammal, preferably a human, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof.

[0198] The compounds of this disclosure and the pharmaceutically acceptable salts thereof are useful for the treatment of non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), pancreatic cancer, arterio-nephrosclerosis and in treating or ameliorating comorbidities such as hypertension, atherosclerosis, sepsis, sickle cell disease andCovid-19 infection. Accordingly, in one embodiment, the disclosure provides a method for treating a condition in a mammal, such as a human, selected from the conditions above, comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to the mammal. The mammal is preferably a mammal in need of such treatment or prevention.

[0199] In some embodiments, the compounds of the disclosure are useful for treatment and / or prophylaxis of chronic kidney disease including the treatment of renal disorders, including renal insufficiency and kidney failure. Renal insufficiency and kidney failure comprise both acute and chronic manifestations (chronic kidney disease; CKD) thereof, as well as underlying or related kidney diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney graft rejection and immunocomplex-induced kidney diseases, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, diabetic kidney diseases (DKD), pyelonephritis, renal cysts and polycystic kidney disease, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which can be characterized diagnostically for example by abnormally reduced creatinine and / or water excretion, abnormally raised blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such as, for example, glutamyl synthetase, altered urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, lesions on glomerulae and arterioles, tubular dilation, hyperphosphataemia and / or need for dialysis. The present disclosure also encompasses the use of the compounds according to the disclosure for treatment and / or prophylaxis of sequelae of renal insufficiency, for example hypertension, pulmonary oedema, heart failure, uremia, anemia, electrolyte disturbances (for example hyperkalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.

[0200] In further embodiments, the compounds of the disclosure are suitable for treatment and / or prevention of urological disorders, for example benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), prostatitis, neurogenic overactive bladder (OAB), incontinence, for example mixed, urge, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, interstitial cystitis (IC) and also erectile dysfunction and female sexual dysfunction.

[0201] In some embodiments, the compounds of this disclosure are suitable lor treatment and / or prevention of APOL l -mediated diseases and disorders.In some embodiments, the APOLl-mediated diseases or disorder are kidney disorders. In other embodiments, the APOL l -mediated diseases or disorders are disorders other than kidney disorders. In yet further embodiments, the compounds of the disclosure are suitable for treatment and / or prevention of coronary artery disease, endothelial cell dysfunction, and diabetic macular edema. In some embodiments, the compounds of the disclosure are suitable for treatment and / or prevention of obesity, hypertension, smooth muscle cell in jury, increased cellular cholesterol content, autophagic flux defect, endolheliopalhy, graft rejection, preeclampsia, felal / neonalal death, or sepsis. [MXFU]Methods of Preparation

[0202] The compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Unless otherwise indicated, X, Y, R1through R11, and n, m, p, and q are as defined above in the reaction schemes and discussion that follow. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. For example, certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry’ (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are both hereby incorporated herein by reference in their entirety. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on thedisclosures herein; all such modifications and alternate routes are within the scope of the claims.

[0203] Compounds of the Formula (I) and Formulae (la), (lb), (lac), (Id), and (le), may be prepared according to the following reaction schemes and accompanying discussion. Unless otherwise indicated, R1through R10, A, X, n, m, and p and structural Formula (I), (la), (lb), (Ic), (Id) and (le) are as defined in the reaction schemes and discussion that follow. In general, the compounds of this disclosure may be made by processes known to those skilled in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of this disclosure are provided as further features of the disclosure and are illustrated by the following reaction schemes. Other processes may be described in the experimental section.

[0204] As an initial note, in the preparation of the Formula I compounds it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in Formula I precursors). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection / deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see Greene's Protective Groups in Organic Synthesis, 5th Edition, Peter G. M. Wuts, ISBN: 978-1-118-05748-3 October 2014.

[0205] For example, certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethylenoxycarbonyl for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionality in the Formula I compound.SCHEME 1SCHEME 2SCHEME 3

[0206] Scheme 1 illustrates the synthesis of compounds of Formula (la’), wherein R1, R2, R3, m, n, and ring A are as defined herein, and X is an oxadiazole having the structure:

[0207] Referring to Scheme 1, a compound of Formula (la’), wherein R3is OH, may be prepared from a hydrazide compound of Formula II by a l,l'-carbonyldiimidazole (CDI) mediated coupling and dehydration cyclization in a solvent such as THF, methylene chloride or DMF at a temperature of from about 0°C to about 30 °C for a period from about 30 minutes to about 6 hours.

[0208] Compounds of Formula II may be prepared from a protected ester compound of Formula III, wherein P1is a protecting groups such as an ester, carbonate, or tosylate, by reaction with hydrazine in a polar solvent such as ethanol at a temperature of about 0°C to about 30 °C for a period from about 5 minutes to about 1 hour.

[0209] Compounds of Formula III, wherein P1is a protecting groups such as an ester, carbonate or tosylate, may be prepared from an aryl iodate compound of Formula IV, wherein P2is a protecting group such as trfluoromethylacetyl or triflate, by coupling with an activated methylene compound of the Formula V, wherein P1is a protecting group such as an ester, carbonate or tosylate, and ring A is an aryl or heteroaryl as defined herein,

[0210] in the presence of Cui, proline and Cesium carbonate in a polar solvent such as dimethylsulfoxide to form a ketoester intermediate followed by deprotection and indole cyclization in the presence of an acid such as HC1 in a polar solvent such as an alcohol such as ethanol at a temperature of from about 30°C to about 150 °C for a period from about 30 minutes to about 4 hours.

[0211] Compounds of Formula IV, wherein P2is an activating group such as trifluoromethyl, may be prepared from an iodo-aniline of Formula VI by reaction with an activated acylating agent such as trifluoroacetic anhydride in the presence of a base such as triethylamine in a solvent such as tetrahydrofuran for a period of about 10 minutes to about 4 hours at a temperature of about -30 °C to about 0°C.

[0212] Compounds of the Formula VI may be prepared from aniline compounds of the Formula VII by reaction with an electrophilic iodination agent such as N-Iodosuccinimide (NIS), with a catalytic amount of a Lewis acid such as trifluoroacetic acid, BF3-H2O, iron(III) triflimide, or silver(I) triflimide in a polar solvent such as acetic acid, acetonitrile, hexafluoroisopropanol or trifluoromethanesulfonic acid for a period of about 10 minutes to about 6 hours at a temperature of from about 30°C to about 70 °C.

[0213] Compounds of Formula VII are commercially available.

[0214] Compounds of the Formula (la’), wherein R3is -OH may be converted to other compounds of Formula (la’), wherein R3is -N(R6)2, -NR6C(O)R6, -NR6C(O)N(R6)2, -NR6C(O)OR6, -SR6, -S(O)R6, -SO2R6, -SO2N(R6)2, -N(R6)SO2R6, more specifically wherein -N(R6)2, is -NH-heterocyclic, by a coupling reaction with a compound of Formula VIII,

[0215] by coupling with a phosphine activating agent such as benzotriazole- 1-yl- oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP, Castro's Reagent), in a polar solvent such as diisopropylethylamine (DIEA) and DMF at a temperature of from about 15 °C to about 40 °C more preferably about 30 °C for a period from about 1 hour to about 24 hours more preferably about 12 hours.

[0216] Compounds of Formula I, wherein R3is an ester, such as CO2alkyl, - C(O)R6, or -C(O)OR6, may be prepared from compounds of the Formula II by reaction with an ethyl chloroglyoxylate in the presence of a base such as triethylamine, DMAP, or Hunigs base in an inert solvent such a THF, DCM, hexane or toluene at a temperature of about -30°C to about 0 °C for a period of about 1 hour to the about 3 hours after which an activated leaving group such as tosyl chloride (TsCl) may be added with additional base and the reaction continued for an additional 12 hours at 0 °C to about room temperature. The ester compounds formed may be converted to other compounds of Formula I by aldol, Claisen condensation reactions, such as by reaction with a hydroxyalkylamine in a polar solvent at a temperature of about 0 °C to about room temperature for a period of about 1 hour to about 12 hours.

[0217] Compounds of the Formula I wherein R3is-C(O)R6, -C(O)OR6, -OC(O)R6, -OR6, -OC(O)OR6, -OC(O)N(R6)2, -N(R6)2, -NR6C(O)R6, -NR6C(O)N(R6)2, -NR6C(O)OR6, -C(O)N(R6)2may be prepared from a compound of Formula I wherein R3is an ester or an amine by reaction with amines Formula R]NHR2, alcohols, acid chlorides or carbonochloridate in the presence of TCFH and NMI in a solvent such as acetonitrile at a temperature of about 0 °C to about room temperature for a period of about 1 hour to about 12 hours.

[0218] Scheme 2 refers to the preparation of compounds of Formula (lb’) or (lb”), wherein X is an oxazolyl group. Referring to Scheme 3, compounds of Formula lb’ or lb” may be prepared from compounds of Formula VIII, wherein L is a halide, such as I or Br, by reaction with an oxazole having the structure:

[0219] by rection with a palladium coupling agent such as tetrakis(triphenylphosphine)palladium(0) in a Negishi, Suzuki, or Stille coupling in the presence of a base such as lithium t-butoxide and a solvent such as dioxane or hexanes.

[0220] Scheme 3 refers to the preparation of compounds of Formula Ic’ or Id’, wherein X is a triazolyl group. Referring to Scheme 3, compounds of Formula Ic’ or Id’ may be prepared from compounds of Formula X, by reaction with an aryl-hydrazine of Formula XI:

[0221] in a polar solvent such as an alcohol at a temperature of about 50°C to about125 °C for a period of about 8 hours to about 12 hours to form an intermediate hydrazide that is cyclized to the indole of Formula Ic’ or Id’ by treatment with an acid such as acetic acid in zinc choride at a temperature of about 80°C to about 120°C for a period of about 8 hours to about 12 hours.

[0222] The compound of Formula X may be prepared from an azide of Formula XII by reaction with an acetylene such as ethyl propiolate and an activating agent such as sodium (5R)-5-[(l>S')-l,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one and CuSCU in an overnight polar solvent such as t-BuOH at a temperature of about 0 °C to about room temperature for a period of about 1 hour to about 12 hours.

[0223] The compound of Formula XII may be prepared from a halide compound (X = Cl, Br, I) of Formula XIII by reaction of sodium azide in a polar solvent, such as dimethylsulfoxide, at a temperature of about 0°C to about 30°C for a period of about 1 hour to about 12 hours.

[0224] Alternatively, compounds of Formula Ic’ or Id’ may be prepared from a compound of Formula Ic’ or Id’, wherein R3is an aldehyde by reaction with an amine with a reducing agent such as sodium triacetoxyborohydride in a solvent such as dichloromethane at a temperature of about 0°C to about 50°C for a period of about 1 hour to about 12 hours.

[0225] The aldehyde of Formula Ic’ or Id’ may be prepared from an R3alcohol compound of Formula I, by reaction with an oxidizing agent such as MnCF in an inert solventreaction, such as dichloromethane, at a temperature of about 0°C to about 50°C for a period of about 6 hours to about 12 hours.

[0226] The alcohol of Formula I may be prepared from an aldehyde or ester compound of Formula I by reaction with a reducing agent such as lithium aluminum hydride in a solvent such as tetrahydrofuran at a temperature of about 0°C to about 30°C for a period of about 1 hour to about 6 hours.

[0227] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of Formula I (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. “Stereochemistry of Organic Compounds” by E. L. Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

[0228] Where a compound of Formula I contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Salts of the present disclosure can be prepared according to methods known to those of skill in the art.

[0229] The compounds of Formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present disclosure from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free baseto a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this disclosure can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.

[0230] Those compounds of Formula I that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this disclosure are those which form non-toxic base salts with the acidic compounds of Formula I. These salts may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. These salts can also be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.

[0231] If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[0232] Pharmaceutically acceptable salts of compounds of formula I may be prepared by one or more of three methods:(i) by reacting the compound of Formula I with the desired acid or base;(ii) by removing an acid- or base-labile protecting group from a suitable precursor; or(iii) by converting one salt of the compound of Formula 1 to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[0233] All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.

[0234] Polymorphs can be prepared according to techniques well-known to those skilled in the art.

[0235] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0236] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[0237] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula I contains an acidic or basic moiety, a base or acid such as 1- phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

[0238] Chiral compounds of the disclosure (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.EXAMPLES

[0239] The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds encompassed herein.Furthermore, other methods for preparing compounds described herein will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. Characterization of the final products via 'H-NMR and LCMS spectra summarized in Tables A, B and D.

[0240] The following preparations can be used to prepare intermediates that are useful in the preparation of compounds of Formula I.SCHEME A

[0241] A mixture of 2,4-difluoroaniline (100 g, 774.5 mmol, 1 equiv.) and NIS (261.3 g, 1.16 mol, 1.5 equiv.) in HOAc (500 mL) was stirred for 24 h at room temperature. Upon completion of reaction, the mixture was concentrated under reduced pressure. The residue was extracted with EtOAc (500 mL) / H20 (1000 mL) for 3 times. The combined organic layers washed with brine (1000 mL); dried over anhydrous NaoSCU; and concentrated underreduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA=10: l to afford 2,4-difhioro-6-iodoaniline (100 g, 50.63%) as a brown solid.Example 2: Synthesis of INT-2INT-1 INT-2

[0242] To a stirred solution of 2,4-difluoro-6-iodoaniline (100 g, 392.1 mmol, 1.00 equiv.) and triethylamine (118.82 g, 1176.4 mmol, 3 equiv.) in THF (500 mL) was added trifluoroacetic acid (TFAA) (98.84 g, 470.5 mmol, 1.2 equiv.) dropwise at -30 °C. The reaction was monitored by TLC. Upon completion of reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA=10:l to afford A-(2,4-difluoro-6-iodophenyl)-2, 2, 2-trifluoroacetamide (90 g, 65.38%) as a red solid.Example 3: Synthesis of INT-3

[0243] To a stirred mixture of A-(2,4-difluoro-6-iodophenyl)-2,2,2- trifluoroacetamide (90 g, 256.4 mmol, 1 equiv.), Cui (4.88 g, 25.6 mmol, 0.10 equiv.), CS2CO3 (334.16 g, 1025.6 mmol, 4.00 equiv.) and L-prolinamide (5.85 g, 51.2 mmol, 0.20 equiv.) in DMSO (250 mL) was added methyl 3-(4-fluorophenyl)-3-oxopropanoate (100.60 g, 512.8 mmol, 2 equiv.) at room temperature under N2 atmosphere. The resulting mixture was stirred for 1 h, and then it was allowed to cool down to 0 °C. 6 M HC1 (400 mL) was added, then this mixture was stirred for 12 h at 75 °C. -30% of desired product was detected on LCMS. The resulting mixture was extracted with EtOAc (500 mLyFLO (1000 mL) for 3 times. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA = 6:1 to afford methyl 2-(4-cyanophenyl)-5,7-difluoro- lH-indole-3-carboxylate (18 g, 22.48%) as a dark yellow solid.Example 4: Synthesis of INT-4

[0244] A solution of methyl 5,7-difluoro-2-(4-fluorophenyl)- 1 H-indole-3- carboxylate (18 g, 58.967 mmol, 1 equiv.) and NFFNHz’FEO (200 mL) in EtOH (400 mL) was stirred for 2 days at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH = 10 / 1 to afford 5,7-difluoro-2-(4-fluorophenyl)-177-indole-3-carbohydrazide (5.5 g, 30.56%) as a yellow solid.Example 5: Synthesis of Compound 1

[0245] A solution of 5, 7-difluoro-2-(4-fluorophenyl)-177-indole-3 -carbohydrazide (5.5 g, 18.017 mmol, 1 equiv.) and CDI (2.92 g, 18.017 mmol, 1 equiv.) in THF (20 mL) and DMF (5 mL) was stirred for 1 h. Upon completion of reaction, the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1FA% H2O and ACN 0% to 50% gradient in 40 min; detector, UV 254 nm. This resulted in 5-[5,7-difluoro-2-(4- fluorophenyl)-17 / -indol-3-yl]-l,3,4-oxadiazol-2-ol (3 g, 50.27%) as a dark yellow solid. Example 6: General Preparation of Aminooxadiazoles

[0246] A solution of 5-[5,7-difluoro-2-(4-fluorophenyl)-177-indol-3-yl]-l,3,4- oxadiazol-2-ol (60 mg, 0.18 mmol, 1 equiv), R6NHR6(0.36 mmol, 2 equiv), ((1H-Benzo[d][l,2,3]triazol-l-yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate(V) (BOP) (160 mg, 0.36 mmol, 2 equiv) and diisopropylethylamine (DIEA) (47 mg, 0.36 mmol,2 equiv) in DMF (2 mL) was stirred overnight at room temperature (It’s necessary to up to 40 °C in some cases). Upon completion of reaction, the reaction mixture was directly purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN / water, 0% to 50% gradient in 20 min; detector, UV 254 / 220 nm. This resulted in final product.

