Tetracyclic compounds containing a fused indole for treating apol1-mediated chronic kidney disease

Abstract

The present disclosure relates to compounds of the formula (I): 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 APOL 1 and the treatment of non-diabetic kidney disease or focal segmental glomerulosclerosis.

Description

TETRACYCLIC COMPOUNDS CONTAINING A FUSED INDOLE FOR TREATING APOL1-MEDIATED CHRONIC KIDNEY DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Prov. Patent App. No.63 / 524,176, titled “TETRACYCLIC COMPOUNDS CONTAINING A FUSED INDOLE FOR TREATING APOL1-MEDIATED CHRONIC KIDNEY DISEASE” and filed on June 29, 2023, the disclosure of which is hereby incorporated herein by reference in its entirety. BACKGROUND Field

[0002] The present disclosure relates to novel tetracyclic compounds including their pharmaceutically acceptable salts. The disclosure also relates to processes for the preparation of intermediates used in the preparation of pharmaceutical compositions containing such compounds and the uses of such compounds in treating focal segmental glomerulosclerosis including non- diabetic kidney disease. 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 forexample, 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 and 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):or a pharmaceutically acceptable salt thereof, wherein: X is O or –(C(R3)2)p–; wherein p is zero, one or two; Y is –(C(R5)2)q–R4; q is an integer from zero to four; each R1is independently selected from the group consisting of: hydrogen, –halo, –CF3, – CF2CF3, -–OCF3, –OCF2CF3, –CN, –NO2, –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)SO2R9, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, – (C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3- C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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: hydrogen, –halo, –CF3, – CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –C(O)R10, –C(O)OR10, –OC(O)R10, –OR10, – OC(O)OR10, –OC(O)N(R10)2, –N(R10)2, –NR10C(O)R10, –NR10C(O)OR10, –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 member)heterocycloalkyl, –(C6- C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, – (C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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)alkylC(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;each R3is independently selected from the group consisting of: hydrogen, –OH, –halo, – CF3, –CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –C(O)R8, –C(O)OR8, –OC(O)R8, –OR8, – OC(O)OR8, –OC(O)N(R8)2, –N(R8)2, –NR8C(O)R8, –NR8C(O)OR8, –NR8C(O)N(R8)2,– C(O)N(R8)2, –SR8, –S(O)R8, –SO2R8, –SO2N(R8)2, –N(R8)SO2R8and –(C1-C6)alkyl-R8; R4is selected from the group consisting of: –C(O)R6, –C(O)OR6, –C(=N)R6, –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)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 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3- C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –CH2OH, –CH2CH2OH, –(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(3-13 member)heterocycloalkyl, –NHC(O)(C1-C6)alkyl, –N(C1-C6)alkylC(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 member)heterocycloalkyl may additionally be optionally substituted with =O; each R5is independently selected from the group consisting of: hydrogen, –OH, –halo, – CF3, –CF2CF3, -OCF3, -OCF2CF3, –CN, –NO2, –(C1-C6)alkyl-R7, –C(O)R7, –C(O)OR7, – OC(O)R7, –OR7, –OC(O)OR7, –OC(O)N(R7)2, –N(R7)2, –NR7C(O)R7, –NR7C(O)OR7, – NR7C(O)N(R7)2,–C(O)N(R7)2, –SR7, –S(O)R7, –SO2R7, –SO2N(R7)2, –N(R7)SO2R7and –(C1- C6)alkyl-R7; each R6is independently selected from the group consisting of: hydrogen, –OH, –(C1- C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of –halo, –OH, –CF3, – CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –CH2OH, –CH2CH2OH, –(C1-C6)alkyl, –C(O)(C1- C6)alkyl, –(C6-C10)aryl, –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)alkylC(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 member)heterocycloalkyl may additionally be optionally substituted with =O; each R7is independently selected from the group consisting of: hydrogen, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6- C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, – (C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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)alkylC(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 R8is independently selected from the group consisting of: hydrogen, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6- C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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)alkylC(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 R9is independently selected from the group consisting of: hydrogen, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6- C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, – (C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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)alkylC(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 R10is independently selected from the group consisting of: hydrogen, –halo, –CF3, – CN, –NO2, –C(O)R11, –C(O)OR11, –OC(O)R11, –OR11, –OC(O)OR11, –N(R11)2, –NR11C(O)R11, – NR11C(O)N(R11)2,–C(O)N(R11)2, –SR11, –S(O)R11, –SO2R11, –SO2N(R11)2, –N(R11)SO2R11, –(C1- C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(C5-C10)cycloalkenyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl;each R11is independently selected from the group consisting of: hydrogen, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(C5-C10)cycloalkenyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; wherein each of said – (C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents selected from the group consisting of hydrogen, –OH, –halo, –CF3, –CN, – NO2, –(C1-C6)alkyl, –(C2-C6)alkenyl and –(C2-C6)alkynyl.

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

[0008] In a further embodiment, provided herein is a pharmaceutical composition, comprising a compound or salt of one or more compounds disclosed herein. In some embodiments, the pharmaceutical composition further comprises an antiviral agent. In some embodiments the antiviral agent is selected from the group consisting of Remdesivir, Nirmatrelvir, Ritonavir, Molnupiravir, Interferon alfa, Interferon lambda and Ivermectin.

[0009] In some embodiments, provided herein is a kit comprising at least two of: (a) a compound or salt disclosed herein; and (b) an antiviral agent. In some embodiments, the antiviral agent is selected from the group consisting of Remdesivir, Nirmatrelvir, Ritonavir, Molnupiravir, Interferon alfa, Interferon lambda and Ivermectin.

[0010] 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.

[0011] 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 apharmaceutically acceptable salt thereof to the mammal. The mammal is preferably a mammal in need of such treatment or prevention.

[0012] 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, hyperphosphatemia 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 edema, heart failure, uremia, anemia, electrolyte disturbances (for example hyperkalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.

[0013] 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 DESCRIPTIONDefinitions

[0014] “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.

[0015] “Subject in need thereof” means a subject identified as in need of a therapy or treatment.

[0016] 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).

[0017] 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.

[0018] “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.

[0019] “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.

[0020] “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.

[0021] “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 anincrease 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.

[0022] “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.

[0023] 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.

[0024] “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.

[0025] “Subcutaneous administration” means administration just below the skin.

[0026] “Intravenous administration” means administration into a vein.

[0027] “Intraarterial administration” means administration into an artery.

[0028] 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.

[0029] “Pharmaceutical agent” means a substance that provides a therapeutic effect when administered to a subject.

[0030] “Pharmaceutical composition” means a mixture of substances suitable for administering to an individual that includes a pharmaceutical agent.

[0031] 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, calcium and 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).

[0032] “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.

[0033] 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 toherein (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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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 optionallysubstituted 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

[0039] 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.

[0040] 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.

[0041] As used herein, the term “heterocycloalkyl” is defined to include a monocyclic, bridged, polycyclic or fused polycyclic saturated or unsaturated non-aromatic 3 to 13 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.

[0042] An "aldehyde" group refers to a carbonyl group where R is hydrogen.

[0043] An "alkoxy" group refers to both an –O-alkyl and an –O-cycloalkyl group, as defined herein.

[0044] An "alkoxycarbonyl" refers to a -C(O)OR.

[0045] An "alkylaminoalkyl" group refers to an -alkyl-NR-alkyl group.

[0046] An "alkylsulfonyl" group refers to a -SO2alkyl.

[0047] An "amino" group refers to an -NH2 or an -NRR'group.

[0048] An "aminoalkyl" group refers to an –alky-NRR' group.

[0049] An "aminocarbonyl" refers to a -C(O)NRR'.

[0050] An "arylalkyl" group refers to -alkylaryl, where alkyl and aryl are defined herein.

[0051] An "aryloxy" group refers to both an –O-aryl and an –O-heteroaryl group, as defined herein.

[0052] An "aryloxycarbonyl" refers to -C(O)Oaryl.

[0053] An "arylsulfonyl" group refers to a -SO2aryl.

[0054] A "C-amido" group refers to a -C(O)NRR' group.

[0055] A "carbonyl" group refers to a -C(O)R.

[0056] A "C-carboxyl" group refers to a -C(O)OR groups.

[0057] A "carboxylic acid" group refers to a C-carboxyl group in which R is hydrogen.

[0058] A "cyano" group refers to a -CN group.

[0059] A "dialkylamionalkyl" group refers to an –(alkyl)N(alkyl)2group.

[0060] A "halo" or "halogen" group refers to fluorine, chlorine, bromine or iodine.

[0061] A "heteroaryloxyl" group refers to a heteroaryl-O group with heteroaryl as defined herein.

[0062] A "hydroxy" group refers to an -OH group.

[0063] An "N-amido" group refers to a -R'C(O)NR group.

[0064] An "N-carbamyl" group refers to a -ROC(O)NR-group.

[0065] A "nitro" group refers to a -NO2group.

[0066] An "N-sulfonamido" group refers to a -NR-SO2R group.

[0067] An "O-carbamyl" group refers to a -OC(O)NRR' group.

[0068] An "O-carboxyl" group refers to a RC(O)O group.

[0069] An “oxo” group refers to a carbonyl moiety such that alkyl substituted by oxo refers to a ketone group.

[0070] A "perfluoroalkyl group" refers to an alkyl group where all of the hydrogen atoms have been replaced with fluorine atoms.

[0071] An "S-sulfonamido" group refers to a -SO2NR-group.

[0072] A "sulfinyl" group refers to a -S(O)R group.

[0073] A "sulfonyl" group refers to a -SO2R group.

[0074] A "C-carboxyl" group refers to a -C(O)OR groups.

[0075] The term "therapeutically effective amount" as used herein refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), a therapeutically effective amount refers to that amount which has the effect of producing the desired effect for which it is administered (e.g., improvement in symptoms of FSGS and / or NDKD, lessening the severity of FSGS and / NDKD or a symptom of FSGS and / or NDKD, and / or reducing progression of FSGS and / or NDKD or a symptom of FSGS and / or NDKD). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0076] In the following Examples and Preparations, “ACN” means acetonitrile; “AlCl3“ means aluminum(III) chloride; “BF3Et2O” means boron trifluoride etherate; “BH3“ means borane “BOC”, “Boc” or “boc” means N-tert-butoxycarbonyl; “CDI” means carbonyldiimidazole; “(COCl)2” means oxalyl chloride; “DCE” means 1,2,-dichloroethane; “DCM” (CH2Cl2) means methylene chloride;“DIAD” means diisopropyl azodicarboxylate; “DIPEA” or “DIEA” means diisopropyl ethyl amine; “DMA” means N,N-dimethylacetamide; “DMAP” means 4- dimethylaminopyridine; “DMEM” means Dulbecco’s Modified Eagle Medium; “DMF” means N- N-dimethyl formamide; “DMSO” means dimethylsulfoxide; “DPPP” means 1,3-bis(diphenylphosphino)propane; “EtOAc” or “EA” means ethyl acetate; “EtOH” means ethanol; “H2O” means water; “H2SO4” means sulfuric acid; “HATU” means 1- [Bis(dimethylamino)methylene]-1H-1,2,3-trazolo[4,5-b]pyridinium 3-oxide; “HEK” means human embryonic kidney; “HEPES” means 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethane-1- sulfonic acid; “HOAc,” “AcOH” or “CH3COOH” means acetic acid; “HCl” means hydrochloric acid; “IPA” means isopropyl alcohol; “K2CO3” means potassium carbonate;“K2OsO4” means potassium osmate; “LAH” means lithium aluminum hydride; “LiBH4“ means lithium borohydride; “LiCl” means lithium chloride; “LiHMDS” means lithium bis(trimethylsilyl)amide; “LiOH” means lithium hydroxide; “MeOH” means methanol; “MgSO4” means magnesium sulphate; “Ms2O” means methanesulfonic anhydride “MTBE” means methyl t-butyl ether; “NaBH4“ means sodium borohydride; “NaCN” means sodium cyanide; “NaH” means sodium hydride; “NaIO4“ means sodium periodate; “NaOH” means sodium hydroxide” “NaSO4” means sodium sulphate; “NH3“ means ammonia; “NH4Cl” means ammonium chloride; “NH4H2O” means hydrazine hydrate; “NMI” means 1-methylimidazole; “NMP” means 1-methyl 2-pyrrolidinone, “Pd / C” means palladium on carbon; “Pd(PPh3)4” means tetrakis(triphenylphosphine)palladium(0); “PE” means petroleum ether; “POCl3” means phosphorus oxychloride; “PPA” means polyphosphoric acid; “PPh3“ means triphenylphosphine; “Py” means pyridine; “TBAF” means tetrabutylammonium fluoride; “TBDPSCl” means tert-butyl(chloro)diphenylsilane; “t-BuOH” means tert-butyl alcohol; “t-BuOK” means potassium tert-butoxide; “TCFH” means N,N,N’,N’- tetramethylchloroformamidinium hexafluorophosphate; “TEA” means triethyl amine; “TFA” means trifluoroacetic acid; “THF” means tetrahydrofuran; “TMSCF3“ means trifluoromethyltrimethylsilane; “TMSCHN2“ means trimethylsilyldiazomethane; “TMSCN” means trimethylsilyl cyanide; “TsCl” means 4-toluenesulfonyl chloride; “TPT” means tetrakis(propan2-yloxy)titanium; Zn(Cl)2means zinc(II) dichloride; “N” means Normal; “M” means molar; “mL” means millilitre; “mmol” means millimoles; ³^PRO´^PHDQV^PLFURPROHV; “eq.” or “equiv.” means equivalent; “qC” means degrees Celsius; “Pa” means pascals.

[0077] The compounds of Formula I are useful for modulating or inhibiting APOL1 activity. Accordingly, these compounds are useful for the prevention and / or treatment of disease states associated with APOL1 dysfunction. The term "APOL1," as used herein, means apolipoprotein L1 protein and the term "APOL1" means apolipoprotein L1 gene.

[0078] 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.

[0079] 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.

[0080] 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).

[0081] 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).

[0082] 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.

[0083] As used herein the terms “Formula I” and “Formula I or pharmaceutically acceptable salts thereof” including Formula (I'), Formula (I"), Formula (Ia), Formula (Ib), Formula (Ic), and Formula (Id) 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.

[0084] 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 characterized 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’).

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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 crystallization, by recrystallization 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).

[0089] 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 more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970).

[0090] 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.

[0091] The compounds of the disclosure include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, stereoisomers isomers thereof (including optical and geometric isomers), and tautomers thereof as hereinafter defined and isotopically-labeled compounds of formula I.

[0092] 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) andBioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

[0093] 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).

[0094] 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 .

[0095] Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

[0096] Moreover, certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.

[0097] 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.

[0098] 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 toindicate 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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 sulfur, such as35S.

[0104] 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.

[0105] 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.

[0106] Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0107] 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.

[0108] Provided herein are compounds that are inhibitors of apolipoprotein L1 (APOL1). In some embodiments the compounds provided herein have the structure of Formulaor a pharmaceutically acceptable salt thereof, wherein: X is O or –(C(R3)2)p–; wherein p is zero, one or two; Y is –(C(R5)2)q–R4; q is an integer from zero to four; each R1is independently selected from the group consisting of: hydrogen, –halo, –CF3, – CF2CF3, -–OCF3, –OCF2CF3, –CN, –NO2, –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)SO2R9, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, – (C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3- C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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: hydrogen, –halo, –CF3, – CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –C(O)R10, –C(O)OR10, –OC(O)R10, –OR10, – OC(O)OR10, –OC(O)N(R10)2, –N(R10)2, –NR10C(O)R10, –NR10C(O)OR10, –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 member)heterocycloalkyl, –(C6- C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, – (C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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)alkylC(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; each R3is independently selected from the group consisting of: hydrogen, –OH, –halo, – CF3, –CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –C(O)R8, –C(O)OR8, –OC(O)R8, –OR8, – OC(O)OR8, –OC(O)N(R8)2, –N(R8)2, –NR8C(O)R8, –NR8C(O)OR8, –NR8C(O)N(R8)2,– C(O)N(R8)2, –SR8, –S(O)R8, –SO2R8, –SO2N(R8)2, –N(R8)SO2R8and –(C1-C6)alkyl-R8; R4is selected from the group consisting of: –C(O)R6, –C(O)OR6, –C(=N)R6, –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)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 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3- C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –CH2OH, –CH2CH2OH, –(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(3-13 member)heterocycloalkyl, –NHC(O)(C1-C6)alkyl, –N(C1-C6)alkylC(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 member)heterocycloalkyl may additionally be optionally substituted with =O; each R5is independently selected from the group consisting of: hydrogen, –OH, –halo, – CF3, –CF2CF3, -OCF3, -OCF2CF3, –CN, –NO2, –(C1-C6)alkyl-R7, –C(O)R7, –C(O)OR7, – OC(O)R7, –OR7, –OC(O)OR7, –OC(O)N(R7)2, –N(R7)2, –NR7C(O)R7, –NR7C(O)OR7, – NR7C(O)N(R7)2,–C(O)N(R7)2, –SR7, –S(O)R7, –SO2R7, –SO2N(R7)2, –N(R7)SO2R7and –(C1- C6)alkyl-R7;each R6is independently selected from the group consisting of: hydrogen, –OH, –(C1- C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; wherein each of said – (C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of –halo, –OH, –CF3, – CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –CH2OH, –CH2CH2OH, –(C1-C6)alkyl, –C(O)(C1- C6)alkyl, –(C6-C10)aryl, –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)alkylC(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 member)heterocycloalkyl may additionally be optionally substituted with =O; each R7is independently selected from the group consisting of: hydrogen, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6- C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, – (C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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)alkylC(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 R8is independently selected from the group consisting of: hydrogen, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6- C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, – (C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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)alkylC(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 R9is independently selected from the group consisting of: hydrogen, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6- C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, – (C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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)alkylC(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 R10is independently selected from the group consisting of: hydrogen, –halo, –CF3, – CN, –NO2, –C(O)R11, –C(O)OR11, –OC(O)R11, –OR11, –OC(O)OR11, –N(R11)2, –NR11C(O)R11, – NR11C(O)N(R11)2,–C(O)N(R11)2, –SR11, –S(O)R11, –SO2R11, –SO2N(R11)2, –N(R11)SO2R11, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(C5-C10)cycloalkenyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; each R11is independently selected from the group consisting of: hydrogen, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(C5-C10)cycloalkenyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; wherein each of said – (C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents selected from the group consisting of hydrogen, –OH, –halo, –CF3, –CN, – NO2, –(C1-C6)alkyl, –(C2-C6)alkenyl and –(C2-C6)alkynyl.

[0109] In some embodiments of Formula (I), the compound of Formula (I) is a compound of Formula (I’)or a pharmaceutically acceptable salt thereof. In some embodiments of Formula (I), the compound of Formula (I) is a compound of Formula (I’’)or a pharmaceutically acceptable salt thereof. In some embodiments of Formula (I), the compound of Formula (I) is a compound of Formula (Ia’) , or a pharmaceutically acceptable salt thereof.In some embodiments of Formula (I), the compound of Formula (I) is a compound of Formula(Ib’), or a pharmaceutically acceptable salt thereof.In some embodiments of Formula (I), the compound of Formula (I) is a compound of Formula (Ic) , or a pharmaceutically acceptable salt thereof. Insome embodiments of Formula (I), the compound of Formula (I) is a compound of Formula (Id),or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments of Formula (I), X can be O. In other embodiments X is – (C(R3)2)p– and p is 0 (i.e., the X unit is absent). In yet other embodiments, X is –(C(R3)2)p– and p is 1. In still yet other embodiments, X is –(C(R3)2)p– and p is 2.

[0111] In some embodiments, each R3is independently hydrogen.

[0112] In some embodiments, each R1is independently selected from the group consisting of: hydrogen, –halo, –CF3, –CF2CF3, -–OCF3, –OCF2CF3, –CN, –NO2, –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)SO2R9, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl. In some embodiments each R1is independently –halo. In other embodiments each R1is fluoro. In some embodiments, m is 2. In some embodiments, m is 2 and each R1is fluoro.

[0113] In some embodiments, each R2is independently selected from the group consisting of: hydrogen, –halo, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –C(O)R10, – C(O)OR10, –OC(O)R10, –OR10, –OC(O)OR10, –OC(O)N(R10)2, –N(R10)2, –NR10C(O)R10, – NR10C(O)OR10, –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 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl. In some embodiments each R2is independently –halo. In other embodiments each R2is fluoro. In some embodiments, n is 1. In some embodiments, n is 1 and R2is fluoro.

[0114] In some embodiments R4is selected from the group consisting of: –C(O)R6, – C(O)OR6, –C(=N)R6, –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)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 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; wherein each of said – (C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: –halo, –OH, –CF3, – CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –CH2OH, –CH2CH2OH, –(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(3-13 member)heterocycloalkyl, –NHC(O)(C1-C6)alkyl, –N(C1-C6)alkylC(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 member)heterocycloalkyl may additionally be optionally substituted with =O.

