2-METHYL-4-PHENYLPIPERIDIN-4-OL DERIVATIVES AS INHIBITORS OF APOL1 AND METHODS OF USING SAME - Patent application

Abstract

The present disclosure provides at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, compositions comprising them, and methods of using them, including use in the treatment of APOL1-mediated diseases, including pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and / or non-diabetic kidney disease (NDKD).

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 307,933, filed February 8, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The present disclosure provides compounds that can inhibit apolipoprotein L1 (APOL1) and methods of using those compounds to treat APOL1-mediated diseases, such as pancreatic cancer, focal segmental glomerulosclerosis (FSGS) and / or non-diabetic kidney disease (NDKD). In some embodiments, FSGS and / or NDKD are associated with at least one of two common APOL1 gene variants (G1:S342G:I384M and G2:N388del:Y389del). In some embodiments, pancreatic cancer is associated with elevated APOL1 levels (e.g., elevated APOL1 levels in pancreatic cancer tissue).

[0003] FSGS is a rare kidney disease with an estimated worldwide incidence of 0.2-1.1 / 100,000 / year. FSGS is a disease of the podocyte (the glomerular visceral epithelial cells) that causes proteinuria and progressive decline in kidney function. NDKD is a kidney disease with damage to the podocyte or glomerular vascular bed not caused by diabetes. NDKD is a disease characterized by hypertension and progressive decline in kidney function. Human genetic analysis supports a causal role for G1 and G2 APOL1 variants in inducing kidney disease. Individuals with two APOL1 alleles are at increased risk of developing end-stage kidney disease (ESKD), including primary (idiopathic) FSGS, human immunodeficiency virus (HIV)-associated FSGS, NDKD, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. See P. Dummer et al., Semin Nephrol. 35(3): 222-236(2015).

[0004] FSGS and NDKD can be divided into different subgroups based on the underlying etiology. One homogeneous subgroup of FSGS is characterized by the presence of independent common sequence variants in the apolipoprotein L1 (APOL1) gene, called G1 and G2, referred to as "APOL1 risk alleles". G1 codes for a correlated pair of nonsynonymous amino acid changes (S342G and I384M), G2 codes for a two amino acid deletion (N388del:Y389del) near the C-terminus of the protein, and G0 is the ancestral (low risk) allele. A distinct phenotype of NDKD is also found in patients with APOL1 genetic risk variants. In both APOL1-mediated FSGS and NDKD, high levels of proteinuria and rapid loss of kidney function occur in patients with two risk alleles compared to patients with the same disease who have none or only one APOL1 genetic risk variant. Alternatively, in AMKD, patients with one risk allele can develop high levels of proteinuria and rapid loss of kidney function. See G. Vajgel et al., J. Rheumatol., November 2019, jrheum.190684.

[0005] APOL1 is a 44 kDa protein that is expressed only in humans, gorillas, and baboons. In humans, the APOL1 gene is expressed in multiple organs, including the liver and kidney. APOL1 is produced primarily by the liver and contains a signal peptide that allows secretion into the bloodstream, where it circulates bound to a subset of high density lipoproteins. APOL1 also contributes to defense against the invasive parasite Trypanosoma Brucei Brucei (T. b. Brucei). APOL1 is endocytosed by T. b. brucei and transported to lysosomes, where it is inserted into the lysosomal membrane and forms a pore that results in the parasite's swelling and death.

[0006] The ability to lyse T. b. brucei is common to all three APOL1 variants (G0, G1, and G2), but the G1 and G2 APOL1 variants confer additional protection against parasite species that have evolved serum resistance-associated proteins (SRA) that inhibit APOL1 G0. The G1 and G2 APOL1 variants also confer additional protection against Trypanosoma species that cause sleeping sickness. The G1 and G2 variants avoid inhibition by SRA, with G1 conferring additional protection against T. b. gambiense (which causes West African sleeping sickness) and G2 conferring additional protection against T. b. rhodesiense (which causes East African sleeping sickness).

[0007] In the kidney, APOL1 is expressed in podocytes, endothelial cells (including glomerular endothelial cells), and some tubular cells. In transgenic mice, podocyte-specific expression of APOL1 G1 or G2 (but not G0) induces structural and functional changes, including albuminuria, renal function loss, podocyte abnormalities, and glomerular sclerosis. Consistent with these data, APOL1 G1 and G2 variants are responsible for inducing and accelerating the progression of FSGS in humans. Individuals carrying APOL1 risk alleles (i.e., homozygous or compound heterozygous for the APOL1 G1 allele or the APOL1 G2 allele) are at increased risk of developing FSGS, and if they do develop FSGS, they are also at risk for rapid decline in renal function. Thus, inhibition of APOL1 may have a beneficial effect in individuals carrying APOL1 risk alleles.

[0008] Although normal plasma concentrations of APOL1 are relatively high and can vary at least 20-fold in humans, circulating APOL1 is not causally associated with renal disease. However, renal APOL1 is thought to contribute to the development of renal diseases, including FSGS and NDKD. Under certain circumstances, synthesis of APOL1 protein can be increased by approximately 200-fold by proinflammatory cytokines, such as interferon or tumor necrosis factor-α. In addition, APOL1 protein is associated with the pH-gated Na+ receptor in the plasma membrane. + / K + This results in the formation of pores and the release of intracellular K + Several studies have shown that this results in a net excretion of inflammatory cytokines, ultimately activating local and systemic inflammatory responses, cell swelling, and death.

[0009] The risk of ESKD is substantially higher in people of recent sub-Saharan African descent compared with people of European descent. In the United States, ESKD accounts for nearly as many years of life lost in women as breast cancer and more years of life lost in men than colorectal cancer.