[0247] Table A refers to examples of Formula I that were prepared according to the methods described herein for Examples 1-6.Table ACompound Structure LCMS1H NMR δ ), 44 m, – ), 6) – .3 z, 67 m, 40 .5, δ = m, – ), 66 δ z, d, 33 71 – z, δ ), .9 94 30Compound Structure LCMS1H NMR δ ), 43 m, ), (s, δ ), 32 26 .3 δ .4 ), .7 ), , J 76 δ z, d, 33 36 .5, z, d, 40Compound Structure LCMS1H NMR δ ), 36 .4 41 δ ), 37 m, 51 .6 δ ), 51 m, d, .8 ) δ ), 34 42 .7 δ ), 48 m, – ), z,Compound Structure LCMS1H NMR 1H NMR (400 MHz, DMSO-d6) δ ), 51 m, d, m, 03 δ ), 37 m, – .6 96 δ ), d, 32 76 .6, ), 84 δ ), 32 87 m, 78 m, δ ), 44 m, d, m, – ). δ ), 33 24 m, m,Compound Structure LCMS1H NMR δ ), = m, d, .6 δ ), 46 22 z, δ ), .8 96 ), δ z, d, 30 84 = δ ), 50 24 94Compound Structure LCMS1H NMR δ ), 48 m, 36 δ ), 42 m, 92 ), δ ), 37 m, 51 .6 δ ), m, – z,Compound Structure LCMS1H NMR δ ), 47 23 m, ), δ ), 40 m, (t, 33 δ ), 42 m, 88 ), δ ), 43 m, 92 ),Compound Structure LCMS1H NMR δ z, d, 50 22 m, δ z, d, 34 85 – ). δ z, d, .5, ), z, δ ), = .9 09 .2 ), δ ), 54 29 14 .Compound Structure LCMS1H NMR 1H MR 4 MH DM ) δ ), – .3 17 ),

[0248] Table B refers to other examples of Formula I which were made by methods analogous to those described for Compounds 1-42 described herein. Table B Compound Structure LC-MS1H NMR ) δ H), = m, 13 6 - ) δ H), m, - H),Compound Structure LC-MS1H NMR ) δ 5 - .6 z, 04 6- ). ) δ (d, 49 06 20 30 ) δ H), m, - H), δ , J .8 ), z,Compound Structure LC-MS1H NMR δ ), , δ ), 56 7 4 δ 8 (s, , J δ ), J 88 z, δ ), ), 2, 1Compound Structure LC-MS1H NMR δ ), d, , , δ , = 38xampe 7: ternate Syntess o reparaton o Compoun 5e o ow gs a a e ae sy ess o co pou . sou o o 5-[5,7- difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-ol (1 g, 3.019 mmol, 1 equiv), (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one (0.70 g, 6.038 mmol, 2 equiv), DIEA (1.56 g, 12.076 mmol, 4 equiv) and BOP (2.67 g, 6.038 mmol, 2 equiv) in DMF (10 mL) was stirred for 12 hours at room temperature, 30% DP was detected on LCMS, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1%FA in H2O / ACN, 0% to 50% gradient in 50 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. The crude product (500 mg, 81.3%) was purified by Prep-HPLC to afford (3S,4R)-3-({5-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-yl}amino)-4-hydroxypyrrolidin-2-one (253 mg, 19.42%) as a white solid ( 99.498% purity, ee% > 95%) after lyophilization.

[0250] LCMS (ESI) [M + H]+: 430.10.1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 8.1 Hz, 1H), 7.92 – 7.74 (m, 3H), 7.63 (dd, J = 9.5, 2.3 Hz, 1H), 7.45 – 7.27 (m, 2H), 7.22 – 7.13 (m, 1H), 5.69 (s, 1H), 4.32 (t, J = 8.0 Hz, 1H), 3.83 (t, J = 8.2 Hz, 1H), 3.45 – 3.32(m,1H) ,2.93 (dd, J = 9.5, 7.5 Hz, 1H). Example 8: Synthesis of Compound 56ol-3-yl]- 1,3,4-oxadiazol-2-ol (0.1 g, 0.3 mmol, 1 equiv) and 2-bromoacetamide (0.05 g, 0.36 mmol, 1.2 equiv) in DMF (2 mL) was added potassium tert-butoxide (t-BuOK) (0.05 g, 0.45 mmol, 1.5 equiv) and the resulting mixture was stirred for 12 hours at room temperature. Upon completion of reaction, the mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1%FA in H2O / Acetonitrile, 0% to 50% gradient in 50 min; detector, UV 254 nm. This resulted in the title compound (29.5 mg, 21.8%) as a white solid.

[0252] LCMS (ESI) [M + H]+: 389.15.1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.80 (t, J = 6.9 Hz, 2H), 7.68 (s, 1H), 7.51 (d, J = 9.5 Hz, 1H), 7.39 (t, J = 8.5 Hz, 3H), 7.22 (t, J = 10.4 Hz, 1H), 4.34 (s, 2H). Example 9: Synthesis Compound 57

[0253] To a stirred solution of 5,7-difluoro-2-(4-fluorophenyl)-1H-indole-3- carbohydrazide (1 g, 3.276 mmol, 1 equiv) and Et3N (0.66 g, 6.552 mmol, 2 equiv) in DCM (10 mL) was added ethyl chloroglyoxylate (0.45 g, 3.276 mmol, 1 equiv) dropwise at 0 ℃. The resulting mixture was stirred for 1 hour at 0 ℃. To the above mixture was added tosyl chloride (TsCl) (0.62 g, 3.276 mmol, 1 equiv) and Et3N (0.66 g, 6.552 mmol, 2 equiv) at 0 ℃. The resulting mixture was stirred for additional 12 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE=1:1 to afford ethyl 5-[5,7-difluoro-2-(4-fluorophenyl)- 1H-indol-3-yl]-1,3,4-oxadiazole-2-carboxylate (290 mg, 23%) as a white solid. LCMS (ESI) [M + H]+: 388.-yl]-1,3,4- oxadiazole-2-carboxylate (50 mg, 0.129 mmol, 1 equiv) and cyclobutylamine (9.18 mg, 0.129 mmol, 1 equiv) in DMF (1 mL) was stirred for 2 hours at 110 ℃. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) in water, 0% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in N-cyclobutyl-5-[5,7-difluoro- 2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazole-2-carboxamide) (12.1 mg, 21.80%) as a light-yellow solid.

[0255] LCMS (ESI) [M + H]+: 413.20.1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.42 (d, J = 7.8 Hz, 1H), 7.90 – 7.81 (m, 2H), 7.72 (dd, J = 9.4, 2.3 Hz, 1H), 7.50 – 7.28 (m, 2H), 7.25 – 7.22 (m, 1H), 4.37 – 4.30 (m, 1H), 2.42 - 1.94 (m, 4H), 1.79 – 1.52 (m, 2H).Example 10: Synthesis of Compound 58 [ indol-3-yl]-1,3,4-oxadiazole-2-carboxylate (150 mg, 0.387 mmol, 1 equiv) in THF (3 mL) and EtOH (3 mL) was treated with LiOH (37.10 mg, 1.548 mmol, 4 equiv) in H2O (1 mL) for 3 hours at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-[5,7-difluoro-2-(4-fluorophenyl)- 1H-indol-3-yl]-1,3,4-oxadiazole-2-carboxylic acid (100 mg, 71.87%) as a yellow solid. LCMS (ESI) [M + H]+: 360, dol-3-yl]- 1,3,4-oxadiazole-2-carbo xylic acid (40 mg, 0.111 mmol, 1 equiv) and (1- aminocyclobutyl)methanol (22.52 mg, 0.222 mmol, 2 equiv) in DMF (4 mL) were added TCFH (46.86 mg, 0.167 mmol, 1.5 equiv) and NMI (45.71 mg, 0.555 mmol, 5 equiv). The mixture was stirred at room temperature under nitrogen atmosphere over 2 hours. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[1- (hydroxymethyl)cyclobutyl]-1,3,4-oxadiazole-2-carboxamide (8.8 mg, 17.87%) as a white solid.

[0258] LCMS (ESI) [M + H]+: 443.15.1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.74 (s, 1H), 7.90 – 7.83 (m, 2H), 7.73 (dd, J = 9.4, 2.3 Hz, 1H), 7.41 – 7.33 (m, 2H), 7.27 – 7.18 (m, 1H), 4.93 (t, J = 6.0 Hz, 1H), 3.62 (d, J = 5.8 Hz, 2H), 2.31 (td, J = 9.5, 3.0 Hz, 2H), 2.09 (tt, J = 10.8, 3.8 Hz, 2H), 1.83 – 1.68 (m, 2H). Example 11: Synthesis of Compound 59 [indol-3-yl]- 1,3,4-oxadiazole-2-carboxylate (50 mg, 0.129 mmol, 1 equiv) in DMF (3 mL) was treated with methylethanolamine (77.57 mg, 1.032 mmol, 8 equiv) for overnight at 105 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-(5,7-difluoro-2-(4- fluorophenyl)-1H-indol-3-yl)-N-(2-hydroxyethyl)-N-methyl-1,3,4-oxadiazole-2-carboxamide (13.7 mg, 25.49%) as a white solid.

[0260] LCMS (ESI) [M + H]+:417.05.1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 7.92 – 7.77 (m, 2H), 7.74 – 7.64 (m, 1H), 7.40 – 7.31 (m, 2H), 7.28 – 7.19 (m, 1H), 4.96 – 4.73 (m, 1H), 3.81 (t, 1H), 3.61 – 3.50 (m, 3H), 3.35 (s, 1H), 3.05 (s, 2H). Example 12: Synthesis of Compound 60

[0261] A so ut on o et y 5-[5,7-d uoro-2-(4- uorop eny )-1H- ndol-3-yl]- 1,3,4-oxadiazole-2-carboxylate (50 mg, 0.129 mmol, 1 equiv) and 2-aminopropanol (58.18 mg, 0.774 mmol, 6 equiv) in DMF (3 mL) was stirred for overnight at 105 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with thefollowing conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-[5,7-difluoro-2-(4- fluorophenyl)-1H-indol-3-yl]-N-(1-hydroxypropan-2-yl)-1,3,4-oxadiazole-2-carboxamide (33.2 mg, 61.77%) as a white solid.

[0262] LCMS (ESI) [M + H]+: 417.05.1H NMR (300 MHz, DMSO-d6) δ12.91(s, 1H), 8.77 (d, J = 8.3 Hz, 1H), 7.91 – 7.81 (m, 2H), 7.72 (dd, J = 9.4, 2.3 Hz, 1H), 7.43 – 7.33 (m, 2H), 7.23 (d, J = 9.4 Hz, 1H), 4.81 (t, J = 5.7 Hz, 1H), 4.07 – 3.90 (m, 1H), 3.48 – 3.41 (m, 2H), 1.13 (d, J = 6.7 Hz, 3H). Example 13: Synthesis of Compound 61

[0263] To a stirred solution of 5-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]- 1,3,4-oxadiazole-2-carboxylic acid (80 mg, 0.223 mmol, 1 equiv) and 1- (methoxymethyl)cyclopropan-1-amine (45.05 mg, 0.446 mmol, 2 equiv) in ACN (3 mL) were added TCFH (93.72 mg, 0.335 mmol, 1.5 equiv) and NMI (91.42 mg, 1.115 mmol, 5 equiv). The mixture was stirred at room temperature under nitrogen atmosphere over 4 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[1- (methoxymethyl)cyclopropyl]-1,3,4-oxadiazole-2-carboxamide (20.1 mg, 20.40%) as a yellow solid.

[0264] LCMS (ESI) [M + H]+: 443.15.1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 9.38 (s, 1H), 7.92 – 7.81 (m, 2H), 7.73 (dd, J = 9.4, 2.3 Hz, 1H), 7.38 (t, J = 8.9 Hz, 2H), 7.23 (ddd, J = 11.6, 9.7, 2.3 Hz, 1H), 3.45 (s, 2H), 3.27 (s, 3H), 0.89 – 0.67 (m, 4H).

[0265] Table C refers to other examples of compounds that may be prepared analogously to the methods described for other oxadiazolyl compounds. Table CCompound Structure LCMS1H NMR 1H NMR (400 MHz, H), 93 = 30 m, z, z, H), 89 = 27 m, z, H), – 74 z, H), 86 = 31 m, .7 m, z, H), 89 = 33 m, z, H), – 46 z, H), 87 = 30 m, z, (s,SCHEME B

[0266] To a solution of p-bromoacetophenone (5 g, 25.120 mmol, 1 equiv) in dimethyl carbonate (50 mL) was added NaH (1.81 g, 75.360 mmol, 3 equiv). The mixture was stirred at 100 °C for 1 h. Upon completion of reaction, the reaction was quenched by the addition of H2O at 0 °C. The resulting mixture was extracted with EA. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product methyl 3-(4-bromophenyl)-3- oxopropanoate (4.9 g, 75.88%) as yellow oil. MS (ESIpos): m / z = 256.97 [M+H]+.[ ] o a so ut on o met y -( - romop eny )- -oxopropanoate ( .8 g, 18.671 mmol, 1 equiv) in DMSO (50 mL, 14.079 mmol) were added 2,2,2-trifluoro-N-(2-fluoro-6- iodo-4-methylphenyl)acetamide (9719.69 mg, 28.006 mmol, 1.5 equiv), CuI (711.18 mg, 3.734 mmol, 0.2 equiv), L-Proline (429.93 mg, 3.734 mmol, 0.2 equiv) and Cs2CO3(18250.11 mg, 56.013 mmol, 3 equiv). The mixture was stirred at RT for 1 h. Upon completion of reaction,Add HCl (25 mL, 0.027 mmol) and MeOH (25 mL, 0.031 mmol) to the mixture, and the mixture was stirred at 80oC for 1 hour. The resulting mixture was extracted with EA. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product methyl 2-(4- bromophenyl)-5,7-difluoro-1H-indole-3-carboxylate (2.1 g, 30.72%) as yellow oil. MS (ESIpos): m / z = 365.99 [M+H]+. [01H-indole-3- carboxylate (2.1 g, 5.735 mmol, 1 equiv) in EtOH (20 mL) was added hydrazine hydrate (20 mL, 411.498 mmol, 71.75 equiv). The mixture was stirred at 100oC for 2 days. Upon completion of reaction, the solvent was removed under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 30 min; detector, UV 254 nm, to give the product 2-(4-bromophenyl)-5,7-difluoro-1H-indole-3-carbohydrazide (1 g, 47.62%) as yellow oil. MS (ESIpos): m / z = 366.00 [M+H]+.

[02] o a so u on o - - romop eny - , - uoro-1H-indole-3- carbohydrazide (1 g, 2.731 mmol, 1 equiv) in DMF (10 mL) was added CDI (1.33 g, 8.193 mmol, 3 equiv). The mixture was stirred at 25oC 2 hours. Upon completion of reaction, the resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the followingconditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 5-[2-(4-bromophenyl)-5,7-difluoro-1H-indol-3-yl]- 1,3,4-oxadiazol-2-ol (500 mg, 46.69%) as a yellow solid. MS (ESIpos): m / z = 391.98 [M+H]+.3-yl]-1,3,4- oxadiazol-2-ol (500 mg, 1.275 mmol, 1 equiv) in DMF (10 mL) were added 3-aminopyrrolidin- 2-one (191.48 mg, 1.912 mmol, 1.5 equiv), BOP (1691.73 mg, 3.825 mmol, 3 equiv) and DIEA (494.37 mg, 3.825 mmol, 3 equiv). The mixture was stirred at 25oC overnight. Upon completion of reaction, the yellow liquid was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 3-({5-[2-(4-bromophenyl)-5,7-difluoro-1H-indol-3-yl]-1,3,4- oxadiazol-2-yl}amino)pyrrolidin-2-one (200 mg, 33.08%) as a white solid. MS (ESIpos): m / z = 474.03 [M+H]+.[ ] o a so u on o - -[ - - romop eny - , - uoro- - ndol-3-yl]- 1,3,4-oxadiazol-2-yl}amino)pyrrolidin-2-one (100 mg, 0.211 mmol, 1 equiv) in NMP (1.5 mL, 228.138 mmol) were added zinc cyanide (99.03 mg, 0.844 mmol, 4 equiv), Pd(dppf)Cl2 (15.43 mg, 0.021 mmol, 0.1 equiv). The mixture was stirred at 80oC for 1 h. Upon completion of reaction, the mixture was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min;detector, UV 254 nm, to give the product 4-(5,7-difluoro-3-{5-[(2-oxopyrrolidin-3-yl)amino]- 1,3,4-oxadiazol-2-yl}-1H-indol-2-yl)benzonitrile (33.8 mg, 33.59%) as a light green solid.1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.08 – 7.75 (m, 5H), 7.47 (dd, J = 10.7, 6.9 Hz, 1H), 7.42 – 7.32 (m, 2H), 4.14 – 4.01 (m, 1H), 3.20 (dd, J = 10.9, 3.9 Hz, 2H), 2.44 – 2.32 (m, 1H), 2.03 – 1.90 (m, 1H).MS (ESIpos): m / z = 420.90 [M+H]+. SCHEME CExample 15: Synthesis of Compound 47

[0272] , . mol, 1 equiv) in THF (20 mL) were added TFAA (1.06 g, 5.063 mmol, 1.2 equiv) and Et3N (1.28 g, 12.657 mmol, 3 equiv). The mixture was stirred for 1 h at 25 ℃. Upon completion of reaction. The resulting mixture was extracted with EA. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4, the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 2,2,2-trifluoro-N-(2-fluoro-6-iodophenyl)acetamide (900 mg, 64.05%) as yellow oil. MS (ESIpos): m / z =334 [M+H]+.mg, 0.510 mmol, 1 equiv) in DMSO (2 mL) were added 2,2,2-trifluoro-N-(2-fluoro-6- iodophenyl)acetamide (203.71 mg, 0.612 mmol, 1.2 equiv), CuI (19.42 mg, 0.102 mmol, 0.2 equiv), L-Proline (11.74 mg, 0.102 mmol, 0.2 equiv) and Cs2CO3 (498.25 mg, 1.530 mmol, 3 equiv). The mixture was stirred at RT for 1 h. Upon completion of reaction, Add HCl (2 mL) and MeOH (2 mL) to the mixture. The mixture was stirred at 80 ℃ for 1 h, The resulting mixture was extracted with EA. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4, the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product methyl 7-fluoro-2-(4-fluorophenyl)-1H-indole-3-carboxylate (30 mg, 20.49%) as yellow oil. MS (ESIpos): m / z = 288 [M+H]+.

[0274] To a solution of methyl 7-fluoro-2-(4-fluorophenyl)-1H-indole-3- carboxylate (250 mg, 0.870 mmol, 1 equiv) in EtOH (2.5 mL) and hydrazine hydrate (2.5 mL). The mixture was stirred at 100 ℃ for 2 days. Upon completion of reaction. The yellow liquid was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 7-fluoro-2- (4-fluorophenyl)-1H-indole-3-carbohydrazide (120 mg, 48.00%) as a yellow oil. MS (ESIpos): m / z = 288 [M+H]+

[0275] To a solution of 7-fluoro-2-(4-fluorophenyl)-1H-indole-3-carbohydrazide (100 mg, 0.348 mmol, 1 equiv) in DMF (2 mL) was added CDI (112.89 mg, 0.696 mmol, 2 equiv). The mixture was stirred for 2 h at 25 ℃. Upon completion of reaction. The resulting mixture was extracted with EA. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4, the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 5-[7-fluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4- oxadiazol-2-ol (70 mg, 64.19%) as a yellow solid. MS (ESIpos): m / z = 314 [M+H]+[027p y ndol-3-yl]-1,3,4- oxadiazol-2-ol (70 mg, 0.223 mmol, 1 equiv) in DMF (2 mL) were added 3-aminopyrrolidin- 2-one (44.74 mg, 0.446 mmol, 2 equiv), BOP (197.66 mg, 0.446 mmol, 2 equiv) and DIEA (115.52 mg, 0.892 mmol, 4 equiv). The mixture was stirred for overnight at 25 ℃. Upon completion of reaction. The yellow liquid was dried. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 3-({5-[7- fluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-yl}amino)pyrrolidin-2-one (11.5 mg, 12.55%) as a light pink solid.