[0115] In some embodiments, R4is –OR6. In some embodiments, Y is –(C(R5)2)q–R4, q is 1, each R5is independently H, R4is –OR6and R6is H. In other embodiments, Y is –(C(R5)2)q– R4, q is 2, each R5is independently H, R4is –OR6and R6is H. In yet other embodiments, Y is – (C(R5)2)q–R4, q is 3, each R5is independently H, R4is –OR6and R6is H.

[0116] In some embodiments R4is –C(O)R6. In other embodiments, R4is –C(O)OR6. In some embodiments, R4is –C(O)OH. In other embodiments, R4is –C(O)O(C1-C6)alkyl. In some such embodiments, R4is –C(O)OCH3. In yet other embodiments, R4is –OC(O)R6. In still yet other embodiments, R4is –OC(O)OR6. In other embodiments, R4is –OC(O)N(R6)2. In some embodiments, R4is –OC(O)N(R6)2, wherein one R6is H and the other R6is optionally substituted –(C1-C6)alkyl. In some embodiments, the –(C1-C6)alkyl is substituted with –OH. In other embodiments, the –(C1-C6)alkyl is substituted with –CH2OH. In some embodiments, R4is – OC(O)N(R6)2, wherein one R6is H and the other R6is optionally substituted –(C3-C10)cycloalkyl. In some embodiments, the –(C3-C10)cycloalkyl is substituted with –CH2OH. In some embodiments, R4is –OC(O)N(R6)2, wherein one R6is H and the other R6is optionally substituted –(3-13 member)heterocycloalkyl. In some embodiments, the –(C2-C9)cycloalkyl is substituted with =O.

[0117] In some embodiments, R4is –N(R6)2. In some embodiments, R4is –NH2. R4is –NH(CH3). In some embodiments, R4is –NH(C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted. In some embodiments, the (C1-C6)alkyl is substituted with at least one of –OH, – CH2OH, –CH2CH2OH or –C(O)O(C1-C6)alkyl. In some embodiments, R4is –NH(3-13 member) heterocycloalkyl. In some embodiments, the –(3-13 member)heterocycloalkyl is substituted with =O. In some embodiments, R4is –NH(C3-C10)cycloalkyl. In some embodiments, the (C3- C10)cycloalkyl is substituted with –OH.

[0118] In some embodiments, R4is –NR6C(O)R6. In some embodiments, R4is – NHC(O)CH3. In some embodiments, R4is –NHC(O)CH2OH. In some embodiments, R4is – NHC(O)(3-13 member)heterocycloalkyl. In some embodiments, the –(3-13 member)heterocycloalkyl is substituted with =O.

[0119] In some embodiments, R4is –NR6C(O)N(R6)2. In some such embodiments, R4is –NHC(O)NH2. In yet other embodiments, R4is –NR6C(O)OR6.

[0120] In some embodiments, R4is –C(O)N(R6)2. In some embodiments, R4is – C(O)N(R6)2, wherein one R6is H and the other R6is optionally substituted –(C1-C6)alkyl. In some embodiments, the –(C1-C6)alkyl is substituted with –OH. In other embodiments, the –(C1-C6)alkyl is substituted with –CH2OH. In some embodiments, R4is –C(O)N(R6)2, wherein one R6is H and the other R6is optionally substituted –(C3-C10)cycloalkyl. In some embodiments, the –(C3- C10)cycloalkyl is substituted with –CH2OH. In some embodiments, R4is –C(O)N(R6)2, whereinone R6is H and the other R6is optionally substituted –(3-13 member)heterocycloalkyl. In some embodiments, the –(3-13 member)heterocycloalkyl is substituted with =O.

[0121] In other embodiments, R4is optionally substituted –(C1-C6)alkyl. In yet other embodiments, R4is optionally substituted –(C3-C10)cycloalkyl. In other embodiments, R4is – (C2-C6)alkynyl. In other embodiments, R4is –C(=N)R6. In some embodiments, R4is –C(=N)R6and R6is –OH.

[0122] In some embodiments, R4is optionally substituted –(5-12 member)heteroaryl. In some embodiments, R4is pyridyl. In other embodiments, R4is pyrimidyl. In other embodiments, R4is pyrazolyl. In yet other embodiments, R4is oxadiazolyl. In other embodiments, R4is imidazolyl. In some embodiments, pyridyl, pyrimidyl, pyrazolyl, oxadiazolyl, and imidazolyl are each optionally substituted with –OH, –CH2OH, –CF3or –NH(3-13 member)heterocycloalkyl, wherein the –(3-13 member)heterocycloalkyl is optionally further substituted with =O.

[0123] In some embodiments, R4is –(C2-C6)alkynyl.

[0124] In some embodiments at least one of R5is –OH. In other embodiments, at least one of R5is –halo. In some embodiments, Y is –(C(R5)2)q–R4, q is 2, at least one of R5is –OH, R4is –OR6and R6is H. In some embodiments, Y is –(C(R5)2)q–R4, q is 2, at least one of R5is –halo, R4is –OR6and R6is H.

[0125] In some embodiments, the compound of Formula (I) is selected from the group consisting of:,pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt thereof.

[0128] In a further embodiment, provided herein is a pharmaceutical composition, comprising a compound or salt of one or more compounds disclosed herein. In some embodiments, the pharmaceutical composition further comprises an antiviral agent. In some embodiments the antiviral agent is selected from the group consisting of Remdesivir, Nirmatrelvir, Ritonavir, Molnupiravir, Interferon alfa, Interferon lambda and Ivermectin.

[0129] 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 ahuman, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof.

[0130] In some embodiments, provided herein is a kit comprising at least two of: (a) a compound or salt disclosed herein; and (b) an antiviral agent. In some embodiments, the antiviral agent is selected from the group consisting of Remdesivir, Nirmatrelvir, Ritonavir, Molnupiravir, Interferon alfa, Interferon lambda and Ivermectin. Pharmaceutical Compositions

[0131] The disclosure also relates to compositions comprising a compound of Formula (I), and Formulae (I)', (I"), (Ia’), (Ib’), (Ic) and (Id) wherein or an acceptable salt thereof (e.g., pharmaceutical compositions). Accordingly, in one embodiment, the disclosure 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.

[0132] 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 pharmaceutical compositions 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.

[0133] 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 selectthe most appropriate dosage form and route of administration for treatment of the proposed indication.

[0134] 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.

[0135] 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.

[0136] 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).

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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).

[0141] 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, pregelatinized 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.

[0142] 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, pregelatinized 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.

[0143] 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.

[0144] 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.

[0145] Other possible ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.

[0146] 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.

[0147] 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.

[0148] The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol.1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0149] 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 plasticizer, a stabilizer or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.

[0150] 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.

[0151] 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 %.

[0152] Other possible ingredients include anti-oxidants, colorants, flavorings and flavor enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.

[0153] 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.

[0154] 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.

[0155] 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 TechnologyOn-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.

[0156] 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.

[0157] 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.

[0158] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0159] 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.

[0160] 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.

[0161] 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, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, whitepetrolatum, 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).

[0162] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

[0163] 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.

[0164] 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 pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, 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.

[0165] The pressurized container, pump, spray, atomizer, or nebulizer 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, solubilizing, 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.

[0166] Prior to use in a dry powder or suspension formulation, the drug product is micronized 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 bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0167] 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 beanhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0168] A suitable solution formulation for use in an atomizer using HOHFWURK\GURG\QDPLFV^WR^SURGXFH^D^ILQH^PLVW^PD\^FRQWDLQ^IURP^^^J^WR^^^PJ^RI^WKH^FRPSRXQG^RI^ WKH^ GLVFORVXUH^ SHU^ DFWXDWLRQ^ DQG^ WKH^ DFWXDWLRQ^ YROXPH^PD\^ YDU\^ IURP^ ^^O^ WR^ ^^^^O^^$^ W\SLFDO^ 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.

[0169] Suitable flavors, 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] The compounds of the disclosure may also be administered directly to the eye or ear, typically in the form of drops of a micronized 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.

[0174] 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.

[0175] 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.

[0176] 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 solubilizer. 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.

[0177] 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.

[0178] 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 transparent plastic 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 isopposite 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.

[0184] In one preferred embodiment the composition comprises a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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 inthe 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.

[0190] 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.

[0191] The amount of the compound of Formula (I), and Formulae (I'), (I"), (Ia’), (Ib’), (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.

[0192] 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.

[0193] 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 or simultaneously, 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.

[0194] 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:

[0195] 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.

[0196] 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,hyperphosphatemia 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.

[0197] 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.

[0198] Examples of additional active agents which may be 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 (PIs) 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; Post-Attachment 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 tri-peptide 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, Verapamil, 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 Tartrate), 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 MEVACOR® 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, alRJOLSWLQ^^RPDULJOLSWLQ^^ OLQDJOLSWLQ^^YLOGDJOLSWLQ^^^ LQVXOLQ^VHQVLWL]HUV^^ LQFOXGLQJ^^L^^ȕ- klotho / FGFRT activating monoclonal antibody (e.g. MK-3655), pan FGFR1-4 / KLB modulators, )*)^^^DQDORJXH^^H^J^^$OGDIHUPLQ^^^LL^^33$5Ȗ^DJRQLVWV^^VXFK^DV^WKH^JOLWD]RQHV^^H^J^^SLRJOLWD]RQH^^ AMG 131, CHS 131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, rosiglitazone, and balaglitazone), and RWKHU^33$5^OLJDQGV^^LQFOXGLQJ^^^^^33$5Į^Ȗ^GXDO^DJRQLVWV^^H^J^^=<+^^^=<+^^^GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, and naveglitazar); (2) PPARU agonists such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, EH]DILEUDWH^^^^^^^VHOHFWLYH^33$5Ȗ^PRGXODWRUV^^633$5Ȗ0^V^^^^H.g., such as those disclosed in WO 02 / 060388, WO 02 / 08188, WO 2004 / 019869, WO 2004 / 020409, WO 2004 / 020408, and WO ^^^^^^^^^^^^^^ ^^^^ 33$5Ȗ^SDUWLDO^ DJRQLVWV^^ ^^^^ 33$5^Į^į^ GXDO^ DJRQLVWV^ ^H^J^^(ODILEUDQRU^^^ ^LLL^^ 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-1B (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, PLWLJOLQLGH^^PHJOLWLQLGHV^^ QDWHJOLQLGH^ DQG^ UHSDJOLQLGH^^^ Į-glucosidase inhibitors (e.g., acarbose, voglibose and miglitol); glucagon receptor antagonists (e.g., MK-3577, MK-0893, LY-2409021 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 CoA: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 RI^ ^^ȕ-hydroxysteroid dehydrogenase type 1 (e.g., such as those disclosed in U.S. Pat. No. 6,730,690, and LY-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 (ACC1 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, butnot 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-1b antibodies, (e.g., XOMA052 and canakinumab), 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., *35^^^DQWDJRQLVW^^^,QWHJULQ^ĮYȕ^^^ĮYȕ^^DQG^ĮYȕ^^LQKLELWRU^^H^J^, 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. Ieronlimab), TNF inhibitor (e.g., / ,91DWH^^^ LQWHJULQ^ ĮYȕ^^ LQKLELWRU^ ^H^J^, MORF beta6), NLRP inflammasome DQWDJRQLVWV^^ VL51$^ ^H^J^^ 2 / ;^ ^^^^^^ GXDO^ 7)*ȕ^+HGJHKRJ^ LQKLELWRU^ ^H^J^, Oxy 200), GPR40 agonist / GPR84 antagonist (e.g., PBI-4547), neutrophil elastase inhibitor (e.g., PHP-303), integrin inhibitor (e.g., PLN-^^^^^^^7*)ȕ^^PRGXODWRU^ ^H^J^, 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); anti-oxidant (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-1 / GRA (e.g., cotadutide, ALT-801, DD 01, G49, PB-718); dual GLP- 1 (e.g. CT 868); GLP-1 / GRA / GIP triple agonist (e.g., HM15211); GRP120 VWLPXODQW^LQIODPPDVRPH^ PRGXODWRU^33$5Ȗ^ GXDO^ DJRQLVW^ ^H^J^, KDT501); GLP-1 / FGF21 (e.g., YH25724); GLP-1 agonist (e.g., Ozempic (semaglutide sc), XW 003); selective thyroid hormone receptor-ȕ^DJRQLVW^ ^H^J^, 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., BioE1115), 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)-FGFR1c receptor complex mAb (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 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 formulations thereof; 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 APOL1 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.

[0199] Another embodiment relates to co-therapy with antiviral compounds such as Remdesivir, Nirmatrelvir / Ritonavir (i.e. Paxlovid®), Molnupiravir, Interferon alfa, Interferon lambda, and Ivermectin.

[0200] 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

[0201] 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 beadministered 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.

[0202] 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

[0203] 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.

[0204] 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.

[0205] 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, hyperphosphatemia 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 edema, heart failure, uremia, anemia, electrolyte disturbances (for example hyperkalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.

[0206] 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. Methods of Preparation

[0207] 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, NewYork (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 the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

[0208] Compounds of the Formula (I) and Formulae (I'), (I"), (Ia’), (Ib’), (Ic) and (Id), may be prepared according to the following reaction schemes and accompanying discussion. 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. 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.

[0209] 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.

[0210] 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 maybe 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.

[0211] Scheme 1 illustrates the synthesis of compounds of Formula I, wherein X is carbon and Y is carbon. Referring to Scheme 1, a compound of the Formula I may be prepared from a compound of Formula II by a Fischer-indole synthesis by reaction with a compound of Formula III to form an intermediate phenylhydrazone which isomerizes to an enamine ('ene- hydrazine'). Suitable reactants for the preparation of the hydrazone include reaction in an alcohol solvent such as methanol, ethanol, propanol with the addition of heat, 80oC, for a period of 15 minutes to about 4 hours, preferably about 2 hours. The intermediate enamine is cyclized to the desired indole of Formula I by acid catalyzed elimination of ammonia. Suitable acid catalysts include addition of zinc chloride in acetic acid followed by the addition of heat, 95oC, for 15 minutes to 6 hours, preferably about 1 hour.

[0212] The compound of Formula II is prepared by intramolecular Michael cyclization of a compound of Formula IV by reaction with a strong, hindered, non-nucleophilic Brønsted base such as hexamethyldisilazide (LiHMDS) or LDA in an inert solvent such as tetrahydrofuran or dioxane DW^DERXW^^^^^

[0213] Compounds of Formula IV are prepared by Grubbs olefin metathesis by reaction of a compound of Formula V with an ethyl acrylate in the presence of a Grubb's catalyst such as 2-[dichloro(phenylmethylidene)(tricyclohexyl-lambda5-phosphanyl)ruthenio]-1,3- bis(2,4,6-trimethylphenyl)imidazolidine in a reaction inert solvent such as dichloroethane at a temperature or 0oC to 30oC, for 15 minutes to 6 hours, preferably about 1 hour.

[0214] Compounds of Formula V are prepared from compounds of Formula VI by Stille coupling with a stannane such as tributyl(prop-2-en-1-yl)stannane in a reaction inert solvent such as tetrahydrofuran followed by the addition of LiCl and Pd(PPh3)4 in portions at a WHPSHUDWXUH^IURP^DERXW^^^^WR^DERXW^^^^^^IRU^DERXW^^^WR^DERXW^^^^KRXUV^^SUHIHUDEO\^DERXW^12 hours.

[0215] Compounds of the Formula V and VI are commercially available or can be made by methods well known to those skilled in the art.

[0216] Alternatively, compounds of Formula I, wherein X is carbon and Y is carbon, may be prepared from compounds of Formula VIII by a multistep synthesis described in Scheme 2. Referring to Scheme 2, a compound of Formula I may be prepared from a compound of Formula IIa, wherein R is methyl, ethyl, or other alkyl, alkylaryl or aryl ester by a Fischer-indole synthesis by reaction with a compound of Formula III, to form an intermediate phenylhydrazone whichisomerizes to an enamine ('ene-hydrazine'). Suitable reactants for the preparation of the hydrazone include reaction in an alcohol solvent such as methanol, ethanol, propanol with the addition of heat, 80oC, for a period of 15 minutes to about 4 hours, preferably about 2 hours. The intermediate enamine is cyclized to the desired indole of Formula I by acid catalyzed elimination of ammonia. Suitable acid catalysts include addition of zinc chloride in acetic acid followed by the addition of heat, 95oC, for 15 minutes to 6 hours, preferably about 1 hour.

[0217] Ester compounds of Formula IIa, wherein R is methyl, may be prepared from Carboxylic acid compounds of Formula IIa, wherein R is hydrogen, by methyl esterification of the carboxylic acid by reaction with a trimethylsilyldiazomethane in a polar solvent such as dichloromethane (DCM), THF, or DCM / MeOH at a temperature from about 30 minutes to about 6 hours, preferably about 2 hours at a temperature from about 0°C to about 30°C, preferably about 20°C.

[0218] Acid compounds of Formula IIa, wherein R is hydrogen may be prepared from compounds of the Formula VII by intramolecular Friedel-Crafts cyclization by reaction with concentrated sulfuric acid (H2SO4) at a temperature from about 0°C to about 1000°C, preferably about 80 °C from about 30 minutes to about 6 hours, preferably about 2 hours.

[0219] Compounds of Formula VII may be prepared from compounds of Formula VIII by a two-step reaction of saponification followed by reduction. The saponification of the ester occurs with a strong base such as sodium hydroxide, lithium hydroxide or potassium hydroxide in a polar solvent such as an alcohol or water or mixtures thereof at a temperature of -10 °C to about 10°C, preferably around 0°C for a period from about 1 hour to about 4 hours, preferably about 2 hours at room temperature. The reduction is performed with Pd / C under a hydrogen atmosphere in a solvent such as EtOH at room temperature for 1 to 5 hours, preferably 3 hours.

[0220] A compound of Formula VIII is prepared from aldol condensation of dimethyl succinate and a benzaldehyde in an acid or base catalyzed coupling. Suitable bases include potassium t-butoxide sodium t-butoxide, preferably potassium t-butoxide. Suitable solvents include alcohols such as t-BuOH. The reaction is performed at a temperature from about 30 to about 100, preferably about 80 °C for a period of about 1 hour to about 8 hours, preferably about 5 hours.

[0221] Succinates and benzaldehydes are commercially available or can be prepared by methods well known to those skilled in the art.

[0222] Scheme 3 refers to the preparation of compounds of the Formula I, wherein X is oxygen and Y is as described herein. The chain length of Y can vary as well as the alcohol protecting group. Referring to Scheme 3, compounds of the Formula I may be prepared from compound of Formula X by deprotection of the alcohol protecting group (for example t- butyldimethylsilyl (TBS)) with tetrabutylammonium fluoride (TBAF). Suitable solvents for the deprotection include ethers such as tetrahydrofuran (THF) for a time period of about 30 minutes to 5 hours, preferably for about 2 hours at a temperature of about 0°C to about 35°C preferably about 20°C (room temperature). Other analogous protection / deprotection methods are described in Green and Wuts as cited herein.

[0223] Compounds of Formula X may be prepared from compounds of Formula XI by a crossed Aldol reaction with 2-[(tert-butyldimethylsilyl)oxy]acetaldehyde in a polar solvent such as 1,4-dioxane, non-polar solvents, such as toluene or xylene, preferably polar solvents, such as 1,4-dioxane, for a period of 30 minutes to 4 hours, preferably for 2 hours at a temperature of about 30 °C to about 140 °C, preferably about 140 °C

[0224] Compounds of the Formula XI may be prepared from the enamine ('ene- hydrazine') of Formula XII by a Fischer-indole cyclization in which the desired indole is formed by acid catalyzed elimination of ammonia. . This reaction can be catalyzed by Brønsted acids such as HCl, H2SO4, polyphosphoric acid and p-toluenesulfonic acid or Lewis acids, such as boron trifluoride, zinc chloride, iron chloride, and aluminum chloride. Fisher-indole cyclization can occur without solvent or with a tartaric acid–dimethylurea melt. The reaction was conducted for about 1 hour to about 8 hours, preferably about 6 hours at a temperature of about 120 °C.

[0225] Enamines ('ene-hydrazine') of Formula XII may be prepared from Compounds of Formula XIII by reaction with a hydrazine of Formula III according to methods analogous to those of Scheme 1. Suitable reactants for the preparation of the hydrazone include reaction in an alcohol solvent such as methanol, ethanol, propanol with the addition of heat, 80°C, for a period of 15 minutes to about 4 hours, preferably about 2 hours.

[0226] Compounds of the Formulae III and XIII are commercially available or can be made by methods well known to those skilled in the art.

[0227] Scheme 4 refers to the preparation of compound of Formula I wherein Y is – (C(R7)2)q-R3; q is 1, 2 or 3, R3is a (3-13 member)heterocycloalkyl or (5-12 member)heteroaryl and X is oxygen. Referring to Scheme 4, a compound of Formula I may be prepared from aprotected alcohol compound of Formula XIV wherein TBDPSO refers to the protecting group tert- butyldiphenylsilyl, by deprotection of the alcohol protecting group with tetrabutylammonium fluoride (TBAF). Suitable solvents for the deprotection include ethers such as tetrahydrofuran (THF) for a time period of about 30 minutes to 48 hours, preferably for about 48 hours at a temperature of about 0°C to about 35°C preferably about 20°C (room temperature).