[0010] FSGS and NDKD are caused by damage to podocytes, which are part of the glomerular filtration barrier, resulting in proteinuria. Patients with proteinuria are at high risk of developing end-stage kidney disease (ESKD) and proteinuria-related complications such as infection or thromboembolic events. There are no standardized treatment regimens or approved drugs for FSGS or NDKD. Currently, FSGS and NDKD are managed with symptomatic treatments (including blood pressure control using blockers of the renin-angiotensin system), and patients with FSGS and severe proteinuria may be prescribed high-dose steroids. Current treatment options for NDKD are fixed on blood pressure control and blockade of the renin-angiotensin system.

[0011] Corticosteroids, alone or in combination with other immunosuppressants, induce remission in a small number of patients (e.g., remission of proteinuria in a small number of patients), but are also associated with numerous side effects. However, even in patients who initially respond to corticosteroid and / or immunosuppressant treatment, remission is often short-lived. As a result, patients, especially those of modern sub-Saharan African descent who carry two APOL1 risk alleles, rapidly progress to end-stage renal disease (ESRD). Thus, there is an unmet medical need for the treatment of FSGS and NDKD. Specifically, given the evidence that APOL1 plays a causative role in the induction and accelerated progression of renal disease, inhibition of APOL1 should have a positive effect on patients with APOL1-mediated renal disease, especially those who carry two APOL1 risk alleles (i.e., homozygous or compound heterozygous for the G1 or G2 allele). Furthermore, APOL1 is a gene that is aberrantly expressed in multiple cancers (Lin et al., Cell Death and Disease (2021), 12:760). Recently, APOL1 has been found to be abnormally elevated in human pancreatic cancer tissues compared to adjacent tissues and has been associated with poor prognosis in pancreatic cancer patients. In vivo and in vitro experiments have shown that knockdown of APOL1 inhibits cancer cell proliferation and promotes apoptosis of pancreatic cancer cells. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] P. Dummer et al., Semin Nephrol. 35(3): 222-236(2015) [Non-Patent Document 2] G. Vajgel et al., J. Rheumatol., November 2019, jrheum.190684 [Non-Patent Document 3] Lin et al., Cell Death and Disease (2021), 12:760 Summary of the Invention