[0277] MS (ESIpos): m / z = 396.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.46 (s, 1H), 7.95 – 7.75 (m, 5H), 7.42 – 7.28 (m, 2H), 7.23 – 7.03 (m, 2H), 4.06 (dt, J = 10.5, 8.3 Hz, 1H), 3.24 – 3.10 (m, 2H), 2.44 – 2.28 (m, 1H), 2.04 – 1.87 (m, 1H). SCHEME D

[0278] To a solution of 4,5-difluoro-2-iodoaniline hydrofluoride (2 g, 7.272 mmol, 1 equiv) in THF (20 mL) were added TFAA (2.29 g, 10.908 mmol, 1.5 equiv) and Et3N (1.10 g, 10.908 mmol, 1.5 equiv). The mixture was stirred at 25 ℃ for 1 h. Upon completion of reaction, the resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product N-(4,5-difluoro-2-iodophenyl)- 2,2,2-trifluoroacetamide (2.3 g, 90.10%) as yellow oil. MS (ESIpos): m / z = 351.92 [M+H]+.2 g, 11.214mmol, 1 equiv) in DMSO (50 mL) were added N-(4,5-difluoro-2-iodophenyl)-2,2,2- trifluoroacetamide (5.90 g, 16.821 mmol, 1.5 equiv), CuI (0.43 g, 2.243 mmol, 0.2 equiv), Cs2CO3 (10.96 g, 33.642 mmol, 3 equiv) and (S)-Proline (0.26 g, 2.243 mmol, 0.2 equiv). The mixture was stirred at RT for 1 hour. Add conc. HCl (50 mL) and MeOH (50 mL) to the mixture. The mixture was stirred at 80 ℃ for 1 h. The resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient in 30 min; detector, UV 254 nm, to give the product methyl 5,6-difluoro-2-(4-fluorophenyl)-1H-indole-3-carboxylate (900 mg, 26.29%) as yellow oil. MS (ESIpos): m / z = 306.07 [M+H]+. [0, 1H-indole-3- carboxylate (900 mg, 2.948 mmol, 1 equiv) in EtOH (10 mL) was added hydrazine hydrate (10 mL). The mixture was stirred at 100 ℃ for 2 days. Upon completion of reaction, the solvent was removed under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 5,6-difluoro-2-(4-fluorophenyl)- 1H-indole-3-carbohydrazide (350 mg, 38.89%) as yellow oil. MS (ESIpos): m / z = 306.08 [M+H]+.[02 )-1H-indole-3-carbohydrazide (400 mg, 1.310 mmol, 1.00 equiv) in DMF (5 mL) was added CDI (637.4 mg, 3.930 mmol, 3 equiv). The mixture was stirred at 25 ℃ for 2 h. Upon completion of reaction, the resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 5-[5,6-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]- 1,3,4-oxadiazol-2-ol (200 mg, 46.08%) as a yellow solid. MS (ESIpos): m / z = 332.06 [M+H]+. [0, ol-3-yl]-1,3,4- oxadiazol-2-ol (100 mg, 0.302 mmol, 1 equiv) in DMF (2 mL) were added 3-aminopyrrolidin- 2-one hydrochloride (82.5 mg, 0.604 mmol, 2 equiv), BOP (267.0 mg, 0.604 mmol, 2 equiv) and DIEA (117.1 mg, 0.906 mmol, 3 equiv). The mixture was stirred at 25 ℃ overnight. Upon completion of reaction, the mixture was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 20% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 3-({5-[5,6-difluoro-2-(4- fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-yl}amino)pyrrolidin-2-one (19.0 mg, 18.56%) as a light pink solid.

[0283] MS (ESIpos): m / z = 413.90 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.08 – 7.75 (m, 5H), 7.47 (dd, J = 10.7, 6.9 Hz, 1H), 7.42 – 7.32 (m, 2H), 4.14 – 4.01 (m, 1H), 3.20 (dd, J = 10.9, 3.9 Hz, 2H), 2.44 – 2.32 (m, 1H), 2.03 – 1.90 (m, 1H).SCHEME EExample 17: Synthesis of Compound 44

[0284] To a solution of 2,3-difluoro-6-iodoaniline (2 g, 7.843 mmol, 1 equiv) in THF (20 mL) were added TFAA (2470.89 mg, 11.764 mmol, 1.5 equiv) and Et3N (1190.48 mg, 11.764 mmol, 1.5 equiv). The mixture was stirred at 25 ℃ for 1 h. Upon completion of reaction. The resulting mixture was extracted with EA. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4, the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product N-(2,3-difluoro-6-iodophenyl)-2,2,2- trifluoroacetamide (2.2 g, 79.91%) as yellow oil. MS (ESIpos): m / z =352 [M+H]+.

[0285] To a solution of methyl 6,7-difluoro-2-(4-fluorophenyl)-1H-indole-3- carboxylate (800 mg, 2.621 mmol, 1 equiv) in ETOH (1 mL) and hydrazine hydrate (1 mL). The mixture was stirred at 100 ℃ for 2 days. Upon completion of reaction. The yellow liquid was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 6,7-difluoro- 2-(4-fluorophenyl)-1H-indole-3-carbohydrazide (400 mg, 50.00%) as yellow oil. MS (ESIpos): m / z = 306 [M+H]+.

[0286] , enyl)-1H-indole-3- carbohydrazide hydrofluoride (400 mg, 1.230 mmol, 1 equiv) in DMF (4 mL) was added CDI (398.82 mg, 2.460 mmol, 2 equiv). The mixture was stirred for 2 h at 25 ℃. Upon completion of reaction. The resulting mixture was extracted with EA. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4, the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 5-[6,7-difluoro-2-(4-fluorophenyl)-1H- indol-3-yl]-1,3,4-oxadiazol-2-ol (200 mg, 49.10%) as a yellow solid.MS (ESIpos): m / z = 332 [M+H]+.[02ol-3-yl]-1,3,4- oxadiazol-2-ol (200 mg, 0.604 mmol, 1 equiv) in DMF (2 mL) were added 3-aminopyrrolidin- 2-one (120.90 mg, 1.208 mmol, 2 equiv), BOP (534.08 mg, 1.208 mmol, 2 equiv) and DIEA (234.10 mg, 1.812 mmol, 3 equiv). The mixture was stirred for overnight at 25 ℃. Upon completion of reaction. The yellow liquid was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 3-({5-[6,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4- oxadiazol-2-yl}amino)pyrrolidin-2-one (13.3 mg, 4.529%) as a light yellow solid.

[0288] MS (ESIpos): m / z = 413.95 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.00 – 7.75 (m, 5H), 7.41 – 7.31 (m, 2H), 7.24 (ddd, J = 11.3, 8.8, 7.1 Hz, 1H), 4.06 (dt, J = 10.6, 8.3 Hz, 1H), 3.24 – 3.12 (m, 2H), 2.36 (dddd, J = 11.7, 8.3, 5.5, 2.8 Hz, 1H), 1.95 (dq, J = 12.0, 9.3 Hz, 1H). SCHEME FE[0(5 g, 19.449 mmol, 1 equiv) in DMSO (150 mL) were added 2,2,2-trifluoro-N-(4-fluoro-2- iodophenyl)acetamide (9.72 g, 29.174 mmol, 1.5 equiv), CuI (0.74 g, 3.890 mmol, 0.2 equiv), L-Proline (0.45 g, 3.890 mmol, 0.2 equiv) and Cs2CO3(19.01 g, 58.347 mmol, 3 equiv). The mixture was stirred at RT for 1 h. Upon completion of reaction, HCl (50 mL) and MeOH (50 mL) were added into the mixture. The mixture was stirred at 80 ℃ for 1 h, The resulting mixture was extracted with EA. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4, the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product methyl 2-(4-bromophenyl)-5-fluoro-1H-indole-3-carboxylate (2 g, 29.54%) as yellow oil. MS (ESIpos): m / z = 348 [M+H]+.

[0290] To a solution of methyl 2-(4-bromophenyl)-5-fluoro-1H-indole-3- carboxylate (2 g, 5.744 mmol, 1 equiv) in hydrazine hydrate (20 mL) and EtOH (20 mL). The mixture was stirred at 100 ℃ for 2 days. The white liquid was concentrated under reduced pressure. Upon completion of reaction. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 2-(4- bromophenyl)-5-fluoro-1H-indole-3-carbohydrazide (1.5 g, 75.00%) as yellow oil. MS (ESIpos): m / z = 348 [M+H]+.

[0291] To a solution of 2-(4-bromophenyl)-5-fluoro-1H-indole-3-carbohydrazide (1.5 g, 4.308 mmol, 1 equiv) in DMF (20 mL) was added CDI (1.40 g, 8.616 mmol, 2 equiv). The mixture was stirred for 2 h at 25 ℃. Upon completion of reaction. The yellow liquid was dried. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 5-[2-(4-bromophenyl)-5-fluoro-1H-indol-3-yl]-1,3,4- oxadiazol-2-ol (750 mg, 46.53%) as yellow oil. MS (ESIpos): m / z = 374 [M+H]+.[l-3-yl]-1,3,4- oxadiazol-2-ol (450 mg, 1.203 mmol, 1 equiv) in DMF (8 mL) were added 3-aminopyrrolidin- 2-one (240.82 mg, 2.406 mmol, 2 equiv), BOP (1063.85 mg, 2.406 mmol, 2 equiv) and DIEA (621.76 mg, 4.812 mmol, 4 equiv). The mixture was stirred for overnight at 25 ℃. Upon completion of reaction. The yellow liquid was dried. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 3-({5-[2- (4-bromophenyl)-5-fluoro-1H-indol-3-yl]-1,3,4-oxadiazol-2-yl}amino)pyrrolidin-2-one (130 mg, 23.69%) as a white solid.

[0293] MS (ESIpos): m / z = 455.90 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H), 7.92 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.73 (s, 5H), 7.49 (dd, J = 8.9, 4.6 Hz, 1H), 7.12 (td, J = 9.2, 2.6 Hz, 1H), 4.08 (dt, J = 10.5, 8.3 Hz, 1H), 3.20 (dd, J = 9.6, 4.4 Hz, 2H), 2.38 (ddt, J = 12.3, 8.3, 3.8 Hz, 1H), 2.11 – 1.87 (m, 1H).

[02] o a so u on o - -[ - - romop eny - - uoro- - n ol-3-yl]-1,3,4- oxadiazol-2-ylamino) pyrrolidin-2-one (100 mg, 0.219 mmol, 1 equiv) in NMP (3 mL) were added zinc cyanide (77.20 mg, 0.657 mmol, 3 equiv) and Pd(dppf)Cl2 (16.04 mg, 0.022 mmol, 0.1 equiv). The mixture was stirred for 1 h at 80 ℃. Upon completion of reaction. The yellow liquid was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCNin water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 4-(5-fluoro- 3-{5-[(2-oxopyrrolidin-3-yl) amino]-1,3,4-oxadiazol-2-yl}-1H-indol-2-yl)benzonitrile (28.4 mg, 31.99%) as a light green solid.

[0295] MS (ESIpos): m / z = 403.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 7.99 (s, 4H), 7.95 – 7.87 (m, 2H), 7.79 (dd, J = 9.9, 2.6 Hz, 1H), 7.52 (dd, J = 8.8, 4.5 Hz, 1H), 7.16 (td, J = 9.1, 2.6 Hz, 1H), 4.09 (dt, J = 10.3, 8.2 Hz, 1H), 3.25 – 3.14 (m, 2H), 2.40 (tdd, J = 9.0, 5.3, 2.7 Hz, 1H), 2.05 – 1.91 (m, 1H). SCHEME G O O O O O NH2

[0296] To a stirred solution of 2-aminoethanesulfonamide (500 mg, 4.027 mmol, 1 equiv.) and benzaldehyde (854.74 mg, 8.054 mmol, 2 equiv.) in EtOH (15 mL) was added NaBH3CN (379.59 mg, 6.040 mmol, 1.5 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 1 h at 90 °C. Upon completion of reaction, the reaction mixture was quenched with water. THF was removed under reducedpressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-(benzylamino) ethanesulfonamide (300 mg, 34.77%) as white oil. LCMS (ESI) [M + H]+: 215.

[0297] To a stirred solution of 2-(benzylamino)ethanesulfonamide (300 mg, 1.400 mmol, 1 equiv.) and K2CO3(580.48 mg, 4.200 mmol, 3 equiv.) in DMF (20 mL) was added MeI (198.72 mg, 1.400 mmol, 1 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2- [benzyl(methyl)amino]ethanesulfonamide (317 mg, 99.17%) as a white oil. LCMS (ESI) [M + H]+: 228.

[0298] To a stirred mixture of 2-[benzyl(methyl)amino]ethanesulfonamide (300 mg, 1.314 mmol, 1 equiv.) in THF (20 mL) was added Pd / C (279.67 mg, 10% Pd in active carbon, 2.628 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The mixture was purified by filtration and the filter cake was washed with THF (3x10 mL). The filtrate was concentrated under reduced pressure to afford 2-(methylamino) ethanesulfonamide (133 mg, 73.25%) as a white oil. LCMS (ESI) [M + H]+: 139.

[0299] 100 mg, 0.724 mmol, 2 equiv.), 3-(5-bromo-1,3,4-oxadiazol-2-yl)-5,7-difluoro-2-(4-fluorophenyl)-1H-indole (142.61 mg, 0.362 mmol, 1 equiv.) in DMF (5 mL). The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The crude product (17 mg) was purified by Prep-HPLC with the following conditions, Column: Sunfire prep C18 column 30*150 mm, 5m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 26% B to 40% B in 9 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.68. This resulted in 2-({5-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2- yl}(methyl)amino)ethanesulfonamide (5.5 mg, 3.30%) as a white solid.

[0300] LCMS (ESI) [M + H]+: 452.00.1H NMR (400 MHz, Methanol-d4) δ 7.77 – 7.68 (m, 2H), 7.68 – 7.61 (m, 1H), 7.27 (td, J = 8.9, 2.3 Hz, 2H), 6.90 (t, J = 10.3 Hz, 1H), 3.84 – 3.76 (m, 2H), 3.39 – 3.31 (m, 2H), 3.01 (d, J = 2.3 Hz, 3H).SCHEME Hp y p

[0301] To a solution of 2-bromo-5-methoxypyridine (5 g, 26.592 mmol, 1 equiv) in ACN (50 mL) were added CuI (1.01 g, 5.318 mmol, 0.2 equiv), Pd(PPh3)2Cl2 (1.87 g, 2.659 mmol, 0.1 equiv), tributyl(1-ethoxyethenyl)stannane (11.52 g, 31.910 mmol, 1.2 equiv). The mixture was stirred at 80 °C for 2 h. Upon completion of reaction, diluted HCl aq. (30 mL) was added to the mixture and the mixture was stirred at RT for 1 h. The resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silicagel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 1-(5-methoxypyridin-2-yl)ethanone (2.6 g, 64.68%) as yellow oil. MS (ESIpos): m / z = 152 [M+H]+.

[0302] To a solution of 1-(5-methoxypyridin-2-yl)ethanone (2.6 g, 17.200 mmol, 1 equiv) in toluene (30 mL) were added NaH (1.24 g, 51.600 mmol, 3 equiv) and dimethyl carbonate (2.32 g, 25.800 mmol, 1.5 equiv). The mixture was stirred at 100 °C for 1 h. Upon completion of reaction, the reaction was quenched by the addition of H2O at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product methyl 3-(5-methoxypyridin-2-yl)-3-oxopropanoate (1.5 g, 41.69%) as yellow oil. MS (ESIpos): m / z = 210 [M+H]+.

[0303] To a solution of methyl 3-(5-methoxypyridin-2-yl)-3-oxopropanoate (1.25 g, 5.982 mmol, 1.50 equiv) in DMSO (20 mL) were added N-(2,4-difluoro-6-iodophenyl)- 2,2,2-trifluoroacetamide (1.4 g, 3.988 mmol, 1.00 equiv), CuI (0.15 g, 0.798 mmol, 0.2 equiv), L-proline (92.63 mg, 0.798 mmol, 0.2 equiv) and Cs2CO3(3.90 g, 11.964 mmol, 3 equiv). The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The residue was dissolved in water (20 mL). The aqueous layer was extracted with EtOAc (3x20 mL). The organic layers were combined, washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. To a stirred solution of the above residue were added MeOH (20 mL) and HCl (20 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The organic solvent was removed under vacuum and then ice water was added. The mixture was neutralized with sat. NaHCO3 aq. solution in an ice bath. The resulting solution was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product methyl 5,7-difluoro-2-(5-methoxypyridin-2-yl)-1H-indole-3-carboxylate (400 mg, 31.51%) as a yellow solid. MS (ESIpos): m / z = 319 [M+H]+[ ] o a so ut on o met y , - uoro- -( -met oxypyr n- -y )- -indole- 3-carboxylate (400 mg, 1.257 mmol, 1 equiv) in EtOH (4 mL) was added hydrazine hydrate (4 mL, 82.300 mmol, 65.49 equiv). The mixture was stirred at 100oC for 2 days. Upon completion of reaction, the yellow liquid was dried. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give 5,7-difluoro-2-(5- methoxypyridin-2-yl)-1H-indole-3-carbohydrazide (205 mg, 51.25%) as a yellow solid. MS (ESIpos): m / z = 319 [M+H]+.

[0305] To a solution of 5,7-difluoro-2-(5-methoxypyridin-2-yl)-1H-indole-3- carbohydrazide (175 mg, 0.550 mmol, 1 equiv) in DMF (3 mL) was added CDI (267.46 mg, 1.650 mmol, 3 equiv). The mixture was stirred at 25oC for 2 h. Upon completion of reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure. The yellow liquid was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give the product 5- [5,7-difluoro-2-(5-methoxypyridin-2-yl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-ol (95 mg, 50.19%) as a yellow solid. MS (ESIpos): m / z = 345 [M+H]+.