[0228] The compound of Formula XIV may be prepared from a compound of Formula XI by reaction with an oxetane such as 2-{3-[(tert-butyldiphenylsilyl)oxy]oxetan-3- yl}acetaldehyde LQ^D^SRODU^VROYHQW^VXFK^DV^GLR[DQH^DW^D^WHPSHUDWXUH^RI^DERXW^^^^^^^IRU^D^SHULRG^ from about 1 hour to 5 hours, preferably 3 hrs.

[0229] Oxetanes such as 2-{3-[(tert-butyldiphenylsilyl)oxy]oxetan-3-yl}acetaldehyde can be made by methods well known to those skilled in the art.

[0230] Scheme 5 refers to the preparation of compounds of Formula Ia wherein X is - (C(R8)2)p-; wherein p is two; and Y is as described herein. Referring to Scheme 5, a compound of Formula Ia may be prepared from a compound of Formula XV by a Fischer-indole synthesis by reaction with a compound of Formula III to form an intermediate phenylhydrazone which isomerizes to an enamine ('ene-hydrazine'). Suitable reactants for the preparation of the hydrazone include reaction in an alcohol solvent such as methanol, ethanol, propanol with the addition of heat, 80oC, for a period of 15 minutes to about 4 hours, preferably about 2 hours. The intermediate enamine is cyclized to the desired indole of Formula I by acid catalyzed elimination of ammonia. Suitable acid catalysts include addition of zinc chloride in acetic acid followed by the addition of heat, 95oC, for 15 minutes to 6 hours, preferably about 1 hour.

[0231] The compound of Formula XV may be prepared from a compound of Formula XVI, wherein R is alkyl, by saponification of the ester moiety, followed by decarboxylation. The saponification of the ester (wherein R is alkyl) is facilitated with a strong base such as lithium hydroxide in a polar solvent such as THF / MeOH and H2O solution at a temperature of about 0°C to about 20°C, preferably room temperature, for a period of 1 to 5 hours, preferably 2 hours.

[0232] The decarboxylation of Formula XVI, wherein R is hydrogen, may be performed by reaction with an acid such as acetic acid / hydrochloric acid at a temperature of about 50°C to about 100°C preferably about 100°C for a time period of about 30 minutes to 4 hours, preferably for about 2 hours.

[0233] The compound of Formula XVI, wherein R is alkyl, may be prepared from a compound of Formula XVII, wherein R is alkyl, by reaction with oxalyl chloride in a solvent such as dichloromethane followed by the addition of DMF at a temperature of about 0°C. The intermediate may be cyclized to the compound of Formula XVI by reaction with aluminum chloride (AlCl3) in a solvent such as dichloromethane at a temperature of about 0oC to 25oC for a period of about 2 to 4 hours.

[0234] The compound of Formula XVI, wherein R is alkyl, may be prepared from a compound of Formula XVII by Friedel-Crafts acylation with trifluoroacetic acid (TFA) in an inert solvent such as dichloromethane at a temperature of about 0 °C to 30 °C, preferably 20 °C, room temperature, for a period of 30 minutes to 4 hours, preferably 2 hours.

[0235] The compound of Formula XVII may be prepared for a compound of Formula XVIII by activation with NaH in an inert solvent such as THF at 0 °C for a period of 3 minutes to 2 hours, preferably about 0.5 hour, followed by reaction with tert-butyl 2-bromoacetate at a temperature of about 0oC for about 1 hour.

[0236] The di-carboxylate of Formula XVIII may be prepared from a bromoethyl- benzene by reaction with diethyl malonate activated with NaH in a solvent such as DMF at about -10 °C to about 0oC for 0.5 hours to about 2 hours.

[0237] Bromoethyl-benzene and diethyl malonate are commercially available.

[0238] Scheme 6 refers to the preparation of compounds of Formula Ib, wherein X is - (C(R8)2)p-; wherein p is zero; and Y is as described herein. Referring to Scheme 6, compounds of Formula Ib may be prepared from an ester of Formula XIX, wherein P is a protecting group such as BOC by reaction with trifluoroacetic acid in a solvent such as dichloromethane at a temperature of about 0 °C to about 20oC for a period of about 0.5 hours to about 2 hours.

[0239] The compound of Formula XIX, wherein P is a protecting group such as BOC may be prepared from a compound of Formula XX, wherein P is a protecting group such as BOC, by reaction with a haloalkyl compound such as tert-butyl 2-bromoacetate in a solvent such as THF in the presence of a strong base such as lithium hexamethyldisilazide (LiHMDS) at a temperature of about 0°C for a period of about 15 minutes to 2 hours.

[0240] The compound of Formula XX, wherein P is a protecting group such as tert- butyloxycarbonyl (BOC), may be prepared from a compound of Formula XXI by reaction with the protecting group reagent, such as di-tert-butyl decarbonate, in the presence of a suitable basesuch as sodium hydroxide, 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIEA) or sodium bicarbonate. Suitable solvents for the protection reaction include water, water / THF, THF, dioxane, methanol or acetonitrile at a temperature from about room temperature (20°C) to about 40°C for a period of about 1 hour to 24 hours preferably about 2 hours.

[0241] The compound of Formula XXI may be prepared from a hydrazine of Formula III by a Fischer-indole synthesis by reaction with a 2,3-dihydroinden-1-one in a mixture of acetic acid and EtOH to which is added the hydrazine. The reaction to form an intermediate phenylhydrazone which isomerizes to an enamine ('ene-hydrazine') is typically completed after about 4 hours. Suitable reactants for the preparation of the hydrazone include reaction in an alcohol solvent such as methanol, ethanol, propanol with the addition of heat, 80oC, for a period of 15 minutes to about 4 hours, preferably about 2 hours. The intermediate enamine is cyclized to the desired indole of Formula XXI by acid catalyzed elimination of ammonia. Suitable acid catalysts include addition of zinc chloride in acetic acid followed by the addition of heat, 95oC, for 15 minutes to 6 hours, preferably about 1 hour.

[0242] Compounds of Formula I, wherein Y is –(C(R5)2)q-R4and R4is -C(O)OR6and R6is H can be converted to other compounds of Formula I wherein Y is –(C(R5)2)q-R4and R4is - 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, or -C(O)N(R6)2by reaction with an amine, acid chloride, or acylamine either in the presence of a base or following reaction by addition of a base.

[0243] Alternatively, compounds of Formula I, wherein Y is –(C4 42)q-R and R is - C(O)OR6and R6is H can be converted to other compounds of Formula I wherein R4is -OR6and R6is H, by reaction with a reducing agent such as a borane.

[0244] Alternatively, compounds of Formula I, wherein Y is –(C(R5)2)q-R4and R4is- OR6and R6is H can be converted to other compounds of Formula I wherein R4is -OC(O)R6, -C(O)N(R6)2, -SR6, -S(O)R6, -SO2R6, -SO2N(R6)2, -N(R6)SO2R6, by reaction with an acylamide, acid chloride or sulfonyl chloride in the presence of a base. Alternatively, the aforementioned reaction may be facilitated by activation of the R6hydroxyl group with an activating group such as a mesylate followed by reaction with an amine, ammonia species or sulfonamide.

[0245] Alternatively, compounds of Formula I, wherein Y is4and R contains an amine functionality may be converted to compounds of Formula I, wherein Y is –(C(R5)2)q-R4and R4is an amide, urea, or sulfonamide by reaction with an isocyanosilane or an activated acid chloride.

[0246] Compounds of Formula I have chiral centers and may exist as stereoisomers, such as racemates, enantiomers, or diastereomers. Specifically, the compounds of Formula I exist as Formula I' and I". The absolute amount of each enantiomer depends on the particular reaction, conditions and properties of the reactants.I'I"

[0247] 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.

[0248] 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 andfractional crystallization. Salts of the present disclosure can be prepared according to methods known to those of skill in the art.

[0249] 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 base to 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.

[0250] 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.

[0251] If the compound disclosed herein 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.

[0252] 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 (iii) by converting one salt of the compound of Formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[0253] 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.

[0254] Polymorphs can be prepared according to techniques well-known to those skilled in the art.

[0255] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0256] 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).

[0257] 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 / orfractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

[0258] 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

[0259] 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 via1H-NMR and LCMS spectra summarized in Tables A-M.

[0260] The following preparations can be used to prepare intermediates that are useful in the preparation of compounds of Formula I.Scheme AExample 1: Synthesis of Intermediate A2

[0261] To a stirred solution of 1-(2-bromo-4-fluorophenyl)ethanone (100 g, 460.751 mmol, 1 eq) and tributyl(prop-2-en-1-yl)stannane (183.08 g, 552.901 mmol, 1.2 eq) in THF (100 mL) were added LiCl (39.06 g, 921.502 mmol, 2 eq) and Pd(PPh3)4(53.24 g, 46.075 mmol, 0.1 eq) LQ^SRUWLRQV^DW^^^^XQGHU^12atmosphere. The resulting mixture was stirred for additional 12 KRXUV^DW^^^^^^^7KH^UHVXOWLQJ^PL[WXUH^ZDV^FRQFHQWUDWHG^XQGHU^UHGXFHG^SUHVVXUH^^7KH^UHVLGXH^ZDV^ purified by silica gel column chromatography, eluted with EA:PE (5%:95%) to afford 1-[4-fluoro- 2-(prop-2-en-1-yl)phenyl]ethanone (73 g, 82.06%) as a yellow solid.Example 2: Synthesis of Intermediate A3

[0262] A solution of 1-[4-fluoro-2-(prop-2-en-1-yl)phenyl]ethanone (73 g, 409.638 mmol, 1 eq) in DCE (2000 mL) was treated with ethyl acrylate (205.06 g, 2048.190 mmol, 5 eq) mixture was stirred for additional 3 hours at room temperature. The resulting mixture was filtered through a pad of silica gel and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA:PE (5%:95%) to afford ethyl (2E)-4-(2-acetyl-5-fluorophenyl)but-2-enoate (41 g, 39.99%) as dark green oil. LC-MS-5 (ES, m / z): LCMS (ESI) [M + H]+: 251.08 Example 3: Synthesis of Intermediate A4

[0263] To a stirred solution of ethyl (2E)-4-(2-acetyl-5-fluorophenyl)but-2-enoate (41 g, 163.824 mmol, 1 eq) in THF (1000 mL) was added LiHMDS (196.6 mL, 196.589 mmol, 1.2 eq, 1.0 M in THF) The resulting mixture was stirred for additional 0.5 hours at room temperature. The reaction was quenched with the addition of EtOH (15 mL) followed by sat. NH4Cl (100 mL). The resulting mixture was extracted with EA (3 x 500 ml). The combined organic layers were washed with H2O (1x500 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 EA:PE (5%:95%) to afford ethyl 2-(7-fluoro-4-oxo-2,3-dihydro-1H-naphthalen-2-yl)acetate (12 g, 29.27%) as a yellow oil. LC-MS- 6(ES, m / z): LCMS (ESI) [M + H]+: 251.07 Example 4: Synthesis of Intermediate A5

[0264] A solution of ethyl 2-(7-fluoro-4-oxo-2,3-dihydro-1H-naphthalen-2-yl)acetate (11 g, 43.953 mmol, 1 eq) and (2,4-difluorophenyl)hydrazine (11.40 g, 79.115 mmol, 1.8 eq) in (WKDQRO^^^^^^P / ^^ZDV^VWLUUHG^IRU^^^KRXUV^DW^^^^^^XQGHU^D^QLWURJHQ^DWPRVSKHUH^^7KH^UHVXOWLQJ^ mixture was concentrated under reduced pressure. To the above mixture was added zinc chloride (12 g, 2 eq), AcOH (200 mL) LQ^SRUWLRQV^RYHU^^^^^KRXU^DW^^^^^^7KH^Uesulting mixture was stirred IRU^DGGLWLRQDO^^^^^K^DW^^^^^^^7KH^UHVXOWLQJ^PL[WXUH^ZDV^FRQFHQWUDWHG^XQGHU^UHGXFHG^SUHVVXUH^^7KH^ residue was purified by silica gel column chromatography, eluted with EA:PE (5%:95%) to afford ethyl 2-{3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl}acetate (11 g, 69.65%) as an orange solid. LC-MS-8 (ES, m / z): LCMS (ESI) [M + H]+: 360.12 Example 5: Synthesis of Compound 1

[0265] A solution of ethyl 2-{3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6- yl}acetate (8100 mg, 22.541 mmol, 1 eq) and LiOH (2699.3 mg, 112.705 mmol, 5 eq) in H2O (30 P / ^^DQG^0H2+^ ^^^^P / ^^ZDV^ VWLUUHG^ IRU^^^^KRXUV^ DW^ ^^^^^XQGHU^ D^QLWURJHQ^DWPRVSKHUH^^7KH^ mixture was acidified to pH 7 with HCl. The resulting mixture was extracted with ethyl acetate(EA) (3 x 500 ml). The combined organic layers were washed with H2O (1x500 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, H2O in ACN, 10% to 90% gradient in 60 min; detector, UV 254 nm. This resulted in racemic 2-(3,8,10-trifluoro-6,11-dihydro-5H-benzo[a]carbazol-6- yl)acetic acid (7.2 g, 88%) as a light pink solid. LC-MS-1 (ES, m / z): LCMS (ESI) [M - H]-: 330.05 Example 6: Synthesis of Compounds 2 and 3

[0266] The product (7200 mg) was purified by Prep-SFC with the following conditions : Column: CHIRALPAK AD-+^^^^^^^FP^^^^^P^^0RELOH^3KDVH^$^^&22, Mobile Phase B: IPA(0.1% 2M NH3-MeOH); Flow rate: 200 mL / min; Gradient: isocratic 20% B; Column 7HPSHUDWXUH^^^^^ ^^^^ %DFN^ 3UHVVXUH^EDU^^^ ^^^^^ :DYH^ / HQJWK^^ ^^^^ QP^^ 57^^PLQ^^ ^^^^^ DV^ enantiomer 2 ("*" suggested absolute stereochemistry); RT2(min) 9.74 as enantiomer 3 ("*" suggested absolute stereochemistry); Sample Solvent: MeOH: ACN: DCM=1:2:1 (2mM NH3- MeOH); Injection Volume: 3 mL; Number Of Runs: 52. This resulted in 2: [(6S*)-3,8,10-trifluoro- 5H,6H,11H-benzo[a]carbazol-6-yl] acetic acid (3.3 g, 42.83%) as a light yellow solid and 3: [(6R*)-3,8,10-trifluoro- 5H,6H,11H-benzo[a]carbazol-6-yl]acetic acid (3.4 g, 45.20%) as a light pink solid.

[0267] Compound 2: LC-MS-2 (ES, m / z): LCMS (ESI) [M - H]-: 330.05;1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^^V^^^+^^^^^^^^^GG^^J = 8.5, 5.7 Hz, 1H), 7.26 – 7.11 (m, 3H), 7.06-6.96 (m, J = 11.7, 9.7, 2.2 Hz, 1H), 3.72-3.61 (m, J = 7.1, 2.9 Hz,1H), 3.19 (dd, J = 15.9, 6.8 Hz, 1H), 2.98 (dd, J = 16.1, 3.0 Hz, 1H), 2.39 – 2.22 (m, 2H).

[0268] Compound 3: LC-MS-3 (ES, m / z): LCMS (ESI) [M - H]-: 330.05;1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^^V^^^+^^^^^^^^^GG^^J = 8.5, 5.7 Hz, 1H), 7.26 – 7.11 (m, 3H), 6.96 (ddd, J = 11.7, 9.7, 2.2 Hz, 1H), 3.61 (qd, J = 7.1, 2.9 Hz, 1H), 3.19 (dd, J = 15.9, 6.8 Hz, 1H), 2.98 (dd, J = 16.1, 3.0 Hz, 1H), 2.39 – 2.22 (m, 2H).Scheme BExample 7: Synthesis of Compound 4

[0269] In 8 mL tube, [(6S)-3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazole-6-yl]acetic acid (50 mg, 0.151 mmol, 1 eq), (1-aminocyclobutyl)methanol hydrochloride (24.9 mg, 0.181 mmol, 1.2 eq), TCFH (63.5 mg, 0.226 mmol, 1.5 eq) and 1-methyl-1H-imidazole (37.2 mg, 0.453 mmol, 3 eq) were added in DMSO (2 mL). The resulting mixture was stirred for 2 h at room temperature. 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 60%gradient in 20 min; detector, UV 254 nm. This resulted in N-[1-(hydroxymethyl)cyclobutyl]-2- [(6S*)-3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl]acetamide (6.0 mg, 9.6%("*" suggested absolute stereochemistry)) as a white solid.

[0270] LCMS (ESI) [M + H]+: 415.05;1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^ 1H), 7.90 – 7.82 (m, 1H), 7.72 (s, 1H), 7.25 – 7.12 (m, 3H), 6.94 (t, J = 10.3 Hz, 1H), 4.75 (t, J = 5.7 Hz, 1H), 3.59 (m, 2H), 3.50 – 3.40 (m, 1H), 3.13 (d, J = 6.9 Hz, 1H), 2.94 (d, J = 15.9 Hz, 1H), 2.23 (dd, J = 13.7, 6.7 Hz, 1H), 2.11 – 2.03 (m, 1H), 1.97 (t, J = 7.7 Hz, 4H), 1.65 (dd, J = 17.7, 7.8 Hz, 2H).

[0271] This chemistry was used to generate amide Compounds 5-19. Example 8: Synthesis of Compound 20

[0272] In 20 mL tube, [(6S)-3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl]acetic acid (600 mg, 1.811 mmol, 1 eq) and borane-THF (466.9 mg, 5.433 mmol, 3 eq) were added in tetrahydrofuran (5 mL) at 0 °C. The resulting mixture was stirred for 1 hour at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with deionized water (1x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-[(6S)-3,8,10-trifluoro-5H,6H,11H- benzo[a] carbazol-6-yl]ethanol (400 mg, 69.60%) as a white solid.

[0273] LCMS (ESI) [M - H]-: 316.10;1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^ 7.84 (dd, J = 8.5, 5.7 Hz, 1H), 7.21 (d, J = 9.6 Hz, 2H), 7.18 – 7.10 (m, 1H), 7.00 – 6.90 (m, 1H), 4.47 (t, J = 5.0 Hz, 1H), 3.31 (m, 3H), 3.16 (dd, J = 15.7, 6.9 Hz, 1H), 2.99 – 2.90 (m, 1H), 1.53 (dtt, J = 19.8, 13.1, 5.8 Hz, 2H).Example 9: Synthesis of B1

[0274] In 20 mL tube, 2-[(6S)-3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6- yl]ethanol (300 mg, 0.945 mmol, 1 eq), 4-nitrophenyl carbonochloridate (0.23 g, 1.134 mmol, 1.2 eq) and Pyridine (0.15 g, 1.890 mmol, 2 eq) were added in DCM (5 mL). The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4- nitrophenyl 2-[(6S)-3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl]ethyl carbonate (300 mg, 65.78%) as a brown oil. LCMS (ESI) [M + H]+: 483.11 Example 10: Synthesis of Compound 23

[0275] In 8 mL tube, 4-nitrophenyl 2-[(6S)-3,8,10-trifluoro-5H,6H,11H- benzo[a]carbazol-6-yl]ethyl carbonate (50 mg, 0.104 mmol, 1 equiv) , 2-aminopropane-1,3-diol (11.3 mg, 0.125 mmol, 1.2 equiv) and Pyridine (16.4 mg, 0.208 mmol, 2 equiv) were added in DMF (2 mL). The resulting mixture was stirred for 3 h at 80 °C. 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 55% gradient in 10 min; detector, UV 254 nm. This resulted in 2-[(6S)-3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl]ethyl N- (1,3- dihydroxypropan-2-yl)carbamate (26.1 mg, 57.7%) as a white solid.

[0276] LCMS (ESI) [M + H]+: 435.10;1H NMR (300 MHz, DMSO-d6^^į^^^^^^^^V^^ 1H), 7.86 (dd, J = 8.5, 5.7 Hz, 1H), 7.35 – 7.08 (m, 3H), 7.05 – 6.90 (m, 1H), 6.80 (d, J = 6.3 Hz, 1H), 4.59 (s, 2H), 3.92 – 3.80 (m, 2H), 3.40 (s, 4H), 3.34 – 3.26 (m, 2H), 3.18 (dd, J = 15.8, 6.7 Hz, 1H), 3.00 (dd, J = 15.9, 2.4 Hz, 1H), 1.65 – 1.50 (m, 2H).