[0013] One aspect of the present disclosure provides at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, tautomers of formula I, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, which may be used in the treatment of diseases mediated by APOL1, such as FSGS and NDKD. For example, in some embodiments, the at least one compound is a compound of formula I: [ka] A tautomer, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: Ring A is C 6 aryl, and 5- to 12-membered heterocyclyl groups, and 5- and 12-membered heteroaryl groups; R 1 For each occurrence, halogen, -OH, oxo, cyano, phenyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 independently selected from carbocyclyl, 4- to 6-membered heterocyclyl; R 1 The 4- to 6-membered heterocyclyl contains one heteroatom selected from nitrogen and oxygen, R 1 C 1 -C 6 Alkyl is halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 Alkyl) 2 , and C 1 -C 4optionally substituted with 1 to 3 groups independently selected from alkoxy groups; R 1 C 1 -C 6 The alkoxy is optionally substituted with 1 to 3 groups independently selected from -OH, cyano, and halogen groups; R 1 C 3 -C 6 Carbocyclyl is a halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 Alkyl) 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, -C(=O)NH 2 , -C(=O)NH(C 1 -C 4 alkyl), and -C(=O)N(C 1 -C 4 Alkyl) 2 is optionally substituted with 1 to 3 groups independently selected from the group R 1 The phenyl in the formula is halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 Alkyl) 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, -C(=O)NH 2 , -C(=O)NH(C 1 -C 4 alkyl), and -C(=O)N(C 1 -C 4 Alkyl) 2 is optionally substituted with 1 to 3 groups independently selected from the group R 2 and R 3 are hydrogen and C1 -C 4 independently selected from alkyl groups, R 4 is C 1 -C 6 Alkyl, -C(=O)O(C 1 -C 4 alkyl), and [ka] is selected from the group consisting of R 4 C 1 -C 6 Alkyl is halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 Alkyl) 2 , -C(=O)NH 2 , -C(=O)(C 1 -C 4 alkyl), -C(=O)OH, -C(=O)O(C 1 -C 4 alkyl), -C(=O)NH(C 1 -C 4 alkyl), -C(=O)N(C 1 -C 4 Alkyl) 2 , C 1 -C 4 Alkoxy, C 3 -C 6 Carbocyclyl, C 6 Aryl, -O-(C 6 aryl), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl groups, Each C 6 Aryl and -O-(C 6 Aryl) groups are halogen and C 1 -C 4 optionally substituted with 1 to 3 groups independently selected from haloalkyl groups; Ring B is C 3 -C12 Carbocyclyl, 3-12 membered heterocyclyl, C 6 and C 10 aryl, and 5- to 10-membered heteroaryl groups, and ring B is selected from 1, 2, 3, 4, or 5 R a is optionally substituted with a group; R a For each occurrence, halogen, cyano, oxo, C 1 -C 8 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 8 Alkenyl, C 1 -C 6 Haloalkenyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 12 Carbocyclyl, C 6 and C 10 Aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C(=O)NR h R i , -C(=O)OR k , -C(=O)(C 1 -C 4 Alkylene) OR k , -C(=O)R k , -C(=O)(C 1 -C 4 Alkylene)S(=O) p R k , -C(=O)(C 1 -C 4 Alkylene)S(=O) p NR h R i , -C(=O)(C 1 -C 4 Alkylene)NR i S(=O) p R k , -C(=O)(C 1 -C 4 Alkylene)NR h C(=O)R k , -C(=O)C(=O)R k 、-NR h R i 、-NH(CH 2 ) q CHR h R i 、-NH(CH 2 ) q NR h R i 、-NR h C(=O)R k 、-NR h C(=O)OR k 、-NR h C(=O)(C 1 -C 4 アルキレン)OR k 、-NR h C(=O)O(C 1 -C 4 アルキレン)R k 、-NR h C(=O)NR i R j 、-NR h C(=O)(C 1 -C 4 アルキレン)NR i S(=O) p R k 、 -NR h S(=O) p R k 、 -NR h C(=O)(C 1 -C 4 アルキレン)S(=O) p R k 、-NR h S(=O) p (C 1 -C 4 アルキレン)C(=O)OR k 、 -NR h C(=O)[O(CH 2 ) q ] r OC(=O)NR h R i (CH 2 ) q [O(CH 2 ) q] r (C 1 -C 6 alkyl) (optionally substituted with 1 to 3 R groups), -NR h C(=O)(C 1 -C 6 alkylene)[O(CH 2 ) q ] r OC(=O)NR h R i (CH 2 ) q [O(CH 2 ) q ] r (C 1 -C 6 alkyl) (optionally substituted with 1 to 3 R groups), -OR k , -OC(=O)R k , -OC(=O)OR k , -OC(=O)NR h R i , -[O(CH 2 ) q ] r O(C 1 -C 6 Alkyl), -S(=O) p R k , and -S(=O) p NR h R i is independently selected from the group -C(=O)(C 1 -C 4 Alkylene)S(=O) p R k , -C(=O)(C 1 -C 4 Alkylene) OR k , -C(=O)(C 1 -C 4 Alkylene)S(=O) p NR h R i , -C(=O)(C 1 -C 4 (alkylene)-NR i S(=O) p Rk , -C(=O)(C 1 -C 4 (alkylene)-NR h C(=O)R k , -NR h C(=O)O(C 1 -C 4 Alkylene)R k , -NR h C(=O)(C 1 -C 4 Alkylene)-OR k , NR h S(=O) p (C 1 -C 4 Alkylene)C(=O)OR k , and -NR h C(=O)(C 1 -C 4 Alkylene)NR i S(=O) p R k C in each 1 -C 4 The alkylene is optionally substituted with 1 to 3 groups independently selected from: -OH; C 1 -C 8 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, and C 2 -C 8 Each R in alkenyl a is cyano, -C(=O)R k , -C(=O)OR k , -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -NR h C(=O)ORk, -NR h C(=O)NR i R j , -NR hS(=O) p R k 、 -OR k , -[O(CH 2 ) q ] r OH, -OC(=O)R k , -OC(=O)OR k , -OC(=O)NR h R i , -SR k , -S(=O) p R k , -S(=O) p NR h R i , -[O(CH 2 ) q ] r O(C 1 -C 4 alkyl), -O-(C 6 aryl or 5-8 membered heteroaryl) (1-3 R m group), C 3 -C 6 Carbocyclyl (1 to 3 R m group), C 6 -C 10 Aryl (1 to 3 R m 5-10 membered heterocyclyl (1-3 R m aryl (optionally substituted with 1 to 3 R m optionally substituted with 1 to 3 groups independently selected from the group consisting of aryl, aryloxy ... R a C 3 -C 12 Carbocyclyl, 3-12 membered heterocyclyl, C 6 and C 10 Aryl and 5- to 10-membered heteroaryl are each selected from halogen, oxo, cyano, C 1 -C 6 Alkyl (1 to 3 R m group), -C(=O)R k , -C(=O)OR k, -NR h R i , -OR k , S(=O) p R k , -S(=O) p NR h R i , C 6 Aryl (1 to 3 R m and a 5- to 10-membered heterocyclyl group, R h , R i , and R j are hydrogen, C, 1 -C 6 Alkyl, C 6 -C 10 Aryl, C 3 -C 8 Carbocyclyl (1 to 3 R m aryl (optionally substituted with 1 to 3 R m R m (optionally substituted with a substituted or unsubstituted aryl group); R h , R i , and R j Any one of C 1 -C 6 Alkyl is a halogen, cyano, -OH, C 1 -C 4 Alkoxy, -C(=O)NH(C 1 -C 4 Alkyl), C 3 -C 6 Carbocyclyl (1 to 3 R m aryl (optionally substituted with 1 to 3 R m R m optionally substituted with 1 to 3 groups independently selected from the group R kFor each occurrence, hydrogen, C 1 -C 6 Alkyl, benzyl, C 6 Aryl, C 3 -C 6 independently selected from carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, R k One of the C 1 -C 6 Alkyl is halogen, cyano, -NH 2 , -OH, C 1 -C 4 Alkoxy, C 3 -C 6 Cycloalkyl (optionally substituted with 1 to 3 halogen groups), 5 to 10 membered heterocyclyl (optionally substituted with 1 to 3 -OH groups), and 5 to 10 membered heteroaryl (optionally substituted with 1 to 3 -OH groups). -N-, ... R k One of the C 3 -C 6 Carbocyclyl, benzyl, and C6 aryl are each independently selected from halogen, cyano, oxo, -OH, -C(=O)NH 2 , -C(=O)N(CH3) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl (optionally substituted with 1 to 3 halogen groups), C 6 aryl (optionally substituted with 1 to 3 halogen groups), and 5-10 membered heteroaryl (optionally substituted with 1 to 3 halogen groups), wherein C 1 -C 4 The alkyl is optionally substituted with 1 to 3 -OH groups; R k Any one of the 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl is halogen, cyano, -C(=O)CH 3 , -NH 2 , -OH, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 3 -C 6 Cycloalkyl and C 1 -C 4 optionally substituted with 1 to 3 groups independently selected from alkoxy groups; C 1 -C 4 The alkyl is optionally substituted with 1 to 3 -OH groups; R m For each occurrence, halogen, cyano, oxo, -(CH 2 ) n C(=O)NH 2 , -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 Alkyl) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, -C(=O)R k , - S(=O)pR k , -OR k , C 3 -C 6 independently selected from cycloalkyl, and 5- to 10-membered heterocyclyl groups; R m One of the C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and 5-10 membered heterocyclyl are substituted with halogen, cyano, -OH, C 1 -C 4 optionally substituted with 1 to 3 groups independently selected from alkoxy groups; R 5is halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -(CH 2 ) n C(=O)NR n R o , -NR n R o , -NR o C(=O)R p , -NR n S(=O) p R p , -(CH 2 ) n OR p , -S(=O) p R p , -S(=O) p NR n R o , -OS(=O) p NR n R o , and -(CH 2 ) n C(=O)OR p is selected from the group consisting of R n and R o are hydrogen and C for each occurrence, respectively. 1 -C 4 independently selected from alkyl groups, R p For each occurrence, hydrogen, C 1 -C 4 Alkyl, and C 1 -C 4 haloalkyl groups, n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; q and r are each an integer independently selected from 0, 1, 2, and 3 for each occurrence.