[0306] o a so ut on o 5-[5,7- uoro- -(5-met oxypyr n- -y )- - n o -3-yl]- 1,3,4-oxadiazol-2-ol (80 mg, 0.232 mmol, 1 equiv) in DMF (1.5 mL) were added 3- aminopyrrolidin-2-one (34.90 mg, 0.348 mmol, 1.5 equiv), BOP (205.55 mg, 0.464 mmol, 2 equiv) and DIEA (120.13 mg, 0.928 mmol, 4 equiv). The mixture was stirred at 25oC overnight. Upon completion of reaction, the reaction mixture was quenched with water. The resulting mixture was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 30 min; detector, UV 254 nm, to give 3-({5-[5,7-difluoro-2-(5-methoxypyridin-2-yl)-1H-indol-3-yl]- 1,3,4-oxadiazol-2-yl}amino)pyrrolidin-2-one (11.0 mg, 10.92%) as a white solid.

[0307] MS (ESIpos): m / z = 427.30 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.45 (d, J = 3.0 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 9.4 Hz, 2H), 7.62 – 7.52 (m, 2H), 7.22 – 7.10 (m, 1H), 4.18 – 4.07 (m, 1H), 3.92 (s, 3H), 3.21 (dd, J = 9.3, 4.2 Hz, 2H), 2.48 – 2.36 (m, 1H), 2.10 – 1.92 (m, 1H).SCHEME IExample 21: Synthesis of Compound 65

[0308] To a stirred solution of tert-butyl 2,5-dihydropyrrole-1-carboxylate (20 g, 118.187 mmol, 1 equiv) in DCM (1000 mL) was added m-CPBA (101.97 g, 590.935 mmol, 5 equiv) in portions at 0 °C. The resulting mixture was stirred for 12 h at room temperature. The reaction was quenched with Na2SO3 at 0 °C. The aqueous layer was extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (8 g, 36.54%) as a white solid. LCMS (ESI) [M + H]+: 186.

[0309] To a stirred solution of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3- carboxylate (8 g, 43.191 mmol, 1 equiv) in H2O (100 mL) and EtOAc (50 mL) were added NaIO4(13.86 g, 64.787 mmol, 1.5 equiv) and ruthenium(iv) oxide hydrate (1.96 g, 12.957 mmol, 0.3 equiv) in portions at room temperature. The resulting mixture was stirred for 24 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in tert-butyl 2-oxo-6-oxa-3-azabicyclo[3.1.0]hexane-3- carboxylate (8 g, 92.98%) as a white solid. LCMS (ESI) [M + H]+: 200.

[0310] To a stirred solution of tert-butyl 2-oxo-6-oxa-3-azabicyclo[3.1.0]hexane- 3-carboxylate (8 g, 40.159 mmol, 1 equiv) in DCM (30 mL) was added TFA (10 mL, 80.318 mmol) dropwise at 0 °C under N2atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. This resulted in 6-oxa-3- azabicyclo[3.1.0]hexan-2-one (10 g, 251.30%) as a light-yellow solid.

[0311] A solution of 6-oxa-3-azabicyclo[3.1.0]hexan-2-one (10 g, 100.919 mmol, 1 equiv) and Benzylamine (21.63 g, 201.838 mmol, 2 equiv) in ACN (40 mL) was stirred for 2 h at 50 °C under N2 atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA=3 / 1 to afford rac-(3R,4S)-3-(benzylamino)- 4-hydroxypyrrolidin-2-one (4.2 g, 20.18%) as a yellow solid. LCMS (ESI) [M + H]+:207

[0312] A solution of rac-(3R,4S)-3-(benzylamino)-4-hydroxypyrrolidin-2-one (500 mg, 2.424 mmol, 1 equiv) and Pd(OH)2 / C (50 mg, 0.356 mmol, 0.15 equiv) in MeOH (5 mL) was stirred for 12 h at room temperature under H2 atmosphere. The reaction was monitored by TLC. The resulting mixture was filtered, the filter cake was washed with MeOH (5 mL x 3). The filtrate was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification.

[0313] A solution of rac-(3R,4S)-3-amino-4-hydroxypyrrolidin-2-one (300 mg, 2.584 mmol, 1 equiv), 5-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-ol(855.81 mg, 2.584 mmol, 1 equiv), BOP (2285.33 mg, 5.168 mmol, 2 equiv) and DIEA (1001.74 mg, 7.752 mmol, 3 equiv) in DMF (10 mL) was stirred for 12 h at room temperature under N2 atmosphere. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 0.1%FA in H2O / ACN, 0% to 50% gradient in 40 min; detector, UV 254 nm. This resulted in rac-(3R,4S)-3-({5-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4- oxadiazol-2-yl}amino)-4-hydroxypyrrolidin-2-one (120 mg, 10.82%) as a white solid. The product (120 mg) was purified by Chiral-HPLC with the following conditions (Hex(0.1%DEA): EtOH=85:15) to afford (3R,4S)-3-((5-(5,7-difluoro-2-(4-fluorophenyl)-1H- indol-3-yl)-1,3,4-oxadiazol-2-yl)amino)-4-hydroxypyrrolidin-2-one (5.6 mg, 98.366%) as a white solid. LCMS (ESI) [M + H]+: 430.1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.92 – 7.77 (m, 3H), 7.63 (dd, J = 9.5, 2.3 Hz, 1H), 7.43 – 7.29 (m, 2H), 7.17 (ddd, J = 11.6, 9.6, 2.3 Hz, 1H), 5.68 (d, J = 5.4 Hz, 1H), 4.38 – 4.23 (m, 1H), 3.83 (t, J = 8.5 Hz, 1H), 3.40 (d, J = 9.5 Hz, 1H), 2.93 (dd, J = 9.5, 7.6 Hz, 1H). SCHEME JExample 22: Synthesis of Compound 66

[0314] To a stirred mixture of 2-bromo-5-chloropyridine (10 g, 51.964 mmol, 1 equiv.) and tributyl(1-ethoxyethenyl)stannane (28.15 g, 77.946 mmol, 1.5 equiv.) in ACN (100 mL) were added CuI (1.98 g, 10.393 mmol, 0.2 equiv.) and dichloropalladium bis(triphenylphosphane) (7.29 g, 10.393 mmol, 0.2 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. Upon completion of reaction, the reaction was quenched with diluted HCl aq. solution and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 1-(5-chloropyridin-2-yl)ethanone (5 g, 61.85%) as light-yellow oil. LCMS (ESI) [M + H]+: 156.

[0315] To dimethyl carbonate (86.8 g, 964.14 mmol, 30 equiv.) was added NaH (2.57 g, 64.276 mmol, 2 equiv.) and followed by the addition of 1-(5-chloropyridin-2- yl)ethanone (5 g, 32.138 mmol, 1 equiv.). The resulting mixture was stirred at 80 °C for 20 min under nitrogen atmosphere. Upon completion of reaction, the reaction was quenched with diluted hydrochloric acid (2 M) at 0 °C. The resulting solution was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The mixture was purified by reverse phase separationcolumn [Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Gradient: 30% B to 60% B in 30 min] to give methyl 3-(5-chloropyridin-2-yl)-3-oxopropanoate (4.3 g, 62.63%) as a white solid. LCMS (ESI) [M + H]+: 214.

[0316] To a stirred solution of methyl 3-(5-chloropyridin-2-yl)-3-oxopropanoate (4.3 g, 20.129 mmol, 1 equiv.) and N-(2,4-difluoro-6-iodophenyl)-2,2,2-trifluoroacetamide (10.60 g, 30.194 mmol, 1.5 equiv.) in DMSO (20 mL) were added CuI (0.77 g, 4.026 mmol, 0.2 equiv.), L-proline (0.46 g, 4.026 mmol, 0.2 equiv.) and Cs2CO3(19.68 g, 60.387 mmol, 3 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The residue was dissolved in water (50 mL). The aqueous layer was extracted with EtOAc (3x50 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. To a stirred solution of the above residue were added MeOH (50 mL) and HCl (50 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The organic solvent was removed under vacuum and then ice water was added. The mixture was neutralized with sat. NaHCO3 aq. solution in an ice bath. The resulting solution was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 2-(5-chloropyridin-2-yl)-5,7-difluoro-1H-indole-3-carboxylate (600 mg, 9.24%) as a light-yellow solid. LCMS (ESI) [M + H]+: 323.H-indole-3- carboxylate (600 mg, 1.859 mmol, 1 equiv.) in EtOH (10 mL) was added hydrazine hydrate (10 mL) and the resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. Upon completion of reaction, the organic solvent was removed under vacuum to give 120 mg of the crude 2-(5-chloropyridin-2-yl)-5,7-difluoro-1H-indole-3-carbohydrazide as a white solid. LCMS (ESI) [M + H]+: 323. [o a so u o o - -c o opy - -y - , - uo o- H-indole-3- carbohydrazide (110 mg, 0.341 mmol, 1 equiv.) in DMF (2 mL) was added CDI (165.82 mg, 1.023 mmol, 3 equiv.). The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. Upon completion of reaction, the reaction mixture was quenched with water. The mixture was purified by reverse phase separation column [Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Gradient: 30% B to 60% B in 30 min] to give 5-[2- (5-chloropyridin-2-yl)-5,7-difluoro-1H-indol-3-yl]-1,3,4-oxadiazol-2-ol (80 mg, 67.31%) as a white solid. LCMS (ESI) [M + H]+: 349.

[0319] To a solution of 5-[2-(5-chloropyridin-2-yl)-5,7-difluoro-1H-indol-3-yl]- 1,3,4-oxadiazol-2-ol (75 mg, 0.215 mmol, 1 equiv.) in DMF (1 mL) were added (3S)-3- aminopyrrolidin-2-one (43.07 mg, 0.430 mmol, 2 equiv.), BOP (190.26 mg, 0.430 mmol, 2 equiv.) and DIEA (111.20 mg, 0.860 mmol, 4 equiv.). The resulting mixture was stirred at RT overnight under nitrogen atmosphere. Upon completion of reaction, the reaction mixture was quenched with water. The mixture was purified by reverse phase separation column [Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Gradient: 30% B to 60% B in 30 min] to give (3S)-3-({5-[2-(5-chloropyridin-2-yl)-5,7-difluoro-1H-indol-3-yl]-1,3,4- oxadiazol-2-yl}amino)pyrrolidin-2-one (7 mg, 7.33%) as a white solid.

[0320] LCMS (ESI) [M + H]+: 431.20.1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.8 (d, J = 8.4 Hz, 1H), 8.4 (d, J = 8.4 Hz, 1H), 8.3 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.67 – 7.59 (m, 1H), 7.26 – 7.18 (m, 1H), 4.1 (d, J = 5.4 Hz, 1H), 3.28 – 3.24 (m, 2H), 2.5 (t, J = 8.5 Hz, 1H), 2.12 – 1.98 (m, 1H). SCHEME KExample 23: Synthesis of Compound 67

[0321] A solution of 2-bromo-5-(trifluoromethyl)pyridine (15 g, 66.373 mmol, 1 equiv.) in acetonitrile (100 mL) was treated with tributyl(1-ethoxyethenyl)stannane (35.96 g, 99.560 mmol, 1.5 equiv.), dichloropalladium; bis(triphenylphosphane) (2.33 g, 3.319 mmol, 0.05 equiv.), and CuI (0.08 g, 0.443 mmol, 0.1 equiv.) at 25 °C. The mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. Upon completion of reaction, the reaction was quenched with diluted HCl aq. solution and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl N-[(1R)-2- hydroxy-1-{[4-(trifluoromethoxy)phenyl]carbamoyl}ethyl]carbamate (900 mg, 43.76%) as light-yellow oil. LCMS (ESI) [M + H]+: 190.

[0322] To dimethyl carbonate (16.67 g, 185.050 mmol, 5 equiv.) was added NaH (2.66 g, 111.030 mmol, 3 equiv.), followed by addition of 1-[5-(trifluoromethyl)pyridin-2- yl]ethanone (7 g, 37.010 mmol, 1 equiv.). The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. The mixture was purified by reverse phase flash chromatography [Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Gradient: 30% B to 60% B in 30 min] to give methyl 3-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]propanoate (4 g, 43.73%) as light-yellow oil. LCMS (ESI) [M + H]+: 248.

[0323] To a stirred solution of methyl 3-oxo-3-[5-(trifluoromethyl)pyridin-2- yl]propanoate (3.9 g, 15.778 mmol, 1.5 equiv.) and N-(2,4-difluoro-6-iodophenyl)-2,2,2- trifluoroacetamide (3.69 g, 10.519 mmol, 1 equiv.) in DMSO (20 mL) were added CuI (0.40 g, 2.104 mmol, 0.2 equiv.), L-proline (0.48 g, 4.207 mmol, 0.4 equiv.) and Cs2CO3 (10.28 g, 31.556 mmol, 3 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The residue was dissolved in water (50 mL). The aqueous layer was extracted with EtOAc (3x50 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. To a stirred solution of the above residue were added MeOH (5 mL) and HCl (5 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 5,7-difluoro-2-[5-(trifluoromethyl)pyridin- 2-yl]-1H-indole-3-carboxylate (400 mg, 10.67%) as a light-yellow solid. LCMS (ESI) [M + H]+: 357.

[0324] To a solution of methyl 5,7-difluoro-2-[5-(trifluoromethyl)pyridin-2-yl]- 1H-indole-3-carboxylate (350 mg, 0.982 mmol, 1 equiv.) in EtOH (25 mL) was addedhydrazine hydrate (25 mL). The resulting mixture was stirred at 100 °C overnight under nitrogen atmosphere. The mixture was purified by reverse phase separation column [Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Gradient: 30% B to 60% B in 30 min] to give 5,7-difluoro-2-[5-(trifluoromethyl)pyridin-2-yl]-1H-indole-3-carbohydrazide (150 mg, 42.86%) as a white solid. LCMS (ESI) [M + H]+: 357.-2-yl]-1H- indole-3-carbohydrazide (140 mg, 0.393 mmol, 1 equiv.) in THF (2 mL) were added CDI (191.16 mg, 1.179 mmol, 3 equiv.). The resulting mixture was stirred at RT overnight under nitrogen atmosphere. Upon completion of reaction, the reaction was quenched with water. The mixture was purified by reverse phase separation column [Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Gradient: 30% B to 60% B in 30 min] to give 5-{5,7-difluoro-2- [5-(trifluoromethyl)pyridin-2-yl]-1H-indol-3-yl}-1,3,4-oxadiazol-2-ol (80 mg, 53.26%) as a white solid. LCMS (ESI) [M + H]+: 383.

[0326] To a solution of 5-{5,7-difluoro-2-[5-(trifluoromethyl)pyridin-2-yl]-1H- indol-3-yl}-1,3,4-oxadiazol-2-ol (85 mg, 0.222 mmol, 1 equiv.) and (3S)-3-aminopyrrolidin- 2-one (44.53 mg, 0.444 mmol, 2 equiv.) in DMF (1.5 mL) were added BOP (196.70 mg, 0.444 mmol, 2 equiv.) and DIEA (114.96 mg, 0.888 mmol, 4 equiv.). The resulting mixture was stirred at RT overnight under nitrogen atmosphere. Upon completion of reaction, the reaction was quenched with water. The mixture was purified by reverse phase flash chromatography [Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Gradient: 30% B to 60% Bin 30 min] to give (S)-3-((5-(5,7-difluoro-2-(5-(trifluoromethyl)pyridin-2-yl)-1H-indol-3-yl)- 1,3,4-oxadiazol-2-yl)amino)pyrrolidin-2-one (22.8 mg, 21.84%) as a yellow solid.

[0327] LCMS (ESI) [M + H]+: 465.10.1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 9.20 (d, J = 8.4 Hz, 1H), 8.40(d, J =9.3 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.92 – 7.86 (m, 1H), 7.72 – 7.56 (m, 1H), 7.30 (d, J = 5.4 Hz, 1H), 4.36 – 4.24 (m, 1H), 3.23 – 3.16 (m, 2H), 2.65– 2.41 (m, 1H), 2.10 (dd, J = 9.5, 7.6 Hz, 1H). SCHEME L

[0328] To dimethyl carbonate (50 mL) was added NaH (5.33 g, 221.949 mmol, 3 equiv.) in portions, followed by the addition of 1-(4-methylpyridin-2-yl)ethanone (10 g, 73.983 mmol, 1 equiv.) dropwise. The mixture was stirred for 10 min at 80 °C under nitrogen atmosphere. Upon completion of reaction, the mixture was cool down at an ice bath and quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 3-(4-methylpyridin-2-yl)-3- oxopropanoate (5 g, 34.98%) as brown oil. LCMS (ESI) [M+H]+: 194ate (5 g, 25.880 mmol, 1.5 equiv.) in DMSO (20 mL) was treated with CuI (0.66 g, 3.451 mmol, 0.2 equiv.), L-proline (0.40 g, 3.451 mmol, 0.2 equiv.) and Cs2CO3 (16.86 g, 51.760 mmol, 3 equiv.) for 5 min at room temperature under nitrogen atmosphere followed by the addition of N-(2,4-difluoro-6-iodophenyl)-2,2,2-trifluoroacetamide (6.06 g, 17.253 mmol, 1 equiv.) dropwise. The mixture was stirred for 1 h at room temperature. To the above mixture was added HCl (10 mL) and MeOH (10 mL) dropwise over 5 min at room temperature. The resulting mixture was stirred for additional 1 h at 80 °C. The mixture was neutralized to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EA. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford methyl 5,7-difluoro-2-(4-methylpyridin-2-yl)-1H-indole-3-carboxylate (550 mg, 10.55%) as a yellow solid. LCMS (ESI) [M+H]+: 303.

[0330] so u o o e y , - uo o- - - e y py - -yl)-1H-indole-3- carboxylate (550 mg, 1.819 mmol, 1 equiv.) in hydrazine hydrate (5 mL) and EtOH (5 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5,7-difluoro-2-(4- methylpyridin-2-yl)-1H-indole-3-carbohydrazide (210 mg, 38.18%) as a purple solid. LCMS (ESI) [M+H]+: 303.