[0277] Carbamate Compounds 23A-33 were made using the above method. Scheme CExample 11: Synthesis of C2

[0278] To a stirred solution of dimethyl succinate (5 g, 34.213 mmol, 1 eq) and benzaldehyde, 3-fluoro- (3.40 g, 27.370 mmol, 0.8 equiv.) in t-BuOH (180 ml) was added a t- BuOK (3.46 g, 30.792 mmol, 0.9 eq) solution in t-BuOH (70 mL) dropwise at 80 °C under nitrogen atmosphere. The resulting mixture was stirred for 5 h at 80 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). 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 (4:1) to afford 1,4-dimethyl (2Z)-2-[(3-fluorophenyl)methylidene]butanedioate (2.5 g, 28.97%) as a colorless oil. Example 12: Synthesis of C3

[0279] To a stirred solution of 1,4-dimethyl (2Z)-2-[(3- fluorophenyl)methylidene]butanedioate (2.5 g, 9.911 mmol, 1 eq) in MeOH / H2O (40 mL, v / v= 3 / 1) was added NaOH (0.79 g, 19.822 mmol, 2 eq) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The mixture was concentrated under reduced pressure. Additional water was added and the mixture was adjusted to pH= 4 with diluted HCl aqueous solution. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were 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 (0.1% FA), 0% to 20% gradient in 15 min; detector, UV 220 nm. This resulted in(Z)-2-(3-fluorobenzylidene)succinic acid (1.2 g, 54.01%) as colorless oil. MS (ESIpos): m / z = 223.05 [M-H]-. Example 13: Synthesis of C4

[0280] To a solution of (2Z)-2-[(3-fluorophenyl)methylidene]butanedioic acid (1.2 g, 5.353 mmol, 1 eq) in EtOH (30 ml) was added Pd / C (2.85 g, 26.765 mmol, 5 equiv.) at room temperature under N2atmosphere. After the addition, the N2atmosphere was replaced by hydrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. After completion of the reaction, the mixture was filtered, the filter cake was washed with EtOH (3x20 mL). 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 (0.1% FA), 0% to 20% gradient in 20 min; detector, UV 220 nm. This resulted in 2-(3-fluorobenzyl) succinic acid (700 mg, 57.81%) as a colorless oil. MS (ESIpos): m / z =225.05 [M-H]-. Example 14: Synthesis of C5

[0281] A solution of 2-(3-fluorobenzyl)succinic acid (700 mg, 3.095 mmol, 1 eq) in concentrated H2SO4(18 mL) was stirred for 2 hours at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with ice water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combinedorganic layers were 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 (0.1% FA), 0% to 10% gradient in 20 min; detector, UV 220 nm. This resulted in 7-fluoro-4-oxo-1,2,3,4- tetrahydronaphthalene-2-carboxylic acid (200 mg, 31.04%) as a red solid. MS (ESIpos): m / z =207.05 [M-H]-. Example 15: Synthesis of C6

[0282] To a stirred solution of 7-fluoro-4-oxo-1,2,3,4-tetrahydronaphthalene-2- carboxylic acid (200 mg, 0.961 mmol, 1 eq.) in solution of DCM / MeOH (10 ml, v / v= 1 / 1) was added TMSCHN2(380 μL, 2.5 M in DCM, 1 eq.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (2x20 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 (3:1) to afford methyl 7-fluoro-4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (80 mg, 37.48%) as a red solid. Example 16: Synthesis of Compound 34

[0283] A solution of methyl 7-fluoro-4-oxo-1,2,3,4-tetrahydronaphthalene-2- carboxylate (50 mg, 0.225 mmol, 1 eq) and (2,4-difluorophenyl)hydrazine hydrochloride (40 mg, 0.225 mmol, 1 eq) in EtOH (5 ml) was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was dissolved with HOAc (3 mL), and then ZnCl2(0.8 mL, 0.7M in THF, 2.5 equiv.) was added. The resulting mixture was stirred for 2 h at 95 °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), 60% to 70% gradient in 15 min; detector, UV 220 nm. This resulted in methyl 3,8,10-trifluoro-6,11-dihydro-5H-benzo[a]carbazole-6-carboxylate (4.6 mg, 6.17%) as a white solid.1H NMR (400 MHz, CDCl3) į 8.47 (s, 1H), 7.29 – 7.35 (m, 1H), 7.07 – 7.00 (m, 2H), 6.97 – 6.92 (m, 1H), 6.73 – 6.65 (m, 1H), 4.10 – 4.05 (m, 1H), 3.65 (s, 3H), 3.47 – 3.42 (m, 1H), 3.29 – 3.25 (m, 1H) MS (ESIpos): m / z =332.05 [M+H]+. Example 17: Synthesis of Compound 35

[0284] To a stirred solution of methyl 3,8,10-trifluoro-6,11-dihydro-5H- benzo[a]carbazole-6-carboxylate (60 mg, 0.181 mmol, 1 eq) in THF (3 ml) was added NaBH4(13.70 mg, 0.362 mmol, 2 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 by the addition of sat. NH4Cl (aq.) (0.5 mL) at 0 °C. 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 15 min; detector, UV 220 nm. This resulted in {3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl}methanol (10.8 mg, 19.66%) as a white solid.

[0285] 1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^GG^^J = 8.5, 5.7 Hz, 1H), 7.21 – 7.09 (m, 3H), 6.95 (ddd, J = 11.9, 9.8, 2.2 Hz, 1H), 4.85 – 4.77 (m, 1H), 3.47 – 3.40 (m, 1H), 3.23 – 3.12 (m, 3H), 3.10 – 3.03 (m, 1H). MS (ESIpos): m / z =302.15 [M-H]–.Example 18: Synthesis of C7

[0286] To a stirred solution of methyl 3,8,10-trifluoro-6,11-dihydro-5H- benzo[a]carbazole-6-carboxylate (60 mg, 0.181 mmol, 1 eq) in MeOH / H2O (2 mL, v / v= 3 / 1) was added NaOH (14.49 mg, 0.362 mmol, 2 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The mixture was concentrated under reduced pressure. Additional water was added and the mixture was adjusted to pH= 4 with diluted HCl aqueous solution. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers 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 (0.1% FA), 0% to 10% gradient in 15 min; detector, UV 220 nm. This resulted in 3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazole-6-carboxylic acid (40 mg, 69.61%) as a white solid. MS (ESIpos): m / z =316.07 [M-H]–. Example 19: Synthesis of Compound 36

[0287] To a stirred solution of 3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazole-6- carboxylic acid (35 mg, 0.110 mmol, 1 equiv.), (3S)-3-aminopyrrolidin-2-one (5.52 mg, 0.055 mmol, 0.5 equiv.) and TCFH (30.95 mg, 0.110 mmol, 1 equiv.) in MeCN was added NMI (22.64 mg, 0.275 mmol, 2.5 equiv.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixturewas stirred for 1 h 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), 40% to 70% gradient in 20 min; detector, UV 220 nm. This resulted in 3,8,10-trifluoro-N-((S)-2-oxopyrrolidin-3-yl)-6,11-dihydro-5H- benzo[a]carbazole-6-carboxamide (6.3 mg, 15.34%) as a white solid.

[0288] 1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^ – 8.53 (m, 1H), 7.98 – 7.83 (m, 2H), 7.49 (dd, J = 9.9, 2.3 Hz, 1H), 7.18 (dd, J = 27.2, 8.8 Hz, 2H), 7.00 – 6.88 (m, 1H), 4.49 – 4.44 (m, 1H), 4.00 – 3.94 (m, 1H), 3.26 – 3.02 (m, 4H), 2.35 (d, J = 4.3 Hz, 1H), 1.84 (t, J = 11.3 Hz, 1H). MS (ESIpos): m / z =400.00 [M+H]+. Scheme DExample 20: Synthesis of D1

[0289] In 20 mL tube, 2-{3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl}ethanol (780 mg, 2.458 mmol, 1 eq) and TEA (746.2 mg, 7.374 mmol, 3 eq) in DCM (5 mL) was added Ms2O (642.3 mg, 3.687 mmol, 1.5 eq). The resulting mixture was stirred for 1 h at room temperature. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 2-{3,8,10- trifluoro-5H,6H,11H -benzo[a]carbazol-6-yl}ethyl methanesulfonate (356 mg, 36.6%) as brown solid. LCMS (ESI) [M + H]+: 396.08 Example 21: Synthesis of D2

[0290] In 20 mL tube, 2-{3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl}ethyl methanesulfonate (350 mg, 0.885 mmol, 1 equiv) in DMF (5 mL) was added NaCN (127 mg, 2.6 mmol, 3 equiv). The resulting mixture was stirred for 1 h at 50 °C. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-{3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl} propanenitrile (150 mg, 51.9%) as a brown solid.LCMS (ESI) [M + H]+: 327.10 Example 22: Synthesis of Compound 37

[0291] In 8 ml tube, 3-{3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6- yl}propanenitrile (50 mg, 0.153 mmol, 1 equiv) in the mixed solvents of MeOH (1 mL) and H2O (1 mL) was added NaOH (30.6 mg, 0.765 mmol, 5 equiv). The mixture was stirred at 60 °C for 16h. 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 15 min; detector, UV 254 nm. This resulted in 3-{3,8,10-trifluoro-5H,6H,11H-benzo [a] carbazol-6-yl}propanoic acid (15.4 mg, 28.7%) as a white solid.

[0292] LCMS (ESI) [M + H]+: 345.95.1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^ 1H), 7.82 (dd, J = 8.5, 5.6 Hz, 1H), 7.20 – 7.10 (m, 3H), 6.92 (t, J = 10.4 Hz, 1H), 3.19 – 3.05 (m, 2H), 2.94 (d, J = 15.2 Hz, 1H), 2.15 – 2.06 (m, 1H), 2.00 – 1.92 (m, 1H), 1.66 – 1.48 (m, 2H).

[0293] Amide 39 was generated by methods used to generate compound 36. Example 23: Synthesis of D3

[0294] In an 8 ml tube, 3-{3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6- yl}propanoic acid (50 mg, 0.145 mmol, 1 eq) and oxolane borane (1.5 mL, 1 M in THF) were added in THF (1 mL). The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with water at 0 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 30% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in 3- {3,8,10-trifluoro- 5H,6H,11H-benzo[a]carbazol- 6-yl}propan-1-ol (7.4 mg, 15.0%) as a yellow solid.

[0295] LCMS (ESI) [M + H]+: 332.00.1H NMR (400 MHz, DMSO-d6) į^^^^^^^^V^^ 1H), 7.84 (dd, J = 8.5, 5.7 Hz, 1H), 7.25 – 7.15 (m, 3H), 7.00 – 6.90 (m, 1H), 4.40 – 4.30 (m, 1H), 3.40 – 3.25 (m, 2H), 3.18 – 3.11 (m, 2H), 3.00 – 2.90 (m, 1H), 1.60 – 1.24 (m, 4H).Example 24: Chiral Separation of Compounds 39 and 40

[0296] The product (D3 20 mg) was purified by Chiral HPLC with the following FRQGLWLRQV^^ &ROXPQ^^ &+,5$ / 3$.^ ,*^^ ^^^^^ FP^^ ^^ ^P^^0RELOH^ 3KDVH^ $^^ +H[^^^^P0^1+3- MeOH), Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 6 min; Wave Length: 244 / 203 nm; RT1(min): 2.8225 as 39; RT2(min) ("*" suggested absolute stereochemistry): 4.01 as 40; Sample Solvent: EtOH--HPLC; Injection Volume: 0.4 mL; Number Of Runs: 2. This resulted in 39: 3-[(6S*)-3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6- yl]propan-1-ol (5.0 mg, 10.4% ("*" suggested absolute stereochemistry)) as a white solid and 40: 3-[(6R*)-3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl]propan-1-ol (4.9 mg, 10.18% ("*" suggested absolute stereochemistry)) as a white solid.

[0297] Compound 39: LCMS (ESI) [M + H]+: 332.10.1H NMR (400 MHz, DMSO- d6) į^^^^^^^^V^^^+^^^^^^^ – 7.80 (m, 1H), 7.25 – 7.10 (m, 3H), 7.00 – 6.85 (m, 1H), 4.35 – 4.25 (m, 1H), 3.32 – 3.29 (m, 2H), 3.20 – 3.10 (m, 2H), 3.00 – 2.90 (m, 1H), 1.62 – 1.28 (m, 4H).

[0298] Compound 40: LCMS (ESI) [M + H]+: 332.10.1H NMR (400 MHz, DMSO- d6) į^^^^^^^^V^^^+^^^^^^^^^GG, J = 8.4, 5.4 Hz, 1H), 7.25 – 7.09 (m, 3H), 7.00 – 6.90 (m, 1H), 4.36 (t, J = 5.1 Hz, 1H), 3.30 (d, J = 5.8 Hz, 2H), 3.20 – 3.12 (m, 2H), 3.00 – 2.91 (m, 1H), 1.60 – 1.23 (m, 4H).

[0299] The compounds in Table A were prepared according to the methods described herein in Examples 1-24. Table Aį^^^^^^^^V^^^+^^^^^^^^^GG^^-^ ^^^^^ 5.7 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 9.5, 2.6 Hz, 3H), 7.04 - 6.95 (m, 1H), 4.61 (t, 12 389.25 [M+H]+J = 5.6 Hz, 1H), 3.81 - 3.71 (m, 1H), 3.68 - 3.60 (m, 1H), 3.32 - 3.25 (m, 1H), 3.20 - 3.10 (m, 2H), 2.94 (dd, J = 16.0, 2.5 Hz, 1H), 222 215 (m 1H) 210 202 į ( 1H), 7.23 - 7.11 (m, 4H), 7.00 - 6.90 (m, 1H), 4.80 (t, J = 6.0 Hz, 1H), 3.65 - 3.55 (m , 1H), 3.38 - 14 403.05 [M+H]+3.36 (m, 1H), 3.24 (dd, J = 10.7, 5.8 Hz, 1H), 3.15 (dd, J = 15.9, 7.0 Hz, 1H), 2.92 (dd, J = 16.0, 2.6 Hz, 1H), 2.24 (dd, J = 13.8, 7.3 Hz, 1H), 2.07 (dd, J = 13.8,1H-NMR 1H NMR (400 MHz, DMSO-d6) į^^^^^^^ ^^^ ^ ^^^^^^^^ 82 (Scheme EExample 25: Synthesis of Intermediate E2

[0300] A solution of 1-(4-fluoro-2-hydroxyphenyl)ethanone (100 g, 648.761 mmol, 1 equiv) and (2,4-difluoro phenyl) hydrazine (140.25 g, 973.141 mmol, 1.5 equiv) in 1000 mL of EtOH was stirred for 16 h at 80 °C under nitrogen 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 (5:1) to afford 2-[(1E)-1-[2- (2,4-difluorophenyl)hydrazin-1-ylidene]ethyl]-5-fluorophenol (125 g, 68.75%) as a yellow solid. (ES, m / z): LCMS (ESI) [M + H]+: 281.0. Example 26: Synthesis of Intermediate E3

[0301] A solution of 2-[(1E)-1-[2-(2,4-difluorophenyl)hydrazin-1-ylidene]ethyl]-5- fluorophenol (125 g, 3.568 mmol, 1 equiv) in 400 mL of Polyphosphoric acid was stirred for 6 h at 120 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with EtOAc (2000 mL). The resulting mixture was adjusted to pH = 7.0 with saturated NaOH aq. solution. The resulting mixture was extracted with EtOAc (1000 mL) for 3 times. The combined organic layers was 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 (4:1) to afford 2-(5,7-difluoro-1H-indol-2-yl)-5- fluorophenol (12.5 g, 10.65%) as a brown solid. (ES, m / z): LCMS (ESI) [M + H]+: 264.0.Example 27: Synthesis of Intermediate E4

[0302] A solution of 2-(5,7-difluoro-1H-indol-2-yl)-5-fluorophenol (100 mg, 0.380 mmol, 1.0 eq) in 1,4-dioxane was treated with 2-[(tert-butyldimethylsilyl)oxy]acetaldehyde (100 mg, 0.574 mmol, 1.5 eq) for 2 h at 140 °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 (10 mmol / L NH4HCO3), 50% to 100% gradient in 15 min; detector, UV 254 nm. This resulted in 6-{[(tert-butyldimethylsilyl)oxy]methyl}-3,8,10-trifluoro-6H,11H- chromeno[4,3-b]indole (80 mg, 50.19%) as a yellow liquid. LCMS (ESI) [M - H]+: 418.10 Example 28: Synthesis of Intermediate E5

[0303] A solution of 6-{[(tert-butyldimethylsilyl)oxy]methyl}-3,8,10-trifluoro- 6H,11H-chromeno[4,3-b]indole (150 mg, 0.358 mmol, 1 equiv) and TBAF (186.97 mg, 0.716 mmol, 2 equiv) in 2 mL of THF was stirred for 2 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (NH4HCO3system) to afford {3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6-yl}methanol (42 mg, 38.43%) as a white solid. LCMS (ESI) [M - H]+: 304.15;1H NMR (300 MHz, DMSO-d6^^į^ 12.18 (s, 1H), 7.78 (m, 1H), 7.19 (m, 1H), 7.06 – 6.95 (m, 1H), 6.90 – 6.75 (m, 2H), 5.79 (m, 1H), 5.05 (s, 1H), 3.77 – 3.65 (m, 2H).Example 29: Resolution to Generate Compounds 41 and 42

[0304] Compound E5 (42 mg) was purified by Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-6$^^^^^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^P0^ NH3-MeOH), Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 10% B to 10% B in 13.5 min; Wave Length: 212 / 240 nm; RT1(min) 7.99 as 41; RT2(min) 10.195 as 42: Sample Solvent: EtOH--HPLC; Injection Volume: 0.45 mL; Number Of Runs: 5). This resulted in 41: [(6S*)-3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6-yl] methanol (15.0 mg, 35.71% ("*" suggested absolute stereochemistry)) as a white solid and 42: [(6R*)-3,8,10-trifluoro-6H,11H- chromeno[4,3-b]indol-6-yl]methanol (13.5 mg, 32.14% ("*" suggested absolute stereochemistry)) as a white solid.

[0305] Compound 41: (ES, m / z): LCMS (ESI) [M - H]–: 303.95;1H NMR (300 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^GG^^J = 8.4, 6.6 Hz, 1H), 7.20 (dd, J = 9.6, 2.2 Hz, 1H), 7.04 – 7.01 (m, 1H), 6.89 – 6.77 (m, 2H), 5.79 (t, J = 4.6 Hz, 1H), 5.03 (t, J = 5.7 Hz, 1H), 3.79 – 3.73 (m, 2H).

[0306] Compound 42: (ES, m / z): LCMS (ESI) [M - H]–: 303.95;1H NMR (300 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^GG^^J = 8.4, 6.5 Hz, 1H), 7.19 (dd, J = 9.6, 2.2 Hz, 1H), 7.08 – 6.95 (m, 1H), 6.90 – 6.78 (m, 2H), 5.79 (t, J = 4.6 Hz, 1H), 5.03 (t, J = 5.7 Hz, 1H), 3.79 – 3.75 (m, 2H).

[0307] Table B describes compounds prepared according to the methods described herein in Examples 25-29. Synthesis of Compounds 43-46 were carried out similarly to Compounds 41 and 42.Table BScheme FExample 30: Synthesis of F2

[0308] A solution of 2-{3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6-yl}ethyl methanesulfonate (200 mg, 0.503 mmol, 1 equiv) and NH3(25.7 mg, 1.509 mmol, 3 equiv) in 2 mL of MeOH was stirred for 3 h at 80 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with the following conditions (0.1% formic acid system) to afford 2-{3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6- yl}ethanamine; formic acid salt (45 mg, 28.1%) as a light yellow semi-solid.

[0309] Compound F2: LCMS (ESI) [M + H]+: 319.10;1H NMR (300 MHz, DMSO- d6^^į^^^^^^– 8.50 (m, 1H), 7.82 (dd, J = 9.2, 6.4 Hz, 1H), 7.25 (d, J = 9.4 Hz, 1H), 7.02 (t, J = 10.5 Hz, 1H), 6.89 (dd, J = 9.6, 5.9 Hz, 2H), 5.95 (t, J = 5.7 Hz, 1H), 3.03 – 2.93 (m, 2H), 2.27 – 2.19 (m, 2H) Example 31: Synthesis of Compounds 47 and 48

[0310] Compound F2 (20 mg) was further purified by Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-&^1(2^^^^^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^ mM NH3-MeOH), Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 12.7 min; Wave Length: 212 / 240 nm; RT1(min) : 5 as compound 47 RT2(min) : 8.6 as compound 48; Sample Solvent: EtOH: MeOH=1: 2 -HPLC; Injection Volume: 0.6 mL; Number Of Runs: 4). This resulted in Compound 47: 2-[(6R*)-3,8,10-trifluoro-6H,11H-chromeno[4,3- b]indol-6-yl]ethanamine (4.8 mg, 2.93% ("*" suggested absolute stereochemistry)) as an off-white solid and Compound 48: 2-[(6S*)-3,8,10-trifluoro-6H,11H-chromeno [4,3-b]indol-6- yl]ethanamine (5.3 mg, 3.26% ("*" suggested absolute stereochemistry)) as an off-white solid.