[0014] In some embodiments of Formula I, R 2 and R 3At least one of them is hydrogen and the other is C 1 -C 4 In these embodiments, the compound of formula I is a compound represented by the enantiomeric structures of formula IIa and formula IIb: [ka] and [ka] or a tautomer thereof, a deuterated derivative of said compound and tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein R 2 and R 3 is C 1 -C 4 alkyl group; rings A and R 1 , R 4 , and R 5 is as defined above for formula I.

[0015] In one aspect of the disclosure, the compounds of formula I, IIa, and IIb are selected from compounds 1-26, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharma- ceutically acceptable salts of any of the foregoing.

[0016] In some embodiments, the disclosure provides pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions may comprise at least one compound selected from compounds 1-26, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. These compositions may further comprise at least one additional pharma- ceutically active ingredient and / or at least one carrier.

[0017] Another aspect of the present disclosure provides a method for treating an APOL1 mediated disease, comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-26, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing.

[0018] Another aspect of the present disclosure provides a method of treating APOL1-mediated cancer (e.g., pancreatic cancer), comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-26, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing.

[0019] Another aspect of the present disclosure provides a method for treating APOL1-mediated kidney disease (e.g., ESKD, FSGS, and / or NDKD) comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-26, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing.

[0020] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one additional active agent in the same pharmaceutical composition or as a separate composition with at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-26, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, together with at least one additional active agent, either in the same pharmaceutical composition or as a separate composition.

[0021] Also provided are methods of inhibiting APOL1, comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, or pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt. In some embodiments, the method of inhibiting APOL1 comprises administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-26, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, or pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] definition The term "APOL1" as used herein means apolipoprotein L1 protein, and the term "APOL1" means apolipoprotein L1 gene.

[0023] The term "APOL1-mediated disease" refers to a disease or condition associated with abnormal APOL1 (e.g., a particular APOL1 gene variant, elevated APOL1 levels). In some embodiments, the APOL1-mediated disease is an APOL1-mediated renal disease. In some embodiments, the APOL1-mediated disease is associated with patients with two APOL1 risk alleles, e.g., homozygous or compound heterozygous for the G1 allele or the G2 allele. In some embodiments, the APOL1-mediated disease is associated with patients with one APOL1 risk allele.

[0024] The term "APOL1-mediated renal disease" refers to a disease or condition that impairs renal function and can be attributed to APOL1. In some embodiments, APOL1-mediated renal disease is associated with a patient who has two APOL1 risk alleles, for example, homozygous or compound heterozygous for the G1 allele or the G2 allele. In some embodiments, the APOL1-mediated renal disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arteriolar nephrosclerosis, lupus nephritis, microalbuminuria, and chronic renal disease. In some embodiments, the APOL1-mediated renal disease is chronic renal disease or proteinuria.

[0025] As used herein, the term "FSGS" means focal segmental glomerulosclerosis, a disease of the podocytes (glomerular visceral epithelial cells) that causes proteinuria and progressive decline in renal function and is associated with two common APOL1 gene variants (G1:S342G:I384M and G2:N388del:Y389del).

[0026] The term "NDKD" as used herein means non-diabetic kidney disease characterized by severe hypertension and progressive decline in renal function and associated with two common APOL1 gene variants (G1:S342G:I384M and G2:N388del:Y389del).

[0027] The terms "ESKD" and "ESRD" are used interchangeably herein and refer to end stage renal disease or end stage renal disease. ESKD / ESRD refers to end stage renal disease, i.e., kidney failure, where the kidneys do not function well enough that the patient cannot survive without dialysis or a kidney transplant. In some embodiments, ESKD / ESRD is associated with two APOL1 risk alleles.

[0028] The term "compound", when referring to a compound of the present disclosure, refers to a collection of molecules having the same chemical structure, unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic variations may exist between the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown also contains a lesser amount of isotopic substitutions having a hydrogen atom at one or more of the designated deuterium positions in the structure. The relative amount of such isotopic substitutions in the compounds of the present disclosure will depend on several factors, including the isotopic purity of the reagents used to make the compound, and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as described above, the relative amount of such isotopic substitutions overall will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitutions overall will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compounds.

[0029] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally," refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions. Combinations of substituents envisioned by the present disclosure are those that result in the formation of stable or chemically feasible compounds.

[0030] The term "isotopically modified" refers to a species whose chemical structure differs from a reference compound only in its isotopic composition. Additionally, unless otherwise stated, structures depicted herein are also intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of carbon with C, are within the scope of this disclosure.

[0031] Unless otherwise indicated, structures depicted herein are also intended to include all isomeric forms of the structure, such as racemic mixtures, cis / trans isomers, (Z) and (E) double bond isomers, and geometric (or conformational) isomers, such as (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds are within the scope of the disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0032] The term "tautomer" as used herein refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchanged by migration of atoms, e.g., hydrogen atoms or groups, within the molecule.

[0033] As used herein, "stereoisomers" refers to enantiomers and diastereomers.