[0331] A solution of 5,7-difluoro-2-(4-methylpyridin-2-yl)-1H-indole-3- carbohydrazide (210 mg, 0.695 mmol, 1 equiv.) and CDI (337.95 mg, 2.085 mmol, 3 equiv.) in tetrahydrofuran (5 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. Upon completion of reaction, the reaction was quenched with water. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-[5,7-difluoro-2- (4-methylpyridin-2-yl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-ol (150 mg, 65.77%) as a purple solid. LCMS (ESI) [M+H]+: 329., 1H-indol- 3-yl]-1,3,4-oxadiazol-2-ol (150 mg, 0.457 mmol, 1 equiv.) and (3S)-3-aminopyrrolidin-2-one (91.50 mg, 0.914 mmol, 2 equiv.) in DMF (3 mL) were added BOP (404.19 mg, 0.914 mmol, 2 equiv.) and DIEA (236.23 mg, 1.828 mmol, 4 equiv.). The mixture was stirred at room temperature under nitrogen atmosphere overnight. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (3S)-3-({5-[5,7-difluoro-2-(4-methylpyridin-2-yl)-1H-indol-3-yl]-1,3,4-oxadiazol- 2-yl}amino)pyrrolidin-2-one (28.7 mg, 15.24%) as a yellow solid.

[0333] LCMS (ESI) [M+H]+: 411.10.1H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 8.60 (d, J = 5.1 Hz, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.94 – 7.86 (m, 2H), 7.61 (dd, J = 9.5,2.3 Hz, 1H), 7.33 (dd, J = 5.2, 1.6 Hz, 1H), 7.25 – 7.11 (m, 1H), 4.15 – 4.05 (m, 1H), 3.25 – 3.16 (m, 2H), 2.42 – 2.36 (s, 4H), 2.06 – 1.88 (m, 1H). SCHEME M

[0334] To a stirred solution of 2,3-difluoro-6-iodoaniline (2 g, 7.843 mmol, 1 equiv) and TFAA (2.47 g, 11.764 mmol, 1.5 equiv) in THF (5 mL) was added Et3N (2.38 g, 23.529 mmol, 3 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. Thisresulted in N-(2,3-difluoro-6-iodophenyl)-2,2,2-trifluoroacetamide (2 g, 72.65%) as a light- yellow solid. LCMS (ESI) [M+H]+: 351.9.

[0335] To a stirred solution of N-(4,5-difluoro-2-iodophenyl)-2,2,2- trifluoroacetamide (2 g, 5.698 mmol, 1 equiv) and methyl 3-(4-fluorophenyl)-3-oxopropanoate (2.24 g, 11.396 mmol, 2 equiv) in DMSO (10 mL) were added CuI (0.11 g, 0.570 mmol, 0.1 equiv), L-proline (0.13 g, 1.140 mmol, 0.2 equiv) and Cs2CO3(3.71 g, 11.396 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The residue was dissolved in water (50 mL). The aqueous layer was extracted with EtOAc (3x50 mL). The resulting mixture was concentrated under reduced pressure. To a stirred solution of the above residue was added MeOH (10 mL) and HCl (10 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in methyl 5,6-difluoro-2-(4-fluorophenyl)-1H-indole-3-carboxylate (0.9 g, 51.75%) as a light-yellow solid. LCMS (ESI) [M+H]+: 306.

[0336] To a stirred solution of methyl 5,6-difluoro-2-(4-fluorophenyl)-1H-indole- 3-carboxylate (900 mg, 2.948 mmol, 1 equiv) in EtOH (10 mL) were added hydrazine hydrate (10 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirredovernight at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5 ,6-difluoro-2-(4- fluorophenyl)- 1H-indole-3-carbohydrazide (800 mg, 88.89%) as a light-yellow solid. LCMS (ESI) [M+H]+: 306. [033, yl)-1H-indole-3- carbohydrazide (800 mg, 2.621 mmol, 1 equiv) and CDI (2124.77 mg, 13.105 mmol, 5 equiv) in DMF (5 mL, 64.608 mmol, 24.65 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 50 °C under nitrogen atmosphere. Upon completion of reaction, the reaction was quenched with water. The crude product was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-[5,6-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2- ol (200 mg, 23.04%) as a light-yellow solid. LCMS (ESI) [M+H]+: 332.

[0338] To a stirred solution of 5-[5,6-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]- 1,3,4-oxadiazol-2-ol (100 mg, 0.302 mmol, 1 equiv) and (3S)-3-aminopyrrolidin-2-one (36.27 mg, 0.362 mmol, 1.2 equiv) in DMF (2 mL) was added BOP (267.04 mg, 0.604 mmol, 2 equiv) and DIEA (195.09 mg, 1.510 mmol, 5 equiv) dropwise at room temperature. The resultingmixture was stirred overnight at room temperature. Upon completion of reaction, the reaction was quenched with water. The crude product was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (3S)-3-({5-[5,6-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]- 1,3,4-oxadiazol -2- yl}amino)pyrrolidin-2-one (35.5 mg, 27.87%) as a white solid.

[0339] LCMS (ESI) [M + H]+: 414.05.1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 7.98 – 7.94 (m, 1H), 7.92 (d, J = 6.5 Hz, 1H), 7.86 – 7.79 (m, 3H), 7.47 (dd, J = 10.7, 6.9 Hz, 1H), 7.40 – 7.33 (m, 2H), 4.08 (dt, J = 10.4, 8.2 Hz, 1H), 3.22 – 3.14 (m, 2H), 2.43 – 2.33 (m, 1H), 2.02 – 1.89 (m, 1H). Example 26: Synthesis of Compound 70

[0340] To a st rred m xture o 5-[5,6-d uoro-2-(4- uorop eny )-1H-indol-3-yl]- 1,3,4-oxadiazol-2-ol (100 mg, 0.302 mmol, 1 equiv.) and (3S,4R)-3-amino-4- hydroxypyrrolidin-2-one (42.07 mg, 0.362 mmol, 1.2 equiv.) in DMF (2 mL) were added BOP (267.04 mg, 0.604 mmol, 2 equiv.) and DIEA (195.09 mg, 1.510 mmol, 5 equiv.) dropwise at room temperature. The resulting mixture was stirred overnight at room temperature under air atmosphere. The crude product was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (3S,4R)-3- ({5-[5,6- difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-yl}amino)-4- hydroxypyrrolidin-2-one (27.6 mg, 20.88%) as a white solid.

[0341] LC-MS (ES, m / z): [M + H]+: 430.05.1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 7.99 – 7.89 (m, 2H), 7.88 – 7.84 (m, 1H), 7.84 – 7.76 (m, 2H), 7.47 (dd, J = 10.7, 7.0 Hz, 1H), 7.41 – 7.31 (m, 2H), 5.68 (d, J = 5.5 Hz, 1H), 4.37 – 4.26 (m, 1H), 3.84 (t, J = 8.5 Hz, 1H), 3.39 (ddd, J = 9.5, 7.6, 1.8 Hz, 1H), 2.94 (dd, J = 9.5, 7.6 Hz, 1H).SCHEME NExample 27: Synthesis of Compound 71

[0342] A solution of 2,3-difluoro-6-iodoaniline (4 g, 15.686 mmol, 1 equiv.) in THF (50 mL) was treated with TFAA (4.94 g, 23.529 mmol, 1.5 equiv.) dropwise at 0 °C under nitrogen atmosphere followed by the addition of Et3N (2.38 g, 23.529 mmol, 1.5 equiv.) dropwise. The mixture was stirred for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford N-(2,3-difluoro-6-iodophenyl)-2,2,2-trifluoroacetamide (4 g, 72.65%) as yellow oil. LCMS (ESI) [M + H]+: 352., 17.094mmol, 1.5 equiv.) in DMSO (30 mL) was treated with CuI (0.43 g, 2.279 mmol, 0.2 equiv.), L-proline (0.26 g, 2.279 mmol, 0.2 equiv.) and Cs2CO3 (11.14 g, 34.188 mmol, 3 equiv.) for 5 min at room temperature under nitrogen atmosphere, followed by the addition of N-(2,3- difluoro-6-iodophenyl)-2,2,2-trifluoroacetamide (4 g, 11.396 mmol, 1 equiv.) dropwise. The mixture was stirred for 1 h at room temperature. To the above mixture was added HCl (10 mL) and MeOH (30 mL) dropwise over 5 min at room temperature. The mixture was stirred for additional 2 hours at 80 °C. Upon completion of reaction, the resulting mixture was neutralized to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford methyl 6,7-difluoro-2-(4-fluorophenyl)- 1H-indole-3-carboxylate (1.6 g, 46.00%) as a yellow solid. LCMS (ESI) [M+H]+: 306.

[0344] A solution of 6,7-difluoro-2-(4-fluorophenyl)-1H-indole-3-carbohydrazide (1.1 g, 3.603 mmol, 1 equiv.) and CDI (0.88 g, 5.405 mmol, 1.5 equiv.) in DMF (8 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. Upon completion of reaction, the reaction was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5- [6,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-ol (80 mg, 6.70%) as a white solid. LCMS (ESI) [M + H]+: 332.[-indol-3-yl]- 1,3,4-oxadiazol-2-ol (50 mg, 0.151 mmol, 1 equiv.) and (3S)-3-aminopyrrolidin-2-one (30.22 mg, 0.302 mmol, 2 equiv.) in DMF (2 mL) were added BOP (133.52 mg, 0.302 mmol, 2 equiv.) and DIEA (78.03 mg, 0.604 mmol, 4 equiv.). The mixture was stirred at 35 °C under nitrogen atmosphere overnight. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (3S)-3-({5-[6,7- difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-yl}amino)pyrrolidin-2-one (25.2 mg, 40.11%) as a white solid.

[0346] LCMS (ESI) [M + H]+: 414.30.1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.90 (s, 1H), 7.87 – 7.76 (m, 4H), 7.43 – 7.30 (m, 2H), 7.29 – 7.22 (m, 1H), 4.17 – 4.00 (m, 1H), 3.25 – 3.14 (m, 2H), 2.40 – 2.32 (m, 1H), 2.03 – 1.88 (m, 1H).SCHEME O

[0347] To a st rred so ut on o 5-[6,7-d uoro-2-(4- uorop eny )-1H-indol-3-yl]- 1,3,4-oxadiazol-2-ol (100 mg, 0.302 mmol, 1 equiv) and (3S,4R)-3-amino-4- hydroxypyrrolidin-2-one (70.11 mg, 0.604 mmol, 2 equiv) in DMF (2 mL) were added BOP (267.04 mg, 0.604 mmol, 2 equiv) and DIEA (156.07 mg, 1.208 mmol, 4 equiv) in portions at 35 °C. The mixture was stirred at room temperature under nitrogen atmosphere overnight. Upon completion of reaction, the mixture was quenched with water. The residuewas purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (3S,4R)-3-({5-[6,7-difluoro-2-(4-fluorophenyl)-1H- indol-3-yl]-1,3,4-oxadiazol-2-yl}amino)-4-hydroxypyrrolidin-2-one (18 mg, 13.40%) as a white solid.

[0348] LCMS (ESI) [M+H]+: 430.10.1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.89 – 7.72 (m, 4H), 7.36 (t, J = 8.8 Hz, 2H), 7.31-7.19 (m, 1H), 5.67 (d, J = 5.5 Hz, 1H), 4.38-4.24 (m, 1H), 3.82 (t, J = 8.5 Hz, 1H), 3.40 (s, 1H), 2.93 (dd, J = 9.5, 7.6 Hz, 1H). Example 29: Synthesis of Compound 73

[03] o a s rre so u on o - me y am no e anesu onam e mg, 0.724 mmol, 2 equiv.), 3-(5-bromo-1,3,4-oxadiazol-2-yl)-5,7-difluoro-2-(4-fluorophenyl)-1H-indole (142.61 mg, 0.362 mmol, 1 equiv.) in DMF (5 mL). The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. Upon completion of reaction, the mixture was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.). This resulted in 2-({5-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2- yl}(methyl)amino)ethanesulfonamide (5.5 mg, 3.30%) as a white solid.

[0350] LCMS (ESI) [M + H]+: 412.15.1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.90 – 7.83 (m, 2H), 7.86 – 7.76 (m, 2H), 7.41 – 7.30 (m, 2H), 7.18 (td, J = 7.9, 4.9 Hz, 1H), 7.14 – 7.06 (m, 1H), 5.68 (d, J = 5.4 Hz, 1H), 4.38 – 4.27 (m, 1H), 3.84 (t, J = 8.6 Hz, 1H), 3.44 – 3.34 (m, 1H), 2.94 (dd, J = 9.5, 7.6 Hz, 1H).SCHEME P

[0351] To a stirred solution of P-bromoacetophenone (10.00 g, 50.239 mmol, 1.0 eq.) in dimethyl carbonate (100 mL) was added NaH (3.62 g, 150.717 mmol, 3.0 eq.) in portions at 0 °C. The resulting mixture was stirred overnight at 70 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 3-(4-bromophenyl)-3-oxopropanoate (12 g, 92.91%) as yellow oil.

[0352] MS (ESIpos): m / z = 258.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.92 – 7.86 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H), 4.22 (s, 2H), 3.65 (d, J = 0.8 Hz, 3H).00 g, 46.678 mmol, 1.0 eq.), Cs2CO3(15.20 g, 46.678 mmol, 1.0 eq.) and 4-fluoro-2-iodoaniline (11.06 g, 46.678 mmol, 1.0 eq.) in DMSO (120 mL) was added L-proline (1.07 g, 9.336 mmol, 0.2 eq.) and CuI (888.8 mg, 4.668 mmol, 0.1 eq.). The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 2-(4- bromophenyl)-5-fluoro-1H-indole-3-carboxylate (2 g, 12.31%) as a yellow solid.

[0354] MS (ESIpos): m / z = 346.0 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 7.75 – 7.69 (m, 3H), 7.67 – 7.62 (m, 2H), 7.47 (d, J = 8.8, 4.6 Hz, 1H), 7.10 (d, J = 9.2, 2.7 Hz, 1H), 3.74 (s, 3H).

[0355] To a stirred solution of methyl 2-(4-bromophenyl)-5-fluoro-1H-indole-3- carboxylate (2 g, 5.744 mmol, 1.0 eq.) in EtOH (10 mL) and hydrazine hydrate (10 mL). The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 40% gradient in 20 min; UV 254 nm. This resulted in 2-(4- bromophenyl)-5-fluoro-1H-indole-3-carbohydrazide (940 mg, 47.00%) as a yellow solid.

[0356] MS (ESIpos): m / z = 348.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 7.72 – 7.63 (m, 4H), 7.45 – 7.32 (m, 2H), 7.03 (d, J = 9.2, 2.5 Hz, 1H), 4.55 (s, 2H), 3.34 (s, 1H).[0] o a st rre so ut on o -( - romop eny )- - uoro-1H-indole-3- carbohydrazide (940.0 mg, 2.700 mmol, 1.0 eq.) and CDI (1.31 g, 8.100 mmol, 3.0 eq.) in DMF (10 mL). The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. Upon completion of reaction, the mixture was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 20 min; UV 254 nm. This resulted in 2-(4-bromophenyl)-5-fluoro-3-(5-methoxy-1,3,4-oxadiazol-2-yl)-1H- indole (387 mg, 36.93%) as a yellow solid.

[0358] MS (ESIpos): m / z = 372.0 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 2H), 7.77 – 7.72 (m, 2H), 7.70 – 7.62 (m, 3H), 7.50 (d, J = 8.9, 4.5 Hz, 1H), 7.14 (d, J = 9.1, 2.6 Hz, 1H).

[0359] To a stirred solution of 2-(4-bromophenyl)-5-fluoro-3-(5-methoxy-1,3,4- oxadiazol-2-yl)-1H-indole (160.0 mg, 0.412 mmol, 1.0 eq.) and (3S)-3-aminopyrrolidin-2-one (112.5 mg, 0.824 mmol, 2.0 eq.) in DMF (2 mL) was added DIEA (213.0 mg, 1.648 mmol, 4.0 eq.) and (1H-1,2,3-benzotriazol-1-yloxy)tris(dimethylamino)phosphanium hexafluoro- lambda5-phosphanuide (364.5 mg, 0.824 mmol, 2.0 equiv). The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. Upon completion of reaction, the mixture was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 20 min; UV 254 nm. This resulted in (3S)-3-({5-[2-(4-bromophenyl)-5-fluoro-1H-indol-3-yl]-1,3,4-oxadiazol-2-yl}amino)pyrrolidin-2-one (130 mg, 69.13%) as a yellow solid.

[0360] MS (ESIpos): m / z = 456.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.86 (s, 1H), 7.78 – 7.73 (m, 3H), 7.49 (d, J = 8.8, 4.6 Hz, 1H), 7.12 (m, 1H), 4.08 (d, J = 8.7 Hz, 1H), 3.24 – 3.14 (m, 2H), 2.42 – 2.33 (m, 1H), 1.97 (d, J = 11.4, 9.2 Hz, 1H).o-1H-indol- 3-yl]-1,3,4-oxadiazol-2-yl}amino)pyrrolidin-2-one (100.0 mg, 0.219 mmol, 1.0 eq.) and zinc cyanide (257.3 mg, 2.190 mmol, 10.0 eq.) in N,N-dimethylacetamide (1 mL) was added tetrakis(triphenylphosphine)palladium(0) (25.3 mg, 0.022 mmol, 0.1 eq.). The resulting mixture was stirred for 1 h at 100 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 0% to 40% gradient in 20 min; UV 254 nm. This resulted in 4-[5-fluoro-3-(5-{[(3S)-2-oxopyrrolidin-3-yl]amino}-1,3,4-oxadiazol-2- yl)-1H-indol-2-yl]benzonitrile (55.5 mg, 62.93%) as a yellow solid.

[0362] MS (ESIpos): m / z = 403.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 7.99 (s, 4H), 7.95 – 7.87 (m, 2H), 7.79 (d, J = 10.0, 2.6 Hz, 1H), 7.52 (d, J = 8.9, 4.5 Hz, 1H), 7.16 (d, J = 9.2, 2.6 Hz, 1H), 4.09 (m, 1H), 3.25 – 3.16 (m, 2H), 2.45 – 2.35 (m, 1H), 1.98 (m, 1H).Example 44: Synthesis of Compound 75 [xy-1,3,4- oxadiazol-2-yl)-1H-indole (200.0 mg, 0.515 mmol, 1.0 eq.) and (3S,4R)-3-amino-4- hydroxypyrrolidin-2-one (119.6 mg, 1.030 mmol, 2.0 eq.) in DMF (2 mL) was added DIEA (266.3 mg, 2.060 mmol, 4.0 eq.) and (1H-1,2,3-benzotriazol-1- yloxy)tris(dimethylamino)phosphanium hexafluoro-lambda5-phosphanuide (455.7 mg, 1.030 mmol, 2.0 eq.). The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. Upon completion of reaction, the mixture was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 0% to 50% gradient in 20 min;, UV 254 nm. This resulted in (3S,4R)-3-({5-[2-(4-bromophenyl)-5-fluoro-1H-indol-3- yl]-1,3,4-oxadiazol-2-yl}amino)-4-hydroxypyrrolidin-2-one (80 mg, 32.88%) as a yellow solid.