[0311] Compound 47: LC-MS-53 (ES, m / z): LCMS (ESI) [M - H]-: 317.00;1H NMR (400 MHz, DMSO-d6^^į^^^^^^– 7.75 (m, 1H), 7.21 (d, J = 9.3 Hz, 1H), 7.02 (t, J = 10.5 Hz, 1H), 6.89 – 6.86 (m, 2H), 5.94 (dd, J = 7.8, 4.6 Hz, 1H), 2.72 – 2.71(m, 2H), 2.00 – 1.95 (m, 2H).

[0312] Compound 48: LC-MS-54 (ES, m / z): LCMS (ESI) [M - H]-: 317.00;1H NMR (400 MHz, DMSO-d6^^į^^^^^^– 7.74 (m, 1H), 7.21 (d, J = 9.3 Hz, 1H), 7.02 (t, J = 10.5 Hz, 1H), 6.91 – 6.80 (m, 2H), 5.94 (dd, J = 7.8, 4.6 Hz, 1H), 2.72 – 2.70 (m, 2H), 1.98 – 1.95 (m, 2H).Example 32: Synthesis of Compound 49

[0313] A solution of 2-{3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6- yl}ethanamine (40 mg, 0.126 mmol, 1 equiv) and isocyanatotrimethylsilane (28.96 mg, 0.252 mmol, 2 equiv) in 1 mL of toluene was stirred for 2 h at 90 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash chromatography with the following conditions (0.1% formic acid system) to afford 2-{3,8,10-trifluoro-6H,11H-chromeno [4,3-b] indol-6-yl}ethylurea (7.6 mg, 16.02%) as an off-white solid.

[0314] LC-MS-55 (ES, m / z): LCMS (ESI) [M - H]-: 360.05;1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^– 7.77 (m, 1H), 7.20 (dd, J = 9.5, 2.2 Hz, 1H), 7.05 – 7.02 (m, 1H), 6.91 – 6.84 (m, 2H), 6.04 (t, J = 5.6 Hz, 1H), 5.85 (t, J = 6.0 Hz, 1H), 5.43 (s, 2H), 3.15 (dd, J = 9.3, 4.4 Hz, 2H), 2.01 – 1.99 (m, 2H). Example 33: Synthesis of Compound 50

[0315] A solution of 2-{3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6- yl}ethanamine (40 mg, 0.126 mmol, 1 equiv), glycolic acid (11.47 mg, 0.151 mmol, 1.2 equiv), TCFH (42.31 mg, 0.151 mmol, 1.2 equiv) and NMI (51.59 mg, 0.630 mmol, 5 equiv) in 2 mL ofDMSO was stirred for 3 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The residue product was purified by reverse phase flash chromatography with the following conditions (0.1% formic acid system) to afford 2-hydroxy-N-(2-{3,8,10- trifluoro-6H,11H-chromeno[4,3-b]indol-6-yl}ethyl)acetamide (4.2 mg, 8.51%) as an off-white solid.

[0316] LC-MS-56 (ES, m / z): LCMS (ESI) [M + H]+: 377.10;1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^– 7.77 (m, 2H), 7.25 (dd, J = 9.6, 2.2 Hz, 1H), 7.05 – 7.02 (m, 1H), 6.91 – 6.84 (m, 2H), 5.88 (dd, J = 7.5, 4.3 Hz, 1H), 5.50 – 5.43 (m, 1H), 3.78 (d, J = 3.5 Hz, 2H), 3.42 – 3.34 (m, 2H), 2.13 – 2.04 (m, 2H).

[0317] Compounds 51 and 52 were prepared using standard methods.Example 34: Synthesis of Compound 53

[0318] A solution of 2-{3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6-yl}ethyl methanesulfonate (150 mg, 0.377 mmol, 1 equiv), 2,2-dimethyl-1,3-dioxan-5-amine (148.6 mg, 1.131 mmol, 3 equiv) and TEA (191 mg, 1.885 mmol, 5 equiv) in 3 mL of 1,4-dioxane was stirred for 8 h at 100 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The residue product was purified by reverse phase flash chromatography with the following conditions(0.1% formic acid system) to afford 2,2-dimethyl-N-(2-{3,8,10-trifluoro-6H,11H-chromeno[4,3- b]indol-6-yl}ethyl)-1,3- dioxan-5-amine (80 mg, 51.14%) as a yellow solid. (ES, m / z): LCMS (ESI) [M + H]+:433.0.

[0319] A solution of 2,2-dimethyl-N-(2-{3,8,10-trifluoro-6H,11H-chromeno[4,3- b]indol-6-yl}ethyl)-1,3- dioxan-5-amine (80 mg, 0.185 mmol, 1 equiv) and 4-methylbenzene-1- sulfonic acid hydrate (70.38 mg, 0.370 mmol, 2 equiv) in 2 mL of MeOH was stirred for 3 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with the following conditions (0.1% formic acid system) to afford Compound 53: 2-[(2-{3,8,10-trifluoro-6H,11H-chromeno [4,3-b] indol-6- yl}ethyl)amino]propane-1,3-diol (14.7 mg, 20.12%) as a white solid.

[0320] (ES, m / z): LCMS (ESI) [M + H]+: 393.15;1H NMR (300 MHz, DMSO-d6^^į^ 12.19 (s, 1H), 7.79 (dd, J = 8.4, 6.6 Hz, 1H), 7.22 (dd, J = 9.5, 2.3 Hz, 1H), 7.06 – 6.96 (m, 1H), 6.91 – 6.81 (m, 2H), 5.93 (t, J = 6.1 Hz, 1H), 4.48 – 4.35 (m, 2H), 3.45 – 3.25 (m, 4H), 2.80 – 2.73 (m, 2H), 2.50 – 2.47 (m, 1H), 2.03 – 1.95 (m, 2H).

[0321] Compounds 54-55 were prepared from mesylate F1 using chemistry described above.Scheme G

[0322] Compounds 56 and 57 were prepared from alcohol G3 using the chemistry described in Scheme F. Example 35: Synthesis of G4

[0323] To a stirred solutionof 1-{3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6- yl}methanamine (50 mg, 0.164 mmol, 1 equiv) and pyroglutamic acid (31.83 mg, 0.246 mmol, 1.5 equiv) in ACN (2 mL) was added TCFH (69.16 mg, 0.246 mmol, 1.5 equiv), NMI (26.98 mg, 0.328 mmol, 2 equiv) in portions at 0oC. The resulting mixture was stirred for additional 2 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, 10% to 90% gradient in 40 min; detector, UV 254 nm. This resulted in (2S)-5-oxo-N-({3,8,10-trifluoro-6H,11H- chromeno[4,3-b]indol-6-yl}methyl)pyrrolidine-2-carboxamide (30 mg, 43.95%) as a white solid. LC-MS-G2 (ES, m / z): LCMS (ESI) [M-H]–: 414.05. Example 36: Synthesis of Compounds 58 and 59

[0324] The crude product (2S)-5-oxo-N-({3,8,10-trifluoro-6H,11H-chromeno[4,3- b]indol-6-yl}methyl)pyrrolidine-2-carboxamide (30 mg, 0.072 mmol, 1 equiv) was purified by Prep-Chiral-HPLC with the following conditions: Column: NB--CHIRAL ART Cellulose-SZ, 20*250 mm, 5.0 um; Mobile Phase A: Hex(10 mM NH3-MeOH), Mobile Phase B: IPA--HPLC; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 18.5 min; Wave Length: 211 / 229 nm; RT1(min) 9.5 as 66; RT2(min) 14 as 67. Sample Solvent: MeOH: DCM=1: 2; Injection Volume: 0.55 mL; Number Of Runs: 62. This resulted in 66 (2S)-5-oxo-N-{[(6S*)-3,8,10-trifluoro-6H,11H- chromeno[4,3-b]indol-6-yl]methyl}pyrrolidine-2-carboxamide (7.8 mg, 26.00% ("*" suggested absolute stereochemistry)) as a white solid and 67: (2S)-5-oxo-N-{[(6R*)-3,8,10-trifluoro- 6H,11H-chromeno[4,3-b]indol-6-yl]methyl}pyrrolidine-2-carboxamide (8.4 mg, 28.00% ("*" suggested absolute stereochemistry) ) as a white solid.

[0325] Compound 58: LC-MS-66 (ES, m / z): LCMS (ESI) [M - H]-: 414.05;1H NMR (300 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^W^^J = 6.0 Hz, 1H), 7.80 (dd, J = 8.5, 6.5 Hz, 1H), 7.74 (s, 1H), 7.14 (dd, J = 9.3, 2.2 Hz, 1H), 7.10 – 6.97 (m, 1H), 6.90 – 6.80 (m, 1H), 6.78 (dd, J = 10.4,2.6 Hz, 1H), 5.86 (t, J = 5.2 Hz, 1H), 3.99 – 3.92 (m, 1H), 3.55 – 3.49 (m, 2H), 2.21 – 1.96 (m, 3H), 1.61 – 1.50 (m, 1H).

[0326] Compound 59: LC-MS-67 (ES, m / z): LCMS (ESI) [M - H]-: 414.05;1H NMR (300 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^W^^J = 6.0 Hz, 1H), 7.85 – 7.73 (m, 2H), 7.18 (dd, J = 9.3, 2.2 Hz, 1H), 7.10 – 6.97 (m, 1H), 6.88 – 6.78 (m,1H), 6.76 (dd, J = 10.4,

[0327] Compounds in Table C were prepared according to the methods described herein in Examples 30-36. Identical methods to the above chemistry using the enantiomer of pyroglutamic acid afforded Compounds 60 and 61. Standard amine, amide and sulfonamide syntheses were used to generate Compounds 62-66. Table CScheme HExample 37: Synthesis of Intermediate H2

[0328] To a stirred solution of 3-oxetanone (5 g, 69.384 mmol, 1 equiv) in Et2O (50 mL) was added allyl magnesium bromide (78 mL) dropwise at 10 ^ under nitrogen atmosphere and the resulting mixture was stirred for 8 h. This resulted in 3-(prop-2-en-1-yl)oxetan-3-ol (3 g, 37.88%) as a yellow oil. The crude product mixture was used in the next step directly without further purification. Example 38: Synthesis of Intermediate H3

[0329] To a stirred mixture of 3-(prop-2-en-1-yl)oxetan-3-ol (2 g, 17.522 mmol, 1 equiv) and TBDPSCl (6.26 g, 22.779 mmol, 1.3 equiv) in DCM (50 ml) was added Imidazole (3.58 g, 52.566 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere and the resulting mixture was stirred for 12 h. 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 tert-butyldiphenyl{[3-(prop-2-en-1-yl)oxetan-3-yl]oxy}silane (4.5 g, 72.85%) as a yellow oil. LCMS (ESI) [M + H]+: 353Example 39: Synthesis of Intermediate H4

[0330] To a stirred mixture of tert-butyldiphenyl{[3-(prop-2-en-1-yl)oxetan-3-yl]oxy}silane (800 mg, 2.26 mmol, 1 equiv), NaIO4(728 mg, 3.4 mmol, 1.5 equiv) and lutidine(364 mg, 3.4 mmol, 1.5 equiv) in H2O (40 mL) and Dioxane (40 mL) was added K2OsO2(OH)4(142 mg, 0.46 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere and the resulting mixture was stirred for 3 h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 2:1) to afford 2-{3-[(tert-butyldiphenylsilyl)oxy]oxetan-3- yl}acetaldehyde (404 mg, 49.72%) as a yellow oil. LCMS (ESI) [M + H]+: 355 Example 40: Synthesis of Intermediate H5

[0331] A mixture of 2-(5,7-difluoro-1H-indol-2-yl)-5-fluorophenol (100 mg, 0.38 mmol, 1 equiv) and 2-{3-[(tert-butyldiphenylsilyl)oxy]oxetan-3-yl}acetaldehyde (404 mg, 1.14 mmol, 3 equiv) in Dioxane (0.8 mL) ZDV^VWLUUHG^DW^^^^^^^under nitrogen atmosphere for 3 h. The residue was purified by Prep-TLC (PE / EA = 2:1) to afford 6-({1-[(tert- butyldiphenylsilyl)oxy]cyclobutyl}methyl)-3,8,10-trifluoro-6H,11H-chromeno[4,3-b] indole (50 mg, 22.02%) as a yellow solid. LCMS (ESI) [M + H]+: 600.Example 41: Synthesis of Compound 67

[0332] A mixture of 6-({3-[(tert-butyldiphenylsilyl)oxy]oxetan-3-yl}methyl)-3,8,10- trifluoro-6H,11H-chromeno[4,3-b]indole (50 mg, 0.083 mmol, 1 equiv) and TBAF (40.3 mg, 0.250 mmol, 3.00 equiv) in Tetrahydrofuran (1 mL) was stirred at room temperature under nitrogen atmosphere for 48 h. The crude product (30 mg) was purified by Prep- HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column, 19*250 mm, ^^^P^^0REile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 56% B in 9 min, 56% B; Wave Length: 254 / 220 nm; RT1(min): 6.08) to afford 3- ({3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6-yl}methyl)oxetan-3-ol (13.4 mg, 44.05%) as a white solid.

[0333] LCMS (ESI) [M + H]+: 362.05;1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^ 1H), 7.82 (dd, J = 8.5, 6.5 Hz, 1H), 7.13 (dd, J = 9.4, 2.2 Hz, 1H), 7.06 – 6.98 (m, 1H), 6.95 – 6.87 (m, 1H), 6.83 (dd, J = 10.3, 2.5 Hz, 1H), 6.05 (dd, J = 10.0, 3.1 Hz, 1H), 5.93 (s, 1H), 4.59 (s, 2H), 4.38 (d, J = 6.3 Hz, 1H), 4.23 (d, J = 6.3 Hz, 1H), 2.38 (dd, J = 14.6, 9.9 Hz, 1H), 2.11 – 2.02 (m, 1H).

[0334] Compounds 68-75 were prepared from 2-(5,7-difluoro-1H-indol-2-yl)-5- fluorophenol and the available aldehydes as shown in the conversion of H4 to H5.

[0335] Table D describes compounds prepared according to the methods described herein in Examples 37-41. Table DScheme IExample 42: Synthesis of I2

[0336] To a solution of diethyl malonate (394.40 mg, 2.462 mmol, 1 equiv) in DMF (10 mL) was added NaH (70.91 mg, 2.954 mmol, 1.2 equiv) in portions at 0 °C. The mixture was stirred at 0oC for 0.5 h. Then 1-(2-bromoethyl)-3-fluorobenzene (500 mg, 2.462 mmol, 1 equiv) was added into the mixture. The mixture was stirred at 50 °C for 1 h. Upon completion of reaction. The white liquid was concentrated. 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 1,3-diethyl 2-[2-(3- fluorophenyl)ethyl]propanedioate (300 mg, 43.16%) as yellow oil. MS (ESIpos): m / z = 283 [M+H]+. Example 43: Synthesis of I3

[0337] To a solution of 1,3-diethyl 2-[2-(3-fluorophenyl)ethyl]propanedioate (300 mg, 1.063 mmol, 1 equiv) in THF (5 mL) was added NaH (30.60 mg, 1.276 mmol, 1.2 equiv) in portions at 0 °C. The mixture was stirred at 0oC for 0.5 h. Then tert-butyl 2-bromoacetate (207.28 mg, 1.063 mmol, 1 equiv) was added into the mixture. The mixture was stirred at 0oC for 1 h. Upon completion of reaction. The mixture was concentrated. 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-tert-butyl 1,1-diethyl 1-[2-(3-fluorophenyl)ethyl]ethane-1,1,2-tricarboxylate (400 mg, 94.95%) as yellow oil. MS (ESIpos): m / z = 397[M+H]+. Example 44: Synthesis of I4

[0338] To a solution of 2-tert-butyl 1,1-diethyl 1-[2-(3-fluorophenyl)ethyl]ethane- 1,1,2-tricarboxylate (400 mg, 1.009 mmol, 1 equiv) in DCM (4 mL) was added TFA (4 mL). The mixture was stirred at RT for 2 h. Upon completion of reaction. The mixture was concentrated. 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 3,3-bis(ethoxycarbonyl)-5-(3-fluorophenyl)pentanoic acid (200 mg, 58.24%) as yellow oil. MS (ESIpos): m / z = 341 [M+H]+. Synthesis of I5

[0339] To a solution of 3,3-bis(ethoxycarbonyl)-5-(3-fluorophenyl)pentanoic acid (200 mg, 0.588 mmol, 1 equiv) in DCM (2 mL) was added (COCl)2(111.87 mg, 0.882 mmol, 1.5 equiv) dropwise followed by the addition of DMF (8.59 mg, 0.118 mmol, 0.2 equiv) at 0 °C. The mixture was stirred at 25oC for 2 h. Then the resulting mixture was added into a solution of AlCl3(391.75 mg, 2.940 mmol, 5 equiv) in DCM (2 mL) dropwise. The mixture was stirred at 25oC for 4 h. 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 7,7-diethyl 2-fluoro-5-oxo-8,9-dihydro-6H-benzo[7]annulene-7,7- dicarboxylate (80 mg, 42.24%) as yellow oil. MS (ESIpos): m / z = 323 [M+H]+.Example 45: Synthesis of I6

[0340] To a solution of 7,7-diethyl 2-fluoro-5-oxo-8,9-dihydro-6H-benzo[7]annulene- 7,7-dicarboxylate (20 mg, 0.062 mmol, 1 equiv) in THF (1 mL), MeOH (0.25 mL) and H2O (0.25 mL) was added LiOH (7.43 mg, 0.310 mmol, 5 equiv). The mixture was stirred at RT for 2 h. Upon completion of reaction. The mixture was concentrated. 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- fluoro-5-oxo-8,9-dihydro-6H-benzo[7]annulene-7,7-dicarboxylic acid (12 mg, 72.65%) as yellow oil. MS (ESIpos): m / z = 267 [M+H]+. Example 46: Synthesis of I7

[0341] To a solution of 2-fluoro-5-oxo-8,9-dihydro-6H-benzo[7]annulene-7,7- dicarboxylic acid (100 mg, 0.376 mmol, 1 equiv) in HOAc (1 mL) was added HCl (1 mL). The mixture was stirred at 100 °C for 2 h. Upon completion of reaction. The yellow liquid was concentrated. 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-fluoro-5-oxo-6,7,8,9-tetrahydrobenzo [7]annulene-7- carboxylic acid (70 mg, 83.86%) as yellow oil. MS (ESIpos): m / z = 223 [M+H]+Example 47: Synthesis of I8

[0342] To a solution of 2-fluoro-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene-7- carboxylic acid (70 mg, 0.315 mmol, 1 equiv) in EtOH (1 mL) was added (2,4- difluorophenyl)hydrazine (54.48 mg, 0.378 mmol, 1.2 equiv). The mixture was stirred at 80 °C for 2 h. Upon completion of reaction. The yellow liquid was concentrated. Then ZnCl2(64.39 mg, 0.473 mmol, 1.5 equiv) and AcOH (1 mL) were added into the mixture. The mixture was stirredat 95 °C for 1 h. 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 ethyl 3,9,11-trifluoro- 5,6,7,12-tetrahydrobenzo[6,7]cyclohepta[1,2-b]indole-7-carboxylate (30 mg, 26.50%) as yellow oil.. MS (ESIpos): m / z = 360[M+H]+Example 48: Synthesis of Compound 76

[0343] To a solution of ethyl 3,9,11-trifluoro-5,6,7,12- tetrahydrobenzo[6,7]cyclohepta[1,2-b]indole-7-carboxylate (30 mg, 0.083 mmol, 1 equiv) in THF (1 mL) was added LiOH (10.00 mg, 0.415 mmol, 5 equiv). The mixture was stirred at 25 °C for 1 h. Upon completion of reaction. The resulting mixture was concentrated. 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 3,9,11-trifluoro-5,6,7,12-tetrahydrobenzo[6,7]cyclohepta[1,2-b]indole-7-carboxylic acid (11.2 mg, 40.33%) as a white solid.

[0344] 1H NMR (300 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^^V^^^+^^^^^^^^– 7.85 (m, 1H), 7.27 – 7.13 (m, 2H), 7.03 (d, J = 9.7 Hz, 2H), 4.14 (dd, J = 10.9, 4.7 Hz, 1H), 2.95 (dd, J = 14.1, 8.0 Hz, 1H), 2.75 (t, J = 12.1 Hz, 1H), 2.41 (s, 1H), 2.15 (s, 1H). MS (ESIpos): m / z = 329.90 [M-H]–. Example 49: Synthesis of Compound 77

[0345] To a solution of ethyl 3,9,11-trifluoro-5,6,7,12- tetrahydrobenzo[6,7]cyclohepta[1,2-b]indole-7-carboxylate (120 mg, 0.334 mmol, 1 equiv) inTHF (2 mL) was added LAH (31.68 mg, 0.835 mmol, 2.5 equiv) at 0 °C. The mixture was stirred at 25oC for 1 h. Upon completion of reaction, the reaction was quenched with water and filtered through a pad of silica gel. The filtrated 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 (3,9,11-trifluoro-5,6,7,12-tetrahydrobenzo[6,7]cyclohepta[1,2-b]indol-7-yl)methanol (14.1 mg, 13.21%) as a white solid.