[0034] As used herein, a "deuterated derivative" has the same chemical structure as a reference compound, but contains a deuterium atom ("D" or " 2Deuterated derivatives of the compounds of the present disclosure refer to compounds having one or more hydrogen atoms replaced with deuterium at or above its natural isotopic abundance (H). It will be recognized that some variation in natural isotopic abundance will occur in synthesized compounds depending on the source of the chemicals used in the synthesis. The concentration of naturally occurring stable hydrogen isotopes, despite this variation, is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Thus, unless otherwise specified, when a "deuterated derivative" of a compound of the present disclosure is referred to, at least one hydrogen is replaced with deuterium well above its natural isotopic abundance, which is typically about 0.015%. In some embodiments, deuterated derivatives of the disclosure have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).

[0035] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0036] The term "alkyl" or "aliphatic" as used herein means a straight-chain (i.e., linear or unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated. Unless otherwise specified, an alkyl group contains 1-20 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-10 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1-8 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1-6 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-4 alkyl carbon atoms, in other embodiments, an alkyl group contains 1-3 alkyl carbon atoms, and in still other embodiments, an alkyl group contains 1 or 2 alkyl carbon atoms. In some embodiments, an alkyl group is linear or straight-chained or unbranched. In some embodiments, an alkyl group is branched.

[0037] As used herein, the terms "cycloalkyl" and "cyclic alkyl" refer to a fully saturated monocyclic C 3-8 Hydrocarbon, or spirocyclic, fused, or bridged bicyclic or tricyclic C 8-14 In some embodiments, cycloalkyl refers to a hydrocarbon, and any individual ring within the bicyclic ring system has 3 to 7 members. ... 3 -C 12 In some embodiments, cycloalkyl is C 3 -C 8 In some embodiments, cycloalkyl is C 3 -C 6 Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0038] As used herein, the term "carbocyclyl" or "cycloaliphatic" encompasses the terms "cycloalkyl" or "cyclic alkyl" and refers to a monocyclic C ring alkyl group that is fully saturated or partially saturated so as to contain one or more saturated units, but is not aromatic. 3-8Hydrocarbon, or spirocyclic, fused, or bridged bicyclic or tricyclic C 8-14 refers to a hydrocarbon, where any individual ring of the bicyclic ring system has 3 to 7 members. Bicyclic carbocyclyl includes the combination of a monocyclic carbocycle fused to a phenyl. In some embodiments, carbocyclyl is C 3 -C 12 In some embodiments, the carbocyclyl is C 3 -C 10 In some embodiments, the carbocyclyl is C 3 -C 8 It is a carbocyclyl.

[0039] As used herein, the term "heteroalkyl" or "heteroaliphatic" means an alkyl or aliphatic group, as defined above, in which one or two carbon atoms are independently replaced by one or more oxygen, sulfur, nitrogen, phosphorus, or silicon.

[0040] As used herein, the term "alkenyl" refers to a straight-chain (i.e., linear or unbranched) or branched hydrocarbon chain containing one or more double bonds. In some embodiments, an alkenyl group is straight-chain. In some embodiments, an alkenyl group is branched-chain.

[0041] The terms "heterocycle", "heterocyclyl", and "heterocyclic" are used interchangeably herein to refer to non-aromatic (i.e., fully saturated or partially saturated, but not aromatic, as it contains one or more units of unsaturation), monocyclic, or spirocyclic, fused, or bridged bicyclic or tricyclic ring systems in which one or more ring members are independently selected heteroatoms. Bicyclic heterocyclyls include the following combinations of monocyclic rings: monocyclic heteroaryl fused to a monocyclic heterocyclyl; monocyclic heterocyclyl fused to another monocyclic heterocyclyl; monocyclic heterocyclyl fused to a phenyl; monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl.

[0042] In some embodiments, a "heterocycle", "heterocyclyl", "heteroalicyclic", or "heterocyclic" group has 3-14 ring members, with one or more ring members being heteroatoms independently selected from oxygen, sulfur, nitrogen, silicon, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3-7 ring members. In some embodiments, a heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, a heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, a heterocycle has one heteroatom independently selected from oxygen, sulfur, nitrogen, silicon, and phosphorus, a quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, such as N (in the case of 3,4-dihydro-2H-pyrrolyl), NH (in the case of pyrrolidinyl), or NR +(in the case of N-substituted pyrrolidinyl). In some embodiments, the heterocycle has one heteroatom which is a nitrogen atom. In some embodiments, the heterocycle has one heteroatom which is an oxygen atom. In some embodiments, the heterocycle has two heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle has three heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl, tetrahydrothiophenyl 1,1-dioxide, and the like.

[0043] The term "unsaturated" as used herein means that a moiety has one or more units or degrees of unsaturation. Unsaturation is a situation in which not all of the available valence bonds in a compound are satisfied by substituents, thus causing the compound to contain double or triple bonds.

[0044] The term "alkoxy" or "thioalkyl" as used herein refers to an alkyl group, as previously defined, in which one carbon of the alkyl group is replaced by an oxygen ("alkoxy") or sulfur ("thioalkyl") atom, respectively, provided that the oxygen and sulfur atoms are linked between two carbon atoms. "Cyclic alkoxy" refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group, but is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl.

[0045] As used herein, the terms "haloalkyl", "haloalkenyl" and "haloalkoxy" refer to straight or branched alkyl, alkenyl or alkoxy, respectively, substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF 2 , -CH 2 F, -CF 3 , -CF 2 - and, for example, -CF 2 CF 3 Non-limiting examples of haloalkoxy groups include -OCHF 2 , -OCH 2 F, -OCF 3 , and -OCF 2 Examples include:

[0046] The term "halogen" includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.

[0047] The term "aminoalkyl" means an alkyl group that is substituted with or contains an amino group.

[0048] As used herein, "amino" refers to a group that is a primary, secondary, or tertiary amine.

[0049] As used herein, the terms "oxo" and "=O" refer to a substituent oxygen atom that is attached by a double bond to another atom.

[0050] As used herein, a "carbonyl" group refers to C=O.