[0364] MS (ESIpos): m / z = 472.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.88 – 7.83 (m, 1H), 7.72 (s, 4H), 7.49 (d, J = 8.9, 4.6 Hz, 1H), 7.13 (d, J = 9.1, 2.6 Hz, 1H), 5.69 (d, J = 5.4 Hz, 1H), 4.34 (q, J = 6.3, 5.0 Hz, 1H), 3.84 (t, J = 8.5 Hz, 1H), 2.94 (d, J = 9.5, 7.6 Hz, 1H).

[0365] To a stirred solution of (3S,4R)-3-({5-[2-(4-bromophenyl)-5-fluoro-1H- indol-3-yl]-1,3,4-oxadiazol-2-yl}amino)-4-hydroxypyrrolidin-2-one (70.0 mg, 0.148 mmol, 1.0 eq.) and zinc cyanide (174.0 mg, 1.480 mmol, 10.0 eq.) in DMA (1 mL) was added Pd(PPh3)4(17.1 mg, 0.015 mmol, 0.1 eq.). The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. Upon completion of reaction, the mixture was extracted with EtOAc and concentrated under vacuum. The crude product was purified by Prep-HPLC (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5m; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 35% B to 62% B in 9 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.8) .This resulted in 4-[5-fluoro-3- (5-{[(3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl]amino}-1,3,4-oxadiazol-2-yl)-1H-indol-2- yl]benzonitrile (11.1 mg, 17.90%) as a yellow solid.

[0366] MS (ESIpos): m / z = 417.20 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 7.98 (s, 5H), 7.87 (s, 1H), 7.77 (m, 1H), 7.53 (m, 1H), 7.16 (m, 1H), 5.68 (d, J = 5.4 Hz, 1H), 4.38 – 4.27 (m, 1H), 3.85 (d, J = 8.5 Hz, 1H), 3.39 (d, J = 8.4 Hz, 1H), 2.99 – 2.91 (m, 1H). SCHEME QExample 32: Synthesis of Compound 76

[0367] To a stirred solution of 2-fluoro-4-methylaniline (5 g, 39.953 mmol, 1 equiv) in AcOH (50 mL) was added NIS (13.48 g, 59.930 mmol, 1.5 equiv) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-fluoro-6-iodo-4-methylaniline (5 g, 49.85%) as a light-yellow solid. LCMS (ESI) [M + H]+: 252.

[0368] ne (5 g, 19.917 mmol, 1 equiv) and DIEA (7.72 g, 59.751 mmol, 3 equiv) in DCM (20 mL) was added TFAA (6.27 g, 29.876 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2,2,2-trifluoro-N-(2-fluoro-6-iodo-4- methylphenyl)acetamide (5 g, 72.34%) as a light-yellow solid. LCMS (ESI) [M + H]+: 348.

[0369] To a stirred solution of 2,2,2-trifluoro-N-(2-fluoro-6-iodo-4- methylphenyl)acetamide (5 g, 14.407 mmol, 1 equiv) and methyl 3-(4-fluorophenyl)-3- oxopropanoate (4.24 g, 21.611 mmol, 1.5 equiv) in DMSO (10 mL) were added CuI (0.27 g,1.441 mmol, 0.1 equiv), L-proline (0.33 g, 2.881 mmol, 0.2 equiv) and Cs2CO3(4.69 g, 14.407 mmol, 1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The residue was dissolved in NH4Cl aq. solution (50 mL). The aqueous layer was extracted with EtOAc (3x50 mL). The resulting mixture was concentrated under reduced pressure. The crude product was diluted with MeOH (10 mL) and HCl (10 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm., to afford methyl 7-fluoro-2-(4-fluorophenyl) -5-methyl-1H-indole-3- carboxylate (1.5 g, 34.56%) as a light-yellow solid. LCMS (ESI) [M + H]+: 302. [0o a s e so u o o e y - uo o- - - uo op e y - -methyl-1H- indole-3-carboxylate (1.5 g, 4.979 mmol, 1 equiv) in EtOH (10 mL) was added hydrazine hydrate (10 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: [column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm] to afford 7-fluoro-2-(4-fluorophenyl)- 5-methyl-1H-indole-3-carbohydrazide (1.2 g, 80.00%) as a light-yellow solid. LCMS (ESI) [M + H]+: 302.

[0371] To a stirred solution of 7-fluoro-2-(4-fluorophenyl)-5-methyl-1H-indole-3- carbohydrazide (1.2 g, 3.983 mmol, 1 equiv) in DMF (10 mL) was added CDI (3.23 g, 19.915 mmol, 5 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: [column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.] to afford 5-[7-fluoro-2-(4-fluorophenyl)-5-methyl-1H-indol-3-yl]- 1,3,4-oxadiazol-2-ol (0.4 g, 30.69%) as a light-yellow solid. LCMS (ESI) [M + H]+: 328.

[0372] To a stirred solution of 5-[7-fluoro-2-(4-fluorophenyl)-5-methyl-1H-indol- 3-yl]-1,3,4-oxadiazol-2-ol (100 mg, 0.306 mmol, 1 equiv) and (3S,4R)-3-amino-4- hydroxypyrrolidin-2-one (39.03 mg, 0.337 mmol, 1.1 equiv) in DMSO (2 mL) were added BOP (270.27 mg, 0.612 mmol, 2 equiv) and DIEA (197.45 mg, 1.530 mmol, 5 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. Upon completion of reaction, the reaction was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.) toafford (3S,4R)-3-({5-[7-fluoro-2-(4-fluorophenyl)-5-methyl-1H-indol-3-yl]-1,3,4-oxadiazol- 2-yl}amino)-4-hydroxypyrrolidin-2-one (18.7 mg, 14.05%) as a white solid.

[0373] LCMS (ESI) [M + H]+:426.10.1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H),7.85 (d, J = 8.5 Hz, 1H), 7.80 – 7.76 (m, 1H), 7.76 – 7.66 (m, 2H), 7.59 (d, J = 1.2 Hz, 1H), 7.32 – 7.20 (m, 2H), 6.87 (dd, J = 12.1, 1.4 Hz, 1H), 5.61 (d, J = 5.3 Hz, 1H), 4.30 – 4.19 (m, 1H), 3.75 (t, J = 8.6 Hz, 1H), 3.32 (s, 1H), 2.86 (dd, J = 9.5, 7.6 Hz, 1H), 2.37 (s, 3H). SCHEME R

[0374] To a stirred mixture of methyl 3-(4-fluorophenyl)-3-oxopropanoate (3.00 g, 15.292 mmol, 1.0 eq.) and 4-chloro-2-iodoaniline (3.88 g, 15.292 mmol, 1.0 eq.) in DMSO (30 mL) was added CuI (0.29 g, 1.529 mmol, 0.1 eq.), Cs2CO3(4.98 g, 15.292 mmol, 1.0 equiv) and [1,1'-binaphthalene]-2,2'-diol (875.7 mg, 3.058 mmol, 0.2 eq.). The resulting mixture was stirred overnight at 50 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to affordmethyl 5-chloro-2-(4-fluorophenyl)-1H-indole-3-carboxylate (1.80 g, 32.17%) as a yellow solid.

[0375] MS (ESIpos): m / z = 304.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.79 – 7.72 (m, 2H), 7.47 (d, J = 8.6 Hz, 1H), 7.40 – 7.32 (m, 2H), 7.25 (d, J = 8.6, 2.1 Hz, 1H), 3.75 (s, 3H).

[0376] To a stirred mixture of methyl 5-chloro-2-(4-fluorophenyl)-1H-indole-3- carboxylate (1.00 g, 3.293 mmol, 1.0 eq.) in EtOH (10 mL) was added hydrazine hydrate (10 mL). The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in Water (0.1% FA), 0% to 50% gradient in 30 min; UV 254 nm. This resulted in 5-chloro-2-(4-fluorophenyl)-1H-indole-3-carbohydrazide (550.0 mg, 55.00%) as a yellow solid.

[0377] MS (ESIpos): m / z = 303.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 9.12 (s, 1H), 7.77 (d, J = 8.6, 5.5 Hz, 2H), 7.65 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.6, 2.1 Hz, 1H), 4.48 (s, 2H).

[0378] To a stirred mixture of 5-chloro-2-(4-fluorophenyl)-1H-indole-3- carbohydrazide (550.0 mg, 1.811 mmol, 1.0 eq.) in DMF (5 mL) was added CDI (880.9 mg, 5.433 mmol, 3.0 eq.). The resulting mixture was stirred for 30 min at 40 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50%gradient in 30 min; UV 254 nm. This resulted in 5-[5-chloro-2-(4-fluorophenyl)-1H-indol-3- yl]-1,3,4-oxadiazol-2-ol (430.0 mg, 72.02%) as a yellow solid.

[0379] MS (ESIpos): m / z = 330.1 [M+H]+.1H NMR (400 MHz, Chloroform-d) δ 8.48 (s, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 8.6, 5.3 Hz, 3H), 7.36 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H). [0-indol-3-yl]- 1,3,4-oxadiazol-2-ol (140.0 mg, 0.425 mmol, 1.0 eq.) and (3S,4R)-3-amino-4- hydroxypyrrolidin-2-one (49.3 mg, 0.425 mmol, 1.0 eq.) in DMF (2 mL) was added DIEA (219.5 mg, 1.700 mmol, 4.0 eq.) and BOP (375.6 mg, 0.850 mmol, 2.0 eq.). The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. Upon completion of reaction, the reaction was quenched with water. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 60% B to 82% B in 7 min; Wave Length: 254 / 220 nm; RT1(min): 5.20) to afford (3S,4R)-3-({5-[5-chloro-2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-yl} amino)-4-hydroxypyrrolidin-2-one (38.6 mg, 21.25%) as a light yellow solid.

[0381] MS (ESIpos): m / z = 427.95 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.88 – 7.79 (m, 3H), 7.49 (d, J = 8.6 Hz, 1H), 7.41 – 7.32 (m, 2H), 7.27 (d, J = 8.6, 2.1 Hz, 1H), 5.68 (d, J = 5.4 Hz, 1H), 4.40 – 4.27 (m, 1H), 3.84 (d, J = 8.6 Hz, 1H), 3.43 – 3.36 (m, 1H), 2.94 (d, J = 9.5, 7.6 Hz, 1H).SCHEME S

[0382] To a stirred solution of 4-bromo-2-methylaniline (2 g, 10.750 mmol, 1 equiv.) in AcOH (20 mL) was added NIS (3.63 g, 16.125 mmol, 1.5 equiv.) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 4-bromo-2-iodo-6-methylaniline (2 g, 59.64%) as a light-yellow solid. LCMS (ESI) [M + H]+: 312.

[0383] To a stirred solution of 4-bromo-2-iodo-6-methylaniline (2 g, 6.411 mmol, 1 equiv.) and TFAA (2.02 g, 9.616 mmol, 1.5 equiv.) in THF (20 mL) was added Et3N (3.24 g, 32.055 mmol, 5 equiv.) dropwise at 0 °C. The resulting mixture was stirred for 1 h at roomtemperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA ( 1 : 1 ) to afford A-(4-bromo- 2-iodo-6-methylphenyl)-2,2,2-trifluoroacetamide (2 g, 76.47%) as a light-yellow solid. LCMS (ESI) [M + H]+: 408.

[0384] To a stirred solution of A-(4-bromo-2-iodo-6-methylphenyl)-2,2,2- trifluoroacetamide (2 g, 4.902 mmol, 1 equiv.) and methyl 3-(4-fluorophenyl)-3- oxopropanoate (1.92 g, 9.804 mmol, 2 equiv.) in DMSO (10 mL) were added Cui (0.09 g, 0.490 mmol, 0.1 equiv.), L-proline (0.23 g, 1.961 mmol, 0.4 equiv.) and CS2CO3 (3.19 g, 9.804 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The residue was dissolved in water (50 mL). The aqueous layer was extracted with EtOAc (3x50 mL). The resulting mixture was concentrated under reduced pressure. The crude product was diluted with MeOH (10 mL) and HC1 (10 mL) drop wise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in water (lOmmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.) to afford methyl 5-bromo-2-(4-fluorophenyl)-7-methyl-177-indole-3-carboxylate (0.5 g, 28.16%) as a light-yellow solid. LCMS (ESI) [M + H]+: 362.

[0385] To a stirred solution of methyl 5-bromo-2-(4-fluorophenyl)-7-methyl-17f- indole-3-carboxylate (500 mg, 1.380 mmol, 1 equiv.) in MeOH (20 mL) was added Pd / C (500mg, 0.470 mmol, 0.34 equiv, 10% on active carbon) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered; the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. This resulted in methyl 2-(4- fluorophenyl)-7-methyl-177-indole-3-carboxylate (400 mg, 23.04%) as a light-yellow solid. The resulting mixture was used in the next step directly without further purification. LCMS (ESI) [M + H]+: 284.INT-68 I NT-69

[0386] To a stirred solution of methyl 2-(4-fluorophenyl)-7-methyl-l H-indole-3- carboxylate (400 mg, 1.412 mmol, 1 equiv.) in EtOH (10 mL) was added hydrazine hydrate (10 mL) drop wise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine (20 mL), dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure. The resulted in 2-(4-fluorophenyl)-7-methyl- lH-indole-3-carbohydrazide (300 mg, 75.00%) as a light-yellow solid. The mixture was used in the next step directly without further purification. LCMS (EST) [M + H]+: 284.

[0387] To a stirred solution of 2-(4-fluorophenyl)-7-methyl- 1 / / -indole-3- carbohydrazide (300 mg, 1.059 mmol, 1 equiv.) and in DMSO (10 mL) was added CDI (1717.07 mg, 10.590 mmol, 10 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and quenched with water. The residueproduct was purified by reverse phase flash chromatography with the following conditions (The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.) to afford 5-[2-(4-fluorophenyl)-7-methyl- 1H-indol-3-yl]-1,3,4-oxadiazol-2-ol (100 mg, 30.53%) as a light yellow solid. LCMS (ESI) [M + H]+: 310. [0388-indol-3-yl]- 1,3,4-oxadiazol-2-ol (50 mg, 0.162 mmol, 1 equiv.) and (3S,4R)-3-amino-4- hydroxypyrrolidin-2-one (20.65 mg, 0.178 mmol, 1.1 equiv.) in DMSO (2 mL) was added BOP (143.00 mg, 0.324 mmol, 2 equiv.) and DIEA (104.47 mg, 0.810 mmol, 5 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. Upon completion of reaction, the reaction was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.) to afford (3S,4R)-3-({5- [2-(4-fluorophenyl)-7-methyl-1H-indol-3-yl]-1,3,4-oxadiazol-2-yl}amino)-4- hydroxypyrrolidin-2-one (5.7 mg, 8.61%) as a white solid.

[0389] LCMS (ESI) [M + H]+:408.05.1H NMR (400 MHz, Methanol-d4) δ 7.87 (dt, J = 7.9, 1.0 Hz, 1H), 7.76 – 7.67 (m, 2H), 7.28 – 7.17 (m, 2H), 7.12 – 7.01 (m, 2H), 4.46 (dt, J = 8.6, 7.6 Hz, 1H), 4.04 (d, J = 8.6 Hz, 1H), 3.56 (dd, J = 9.9, 7.7 Hz, 1H), 3.11 (dd, J = 9.8, 7.5 Hz, 1H), 2.55 (s, 3H).SCHEME T

[0390] To a stirred solution of methyl 3-(4-fluorophenyl)-3-oxopropanoate (3.00 g, 15.292 mmol, 1.0 eq.) and 2-iodoaniline (3.35 g, 15.292 mmol, 1.0 eq.) in DMSO (30 mL) were added CuI (291.2 mg, 1.529 mmol, 0.1 eq.), Cs2CO3(4.98 g, 15.292 mmol, 1.0 eq.) and [1,1'-binaphthalene]-2,2'-diol (875.7 mg, 3.058 mmol, 0.2 eq.). The resulting mixture was stirred for 3 days at 50 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford methyl 2-(4-fluorophenyl)-1H-indole-3-carboxylate (1.13 g, 27.44%) as a yellow solid.

[0391] MS (ESIpos): m / z = 270 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.11 – 8.00 (m, 1H), 7.75 (d, J = 8.7, 5.5, 2.6 Hz, 2H), 7.46 (d, J = 6.8, 5.2, 2.8 Hz, 1H), 7.34 (t, J = 8.9 Hz, 2H), 7.21 (d, J = 8.9, 7.2, 4.3, 1.7 Hz, 2H), 3.74 (s, 3H).

[0392] To a stirred solution of methyl 2-(4-fluorophenyl)-1H-indole-3-carboxylate (1.10 g, 4.085 mmol, 1.0 eq.) in hydrazine hydrate (10 mL) and EtOH (10 mL). The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in Water (0.1% FA), 0% to 30% gradient in 20 min; UV 254 nm. The resulting mixture was concentrated under vacuum. This resulted in 2-(4-fluorophenyl)-1H- indole-3-carbohydrazide (430.0 mg, 39.09%) as a white solid.

[0393] MS (ESIpos): m / z =270 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 9.04 (s, 1H), 8.17 (s, 1H), 7.76 (d, J = 8.5, 5.4 Hz, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.51 – 7.26 (m, 4H), 7.16 (d, J = 7.5 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H).

[0394] To a st rred so ut on o 2-(4- uorop eny )-1H- ndo e-3-carbohydrazide (420.0 mg, 1.560 mmol, 1.0 eq.) and CDI (758.7 mg, 4.680 mmol, 3.0 eq.) in DMF (5 mL). The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 0% to 50% gradient in 30 min; UV 254 nm. The resulting mixture was concentrated under vacuum. This resulted in 5-[2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-ol (300.0 mg, 65.14%) as a yellow crude oil. MS (ESIpos): m / z = 294 [M-H]–.[039ndol-3-yl]-1,3,4- oxadiazol-2-ol (130.0 mg, 0.440 mmol, 1.0 eq.) and (3S,4R)-3-amino-4-hydroxypyrrolidin-2- one (51.1 mg, 0.440 mmol, 1.0 eq.) in DMF (2 mL) were added DIEA (227.6 mg, 1.760 mmol, 4.0 eq.) and 1H-Benzotriazol-1-yloxytris(dimethylamino)phosphonium Hexafluorophosphate (389.4 mg, 0.880 mmol, 2.0 eq.). The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. Upon completion of reaction, the reaction was quenched with water. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 20% B to 50% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 23) to afford (3S,4R)-3-({5-[2-(4-fluorophenyl)-1H-indol-3-yl]-1,3,4-oxadiazol-2-yl}amino)-4- hydroxypyrrolidin-2-one (17.8 mg, 10.28%) as a white solid.