[0346] 1H NMR (300 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^GG^^J = 9.5, 5.8 Hz, 1H), 7.39 – 7.12 (m, 3H), 6.98 (ddd, J = 11.6, 9.7, 2.2 Hz, 1H), 4.63 (t, J = 5.6 Hz, 1H), 3.66 (dt, J = 9.1, 4.1 Hz, 1H), 3.37 (dd, J = 7.8, 3.8 Hz, 1H), 3.26 (dt, J = 10.4, 7.0 Hz, 1H), 2.85 (dd, J = 14.1, 7.8 Hz, 1H), 2.75 – 2.61 (m, 1H), 2.29 (dt, J = 14.6, 7.5 Hz, 1H), 1.94 (dd, J = 15.2, 7.7 Hz, 1H). Scheme J

[0347] Chemistry used in Scheme D was used to generate compounds 78 and 79.

[0348] Table E describes compounds prepared according to the methods described in Examples 42-49. Table EScheme KExample 50: Synthesis of K2

[0349] To a stirred solution of (2,4-difluorophenyl)hydrazine (5 g, 34.692 mmol, 1 equiv) in acetic acid (4 mL) and EtOH (12 mL) was added 5-fluoro-2,3-dihydroinden-1-one (5.21 g, 34.692 mmol, 1 equiv), after 4 h the reaction was completed. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2,6,8-trifluoro-5H,10H-indeno[1,2-b]indole (3.5 g, 38.92%) as a yellow solid. LCMS (ESI) [M - H]-:258 Synthesis of K3

[0350] To a stirred solution of 2,6,8-trifluoro-5H,10H-indeno[1,2-b]indole (3.5 g, 13.501 mmol, 1 equiv), DIEA (5.24 g, 40.503 mmol, 3 equiv) and DMAP (0.16 g, 1.350 mmol, 0.1 equiv) in DCM (20 mL) were added di-tert-butyl dicarbonate (4.42 g, 20.252 mmol, 1.5 equiv) dropwise at room temperature under nitrogen atmosphere, The reaction was monitoredby TLC. 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 tert-butyl 2,6,8-trifluoro-10H-indeno[1,2-b]indole-5-carboxylate (2.8 g, 57.71%) as a white solid. LCMS (ESI) [M + H]+:360 Example 51: Synthesis of K4

[0351] To a stirred solution of tert-butyl 2,6,8-trifluoro-10H-indeno[1,2-b]indole-5- carboxylate (500 mg, 1.391 mmol, 1 equiv) and tert-butyl 2-bromoacetate (325.7 mg, 1.669 mmol, 1.2 equiv) in THF (5 mL) was added 1 M LiHMDS in THF (2.09 ml, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere over 15 min. The resulting mixture was stirred for 2 h at 0 °C under N2atmosphere. The reaction was quenched by the addition of Water (50 mL) at room temperature. The residue was purified by Prep-TLC (PE / EA 5:1) to afford tert-butyl 2,6,8- trifluoro-10-(2-isopropoxy-2-oxoethyl)-10H-indeno[1,2-b]indole-5-carboxylate (70 mg, 10.95%) as a yellow solid. LCMS (ESI) [M + H]+:474 Example 52: Synthesis of Compound 80

[0352] To a stirred solution of 3-[4-benzyl-1-(4-fluorophenyl)-5-oxo-2-{[2- (trimethylsilyl)ethoxy]methyl} pyrazol-3-yl]-N-[(3S)-2-oxopyrrolidin-3-yl]propanamide (40 mg, 0.072 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 ml). After 1 h, the resulting mixture wasconcentrated 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), 30% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in 3-[4-benzyl-1-(4- fluorophenyl)-5-oxo-2H-pyrazol-3-yl]-N-[(3S)-2-oxopyrrolidin-3-yl]propanamide (12.7 mg, 41.54%) as a white solid.

[0353] LCMS (ESI) [M + H]+: 318.00.1H NMR (400 MHz, DMSO-d6) į^^^^^^^^s, 1H), 7.61 (dd, J = 8.3, 5.2 Hz, 1H), 7.54 (dd, J = 9.5, 2.4 Hz, 1H), 7.27 – 7.17 (m, 2H), 7.01 – 6.91 (m, 1H), 4.23 (dd, J = 9.5, 5.4 Hz, 1H), 3.06 (dd, J = 16.1, 5.5 Hz, 1H), 2.39 (dd, J = 16.2, 9.6 Hz, 1H). Example 53: Synthesis of Compound 81

[0354] To a stirred solution of {2,6,8-trifluoro-5H,10H-indeno[1,2-b]indol-10- yl}acetic acid (40 mg, 0.126 mmol, 1 equiv) in THF (2.5 mL) was added BH3·THF (0.151 mL, 0.151 mmol, 1.2 equiv, 1 M in THF) dropwise at room temperature under nitrogen atmosphere for overnight. 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-{2,6,8-trifluoro-5H,10H- indeno[1,2-b]indol-10-yl}ethanol (8.7 mg, 22.75%) as a white solid.

[0355] LCMS (ESI) [M + H]+: 304.00.1H NMR (300 MHz, DMSO-d6^^į^^^^^^^^V^^ 1H), 7.63 – 7.58 (m, 1H), 7.48 – 7.44 (m, 1H), 7.28 – 7.18 (m, 2H), 7.00 – 6.93 (m, 1H), 4.84 (d, J = 4.6 Hz, 1H), 4.04 (dd, J = 8.8, 5.5 Hz, 1H), 3.61 (s, 2H), 2.34 (ddd, J = 13.3, 7.7, 5.7 Hz, 1H), 1.64 (ddt, J = 6.2, 4.6, 2.4 Hz, 1H).

[0356] Table F describes compounds that were prepared according to the methods described herein in Examples 50-53.Table FScheme LExample 54: Synthesis of L-2

[0357] In 40 mL tube, 2,2-difluoropropane-1,3-diol L-1 (3.5 g, 31.229 mmol, 1 equiv.), tert-butyl(chloro)diphenyl silane (9.44 g, 34.352 mmol, 1.1 equiv.) and Imidazole (4.25 g, 62.458mmol, 2 equiv.) were added in DMF (20 mL) at 0 °C. The resulting mixture was stirred for 4 h at room temperature. The reaction was quenched with sat. NaHCO3(aq.). 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. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% NH3.H2O), 30% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropan-1-ol (L-2) (4 g, 36.5%) as colorless oil. Example 55: Synthesis of L-3

[0358] To a stirred solution of (COCl)2(2.90 g, 22.826 mmol, 2 equiv.) in DCM (5 mL) under nitrogen atmosphere at -78 °C was added DMSO (2.68 g, 34.239 mmol, 3 equiv.). After stirring for 30 minutes, 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropan-1-ol (4 g, 11.413 mmol, 1 equiv.) was added and the mixture was stirred for 1 hour at – 78 °C under nitrogen atmosphere. Then TEA (6.93 g, 68.478 mmol, 6 equiv.) was added and the resulting mixture was stirred at – 78 °C under nitrogen atmosphere for 10 minutes and warm to room temperature for further half an hour. Upon completion of reaction, water was added. The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with water (3x100 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropanal (L-3)(3.5 g, 88.1%) as colorless oil. The crude product was used in the next step directly without further purification.Example 56: Synthesis of L-4

[0359] In 8 mL microwave tube, 2-(5,7-difluoro-1H-indol-2-yl)-5-fluorophenol (600 mg, 2.279 mmol, 1 equiv.) and 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropanal (3.5 g, 10.044 mmol, 4.41 equiv.) and dioxane (0.5 mL) were added. The resulting mixture was stirred for 2 h at 130 °C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2-(3-{3-[(tert- butyldiphenylsilyl)oxy]-2,2- difluoro-1-hydroxypropyl}-5,7-difluoro-1H-indol-2-yl)-5-fluorophenol (L-4) (500 mg, 35.9%) as a red solid. Example 57: Synthesis of L-5

[0360] To a mixture of 2-(3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoro-1- hydroxypropyl}-5,7-difluoro-1H -indol-2-yl)-5-fluorophenol (500 mg, 0.817 mmol, 1 equiv.) and PPh3(428.80 mg, 1.634 mmol, 2 equiv.) in THF (5 mL) at 0 °C under nitrogen atmosphere was added DIAD (826.45 mg, 4.085 mmol, 5 equiv.). The resulting mixture was stirred for 2 h at room temperature. The residue was purified by silica gel column chromatography, eluted with PE / EA (12:1) to afford 6-{2-[(tert-butyldiphenylsilyl)oxy]-1,1-difluoroethyl}-3,8,10-trifluoro-6H,11H- chrome no[4,3-b]indole (L-5) (320 mg, 65.9%) as a yellow solid. LCMS (ESI) [M + H]+: 594.18 H]-: 610.19Example 58: Synthesis of L-6

[0360] In 8 mL tube, 6-{2-[(tert-butyldiphenylsilyl)oxy]-1,1-difluoroethyl}-3,8,10- trifluoro-6H,11H- chromeno [4,3-b]indole (50 mg, 0.084 mmol, 1 equiv.) and TBAF (66.06 mg, 0.252 mmol, 3 equiv.) were added to THF (2 mL) at 0 °C. The resulting mixture was stirred for 2 h at room temperature. 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 2,2-difluoro- 2-{3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6-yl}ethanol (L-6) (8 mg, 26.4%) as a white solid.

[0361] LCMS (ESI) [M - H]–: 354.10.1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^ 1H), 7.86 (dd, J = 8.4, 6.4 Hz, 1H), 7.18 – 7.05 (m, 2H), 7.00 – 6.84 (m, 2H), 6.21 (dd, J = 17.3, 6.7 Hz, 1H), 5.76 (t, J = 6.2 Hz, 1H), 3.97 – 3.59 (m, 2H). Example 59: Synthesis of Compounds 82 and 83

[0362] The 2,2-difluoro-2-{3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6- yl}ethanol (40 mg, 0.113 mmol, 1 equiv) was purified by Chiral HPLC with the followingconditions: Column: CHIRALPAK IA-^^ ^^^^^^PP^^ ^^P^^0RELOH^ 3KDVH^ $^^ +H[^^^^^'($^^^ IPA=90: 10; detector, UV 254. This resulted in 82: assumed 2,2-difluoro-2-[(6S)-3,8,10-trifluoro- 6H,11H-chromeno[4,3-b]indol-6-yl]ethanol (14.7 mg, 36.75%) as a white solid and 83: assumed 2,2-difluoro-2-[(6R)-3,8,10-trifluoro-6H, 11H- chromeno[4,3-b]indol-6-yl]ethanol (17.4 mg, 43.50%) as a white solid.

[0363] Table G describes compounds that were prepared according to the methods described in Examples 54-59. Similar methods were used to generate compounds 84-89. Table GScheme MExample 60: Synthesis of M-1

[0364] A solution of 2-(5,7-difluoro-1H-indol-2-yl)-5-fluorophenol (300 mg, 1.140 mmol, 1.0 eq) and (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (4449.9 mg, 34.200 mmol, 30.0 eq) in dioxane (1 mL) was stirred for 3 h at 130 °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 50% gradient in 30 min; detector, UV 254 nm. This resulted in 6-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indole (230 mg, 53.76%) as a yellow solid. MS (ESIpos): m / z = 376.10[M+H]+. Example 61: Synthesis of M-2

[0365] A solution of 6-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,8,10-trifluoro-6H,11H- chromeno[4,3-b]indole (50 mg, 0.133 mmol, 1.0 eq) in H2O (0.5 mL) and THF (0.5 mL) was treated with CH3COOH (0.5 mL) for 2 h at 40 °C under nitrogen atmosphere. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 2%'^&ROXPQ^^^^^^^^PP^^^^P^^0RELOH^3KDVH^$^^:DWHU^^^^PPRO^ / ^1+^+&2^^^^0RELOH^3KDVH^ B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 0% B to 48% B in 30 min; Wavelength: 254nm / 220nm nm; RT1(min): 6.23 / 6.88. This resulted in (1R)-1-[(6R*)-3,8,10-trifluoro-6H,11H- chromeno[4,3-b]indol-6-yl]ethane-1,2-diol (41.0 mg, 91.80%) as a white solid. MS (ESIpos): m / z = 334.00 [M-H]-. Separation of the diasteriomers of M-2 provided 90 and 91

[0366] Table H describes compounds that were prepared according to the methods described herein in Examples 60 and 61. Similar methods were used to generate compounds 92- 95. Table HScheme NExample 62: Synthesis of N-2

[0367] A solution of 2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetaldehyde (5 g, 31.615 mmol, 1 equiv) and 2-(5,7-difluoro-1H-indol-2-yl)-5-fluorophenol (2.50 g, 9.484 mmol, 0.3 equiv) in 1 mL of 1,4-dioxane was stirred for 2 h at 130 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was purified by reverse phase flash chromatography [Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Gradient: 10% B to 70% B in 30 min] to afford (5S)-5-({8,10-difluoro-6H,11H-chromeno[4,3-b]indol-6-yl}methyl)-2,2-dimethyl-1,3-dioxolan-4-one (800 mg, 6.57%) as a light brown solid.. LCMS (ESI) [M + H]+:404. Example 63: Synthesis of Compound 96

[0368] A solution of (5S)-2,2-dimethyl-5-({3,8,10-trifluoro-6H,11H-chromeno[4,3- b]indol-6-yl}methyl)-1,3- dioxolan-4-one (750 mg, 1.859 mmol, 1 equiv) in 15mL of AcOH / THF / H2O (1:1:1) was stirred for 8 h at 40 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography [Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Gradient: 10% B to 70% B in 30 min] to afford (2S)-2-hydroxy- 3-{3,8,10-trifluoro- 6H,11H-chromeno[4,3-b]indol-6-yl}propanoic acid (450 mg, 66.62%) as a light yellow solid. LCMS (ESI) [M - H]-:362.00. Example 64: Synthesis of N-3 O

[0369] A solution of (2S)-2-hydroxy-3-{3,8,10-trifluoro-6H,11H-chromeno[4,3- b]indol-6-yl}propanoic acid (100 mg, 0.275 mmol, 1 equiv), NH4Cl (29.45 mg, 0.550 mmol, 2 equiv), HATU (125.60 mg, 0.330 mmol, 1.2 equiv) and DIEA (106.73 mg, 0.825 mmol, 3 equiv) in 3mL of DCM was stirred for 3 h at room temperature under nitrogen atmosphere. Desiredproduct could be detected by LCMS. Upon completion of reaction, the reaction mixture was quenched with water. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography [Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Gradient: 30% B to 40% B in 30 min] to give (2S)-2-hydroxy-3-(3,8,10- trifluoro-6,11-dihydrochromeno[4,3-b]indol-6-yl)propanamide (70 mg) as an off-white solid. LCMS (ESI) [M + H]+: 363. Example 65: Synthesis of Compounds 97 and 98

[0370] (2S)-2-hydroxy-3-(3,8,10-trifluoro-6,11-dihydrochromeno[4,3-b]indol-6- yl)propanamide (70 mg) was separated by Chiral-HPLC with the following conditions, Column: &+,5$ / 3$.^,*^^^^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^0^1+^-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 40 mL / min; Gradient: isocratic 10; Wave Length: 209 / 239 nm; RT1(min) as Compound 97: 9.2; RT2(min) as Compound 98: 12.9; Sample Solvent: EtOH-- HPLC; Injection Volume: 0.4 mL; Number Of Runs: 9). This resulted in 97 assumed (2S)-2- hydroxy-3-[(6R)-3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6-yl]propanamide (26.1 mg, 24.78%) as an off-white solid and 98 assumed (2S)-2-hydroxy-3-[(6S)- 3,8,10-trifluoro-6H,11H- chromeno[4,3-b]indol-6-yl]propanamide (29.9 mg, 28.02%) as an off-white solid.

[0371] Esterification of 96 provided 99. Amide formation as described above was used to convert 96 to amides 100-102. Similar methodology was used to generate 103-109.

[0372] Table I describes compounds that were prepared according to the methods described herein in Examples 62-65. Table I7.80 (m, 1H), 7.51 (dd, J = 19.3, 8.3 Hz, 1H), 7.17 (dd, J = 9.4, 2.2 Hz, 1H), 7.03 (t, J = 10.4 Hz, 1H), 6.94 – 101 421.10 6.78 (m, 2H), 6.02 – [M+H]+5.92 (m, 1H), 5.81 (dd, J = 29.9, 6.3 Hz, 1H), 4.76 – 4.68 (m, 1H), 4.20 – 3.74 (m, 2H), 3.30 – 3.25 (m, 2H), 230 215 ( 1H)= 13.1 Hz, 1H), 7.86 – 7.79 (m, 1H), 7.53 (dd, J = 15.1, 8.4 Hz, 1H), 7.17 (dd, J = 9.4, 2.2 Hz, 1H), 7.02 (d, J = 105 419.10 [M-H]–10.5 Hz, 1H), 6.94 – 6.78 (m, 2H), 6.01 – 5.77 (m, 2H), 4.73 (s, 1H), 4.22 – 3.70 (m, 2H), 3.30 – 3.20 (m, 2H) 233 176 ( HO NH2DMSO-d6^^ į^ ^^^^^^ ^V^ 1H), 7.81 (dd, J = 8.5, (S) 6.5 Hz, 1H), 7.33 (s, F O 1H), 7.18 – 7.13 (m, O 2H), 7.05 – 6.99 (m, 107 361.05 [M-H]–1H), 6.91 – 6.83 (m, 2H), 5.97 (dd, J = 10.5, N 2.7 Hz, 1H), 5.69 (d, J = FHF6.7 Hz, 1H), 4.17 – 4.10 (m 1H) 223 218 (mScheme OExample 66: Synthesis of O-135

[0373] To a stirred solution of {3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6- yl}methanol (160 mg, 0.528 mmol, 1 eq.) in DCM was added Dess-Martin reagent (223.7 mg, 0.528 mmol, 1 eq.). The resulting mixture was stirred for 10 min at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of sat. Na2SO3(aq.) (3 mL) at room temperature. The aqueous layer was extracted with EtOAc (3x5 mL). 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 50% gradient in 10 min; UV 254 nm. This resulted in 3,8,10-trifluoro- 5H,6H,11H-benzo[a]carbazole-6-carbaldehyde (100 mg, 62.92%) as a yellow solid. MS (ESIpos): m / z = 300.0 [M-H]-. Example 67: Synthesis of Compound 110 OH F3C O F F TMS CF3THF, 429-41-4 NFN FFHFH110 O-1

[0374] To a stirred solution of 3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazole-6- carbaldehyde (100 mg, 0.332 mmol, 1 eq.) and TMSCF3(471.9 mg, 3.320 mmol, 10 eq.) in THF was added tetrabutylammonium fluoride tetrahydrofuran solution (221.4 mg, 0.664 mmol, 2 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) (2 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3x5 mL). The organic layer was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLCto afford 2,2,2-trifluoro-1-{3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl}ethanol (12.1 mg, 9.82%) as a white solid. MS (ESIpos): m / z = 370.00 [M-H]-.1H NMR (400 MHz, DMSO-G^^^į^^^^^^^ (s, 1H), 7.97 – 7.81 (m, 1H), 7.25 – 7.02 (m, 3H), 7.01 – 6.90 (m, 1H), 6.38 (s, 1H), 3.84 – 3.67 (m, 1H), 3.50 – 3.34 (m, 2H), 3.17 – 3.06 (m, 1H). Example 68: Synthesis of Compound 111

[0375] To a stirred solution of 3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazole-6- carbaldehyde (100 mg, 0.332 mmol, 1 eq.) and in THF was added bromo(ethynyl)magnesium (64.3 mg, 0.498 mmol, 1.5 eq.) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at -78 °C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) (1 mL) at -78 °C. The aqueous layer was extracted with EtOAc (5x3 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product (50 mg) was purified by Prep-HPLC to afford 1-{3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl}prop-2-yn-1-ol (10.8 mg, 9.94%) as a white solid. MS (ESIpos): m / z = 326.05 [M-H]-.1H NMR (400 MHz, DMSO-G^^^į^^^^^^^^G^^-^ ^^^^^ Hz, 1H), 7.96 – 7.81 (m, 1H), 7.31 – 7.08 (m, 3H), 7.01 – 6.85 (m, 1H), 5.75 – 5.46 (m, 1H), 4.23 – 3.94 (m, 1H), 3.31 – 3.15 (m, 3H), 3.13 – 3.01 (m, 1H). Alcohol 112 was prepared using the chemistry described for 111. Example 69: Synthesis of Compound 113