[0051] As used herein, a "cyano" or "nitrile" group refers to --C.ident.N.

[0052] As used herein, a "hydroxy" group refers to an --OH group.

[0053] As used herein, a "thiol" group refers to -SH.

[0054] As used herein, "tert" and "t-" each refer to tertiary.

[0055] As used herein, an "aromatic group" or "aromatic ring" refers to a chemical group that contains a conjugated planar ring system having delocalized pi orbitals consisting of [4n+2]p orbital electrons, where n is an integer ranging from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0056] The term "aryl" used alone or as part of a larger moiety, such as "arylalkyl", "arylalkoxy", or "aryloxyalkyl", refers to a monocyclic, or spirocyclic, fused or bridged bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, in which all rings in the system are aromatic rings containing only carbon atoms, and in which each ring of a bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C 6 ) and naphthyl (C 10 ) ring.

[0057] The term "heteroaryl" used alone or as part of a larger moiety, such as "heteroarylalkyl" or "heteroarylalkoxy", refers to a monocyclic, or spirocyclic, fused or bridged, bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the bicyclic and tricyclic ring systems contains 3 to 7 ring members. Bicyclic heteroaryls include the following combinations of monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl. In some embodiments, a heteroaryl group has one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group has one heteroatom. In some embodiments, a heteroaryl group has two heteroatoms. In some embodiments, a heteroaryl group is a monocyclic ring system having five ring members. In some embodiments, a heteroaryl group is a monocyclic ring system having six ring members. In some embodiments, the heteroaryl is a 3-12 membered heteroaryl. In some embodiments, the heteroaryl is a 3-10 membered heteroaryl. In some embodiments, the heteroaryl is a 3-8 membered heteroaryl. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-8 membered heteroaryl. In some embodiments, the heteroaryl is a 5 or 6 membered heteroaryl. Non-limiting examples of monocyclic heteroaryls include pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, and the like.

[0058] Non-limiting examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods for adding (a process commonly referred to as "protecting") and removing (a process commonly referred to as "deprotecting") such amine protecting groups are well known in the art and are described, for example, in P. J. Kocienski, Protecting Groups, Thieme, 1994, and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999) and 4th Edition (John Wiley & Sons, New York, 1999), which are incorporated herein by reference in their entireties. th Edition (John Wiley & Sons, New Jersey, 2014).

[0059] Non-limiting examples of suitable solvents that may be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or “methylene chloride” (CH 2 Cl 2 ), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et 2 0), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0060] Non-limiting examples of suitable bases that may be used in the present disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K 2 CO 3 ), N-methylmorpholine (NMM), triethylamine (Et 3 N;TEA), diisopropyl-ethylamine (i-Pr 2 EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCH 3 ), but are not limited to these.

[0061] The present disclosure includes pharma- ceutically acceptable salts of the disclosed compounds. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0062] As used herein, the term "pharmaceutically acceptable" refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0063] Acids commonly employed to form pharma- ceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharma- ceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, and the like. Examples of suitable acid addition salts include benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharma- ceutically acceptable acid addition salts include those formed with mineral acids, such as hydrochloric acid and hydrobromic acid, as well as those formed with organic acids, such as maleic acid.

[0064] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 Alkyl) 4The present disclosure also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Suitable, non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0065] The terms "patient" and "subject" are used interchangeably herein and refer to animals, including humans.

[0066] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of the compound that produces the desired effect for which it is administered (e.g., amelioration of symptoms of FSGS and / or NDKD, reduction in the severity of FSGS and / or NDKD, or alleviation of symptoms of FSGS and / or NDKD, and / or slowing the progression of FSGS and / or NDKD, or slowing the progression of symptoms of FSGS and / or NDKD). The exact amount of the effective dose will depend on the purpose of the treatment and will be ascertainable by one of skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0067] As used herein, the term "treatment" and its cognates refer to slowing or stopping disease progression. As used herein, "treatment" and its cognates include, but are not limited to, complete or partial remission, lower risk of renal failure (e.g., ESRD), and disease-related complications (e.g., edema, susceptibility to infection, or thromboembolic events). Improvement or reduction in severity of any of these symptoms can be easily assessed according to methods and techniques known in the art or subsequently developed.

[0068] The terms "about" and "approximately," when used in connection with a dose, amount, or weight percentage of a component of a composition or dosage form, include a particular dose, amount, or weight percentage value, or a range of doses, amounts, or weight percentages, that would be recognized by one of skill in the art as providing an equivalent pharmacological effect as that obtained from the particular dose, amount, or weight percentage.

[0069] At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of formula I, IIa, and IIb, their tautomers, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, may be administered once daily, twice daily, or three times daily, for example, for the treatment of AMKD, including FSGS and / or NDKD. In some embodiments, at least one compound selected from compounds 1-26, their tautomers, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, may be administered once daily, twice daily, or three times daily, for example, for the treatment of AMKD, including FSGS and / or NDKD. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharma- ceutically acceptable salts of any of the foregoing is administered once a day. In some embodiments, at least one compound selected from compounds 1-26, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing is administered once a day. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharma- ceutically acceptable salts of any of the foregoing is administered twice a day. In some embodiments, at least one compound selected from compounds 1-26, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing is administered twice daily. In some embodiments, at least one compound selected from compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharma- ceutically acceptable salts of any of the foregoing, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts of any of the foregoing is administered three times daily.In some embodiments, at least one compound selected from compounds 1-26, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing are administered three times daily.

[0070] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound selected from Formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing are administered once daily, twice daily, or three times daily. In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound selected from Compounds 1-26, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing are administered once daily, twice daily, or three times daily.