[0396] MS (ESIpos): m / z = 394.00 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.90 (d(d, J = 8.0 Hz, 1H), 7.40 – 7.32 (m, 2H), 7.29 – 7.17 (m, 2H), 5.67 (d, J = 5.4 Hz, 1H), 4.32 (d, J = 8.0, 5.4 Hz, 1H), 3.84 (d, J = 8.6 Hz, 1H), 3.39 (d, J = 9.5, 7.6, 1.8 Hz, 1H), 2.94 (d, J = 9.5, 7.6 Hz, 1H).

[0397] Table D refers to other examples of Formula I that were made by methods analogous to those described for Compounds 1-79 described herein. Table D Compound Structure LCMS1H NMR 1H NMR (400 MHz DMSO- 78 .3 z, ), , J .2 .8 .9 .9 O- = .4 z, ), 88 O- , J m, ), .4, .2 ), .3, m, O- , J 60 z, ), 22 ),Compound Structure LCMS1H NMR 1H NMR (400 MHz, DMSO- , J m, ), ), , J = ), ), – O- , J .8 ), d, – m, ), – O- , J .8 ), , J m, 41 ). O- 68 ), 40 .5 92Compound Structure LCMS1H NMR O- 74 .6 z, z, ), , J m, z, z, ), d, – = 36 z, = = O- , J = m, z, 66 25 z, 93 O- 70 .4 .7 z, 83 , J m,Compound Structure LCMS1H NMR O- 73 ), 77 , J .1, .6 ), ), ), – O- 74 ), 30 81 , J m, O- , J m, 66 24 z, 93 O- 82 ), – .4 ), 38 86 z,Compound Structure LCMS1H NMR O- , J ), ), 15 = .7 ), – m, O- , J .7 ), , J m, ), z, z, O- (s, ), , J 33 z, 91 m, O- , J m, ), ), m, = .6, .6Compound Structure LCMS1H NMR O- ), m, z, 24 z, ), – – .5, z, ), , J = 21 z, ), ), ). O- , J 88 ), d, – .2 ), d, d, z, .1 ), 35 19 z, ), ), ).Example 36: Synthesis of Triazole-INT-1)ethanone (10 g, 46.075 mmol, 1 equiv) in DMSO (200 mL) was added NaN3 (14.98 g, 230.375 mmol, 5 equiv) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with water at 0 °C. The aqueous layer was extracted with EtOAc (3x1 L). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.) to afford 2-azido-1-(4-fluorophenyl)ethanone (8 g, 96.92%) as a light-yellow solid. Example 37: Synthesis of Triazole-INT-2

[0399] To a stirred solution of 2-azido-1-(4-fluorophenyl)ethanone (8 g, 44.654 mmol, 1 equiv) and ethyl propiolate (4.82 g, 49.119 mmol, 1.1 equiv) in t-BuOH (200 mL) was added sodium (5R)-5-[(1S)-1,2- dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one (4.45 g, 22.327 mmol, 0.5 equiv) and CuSO4(3.56 g, 22.327 mmol, 0.5 equiv) in portions at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at 0°C. The aqueous layer was extracted with EtOAc (3x500 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford ethyl 1-[2-(4-fluorophenyl)-2-oxoethyl]-1,2,3-triazole-4-carboxylate (4 g, 32.31%) as a light- yellow solid. LCMS (ESI) [M + H]+: 278.Example 38: Synthesis of Triazole-INT-3

[0400] To a stirred solution of ethyl 1-[2-(4-fluorophenyl)-2-oxoethyl]-1,2,3-triazole- 4-carboxylate (4 g, 14.427 mmol, 1 equiv) in EtOH (100 mL) was added (2,4- difluorophenyl)hydrazine (6.24 g, 43.281 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred overnight at 80 °C. The mixture was allowed to cool down to room temperature. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product mixture was used in the next step directly without further purification. To a stirred solution of crude in HOAc (100 mL) was added ZnCl2 (4.92 g, 36.067 mmol, 2.5 equiv) in portions at room temperature. The resulting mixture was stirred overnight at 100 °C. The mixture was allowed to cool down to room temperature. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ethyl 1-[5,7-difluoro-2- (4-fluorophenyl)-1H- indol-3-yl]-1,2,3-triazole-4-carboxylate (1.3 g, 23.32%) as a light-yellow solid. LCMS (ESI) [M + H]+: 387. Example 39: Synthesis of Triazole-INT-4

[0401] To a solution of methyl 1-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)-1H- 1,2,3-triazole-4-carboxylate (180 mg, 0.482 mmol, 1.00 equiv) in 6 mL of THF / H2O / MeOH (4:1:1) was added LiOH (195 mg, 0.487 mmol, 10.0 equiv) and the mixture was stirred for 6 hours at room temperature under nitrogen atmosphere. Upon completion of reaction, the mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in 1-(5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl)-1H-1,2,3-triazole-4- carboxylic acid (80 mg, 42.67%) as a white solid. MS (ESIpos): m / z = 357. Example 40: Synthesis of Triazoles-A [04, -yl)-1H-1,2,3- triazole-4-carboxylic acid (80 mg, 0.482 mmol, 1.00 equiv) and R1NHR2(1.2 equiv) in 2 ml of ACN were added TCFH (100 mg 0.422 mol, 2 equiv) and NMI (72 mg, 0. 917 mol, 3 equiv). The mixture was stirred for 1 h at room temperature under nitrogen atmosphere. Upon completion of reaction, the mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in Triazoles-A as a white solid. Example 41: Synthesis of Triazole-INT-5

[0403] To a stirred mixture of ethyl 1-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3- yl]-1,2,3-triazole-4- carboxylate (1.3 g, 3.365 mmol, 1 equiv) in THF (20 mL) was added LAH (0.38 g, 10.095 mmol, 3 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with water at 0 °C and extracted with EA for 3 times. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford {1-[5,7-difluoro-2- (4-fluorophenyl)-1H-indol- 3- yl]-1,2,3-triazol-4-yl}methanol (500 mg, 43.16%) as a light yellow solid. LCMS (ESI) [M + H]+: 345. Example 42: Synthesis of Triazole-INT-6

[0404] To a stirred solution of {1-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]- 1,2,3-triazol-4-yl} methanol (300 mg, 0.871 mmol, 1 equiv) in DCM (5 mL) was added MnO2(227.25 mg, 2.613 mmol, 3 equiv) in portions at 0 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was filtered and the filter cake was washed with DCM (3x3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford 1-[5,7-difluoro-2-(4- fluorophenyl)-1H-indol-3-yl]-1,2,3-triazole-4-carbaldehyde (200 mg, 67.06%) as a light yellow solid. LCMS (ESI) [M + H]+: 343.Example 43: Synthesis of Triazoles-B [0-indol-3-yl]- 1,2,3-triazole-4-carbaldehyd e (200 mg, 0.584 mmol, 1 equiv) and NH2R3(115.84 mg, 0.876 mmol, 1.5 equiv) in MeOH (5 mL) was added STAB (619.20 mg, 2.920 mmol, 5 equiv) in portions at 0 °C under nitrogen atmosphere. The final reaction mixture was stirred for 2 h at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford Triazoles-B as a white solid. Example 44: Synthesis of Triazole-INT-7

[0406] To a mixture of 2,4-difluoro-6-iodoaniline (10.0 g, 39.21 mmol, 1.00 equiv) and 1-ethynyl-4-fluorobenzene (7.05 g, 58.82 mmol, 1.50 equiv) in 100 mL of Et3N were added PdCl2(PPh3)2(1.37 g, 1.96 mmol, 0.05 equiv) and CuI (7.45 g, 39.21 mmol, 1 equiv). The mixture was stirred for 2 h at 70 °C under nitrogen atmosphere. Upon completion of reaction, water was added and the mixture was extracted with ethyl acetate for 3 times. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified onto silica gel column with 50% of ethyl acetate in petroleum ether. This resulted in 2,4-difluoro-6-((4-fluorophenyl)ethynyl)aniline (5.00 g, 49.67%) as a white solid. MS (ESIpos): m / z = 248.06 [M+H]+. Example 45: Synthesis of Triazole-INT-8

[0407] To a solution of 2,4-difluoro-6-((4-fluorophenyl)ethynyl)aniline (5.00 g, 20.24 mmol, 1.00 equiv) in 50 mL of ACN was added t-BuONO (4.7 g, 40.48 mmol, 2 equiv) at 0 °C under nitrogen atmosphere, followed by Me3SiN3 (7.86 g, 60.95 mmol, 3.00 equiv). The mixture was stirred for 2 hours at room temperature under nitrogen atmosphere. Upon completion of reaction, water was added and the resulting mixture was extracted with ethyl acetate for 3 times. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified onto silica gel column with 50% of ethyl acetate in petroleum ether. This resulted in 2-azido-1,5-difluoro-3-((4-fluorophenyl)ethynyl)benzene (2.00 g, 41.67%) as a yellow solid. MS (ESIpos): m / z = 274.05 [M+H]+. Example 46: Synthesis of Triazoles-C

[0408] To a m xture o 2-az do-1,5-d uoro-3-((4- uorop eny )et yny )benzene (2.00 g, 7.32 mmol, 1.00 equiv) and methyl 1H-1,2,3-triazole-4-carboxylate (1.41 g, 11.01 mmol, 1.50 equiv) in 50 mL of DCE were added 1,3-Bis(2,6-di-isopropyl phenyl)imidazol-2- ylidenegold(I)chloride (1.41 g, 11.01 mmol, 1.50 equiv) and Silver bis(trifluoromethanesulfonimide) (1.41 g, 11.01 mmol, 1.50 equiv). The mixture was stirred for 48 hours at room temperature to 80 °C under nitrogen atmosphere. Upon completion of reaction, water was added and the mixture was extracted with DCM for 3 times. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in Triazoles-C as a white solid.

[0409] LCMS (ESI) [M + H]+:373.15.1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.16 (s, 1H), 7.44 – 7.18 (m, 5H), 6.99 (dd, J = 8.9, 2.2 Hz, 1H), 3.88 (s, 3H). Example 47: Synthesis of Compound 110

[0410] To a stirred mixture of [(tert-butoxycarbonyl)amino]acetic acid (1 g, 5.708 mmol, 1 equiv) and 2-methoxyethan-1-amine (0.86 g, 11.416 mmol, 2 equiv) in ACN (5 mL) was added TCFH (3.20 g, 11.416 mmol, 2 equiv) and NMI (2.34 g, 28.540 mmol, 5 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford tert-butyl N-{[(2- methoxyethyl)carbamoyl]methyl}carbamate (500 mg, 37.71%) as a light-yellow solid. LCMS (ESI) [M + H]+: 233

[0411] To a stirred solution of tert-butyl N-{[(2- methoxyethyl)carbamoyl]methyl}carbamate (500 mg, 2.153 mmol, 1 equiv) in TFA (2 mL) and DCM (2 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature.Upon completion of reaction, the solvent was removed under vacuum. The crude product was used in the next step directly without further purification. LCMS (ESI) [M + H]+:133 [0-indol-3-yl]- 1,2,3-triazole-4-carbaldehyde (200 mg, 0.584 mmol, 1 equiv) and 2-amino-N-(2- methoxyethyl)acetamide (115.84 mg, 0.876 mmol, 1.5 equiv) in MeOH (5 mL) was added STAB (619.20 mg, 2.920 mmol, 5 equiv) in portions at 0°C under nitrogen atmosphere. The final reaction mixture was stirred for 2h at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 2-[({1-[5,7-difluoro -2-(4-fluorophenyl)-1H-indol-3-yl]-1,2,3- triazol-4-yl}methyl)amino]-N-(2-methoxyethyl)acetamide as a white solid.

[0413] LCMS (ESI) [M + H]+:459.20.1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.34 (s, 1H), 8.22 (t, J = 5.5 Hz, 1H), 8.11 (s, 1H), 7.49 – 7.39 (m, 2H), 7.32 – 7.26 (m, 2H), 7.22 (ddd, J = 11.7, 9.8, 2.2 Hz, 1H), 6.90 (dd, J = 8.8, 2.2 Hz, 1H), 4.11 (s, 2H), 3.43 (s, 2H)3,.36 (t, J = 5.2 Hz, 2H), 3.29 (t, J = 5.4 Hz, 2H), 3.23 (s, 3H).

[0414] Table E refers to other examples of Formula I which were made by methods analogous to those described for Compounds 109 and 110 described herein.Table E Compound Structure LCMS1H NMR 1H NMR (400 MHz DMSO-d6) δ .5 z, d, 10 δ z, m, – .2 ), d4) – ), 30 78 m, d4) ), 83 z, z, z, – ). d4) – ), 32 78 m,d4) ), 86 d4) ), 81 ), d4) – ), .6 ), (s, d4) ), 84 ), δ – ), 65 δ d, 42 , J ), 66 .0, ),1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 9.01 (d, J = 20.8 Hz, 55 .9, z, H), 70

[0415] Add t ona compounds may be prepared by met ods ana ogous to t ose described for compounds in Table E, such as Compound 123, .Example 48: Measuring Apol1 G1-EIK Inhibition

[0416] Compounds described herein, as exemplified in the Examples, showed IC50values in the following ranges: ***: IC50≤ 250 nM; **: IC50≤ 1000 nM; * IC50> 1000 nM; n.d. = not determined.

[0417] On the day prior to experimental testing, HEK-Trex cells stably expressing ApoL1 (G1-EIK) under control of a tetracyline inducible promotor were harvested and seeded into black walled, poly-d-lysine coated 384-well microplates at approximately 18,000 cells / well in growth media (DMEM / high glucose with 10% fetal bovine serum, 2mM Sodium Pyruvate, 10mM HEPES, 50µg / ml Hygromycin B, and 5µg / ml Blasticidin S. Cells were incubated overnight at 37oC, 10% CO2.

[0418] On day of experiment, 1µg / ml Doxycycline was added to all wells to induce expression of ApoL1. Cells plates were incubated at 37oC, 10% CO2for 8 hours prior to testing.

[0419] Test agents were dissolved in DMSO to give 10 mM stock solutions. 10-point concentration response curves were constructed using the Labcyte Echo 655 acoustic dispenser to generate stock concentration response plates in 100% DMSO. Stock concentration response plates were spotted into assay plates for dilution with assay buffer to generate 2x working concentration assay plates to be used in the FLIPR. Final DMSO concentration in the assay was 0.3%. Concentration ranges tested were from either 10µM to 0.02µM or from 0.3µM to 0.0006µM.

[0420] All thallium uptake fluorescence measurements were performed on a Molecular Devices FLIPR™ fluorescence platform. Test agent effects on thallium uptake in ApoL1 expressing cells were determined using the protocol as described below.

[0421] Plates seeded with HEK cells expressing ApoL1 channels had tetracyline containing induction media removed and replaced with 10ul of a thallium sensitive AM-ester fluorescent dye made up in 1X Hanks buffer + 20mM HEPES (Molecular Devices Potassium Assay Kit). The dye loading buffer contains an extracellular fluorescence quenching agent allowing the dye to remain in the plate throughout the assay. Cells were incubated with dye for 45-60 minutes at room temperature, protected from light.

[0422] After the dye loading incubation time, cell plates and assay plates were loaded on to FLIPR fluorescence reader. The FLIPR program measures baseline fluorescence for 20 seconds baseline, after which the 10ul of 2X test agent or controls made up in Chloride free assay buffer (137mM Sodium Gluconate, 3mM Potassium Gluconate, 1.8mm Calcium Gluconate, 0.8mM Magnesium Gluconate, 10mM HEPES) is added to wells via robotic liquid handler. Cells were incubated with test agents for 5 minutes prior to the addition of Thallium. After the 5-minute preincubation, 20µl of 2mM Thallium Sulfate in assay buffer plus 1X test agents or controls was added to the cells. Changes in fluorescence (measured at 490nm excitation and 520nm emission) were measured over a 3-minute time period.

[0423] Assay data metrics were exported as maximum - minimum change in relative fluorescence units (RFU) over the first 2.5 minutes after thallium addition. Percent inhibition of thallium uptake induced fluorescence was calculated using the following equation: % inhibition = 100-(((RFU Test Agent – RFU Max Inhibition Control) / (RFU of DMSO – RFU Max Inhibition Control))*100).

[0424] Concentration of test agent producing half maximal inhibition (IC50) was calculated using IDBS ActivityBase software using a 4-parameter logistic fit.

[0425] Table F shows APOL-1 (G1E1K) inhibition (IC50) data based on dose response curves (DRC) assessed from thallium uptake fluorescence measurements performed on a Molecular Devices fluorescence imaging plate reader (FLIPRTM) platform. Compounds described herein, as exemplified in the Examples, showed IC50 values in the following ranges: ***: IC50 ≤ 250 nM; **: IC50≤ 1000 nM; * IC50> 1000 nM.Table F Compound APOL 1 G1EIK Inhibition Compound APOL 1 G1EIK Inhibition DRC FLIPR Activity IC50 DRC FLIPR Activity IC50Compound APOL 1 G1EIK Inhibition Compound APOL 1 G1EIK Inhibition DRC FLIPR Activity IC50 DRC FLIPR Activity IC50Compound APOL 1 G1EIK Inhibition Compound APOL 1 G1EIK Inhibition DRC FLIPR Activity IC50 DRC FLIPR Activity IC50Example 48: Pharmacokinetic Analysis

[0426] The bioanalytical protocol was consistent across all PK studies. Plasma samples were diluted with acetonitrile to precipitate protein and the diluted supernatant was analyzed by LC / MS / MS using dexamethasone as an internal standard. A standard curve was prepared in naive plasma and processed in the same manner as the samples. Pharmacokinetic parameters were estimated by non-compartmental modeling using WinNonLin (Certara, Princeton, NJ). Compound 5

[0427] Compound 5 was administered intravenously to CD1 mice, Wistar rats, beagle dogs, and cynomolgus monkeys at a dose of 1 mg / kg with a dosing solution of 0.5 mg / mL. Plasma samples were collected from subjects (N=3 animals / treatment) at nine time points over a 24-hr period (0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h). Similarly, Compound 5 was administered orally to CD1 mice, Wistar rats, and beagle dogs, at a dose of 1 mg / kg with a dosing solution of 0.2 mg / mL. Plasma samples were collected from subjects (N=3 animals / treatment) at eight time points over a24-hr period (0.25, 0.5, 1, 2, 4, 6, 8, 24h). The IV and oral formulation for all species was 10%DMSO / 5%Solutol / 85% (10%) HP-β-CD in DI water(w / w) and all subjects were male. The half-life (T1 / 2) and volume of distribution (VDss) is shown for intravenous administration of Compound 5, as is the bioavailability (F) for oral administration of Compound 5. Table 1: Pharmacokinetic Properties for Administration Mouse Rat Dog Monkey

[0428] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to plural as is appropriate to the context and / or application. The various singular / plural permutations can be expressly set forth herein for sake of clarity.