[0376] To a stirred solution of 3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazole-6- carbaldehyde (50 mg, 0.166 mmol, 1 eq.) in MeOH (1 mL) was added hydroxylaminehydrochloride (23.0 mg, 0.332 mmol, 2 eq.). The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The crude product (40 mg) was purified by Prep-HPLC to afford N-({3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl}methylidene)hydroxylamine (10.3 mg, 19.62%) as a white solid. MS (ESIpos): m / z = 317.05 [M+H]+.1H NMR (400 MHz, DMSO-G^^^į^^^^^^^^G^^-^ ^^^^^+]^^^+^^^^^^^^^^G^^-^ ^^^^^^^+]^^^+^^^^^^^^– 7.84 (m, 1H), 7.46 – 6.60 (m, 5H), 4.79 – 3.93 (m, 1H), 3.32 – 2.95 (m, 2H). Example 70: Synthesis of O-2

[0377] To a stirred solution of 3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazole-6- carbaldehyde (100 mg, 0.332 mmol, 1 eq.) and TMSCN (98.7 mg, 0.996 mmol, 3 eq.) in DCM was added tetrakis(propan-2-yloxy)titanium (188.6 mg, 0.664 mmol, 2 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. Then added Et3N•3HF (160.5 mg, 0.996 mmol, 3 eq.) stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (5 mL) at room temperature. The aqueous layer was extracted with EtOAc (3x5 mL). 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 60% gradient in 10 min; UV 254 nm. This resulted in 2-hydroxy-2- {3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl}acetonitrile (80 mg, 73.41%) as a yellow solid. MS (ESIpos): m / z = 327.0 [M-H]-. Example 71: Synthesis of Compound 114

[0378] To a stirred solution of 2-hydroxy-2-{3,8,10-trifluoro-5H,6H,11H- benzo[a]carbazol-6-yl}acetonitrile (50 mg, 0.152 mmol, 1 eq.) in MeOH was added H2SO4(0.1 mL). The resulting mixture was stirred overnight at 70 °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), 0% to 50% gradient in 20 min; UV 254 nm. This resulted in methyl 2-hydroxy-2-{3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl}acetate (10.2 mg, 18.54%) as a white solid. MS (ESIpos): m / z = 360.00 [M-H]-.1H NMR (400 MHz, DMSO-G^^^į^^^^^^^^V^^^+^^^^^^^^^^G^^-^ ^^^^^^+]^^^+^^^^^^^^– 7.72 (m, 1H), 7.27 – 7.01 (m, 3H), 7.00 – 6.85 (m, 1H), 4.04 – 3.69 (m, 1H), 3.56 – 3.38 (m, 1H), 3.20 (d, J = 7.7 Hz, 1H), 3.03 (d, J = 16.3 Hz, 1H). Example 72: Synthesis of Compound 115

[0379] Ester hydrolysis of 114 using standard methods provided acid 115. Example 73: Synthesis of Compound 116

[0380] To a stirred solution of hydroxy({3,8,10-trifluoro-5H,6H,11H- benzo[a]carbazol-6-yl})acetic (50 mg, 0.144 mmol, 1 eq.), DIEA (55.8 mg, 0.432 mmol, 3 eq.) and HATU (65.6 mg, 0.173 mmol, 1.2 eq.) in DMF was added (2S)-2-aminopropan-1-ol (12.9 mg, 0.173 mmol, 1.2 eq.). The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The crude product (30 mg) was purified by Prep-HPLC to afford 2-hydroxy-N-[(2S)-1-hydroxypropan-2-yl]-2-{3,8,10-trifluoro-5H,6H,11H-benzo[a]carbazol-6-yl}acetamide (11.9 mg, 20.44%) as a white solid.

[0381] MS (ESIpos): m / z = 405.00 [M+H]+.1H NMR (400 MHz, DMSO-G^^^į^^^^^^^ (d, J = 16.9 Hz, 1H), 7.98 – 7.76 (m, 1H), 7.43 – 7.21 (m, 1H), 7.21 – 7.03 (m, 3H), 7.00 – 6.82 (m, 1H), 5.44 – 5.17 (m, 1H), 4.59 (d, J = 36.2 Hz, 1H), 3.93 – 3.38 (m, 3H), 3.29 – 2.77 (m, 4H), 1.09 – 0.97 (m, 1.5H), 0.73 – 0.55 (m, 1.5H).

[0382] Compounds in Table J were prepared according to the methods described herein in Examples 66-73. Amides 117 and 118 were prepared from acid 115. Table JScheme P

[0383] A solution of 1,3-diethyl 2-oxopropanedioate (1.98 g, 11.400 mmol, 20.0 eq.) and 2-(5,7-difluoro-1H-indol-2-yl)-5-fluorophenol (150.0 mg, 0.570 mmol, 1.0 eq.) was stirred for 1 h at 130 °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), 0% to 50% gradient in 20 min; UV 254 nm. This resulted in 1,3-diethyl 2-[5,7- difluoro-2-(4-fluoro-2-hydroxyphenyl)-1H-indol-3-yl]-2-hydroxypropanedioate (163 mg, 65.40%) as a light yellow solid. MS (ESIpos): m / z = 438.3 [M+H]+. Example 75: Synthesis of P-2

[0384] A solution of 1,3-diethyl 2-[5,7-difluoro-2-(4-fluoro-2-hydroxyphenyl)-1H- indol-3-yl]-2-hydroxypropanedioate (150.0 mg, 0.343 mmol, 1.0 eq.) in tetrahydrofuran (2 mL) was treated with PPh3(269.8 mg, 1.029 mmol, 3.0 eq.) for 10 min at 0 °C under nitrogen atmosphere followed by the addition of DIAD (208.1 mg, 1.029 mmol, 3.0 eq.) dropwise at 0 °C. 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 6,6-diethyl 3,8,10-trifluoro-11H- chromeno[4,3-b]indole-6,6-dicarboxylate (100 mg, 69.53%) as a white solid. MS (ESIpos): m / z = 420.3 [M+H]+. Example 76: Synthesis of Compound 119

[0385] To a stirred solution of 6,6-diethyl 3,8,10-trifluoro-11H-chromeno[4,3- b]indole-6,6-dicarboxylate (90.0 mg, 0.215 mmol, 1.0 eq.) in MeOH (1 mL) was added LiBH4(14.0 mg, 0.645 mmol, 3.0 eq.) at 0 °C under. The resulting mixture was stirred for 16 h 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 (0.1% FA), 0% to 30% gradient in 20 min; UV 254 nm. This resulted in [3,8,10-trifluoro- 6-(hydroxymethyl)-11H-chromeno[4,3-b]indol-6-yl]methanol (36.2 mg, 50.31%) as a white solid. MS (ESIpos): m / z = 334.05 [M-H]-.1H NMR (400 MHz, Methanol-d4^^į^^^^^^– 7.59 (m, 1H), 7.16 – 7.13 (m, 1H), 6.76 – 6.65 (m, 3H), 4.07 (d, J = 12.0 Hz, 2H), 3.99 (d, J = 12.1 Hz, 2H). Example 77: Synthesis of P-3

[0386] To a stirred solution of 1-[(tert-butyldimethylsilyl)oxy]propan-2-one (4293.2 mg, 22.800 mmol, 20.0 eq.) and 2-(5,7-difluoro-1H-indol-2-yl)-5-fluorophenol (300.0 mg, 1.140 mmol, 1 eq.) in dioxane (15 mL) was added BF3•Et2O (3 mL, 22.806 mmol, 20.0 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 5 mL). 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 reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in {3,8,10- trifluoro-6-methyl-11H-chromeno[4,3-b]indol-6-yl}methanol (75 mg) as a white solid. MS (ESIpos): m / z = 318.05 [M-H]-.Example 78: Synthesis of Compounds 120 and 121

[0387] 3,8,10-trifluoro-6-methyl-11H-chromeno[4,3-b]indol-6-yl}methanol (60 mg) was separated by Chiral_HPLC with followed conditions, Column: CHIRAL ART Cellulose-SB ^^^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^P0^1+^-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 10; Wave Length: 332 / 223 nm; RT1(min): 6.9; RT2(min): 10; Sample Solvent: ETOH: DCM=1: 1; Injection Volume: 0.6 mL; Number Of Runs: 4. This resulted in first eluting isomer, 120, assumed [(6S)-3,8,10-trifluoro-6-methyl-11H-chromeno[4,3-b]indol- 6-yl]methanol (15.9 mg, 53.0%) as a white solid and second eluting isomer, 121, assumed [(6R)- 3,8,10-trifluoro-6-methyl-11H-chromeno[4,3-b]indol-6-yl]methanol (17.6 mg, 58.67%) as a white solid. Example 79: Synthesis of P-4(a) and P-4(b)

[0388] A mixture of 2-(5,7-difluoro-1H-indol-2-yl)-5-fluorophenol (200.00 mg, 760 ^mol, 1.00 equiv.) and methyl 3-oxocyclobutane-1-carboxylate (2.00 g, 15.60 mol, as solvent) was stirred for 1h at 130 ^ under nitrogen atmosphere. The residue was purified by reversed-phaseflash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 30% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in methyl 3,8,10-trifluoro-11H-spiro[chromeno[4,3-b]indole-6,1'-cyclobutane]-3'-carboxylate (150.0 mg, 52.8%) as a white solid. MS (ESIpos): m / z = 374.09 [M+H]+.Methyl 3,8,10-trifluoro-11H- spiro[chromeno[4,3-b]indole-6,1'-cyclobutane]-3'-carboxylate (150.0 mg) was separated by Prep_HPLC to give first eluting isomer as P-4(a), assumed methyl (3's,6s)-3,8,10-trifluoro-11H- spiro[chromeno[4,3-b]indole-6,1'-cyclobutane]-3'-carboxylate (40.0 mg, 28.19% yield) as a white solid and second eluting isomer as P-4(b), assumed methyl (3'r,6r)-3,8,10-trifluoro-11H- spiro[chromeno[4,3-b]indole-6,1'-cyclobutane]-3'-carboxylate (70.0 mgˈ49.35% ) as a white solid. MS (ESIpos): m / z = 374.09 [M+H]+. Example 80: Synthesis of Compound 122

[0389] A solution of methyl (3's,6s)-3,8,10-trifluoro-11H-spiro[chromeno[4,3- b]indole-6,1'-cyclo butane]-3'-carboxylate (40.00 mg, 107.2 ^mol, 1.00 equiv.) in THF (1 mL) was added LAH (120 ^ / , 1 M in THF, 1 equiv.) and the mixture was stirred for 2 h at 0 ^ 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), 30% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in (3's,6s)-3,8,10-trifluoro-11H- spiro[chromeno[4,3-b]indole-6,1'-cyclobutan]-3'-ylmethanol (11.8 mg, 31.89%) as a white solid.

[0390] MS (ESIpos): m / z = 346.20 [M+H]+.1H NMR (400 MHz, DMSO-d6) į 12.18 (s, 1H), 7.79 (dd, J = 8.4, 6.4 Hz, 1H), 7.57 (dd, J = 9.9, 2.2 Hz, 1H), 7.04 (ddd, J = 11.7, 9.7, 2.2 Hz, 1H), 6.87 (t, J = 8.5 Hz, 2H), 4.92 (t, J = 5.1 Hz, 1H), 3.54 (t, J = 4.0 Hz, 2H), 2.75 (ddd, J = 19.0, 13.4, 8.8 Hz, 3H), 2.46 – 2.37 (m, 2H).

[0391] Identical conditions were used to convert P-4(b) into 123. Conditions used to make 120 and 121 were used to make 124-128.

[0392] Compounds in Table K were prepared according to the methods described herein in Examples 74-80. Table KScheme QExample 81: Synthesis of Q-3 and Compounds 129 and 130

[0393] To a solution of N-(benzyloxy)-3,8,10-trifluoro-6H,11H-chromeno[4,3- b]indole-6-carboxamide (120 mg, 0.283 mmol, 1 equiv.) in EA (3 mL) was added Pd / C (150.46 mg, 0.141 mmol, 0.5 equiv, 10%). The mixture was hydrogenated at room temperature for 2 h under hydrogen atmosphere using a hydrogen balloon. Upon completion of reaction, the solid was filtered and 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 (10mmol / L NH4HCO3), 15% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3,8,10-trifluoro-N-hydroxy-6H,11H-chromeno[4,3-b]indole-6- carboxamide (50 mg, 52.9%) as a white solid. 3,8,10-trifluoro-N-hydroxy-6H,11H-chromeno[4,3-b]indole-6-carboxamide (50 mg, 0.150 mmol, 1 equiv.) was purified by Chiral HPLC with the following conditions: column, CHIRALPAK AD-3; mobile phase, MeOH(0.1%DEA); detector, UV 254. This resulted in 129: (6S)-3,8,10- trifluoro-N- hydroxy-6H,11H-chromeno[4,3-b]indole- 6-carboxamide (8.3 mg, 15.97%) as a white solid and 130 (6R)-3,8,10-trifluoro-N-hydroxy- 6H,11H-chromeno[4,3-b]indole-6-carboxamide (6.5 mg, 12.56%) as a white solid.

[0394] Compound 129: MS (ESIpos): m / z = 335.05 [M+H]+.1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^GG^^J = 8.5, 6.3 Hz, 1H), 7.22 (dd, J = 9.5, 2.2 Hz, 1H), 7.04 (td, J = 10.5, 9.6, 2.2 Hz, 1H), 6.88 (d, J = 9.5 Hz, 2H), 6.09 (s, 1H).

[0395] Compound 130: MS (ESIpos): m / z = 335.05NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^GG^^J = 8.5, 6.3 Hz, 1H), 7.22 (dd, J = 9.5, 2.2 Hz, 1H), 7.04 (td, J = 10.5, 9.6, 2.2 Hz, 1H), 6.88 (d, J = 9.5 Hz, 2H), 6.09 (s, 1H). Example 82: Synthesis of Q-4

[0396] A solution of ethyl 3,8,10-trifluoro-6,11-dihydrochromeno[4,3-b]indole-6- carboxylate (1.8 g, 5.183 mmol, 1 equiv.) in ethanol (20 mL) was added hydrazine hydrate (20 mL, 82.300 mmol, 15.88 equiv.). The mixture was stirred for 2 hours at 80 °C. Upon completion of reaction, the organic solvent was removed under vacuum. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3,8,10-trifluoro- 6,11-dihydrochromeno[4,3-b]indole-6-carbohydrazide (800 mg, 46.31%) as a yellow solid. LCMS (ESI) [M+ H]: 334.Example 83: Synthesis of Q-5 and Compounds 131 and 132

[0397] To a solution of 3,8,10-trifluoro-6,11-dihydrochromeno[4,3-b]indole-6- carbohydrazide (300 mg, 0.900 mmol, 1 equiv.) in DMF (5 mL) was added CDI (291.93 mg, 1.800 mmol, 2 equiv.) and the mixture was stirred overnight at room temperature under N2atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, 10% to 90% gradient in 50 min; detector, UV 220 nm. This resulted in 5-(3,8,10-trifluoro-6,11-dihydrochromeno[4,3-b]indol-6-yl)-1,3,4- oxadiazol-2-ol (250 mg, 77.30%) as a yellow solid. LCMS (ESI) [M-H]–: 358. The racemate product 5-(3,8,10-trifluoro-6,11-dihydrochromeno[4,3-b]indol-6-yl)-1,3,4-oxadiazol-2-ol (200 mg, 0.557 mmol, 1 equiv.) was purified by Prep-Chiral-HPLC with the following conditions: &ROXPQ^^&+,5$ / 3$.^,*^^^^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^)$^--HPLC, Mobile Phase B: ACN: EtOH=2: 1; Flow rate: 20 mL / min; Gradient: isocratic 10; Wave Length: 220 / 327 nm; RT1(min), as 131: 7.2; RT2, as 132: 6.835: 12; Sample Solvent: EtOH: ACN: DCM=1: 1: 1; Injection Volume: 0.3 mL; Number Of Runs: 13. This resulted in 131: assumed (S)-5-(3,8,10- trifluoro-6,11-dihydrochromeno[4,3-b]indol-6-yl)-1,3,4-oxadiazol-2-ol (80 mg, 40.00%) as a yellow solid and 132: assumed (R)-5-(3,8,10-trifluoro-6,11-dihydrochromeno[4,3-b]indol-6-yl)- 1,3,4-oxadiazol-2-ol (80 mg, 40.00%) as a yellow solid.

[0398] Compound 131: MS (ESIpos): m / z = 357.90 [M+1H NMR (400 MHz, DMSO- d6^^į^12.50 – 12.45 (m, 2H), 7.94 – 7.85 (m, 1H), 7.14 – 7.04 (m, 2H), 7.04 – 6.96 (m, 3H).H]+

[0399] Compound 132: MS (ESIpos): m / z = 357.90 [M+H]+ 1H NMR (400 MHz, DMSO-d6^^į^^^^^^^– 12.44 (m, 2H), 7.93 – 7.84 (m, 1H), 7.14 – 7.04 (m, 2H), 7.04 – 6.96 (m, 3H).Example 84: Synthesis of Compound 133131 133

[0400] A mixture of 5-[(6S)-3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6-yl]- 1,3,4-oxadiazol-2-ol (30 mg, 0.084 mmol, 1 equiv.), 3-aminopyrrolidin-2-one (10.03 mg, 0.101 mmol, 1.2 equiv.) in DMF (2 mL) were added BOP (73.87 mg, 0.168 mmol, 2 equiv.) and DIEA (21.59 mg, 0.168 mmol, 2 equiv.). The mixture was stirred for 2 h at room temperature under N2atmosphere. Upon completion of reaction, the reaction mixture was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in H2O, 10% to 90% gradient in 50 min; detector, UV 254 nm. This resulted in (3S)-3-({5-[(6S)-3,8,10-trifluoro-6H,11H-chromeno [4,3-b] indol-6-yl]- 1,3,4-oxadiazol-2-yl}amino)pyrrolidin-2-one (10.3 mg, 27.76%) as a white solid. LCMS (ESI) The same procedure was used to generate 134.

[0401] Compound 133: [M-H]-: 439.95.1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^ 8.03 (dd, J = 8.4, 5.6 Hz, 1H), 7.94 – 7.84 (m, 2H), 7.14 (d, J = 1.7 Hz, 1H), 7.11 – 7.07 (m, 1H), 7.03 – 6.91 (m, 3H), 4.18 – 4.05 (m, 1H), 3.16 (dd, J = 9.8, 4.1 Hz, 2H), 2.37 – 2.27 (m, 1H), 1.99 – 1.84 (m, 1H).

[0402] Compound 134: LCMS (ESI) [M-H]-: 439.95.1H NMR (400 MHz, DMSO-d6^^į^ 12.47 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.94 – 7.83 (m, 2H), 7.14 (s, 1H), 7.12 – 7.04 (m, 1H), 7.03 – 6.94 (m, 1H), 6.99 – 6.91 (m, 2H), 4.17 – 4.06 (m, 1H), 3.15 (dd, J = 9.2, 4.3 Hz, 2H), 2.36 – 2.25 (m, 1H), 1.95 – 1.83 (m, 1H).Example 85: Synthesis of Q-6

[0403] To a stirred solution of 3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indole-6- carbohydrazide (500 mg, 1.500 mmol, 1 equiv.) and DIEA (387.81 mg, 3.000 mmol, 2 equiv.) in DCM (12 ml) were added ethyl chloroglyoxylate (245.80 mg, 1.800 mmol, 1.2 equiv.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. To the above mixture was added TsCl (572.03 mg, 3.000 mmol, 2 equiv.) and DIEA (38.78 mg, 0.300 mmol, 2 equiv.) at 0 °C. The resulting mixture was stirred overnight at room temperature. The residue was purified by Prep-TLC (PE / EA 1:1) to afford ethyl 5-{3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indol-6-yl}-1,3,4-oxadiazole-2- carboxylate (406 mg, 57.99%) as a white solid. LCMS (ESI) [M + H]+: 415. Example 86: Synthesis of Compounds 135 and 136

[0404] To a stirred solution of ethyl 5-{3,8,10-trifluoro-6H,11H-chromeno[4,3- b]indol-6-yl}-1,3,4-oxadiazole-2-carboxylate (100 mg, 0.241 mmol, 1 equiv.) in MeOH (8 mL) was added NaBH4(45.54 mg, 1.205 mmol, 5 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 40 min at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4Cl (aq.) 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. Theresidue was purified by Prep-TLC (PE / EA 1:2) to afford (5-{3,8,10-trifluoro-6H,11H- chromeno[4,3-b]indol-6-yl}-1,3,4-oxadiazol-2-yl)methanol (66 mg, 73.43%) as a white solid. LCMS (ESI) [M + H]+: 374.10. Resolution of Q-7 generated compounds 135 and 136.

[0405] Compound 135: LCMS (ESI) 374.10 [M+H]+.1H NMR (400 MHz, DMSO-d6^^į^ 12.53 (s, 1H), 7.95 – 7.87 (m, 1H), 7.40 (s, 1H), 7.14 – 7.03 (m, 1H), 7.06 – 6.94 (m, 3H), 5.90 – 5.83 (m, 1H), 4.59 (dd, J = 6.3, 1.3 Hz, 2H).