[0071] Those skilled in the art will recognize that when the amount of a compound is disclosed, the relative amount of the pharma- ceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. The amounts of compounds, pharma- ceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based on the free base form of the reference compound. For example, "1000 mg of at least one compound or pharma- ceutically acceptable salt selected from the compound of formula I and its pharma- ceutically acceptable salts" includes 1000 mg of the compound of formula I and a pharma- ceutically acceptable salt of the compound of formula I in a concentration equivalent to 1000 mg of the compound of formula I.

[0072] As used herein, the term "ambient conditions" refers to room temperature, outside air conditions, and uncontrolled humidity conditions.

[0073] Compounds and Compositions In some embodiments, at least one compound selected from formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing may be used to treat AMKD, including FSGS and NDKD. In some embodiments, the compound of formula I, IIa, and IIb may be selected from compounds 1-26, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound selected from formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing may be used to treat AMKD, including FSGS and NDKD. In some embodiments, the pharmaceutical composition may comprise at least one compound selected from compounds 1-26, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0074] In some embodiments of Formula I, [ka] Ring A may contain 1, 2, 3, 4, or 5 R 1 Optionally substituted with a C group; 6 aryl, 5- to 12-membered heterocyclyl, and 5- to 12-membered heteroaryl;

[0075] In some embodiments of formula I, ring A is C 6 In some embodiments, Ring A is aryl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is [ka] is selected from.

[0076] In some embodiments of Formula I, ring A is a 5-12 membered heterocyclyl. In some embodiments, ring A is [ka] It is.

[0077] In some embodiments of Formula I (including the embodiments described above defining Ring A), R 1 For each occurrence, halogen, -OH, oxo, cyano, phenyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 is independently selected from carbocyclyl, and 4- to 6-membered heterocyclyl.

[0078] In some embodiments of formula I (including the embodiments described above defining ring A), the variable R 1 is independently selected for each occurrence from halogen. In some embodiments of formula I (including the embodiments described above defining the variable ring A), the variable R 1 is F. In some embodiments of formula I (including the embodiments described above defining the variable ring A), the variable R 1 is Cl.

[0079] In some embodiments of formula I (including the embodiments described above defining ring A), the variable R 1 For each occurrence, C 1 -C 6 In some embodiments of formula I (including the embodiments described above defining the variable Ring A), the variable R 1 For each occurrence, C 1 In some embodiments of formula I (including those described above defining the variable ring A), the variable R 1 For each occurrence, -CH 3 It is.

[0080] In some embodiments of formula I (including the embodiments described above defining ring A), the variable R 1 For each occurrence, C 3 -C 6In some embodiments of Formula I (including the embodiments defined above for Ring A), the variable R 1 is C 3 In some embodiments of formula I (including the embodiments described above defining ring A), the variable R 1 teeth, [ka] It is.

[0081] In some embodiments of Formula I (including the embodiments described above defining Ring A), R 1 The 4- to 6-membered heterocyclyl contains one heteroatom selected from nitrogen and oxygen.

[0082] In some embodiments of Formula I (including the embodiments described above defining Ring A), R 1 C1-C 6 Alkyl is halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 Alkyl) 2 , and C 1 -C 4 In some embodiments of Formula I (including those described above defining Ring A), R 1 C 1 -C 6 The alkyl is optionally substituted with 1 to 3 groups independently selected from halogen. In some embodiments of Formula I (including the embodiments described above defining Ring A), R 1 C 1 -C 6 The alkyl is optionally substituted with three halogens. In some embodiments of Formula I (including the embodiments described above defining Ring A), R 1 C 1 -C 6The alkyl is optionally substituted with three F. In some embodiments of Formula I (including the embodiments described above defining Ring A), R 1 -CF 3 It is.

[0083] In some embodiments of Formula I (including the embodiments described above defining Ring A), R 1 C 1 -C 6 The alkoxy is optionally substituted with 1 to 3 groups independently selected from -OH, cyano, and halogen groups.

[0084] In some embodiments of Formula I (including the embodiments described above defining Ring A), R 1 C 3 -C 6 Carbocyclyl is a halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C4 alkyl) 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, -C(=O)NH 2、 - C(=O)NH(C 1 -C 4 Alkyl) 、 and -C(=O)N(C 1- C 4 Alkyl) 2 is optionally substituted with 1 to 3 groups independently selected from the group.

[0085] In some embodiments of Formula I (including the embodiments described above defining Ring A), R 1 The phenyl in the formula is halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 Alkyl) 2 , C 1 -C 4Alkyl, C 1 -C 4 Alkoxy, -C(=O)NH 2 , -C(=O)NH(C 1 -C 4 alkyl), and -C(=O)N(C 1 -C 4 Alkyl) 2 is optionally substituted with 1 to 3 groups independently selected from the group.

[0086] In some embodiments of Formula I, (rings A and R 1 (including the embodiment described above that defines the variable R 2 and R 3 are hydrogen and C 1 -C 4 In some embodiments of Formula I, (rings A and R 1 (including the embodiment described above that defines the variable R 2 is hydrogen. In some embodiments of Formula I, (rings A and R 1 (including the embodiment described above that defines the variable R 2 is C 1 -C 4 In some embodiments of Formula I, (rings A and R 1 (including the embodiment described above that defines the variable R 3 is hydrogen. In some embodiments of Formula I, (rings A and R 1 (including the embodiment described above that defines the variable R 3 is C 1 -C 4 In some embodiments of Formula I, (rings A and R 1 (including the embodiment described above that defines the variable R 2 is hydrogen, and R 3 is C 1 -C 4 In some embodiments of Formula I, (rings A and R 1 (including the embodiment described above that defines the variable R 2 is C 1 -C 4 is alkyl, R 3is hydrogen. In some embodiments of Formula I, (rings A and R 1 (including the embodiment described above that defines the variable R 2 is hydrogen, and the variable R 3 Ha-CH 3 In some embodiments of formula I, (rings A and R 1 (including the embodiment described above that defines the variable R 2 Ha-CH 3 and the variable R 3 is hydrogen.