[0429] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (for example, bodies of the appended claims) are generally intended as “open” terms (for example, the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims can contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (for example, “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claimrecitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (for example, the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “ a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “ a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0430] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0431] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articlesrefers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0432] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I: I) of, wherein:ring A is C6-10aryl or 5-10-membered heteroaryl; X is a 5- to 10-membered heteroaryl optionally substituted with R8; each R1is independently selected from the group consisting of: H, halo, -CN, -NO2, - C(O)R4, -C(O)OR4, –(C1-C6)haloalkyl, –O(C1-C6)haloalkyl, -OC(O)R4, -OR4, - OC(O)OR4, -OC(O)N(R4)2, -N(R4)2, -NR4C(O)R4, -NR4C(O)OR4, -NR4C(O)N(R4)2, -C(O)N(R4) 2, -SR4, -(O)R4, -SO2R4, -SO2N(R4)2, -N(R4)SO2R4, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1- C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, - OC(O)NH2, -OC(O)NH((C1-C6)alkyl), -OC(O)N((C1-C6)alkyl)2, NH2, -NH(C1-C6)alkyl, -N((C1- C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)-C(O)(C1-C6)alkyl, -NHC(O)NH2, -N((C1- C6)alkyl)C(O)NH2, -NHC(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1- C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1- C6)alkyl,-C(O)NH2, -C(O)NH((C1-C6)alkyl), -C(O)N((C1-C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1- C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1-C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1- C6)alkyl and -N((C1-C6)alkyl)SO2(C1-C6)alkyl; and m is an integer from zero to four; each R2is independently selected from the group consisting of: H, halo, perfluoro(C1- C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OR5, - OC(O)OR5, -OC(O)N(R5)2, -N(R5)2, -NR5C(O)R5, -NR5C(O)OR5, -NR5C(O)N(R5)2, -C(O)N(R5)2, -SR5, -S(O)R5, -SO2R5, -SO2N(R5)2, -N(R5)SO2R5, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl, - OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH((C1-C6)alkyl), -OC(O)N((C1-C6)alkyl)2, NH2, - NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)(C1- C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2,-NHC(O)NH((C1-C6)alkyl),-N((C1- C6)alkyl)C(O)NH((C1-C6)alkyl),-N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1-C6)alkyl), -C(O)N((C1- C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1- C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1-C6)alkyl)SO2(C1-C6)alkyl; and n is an integer from zero to four; R3is selected from the group consisting of: -C(O)R6, -C(O)OR6, -OC(O)R6, -OR6, oxo(=O), -OC(O)OR6, -OC(O)N(R6)2, -N(R6)2, -NR6C(O)R6, -NR6C(O)N(R6)2, -NR6C(O)OR6, -C(O)N(R6)2, -SR6, -S(O)R6, -SO2R6, -SO2N(R6)2, -N(R6)SO2R6, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -halo, -OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1- C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, - OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1-C6)alkyl)2, NH2, NH(C1- C6)alkyl, -N((C1-C6)alkyl)2, -NH(C1-C6)alkyl-C(O)-NH-(C1-C6)alkyl-O-(C1-C6)alkyl, -NH(C1- C6)alkyl-C(O)-NH2, -NH(C1-C6)alkyl-C(O)NH-(C1-C6)alkyl, -NHC(O)(C1- C6)alkyl, -NHC(O)(C1-C6)alkyl-O-(C1-C6)alkyl, -NHC(O)(C3-C10)cycloalkyl, -NHC(O)(3-13 membered)heterocycloalkyl, -NH(3-13 membered)heterocycloalkyl, -N((C1-C6)alkyl)C(O)(C1- C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2,-NHC(O)NH((C1-C6)alkyl),-N((C1- C6)alkyl)C(O)NH((C1-C6)alkyl),-N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1-C6)alkyl,-N((C1-C6)alkyl)C(O)O(C1-C6)alkyl,-C(O)NH2, -C(O)NH((C1-C6)alkyl), -C(O)N((C1- C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1- C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1-C6)alkyl)SO2(C1-C6)alkyl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, and (3-13 membered)heterocycloalkyl may additionally be optionally substituted with =O; each R4is independently selected from the group consisting of: H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -halo, -OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1- C6)alkyl, -OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1-C6)alkyl)2, NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)(C1- C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1-C6)alkyl), -N((C1- C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1- C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl,-C(O)NH2, -C(O)NH((C1-C6)alkyl), -C(O)N((C1- C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1- C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1-C6)alkyl)SO2(C1-C6)alkyl; each R5is independently selected from the group consisting of: H, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -halo, OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1- C6)alkyl, -OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1-C6)alkyl)2, NH2, NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)(C1- C6)alkyl, NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2, -NHC(O)NH((C1-C6)alkyl), -N((C1- C6)alkyl)C(O)NH((C1-C6)alkyl),-N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl,-C(O)NH2, -C(O)NH((C1-C6)alkyl), -C(O)N((C1-C6)alkyl)2,-S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1-C6)alkyl), - SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1-C6)alkyl)SO2(C1-C6)alkyl; each R6is independently selected from the group consisting of: H, –(C1-C6)alkyl-(R7)p, - (C2-C6)alkenyl- (R7)p, -(C2-C6)alkynyl-(R7)p, -C(O)(C1-C6)alkyl-(R7)p, -C(O)O(C1-C6)alkyl-(R7)p, -C(O)NH2, -C( O)NH((C1-C6)alkyl)-(R7)p, -C(O)N((C1-C6)alkyl-(R7)p)2, (C3-C10)cycloalkyl-(R7)p, (3-13 membered)heterocycloalkyl-(R7)p, (C6-C10)aryl-(R7)pand (5-12 membered)heteroaryl-(R7)p, wherein p is an integer from 1-3; each R7is independently selected from hydrogen, halo, OH, oxo(=O), perfluoro(C1- C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, (C1-C6)alkoxy, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl, -OC(O)O(C1- C6)alkyl, -OC(O)NH2, -OC(O)NH((C1-C6)alkyl), -OC(O)N((C1-C6)alkyl)2, NH2, -NH(C1- C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)-C(O)(C1- C6)alkyl, -NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2,-NHC(O)NH((C1-C6)alkyl),-N((C1- C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1-C6)alkyl), -C(O)N((C1- C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1- C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl, -N((C1-C6)alkyl)SO2(C1-C6)alkyl, (C3- C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl and wherein each of said (C1-C6)alkyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6- C10)aryl, and (5-12 membered)heteroaryl moieties is optionally substituted with one to three substituents independently selected from the group consisting of: -halo, OH, oxo, perfluoro(C1- C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, - (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl, -O -C(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1-C6)alkyl)2, NH2, NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)(C1-C6)alkyl, NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2,-NHC(O)NH((C1-C6)alkyl),-N((C1- C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1-C6)alkyl), -C(O)N((C1- C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1- C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1-C6)alkyl)SO2(C1-C6)alkyl;R8is independently selected from the group consisting of: H, OH, -halo, perfluoro(C1- C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, -(C1-C6)alkyl-R9, -C(O)R9, -C(O)OR9, - OC(O)R9, -OR9, -OC(O)OR9, -OC(O)N(R9)2, -N(R9)2, -NR9C(O)R9, -NR9C(O)OR9, - NR9C(O)N(R9)2,-C(O)N(R9)2, -SR9, -S(O)R9, -SO2R9, -SO2N(R9)2, -N(R9)SO2R9and -(C1- C6)alkyl-R9; R9is selected from the group consisting of: H, -C(O)R10, -C(O)OR10, -OC(O)R10, -OR10, -OC(O)OR10, -OC(O)N(R10)2, -N(R10)2, -NR10C(O)OR10, -NR10C(O)R10, -NR10C(O)N(R10)2,- C(O)N(R10)2, -SR10, -S(O)R10, -SO2R10, -SO2N(R10)2, -N(R10)SO2R10, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl and (5-12 membered)heteroaryl; wherein each of said (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (3-13 membered)heterocycloalkyl, (C6-C10)aryl, and (5-12 membered)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: -halo, OH, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkoxy, -CN, -NO2, (C1-C6)alkyl, -C(O)(C1-C6)alkyl, -C(O)O(C1-C6)alkyl, -OC(O)(C1-C6)alkyl, -O(C1-C6)alkyl, - OC(O)O(C1-C6)alkyl, -OC(O)NH2, -OC(O)NH(C1-C6)alkyl, -OC(O)N((C1-C6)alkyl)2, NH2, NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)(C1-C6)alkyl, NHC(O)NH2, -N((C1-C6)alkyl)C(O)NH2,-NHC(O)NH((C1-C6)alkyl),-N((C1- C6)alkyl)C(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1-C6)alkyl, -C(O)NH2, -C(O)NH((C1-C6)alkyl), -C(O)N((C1- C6)alkyl)2, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1- C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl and -N((C1-C6)alkyl)SO2(C1-C6)alkyl; and R10is H or (C1-C6)alkyl.

2. The compound according to claim 1, wherein X is 5-membered heteroaryl optionally substituted with R8.

3. The compound according to claim 1 or claim 2, wherein X is oxadiazolyl, oxazolyl, isoxazolyl, or triazolyl, each of which is optionally substituted with R8.

4. The compound according to any one of claims 1 to 3, wherein X is .

5. The compound according to any one of claims 1 to 4, wherein X is .

6. The compound according to any o s 1 to 4, wherein X is.

7. The compound according to anys 1 to 4, wherein X is .

8. The compound according to any1 to 4, wherein X is .

9. The compound according to any os 1 to 4, wherein X is .

10. The compound according to any os 1 to 4, wherein X is .

11. The compound according to any one of claims 1 to 10, wherein ring A is C6-C10aryl.

12. The compound according to any one of claims 1 to 10, wherein ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl, pyrazolyl, tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothienyl, benzofuryl and indolyl.

13. The compound according to claim 1 having the Formula.

14. The compound according to claim 1 having the Formula .

15. The compound according to claim 1 having the formula.

16. The compound according to claim 1 having the formula .. e compoun o c a m w ere n said compound has the formula .

18. The compound of any one of Claim 1 to 17, wherein each R1is independently halo, - CN, (C1-C6)alkyl, -O(C1-C6)alkyl, (C1-C6)haloalkyl, -O(C1-C6)haloalkyl, or (C3-C10)cycloalkyl.

19. The compound of any one of claims 1 to 18, wherein R1is fluoro and m is 1.

20. The compound of any one of claims 1 to 18, wherein each R1is fluoro and m is 2.

21. The compound of any one of claims 1 to 11 or 13 to 20, wherein ring A is . mpound of any one of claims 1 to 21, wherein each R2independently is -F, -CN,-Br, -OH, -O(C1-C6)alkyl, (C1-C6)haloalkyl, -O(C1-C6)haloalkyl, or -SO2R5.

23. The compound of any one of claims 1 to 22, wherein R3is -OH, oxo(=O), optionally substituted (C1-C6)alkyl, optionally substituted -O-(C1-C6)alkyl, optionally substituted (C2- C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (3-13 membered)heterocycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (5-12 membered)heteroaryl, -SR6, -S(O)R6, -SO2R6, -SO2N(R6)2, - N(R6)SO2R6, -N(R6)2NR6C(O)N(R6)2, -NR6C(O)OR6, –C(O)R6, –C(O)O(R6), or -C(O)N(R6)2.

24. The compound of claim 17, wherein R3is -OH.

25. The compound of claim 17, wherein R3is -O-(C1-C6)alkyl.

26. The compound of claim 17, wherein R3is oxo(=O).

27. compound of claim 17, wherein R3is -N(R6)2.

28. The compound of claim 17, wherein R3is NH2.

29. The compound of claim 23, wherein one of said R6is H or (C1-C6)alkyl; and the other of said R6is (3-13 membered)heterocycloalkyl-(R7)p; p is 1 or 2; and each R7is independently selected from hydrogen, -OH, -(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, or oxo.

30. The compound of claim 27, wherein one of said R6is H or (C1-C6)alkyl; and the other .. p , is H or (C1-C6)alkyl; and the other of said R6is (C3-C10)cycloalkyl-(R7)p; p is 1 or 2; and each R7is independently selected from hydrogen, -OH, -(C1-C6)alkyl, halo, or oxo.

32. The compound of claim 27, wherein one of said R6is H or (C1-C6)alkyl; and the other of said R6is -(C1-C6)alkyl-(R7)p; p is 1; and R7is -SO2(C1-C6)alkyl, -SO2NH2, -SO2NH((C1- C6)alkyl), -SO2N((C1-C6)alkyl)2, -NHSO2(C1-C6)alkyl, or -N((C1-C6)alkyl)SO2(C1-C6)alkyl.

33. The compound of claim 27, wherein one of said R6is H or (C1-C6)alkyl; and the other of said R6is -(C1-C6)alkyl-(R7)p; p is 1; and R7is optionally substituted (C3-C10)cycloalkyl, optionally substituted (3-13 membered)heterocycloalkyl, optionally substituted (C6-C10)aryl, or optionally substituted (5-12 membered)heteroaryl.

34. The compound of claim 27, wherein one of said R6is H or (C1-C6)alkyl; and the other of said R6is -(C1-C6)alkyl-(R7)p; p is 1; and R7is –OH, oxo, or (C1-C6)alkoxy.

35. The compound of claim 27, wherein one of said R6is H or (C1-C6)alkyl; and the other of said R6is -(C1-C6)alkyl-(R7)p; p is 1; and R7is–O(C1-C6)alkyl, NH2, -NH(C1-C6)alkyl, -N((C1- C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -N((C1-C6)alkyl)-C(O)(C1-C6)alkyl, -NHC(O)NH2, -N((C1- C6)alkyl)C(O)NH2, -NHC(O)NH((C1-C6)alkyl), -N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl), - N((C1-C6)alkyl)C(O)N((C1-C6)alkyl)2, -NHC(O)O(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O(C1- C6)alkyl, -C(O)NH2, -C(O)NH((C1-C6)alkyl), -C(O)NH((C3-C10)cycloalkyl)(C1-C6)alkyl))-OH, or -C(O)N((C1-C6)alkyl)2.

36. The compound of claim 35, wherein one of said R6is H and the other of said R6is - CH2CH2OH.

37. The compound of claim 35, wherein R7is -N((C1-C6)alkyl)2, -C(O)NH2, -C(O)NH((C1- C6)alkyl) or -C(O)N((C1-C6)alkyl)2.

38. The compound of claim 23, wherein R3is –C(O)N(R6)2and one of said R6is H or (C1- C6)alkyl; and the other of said R6is (3-13 membered)heterocycloalkyl-(R7)p; p is 1 or 2; and each R7is independently selected from hydrogen, -OH, CH2OH, or oxo.

39. The compound of claim 23, wherein R3is –C(O)N(R6)2and one of said R6is H or (C1- C6)alkyl; and the other of said R6is (C3-C10)cycloalkyl-(R7)p; p is 1 or 2; and each R7is independently selected from hydrogen, -OH, -CH2OH, -CH2OCH3, or oxo.

40. The compound of claim 23, wherein R3is –C(O)N(R6)2and one of said R6is H or (C1- C6)alkyl; and the other of said R6is -(C1-C6)alkyl-(R7)p; p is 1; and R7is -OH or -C(O)NH2.

41. The compound of claim 23, wherein R3is –C(O)O(R6).

42. The compound of claim 41, wherein R3is –C(O)OCH3.

43. The compound of claim 3 wherein R3is optionally substituted (C1-C6)alkyl.

44. The compound of claim 43, wherein R3is (C1-C6)alkyl is substituted with -NHC(O)(C1- C6)alkyl, -NHC(O)(C1-C6)alkyl-O-(C1-C6)alkyl, -NHC(O)(C3-C10)cycloalkyl, -NHC(O) (3-13 membered)heterocycloalkyl, -N((C1-C6)alkyl)C(O)NH((C1-C6)alkyl), N((C1-C6)alkyl)C(O)NH2 or -NH(3-13 membered)heterocycloalkyl.

45. The compound of claim 44, wherein R3is (C1-C6)alkyl substituted with -NHC(O)CH3.

46. The compound of claim 44, wherein R3is (C1-C6)alkyl substituted with -NHC(O)CH2OCH3.

47. The compound of claim 23, wherein R3is –C(O)R6and R6is (3-13 membered)heterocycloalkyl-(R7)p; p is 1 or 2; and each R7is independently selected from -OH, CH2OH or oxo.

48. A compound, or a pharmaceutically acceptable salt thereof, having a structure selected from the group consisting of: , ,49. A compound selected from the group consisting of:

50. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of any of claims 1-49, and a pharmaceutically acceptable carrier.

51. The use of a compound of any one of claims 1-49, or a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament to treat a disease for which APOL 1 inhibition is indicated.

52. The use of a compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof, for the manufacture of medicament for the treatment of non-diabetic kidney disease or focal segmental glomerulosclerosis.

53. A method for the treatment of focal segmental glomerulosclerosis in a mammal, including a human, in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof.

54. A method for the treatment of non-diabetic kidney disease in a mammal, including a human, in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof.

55. A method of treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease comprising administering to a patient in need thereof the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 49.

56. A method of inhibiting APOL1 activity comprising contacting said APOL1 with the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 49.

57. The method according to according to any one of claims 53 to 56, wherein the mammal has an APOL1 genotype.

58. The method according to any one of claims 53 to 56, wherein the mammal has nephrotic range proteinuria.

59. The method according to any one of claims 53 to 56, wherein the mammal does not have nephrotic range proteinuria.

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