[0406] Compound 136: LCMS (ESI) 374.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) į^ 12.53 (s, 1H), 7.92 (dd, J = 8.5, 6.4 Hz, 1H), 7.40 (s, 1H), 7.14 – 6.94 (m, 4H), 5.86 (t, J = 6.3 Hz, 1H), 4.59 (d, J = 6.3 Hz, 2H).

[0407] Compounds in Table L were prepared according to the methods described herein in Examples 81-86. Table LScheme R

[0408] A solution / mixture of 2-(5,7-difluoro-1H-indol-2-yl)-5-fluorophenol (800 mg, 3.039 mmol, 1 equiv) and 2,2-dimethoxyacetaldehyde (949.22 mg, 9.117 mmol, 3 eq.) in dioxanewas stirred for 2 h at 130 °C under nitrogen atmosphere. 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 50% gradient in 10 min; detector, UV 254 nm. This resulted in 6-(dimethoxymethyl)-3,8,10-trifluoro-6H,11H-chromeno[4,3-b]indole (230 mg, 21.66%) as a yellow solid. MS (ESIpos): m / z = 350.31 [M+H]+. Example 88: Synthesis of 137

[0409] To a stirred solution of 6-(dimethoxymethyl)-3,8,10-trifluoro-6H,11H- chromeno[4,3-b]indole (230.0 mg, 0.658 mmol, 1 eq.) and hydroxylamine hydrochloride (137.27 mg, 1.974 mmol, 3 eq.) in DCM (5 mL) and H2O (0.2 mL) was added TFA (2.8 mL) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 h at 25 °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 N-({3,8,10-trifluoro-6H,11H- chromeno[4,3-b]indol-6-yl}methylidene)hydroxylamine (9 mg, 4.29%) as a yellow solid. MS (ESIpos): m / z = 316.95 [M-H]-.1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^G^^J = 3.0 Hz, 1H), 11.27 (s, 1H), 7.83 (dd, J = 8.2, 6.5 Hz, 1H), 7.57 (d, J = 6.4 Hz, 1H), 7.13 – 7.00 (m, 1H), 7.01 – 6.86 (m, 3H), 6.41 (d, J = 6.4 Hz, 1H).

[0410] Table M describes Compound 137 as prepared according to Example 88. Table M Compound Structure LC-MS1H NMRExample 89: Measuring APOL1 G1-EIK Inhibition

[0411] 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.

[0412] 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.

[0413] 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.

[0414] 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.

[0415] 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.

[0416] 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.

[0417] 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).

[0418] Concentration of test agent producing half maximal inhibition (IC50) was calculated using IDBS ActivityBase software using a 4-parameter logistic fit.

[0419] Table N shows APOL1 (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 IC50values in the following ranges: ***: IC50^^ 250 nM; **: IC50^^^^^^^Q0^^^^,&50> 1000 nM. Table N

[0420] 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.

[0421] 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 suchintroduced 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 claim recitations. 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.”

[0422] 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.

[0423] 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 willalso 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 articles refers 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.

[0424] 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):or a pharmaceutically acceptable salt thereof, wherein: X is O or –(C(R3)2)p–; wherein p is zero, one or two; Y is –(C(R5)2)q–R4; q is an integer from zero to four; each R1is independently selected from the group consisting of: hydrogen, –halo, –CF3, – CF2CF3, -–OCF3, –OCF2CF3, –CN, –NO2, –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)SO2R9, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, – (C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3- C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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: hydrogen, –halo, –CF3, –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 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, – (C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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)alkylC(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; each R3is independently selected from the group consisting of: hydrogen, –OH, –halo, – CF3, –CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –C(O)R8, –C(O)OR8, –OC(O)R8, –OR8, – OC(O)OR8, –OC(O)N(R8)2, –N(R8)2, –NR8C(O)R8, –NR8C(O)OR8, –NR8C(O)N(R8)2,– C(O)N(R8)2, –SR8, –S(O)R8, –SO2R8, –SO2N(R8)2, –N(R8)SO2R8and –(C1-C6)alkyl-R8; R4is selected from the group consisting of: –C(O)R6, –C(O)OR6, –C(=N)R6, –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)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 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3- C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –CH2OH, –CH2CH2OH, –(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(3-13 member)heterocycloalkyl, –NHC(O)(C1-C6)alkyl, –N(C1-C6)alkylC(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 member)heterocycloalkyl may additionally be optionally substituted with =O; each R5is independently selected from the group consisting of: hydrogen, –OH, –halo, – CF3, –CF2CF3, -OCF3, -OCF2CF3, –CN, –NO2, –(C1-C6)alkyl-R7, –C(O)R7, –C(O)OR7, – OC(O)R7, –OR7, –OC(O)OR7, –OC(O)N(R7)2, –N(R7)2, –NR7C(O)R7, –NR7C(O)OR7, – NR7C(O)N(R7)2,–C(O)N(R7)2, –SR7, –S(O)R7, –SO2R7, –SO2N(R7)2, –N(R7)SO2R7and –(C1- C6)alkyl-R7; each R6is independently selected from the group consisting of: hydrogen, –OH, –(C1- C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl; wherein each of said – (C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of –halo, –OH, –CF3, – CF2CF3, –OCF3, –OCF2CF3, –CN, –NO2, –CH2OH, –CH2CH2OH, –(C1-C6)alkyl, –C(O)(C1- C6)alkyl, –(C6-C10)aryl, –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)alkylC(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 member)heterocycloalkyl may additionally be optionally substituted with =O; each R7is independently selected from the group consisting of: hydrogen, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6- C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, – (C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and –(5-12member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of: –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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)alkylC(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 R8is independently selected from the group consisting of: hydrogen, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6- C10)aryl and –(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, – (C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and ––(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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)alkylC(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 R9is independently selected from the group consisting of: hydrogen, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6- C10)aryl and ––(5-12 member)heteroaryl; wherein each of said –(C1-C6)alkyl, –(C2-C6)alkenyl, – (C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and ––(5-12 member)heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of –halo, –OH, –CF3, –CF2CF3, –OCF3, –OCF2CF3, –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)alkylC(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 R10is independently selected from the group consisting of: hydrogen, –halo, –CF3, – CN, –NO2, –C(O)R11, –C(O)OR11, –OC(O)R11, –OR11, –OC(O)OR11, –N(R11)2, –NR11C(O)R11, – NR11C(O)N(R11)2,–C(O)N(R11)2, –SR11, –S(O)R11, –SO2R11, –SO2N(R11)2, –N(R11)SO2R11, –(C1- C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(C5-C10)cycloalkenyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and ––(5-12 member)heteroaryl; each R11is independently selected from the group consisting of: hydrogen, –(C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(C5-C10)cycloalkenyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and ––(5-12 member)heteroaryl; wherein each of said – (C1-C6)alkyl, –(C2-C6)alkenyl, –(C2-C6)alkynyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, –(C6-C10)aryl and ––(5-12 member)heteroaryl is optionally substituted with 1-3 substituents selected from the group consisting of hydrogen, –OH, –halo, –CF3, –CN, – NO2, –(C1-C6)alkyl, –(C2-C6)alkenyl and –(C2-C6)alkynyl.

2. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I’) (I'), or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I’’):, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (Ia’):, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (Ib’):, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (Ic):, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound of Formula I is a compound of Formula (Id) , or a pharmaceutically acceptable saltthereof.

8. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 4, wherein X is O.

9. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 3 or 5-6, wherein X is –(C(R3)2)p– and p is 0.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 4 or 5-6, wherein X is –(C(R3)2)p– and p is 1.

11. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 4 or 5-6, wherein X is –(C(R3)2)p– and p is 2.

12. The compound or pharmaceutically acceptable salt thereof of any one of claims 9- 11, wherein each R3is independently hydrogen.

13. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 12, wherein each R1is –halo.

14. The compound or pharmaceutically acceptable salt thereof of claim 12, wherein each R1is –fluoro.

15. The compound or pharmaceutically acceptable salt thereof of claim 12 or 13, wherein m is 2.

16. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 15, wherein R2is –halo.

17. The compound or pharmaceutically acceptable salt thereof of claim 16, wherein R2is –fluoro.

18. The compound or pharmaceutically acceptable salt thereof of claim 16 or 17, wherein n is 1.

20. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19, wherein R4is –C(O)R6.

21. The compound or pharmaceutically acceptable salt thereof of claim 20, wherein R4is –C(O)R6and R6is hydrogen.

22. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19, wherein R4is –C(O)OR6.

23. The compound or pharmaceutically acceptable salt thereof of claim 21, wherein R4is –C(O)OR6and R6is hydrogen or an optionally substituted –(C1-C6)alkyl.

24. The compound or pharmaceutically acceptable salt thereof of claim 22, wherein R4is –C(O)OH or –C(O)OCH3.

25. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19,wherein R4is –OC(O)R6.

26. The compound or pharmaceutically acceptable salt thereof of claim 25,wherein R4is –OC(O)R6and R6is hydrogen or an optionally substituted –(C1-C6)alkyl.

27. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19,wherein R4is –OR6.

28. The compound or pharmaceutically acceptable salt thereof of claim 27,wherein R4is –OR6and R6is hydrogen or an optionally substituted –(C1-C6)alkyl.

29. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19,wherein R4is –OC(O)OR6.

30. The compound or pharmaceutically acceptable salt thereof of claim 29,wherein R4is –OC(O)OR6and R6is hydrogen or an optionally substituted –(C1-C6)alkyl.

31. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19,wherein R4is –OC(O)N(R6)2.

32. The compound or pharmaceutically acceptable salt thereof of claim 31,wherein R4is –OC(O)N(R6)2and each R6is independently selected from the group consisting of hydrogen, – (C1-C6)alkyl, –(C3-C10)cycloalkyl and –(3-13 member)heterocycloalkyl, wherein –(C1-C6)alkyl, – (C3-C10)cycloalkyl and –(3-13 member)heterocycloalkyl are each optionally substituted.

33. The compound or pharmaceutically acceptable salt thereof of claim 32, wherein R4is –OC(O)NH2.

34. The compound or pharmaceutically acceptable salt thereof of claim 32, wherein R4is –OC(O)NH(R6).

35. The compound or pharmaceutically acceptable salt thereof of claim 34, wherein R6is an optionally substituted –(C1-C6)alkyl.

36. The compound or pharmaceutically acceptable salt thereof of claim 35, wherein R6is substituted with at least one of –OH, –CH2OH or –(C1-C6)alkyl.

37. The compound or pharmaceutically acceptable salt thereof of claim 34, wherein R6is an optionally substituted –(C3-C10)cycloalkyl.

38. The compound or pharmaceutically acceptable salt thereof of claim 37, wherein R6is cyclobutyl substituted with –OH or –CH2OH.

39. The compound or pharmaceutically acceptable salt thereof of claim 34, wherein R6is an optionally substituted –(3-13 member)heterocycloalkyl.

40. The compound or pharmaceutically acceptable salt thereof of claim 39, wherein R6is oxetanyl substituted with –OH or –CH2OH.

41. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19, wherein R4is –N(R6)2.

42. The compound or pharmaceutically acceptable salt thereof of claim 41, wherein R4is –N(R6)2and each R6is independently selected from the group consisting of hydrogen, –(C1- C6)alkyl, –SO2(C1-C6)alkyl and –(3-13 member)heterocycloalkyl, wherein –(C1-C6)alkyl and –(3- 13 member)heterocycloalkyl are each optionally substituted.

43. The compound or pharmaceutically acceptable salt thereof of claim 41, wherein R4is –NH2.

44. The compound or pharmaceutically acceptable salt thereof of claim 41, wherein R4is –NH(C1-C6)alkyl, wherein the (C1-C6)alkyl is optionally substituted.

45. The compound or pharmaceutically acceptable salt thereof of claim 44, wherein the –(C1-C6)alkyl is substituted with at least one of –OH, –CH2OH, –CH2CH2OH or –C(O)O(C1- C6)alkyl.

46. The compound or pharmaceutically acceptable salt thereof of claim 41, wherein R4is NH(3-13 member)heterocycloalkyl, wherein the –(3-13 member)heterocycloalkyl is optionally substituted.

47. The compound or pharmaceutically acceptable salt thereof of claim 46, wherein the –(3-13 member)heterocycloalkyl is pyrrolidinyl substituted with =O.

48. The compound or pharmaceutically acceptable salt thereof of claim 41, wherein R4is –NHSO2(C1-C6)alkyl, wherein (C1-C6)alkyl is optionally substituted.

49. The compound or pharmaceutically acceptable salt thereof of claim 48, wherein the – (C1-C6)alkyl is substituted with –OH.

50. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19, wherein R4is –NR6C(O)R6.

51. The compound or pharmaceutically acceptable salt thereof of claim 50, wherein R4is –NR6C(O)R6and each R6is independently selected from the group consisting of hydrogen, – (C1-C6)alkyl and –(C3-C10)cycloalkyl, wherein –(C1-C6)alkyl and –(3-13 member)heterocycloalkyl are each optionally substituted.

52. The compound or pharmaceutically acceptable salt thereof of claim 51, wherein R4is –NHC(O)(C1-C6)alkyl, wherein the –(C1-C6)alkyl is optionally substituted.

53. The compound or pharmaceutically acceptable salt thereof of claim 52, wherein the –(C1-C6)alkyl is substituted with –OH, –CH2OH or –NH2.

54. The compound or pharmaceutically acceptable salt thereof of claim 51, wherein R4is –NHC(O) (3-13 member)heterocycloalkyl, wherein the –(3-13 member)heterocycloalkyl is optionally substituted.

55. The compound or pharmaceutically acceptable salt thereof of claim 54, wherein the –(3-13 member)heterocycloalkyl is optionally substituted oxetanyl.

56. The compound or pharmaceutically acceptable salt thereof of claim 55, wherein oxetanyl is substituted with –OH or –CH2OH.

57. The compound or pharmaceutically acceptable salt thereof of claim 54, wherein the –(3-13 member)heterocycloalkyl pyrrolidinyl substituted with =O.

58. The compound or pharmaceutically acceptable salt thereof of claim 51, wherein R4is –NHC(O)(C3-C10)cycloalkyl, wherein the –(C3-C10)cycloalkyl is optionally substituted.

59. The compound or pharmaceutically acceptable salt thereof of claim 58, wherein the –(C3-C10)cycloalkyl is cyclopropyl substituted with –OH or –CH2OH.

60. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19,wherein R4is –NR6C(O)N(R6)2.

61. The compound or pharmaceutically acceptable salt thereof of claim 60, wherein R4is –NR6C(O)N(R6)2and each R6is independently selected from the group consisting of hydrogen, –(C1-C6)alkyl and –(3-13 member)heterocycloalkyl, wherein –(C1-C6)alkyl and –(3-13 member)heterocycloalkyl are each optionally substituted.

62. The compound or pharmaceutically acceptable salt thereof of claim 61, wherein R4is –NHC(O)NH2.

63. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19, wherein R4is –NR6C(O)OR6.

64. The compound or pharmaceutically acceptable salt thereof of claim 63, wherein R4is –NR6C(O)OR6and each R6is independently hydrogen or an optionally substituted –(C1- C6)alkyl.

65. The compound or pharmaceutically acceptable salt thereof of claim 64, wherein R4is –NHBoc.

66. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19, wherein R4is –C(O)N(R6)2.

67. The compound or pharmaceutically acceptable salt thereof of claim 66, wherein R4is –C(O)N(R6)2and each R6is independently selected from the group consisting of hydrogen, – OH or –O(C1-C6)alkyl, –(C1-C6)alkyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl, wherein –(C1-C6)alkyl, –(C3-C10)cycloalkyl, –(3-13 member)heterocycloalkyl and –O(C1-C6)alkyl are each optionally substituted.

68. The compound or pharmaceutically acceptable salt thereof of claim 67, wherein R4is –C(O)NH2.

69. The compound or pharmaceutically acceptable salt thereof of claim 67, wherein R4is –C(O)N(H)OH.

70. The compound or pharmaceutically acceptable salt thereof of claim 67, wherein R4is –C(O)N(H)(C3-C10)cycloalkyl, wherein –(C3-C10)cycloalkyl is optionally substituted.

71. The compound or pharmaceutically acceptable salt thereof of claim 70, wherein the –(C3-C10)cycloalkyl is cyclobutyl substituted with –OH or CH2OH.

72. The compound or pharmaceutically acceptable salt thereof of claim 67, wherein R4is –C(O)N(H)(C1-C6)alkyl, wherein the –(C1-C6)alkyl is optionally substituted.

73. The compound or pharmaceutically acceptable salt thereof of claim 72, wherein the –(C1-C6)alkyl is substituted with at least one of –OH, –CH2OH, –NH2, –(C1-C6)alkyl.

74. The compound or pharmaceutically acceptable salt thereof of claim 67, wherein R4is –C(O)N(H) (3-13 member)heterocycloalkyl, wherein the –(3-13 member)heterocycloalkyl is optionally substituted.

75. The compound or pharmaceutically acceptable salt thereof of claim 74, wherein the –(3-13 member)heterocycloalkyl is pyrrolidinyl substituted with =O.

76. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19; wherein R4is optionally substituted ––(5-12 member)heteroaryl.

77. The compound or pharmaceutically acceptable salt thereof of claim 76, wherein R4is selected from the group consisting of pyridyl, pyrimidyl, pyrazolyl, oxadiazolyl, imidazolyl, wherein pyridyl, pyrimidyl, pyrazolyl, oxadiazolyl, and imidazolyl are each optionally substituted.

78. The compound or pharmaceutically acceptable salt thereof of claim 77, wherein R4is substituted with –OH, –CH2OH, –CF3or –NH(3-13 member)heterocycloalkyl, wherein the –(3- 13 member)heterocycloalkyl is optionally further substituted with =O.

79. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19, wherein R4is optionally substituted –(3-13 member)heterocycloalkyl.

80. The compound or pharmaceutically acceptable salt thereof of claim 79, wherein R4is morpholinyl, oxetanyl, pyrrolidinyl or imidazolidinyl, wherein morpholinyl, oxetanyl, pyrrolidinyl and imidazolidinyl are each optionally substituted.

81. The compound or pharmaceutically acceptable salt thereof of claim 80, wherein oxetanyl is substituted with –OH or –CH2OH.

82. The compound or pharmaceutically acceptable salt thereof of claim 80, wherein imidazolidinyl or pyrrolidinyl is substituted with =O.

83. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19, wherein R4is optionally substituted –(C1-C6)alkyl.

84. The compound or pharmaceutically acceptable salt thereof of claim 83, wherein R4is substituted with at least one of –CN, –CF3, –OH or –CH2OH.

85. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19, wherein R4is optionally substituted –(C3-C10)cycloalkyl.

86. The compound or pharmaceutically acceptable salt thereof of claim 85, wherein R4is optionally substituted with at least one of –OH, –CH2OH, –CH2CH2OH or –(C1-C6)alkyl.

87. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19, wherein R4is –(C2-C6)alkynyl.

88. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 19, wherein R4is –C(=N)R6.

89. The compound or pharmaceutically acceptable salt thereof of claim 88, wherein R6is –OH.

90. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 89, wherein at least one of R5is –OH.

91. The compound or pharmaceutically acceptable salt thereof of any one of claims 1- 90, wherein at least one of R5is –halo.

92. The compound or salt of claim 97, wherein the (C3-C10)cycloalkyl is substituted with at least one of –OH, –CH2OH or –CH2CH2OH.

93. The compound or pharmaceutically acceptable salt thereof of claim 1 wherein said compound is selected from the group consisting of:pharmaceutically acceptable salt thereof.

94. The compound or pharmaceutically acceptable salt thereof of claim 99 wherein said compound is selected from the group consisting of:pharmaceutically acceptable salt thereof.

95. The compound or pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:, or a pharmaceutically acceptable salt thereof.

96. A pharmaceutical composition comprising a compound or salt of any one of claims 1-95, and a pharmaceutically acceptable carrier.

97. The pharmaceutical composition of claim 96 additionally comprising an antiviral agent.

98. The pharmaceutical composition of claim 97, wherein the antiviral agent is selected from the group consisting of Remdesivir, Nirmatrelvir, Ritonavir, Molnupiravir, Interferon alfa, Interferon lambda and Ivermectin.

99. The use of a compound of any one of claims 1-95, or a pharmaceutically acceptable salt or composition thereof for the manufacture of a medicament to treat a disease for which APOL1 inhibition is indicated.

100. The use of a compound of any one of claims 1-95, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of non-diabetic kidney disease or focal segmental glomerulosclerosis.

101. 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 1-95 or a pharmaceutically acceptable salt thereof.

102. 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 1-95 or a pharmaceutically acceptable salt thereof.

103. A pharmaceutical composition comprising the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of any one of claims 1 to 95 and a pharmaceutically acceptable carrier.

104. 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 of any one of claims 1 to 95.

105. A method of inhibiting APOL1 activity comprising contacting said APOL1 with the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 95.

106. A kit comprising at least two of: (a) compound of Formula I; and (b) an antiviral agent selected from the group consisting of Remdesivir, Nirmatrelvir, Ritonavir, Molnupiravir, Interferon alfa, Interferon lambda, Ivermectin and combinations thereof.

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