[0087] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R 4 is C 1 -C 6 Alkyl, -C(=O)O(C 1 -C 4 alkyl), and [ka] In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R 4 teeth [ka] In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R 4 teeth [ka] is selected from.

[0088] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R 4C 1 ~C 6 Alkyl is halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 Alkyl) 2 , -C(=O)NH 2 , -C(=O)(C 1 -C 4 alkyl), -C(=O)OH, -C(=O)O(C 1 -C 4 alkyl), -C(=O)NH(C 1 -C 4 alkyl), -C(=O)N(C 1 -C 4 Alkyl) 2 , C 1 -C 4 Alkoxy, C 3 -C 6 Carbocyclyl, C 6 Aryl, -O-(C 6 aryl), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl groups. In some embodiments, R 4 C 1 -C 6 Alkyl C 6 Aryl groups and -O-(C 6 aryl) groups are each a halogen group and a C1-C 4 It is optionally substituted with 1 to 3 groups independently selected from haloalkyl groups.

[0089] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R 4 Ring B of C 3 -C 12 Carbocyclyl, 3-12 membered heterocyclyl, C 6 and C 10 In some embodiments of Formula I, (rings A, R 1 , R2 , and R 3 (including the embodiment defined above), R 4 In some embodiments of formula I, ring B is a 3- to 12-membered heterocyclyl. 1 , R 2 , and R 3 (including the embodiment defined above), R 4 Ring B is C 6 In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R 4 In some embodiments of Formula I, ring B is a 5-10 membered heteroaryl group. 1 , R 2 , and R 3 (including the embodiment defined above), R 4 Ring B may contain 1, 2, 3, 4, or 5 R a In some embodiments of Formula I, (ring A, R 1 , R 2 , and R 3 (including the embodiment defined above), R 4 Ring B may contain 1, 2, or 3 R a Groups are optionally substituted.

[0090] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the above embodiments defining R in ring B) 4 teeth, [ka] is selected from.

[0091] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiments described above), R in ring B 4 teeth, [ka] is selected from.

[0092] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above), the variable R a For each occurrence, halogen, cyano, oxo, C 1 -C 8 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 8 Alkenyl, C 1 -C 6 Haloalkenyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 12 Carbocyclyl, C 6 and C 10 Aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, -C(=O)NR h R i , -C(=O)OR k , -C(=O)(C 1 -C 4 Alkylene) OR k , -C(=O)R k , -C(=O)(C 1 -C 4 Alkylene)S(=O) p R k , -C(=O)(C 1 -C 4 Alkylene)S(=O) p NR h R i , -C(=O)(C 1 -C 4 Alkylene)NR i S(=O) p R k , -C(=O)(C 1 -C 4 Alkylene)NR h C(=O)R k , -C(=O)C(=O)Rk , -NR h R i , -NH(CH 2 ) q CHR h R i , -NH(CH 2 ) q NR h R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h C(=O)(C 1 -C 4 Alkylene) OR k , -NR h C(=O)O(C 1 -C 4 Alkylene)R k , -NR h C(=O)NR i R j , -NR h C(=O)(C 1 -C 4 Alkylene)NR i S(=O) p R k , -NR h S(=O) p R k 、 -NR h C(=O)(C 1 -C 4 Alkylene)S(=O) p R k , -NR h S(=O) p (C 1 -C 4 Alkylene)C(=O)OR k 、 -NR h C(=O)[O(CH 2 ) q ] r OC(=O)NR h R i (CH 2 ) q [O(CH 2 ) q] r (C 1 -C 6 alkyl) (1 to 3 R m group), -NR h C(=O)(C 1 -C 6 alkylene)[O(CH 2 ) q ] r OC(=O)NR h R i (CH 2 ) q [O(CH 2 ) q ] r (C 1 -C 6 alkyl) (1 to 3 R m -OR k , -OC(=O)R k , -OC(=O)OR k , -OC(=O)NR h R i , -[O(CH 2 ) q ] r O(C 1 -C 6 Alkyl), -S(=O) p R k , and -S(=O) p NR h R i are independently selected from the group.

[0093] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), at least one R a is oxo.

[0094] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R a is C 1 -C 8 In some embodiments of Formula I, (rings A, R1 , R 2 , and R 3 (including the embodiment described above that defines the variable R a is C 1 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R a Ha-CH 3 In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R a is C 2 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R a is C 3 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R a -CH(CH 3 ) 2 It is.

[0095] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R a is 3-12 membered heterocyclyl. In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R a is a 5-membered heterocyclyl. In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R a teeth [ka] It is.

[0096] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R a is a 5-10 membered heteroaryl. In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R a is a 6-membered heteroaryl. In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R a teeth [ka] It is.

[0097] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R a is -C(=O)NR h R i In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h and R i are hydrogen and C for each occurrence, respectively. 1 -C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h and R i is hydrogen. In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable Rh and R i is C 1 -C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h and R i One of them is hydrogen and the other is C 1 -C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h and R i One of them is hydrogen and the other is -CH 3 In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h and R i are -CH 3 It is.

[0098] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R a -C(=O)(C 1 -C 4 Alkylene)S(=O) p R k C in each 1 -C 4 Alkylene, -C(=O)(C 1 -C 4 Alkylene) OR k , -C(=O)(C 1 -C 4 Alkylene)S(=O) p NR h R i , -C(=O)(C 1 -C 4 Alkylene)NR i S(=O)p R k , -C(=O)(C 1 -C 4 Alkylene)NR h C(=O)R k , -NR h C(=O)O(C 1 -C 4 Alkylene)R k , -NR h C(=O)(C 1 -C 4 Alkylene) OR k , -NR h S(=O) p (C 1 -C 4 Alkylene)C(=O)OR k , and -NR h C(=O)(C 1 -C 4 Alkylene)NR i S(=O) p R k is optionally substituted with 1 to 3 groups independently selected from -OH.

[0099] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R a C 1 -C 8 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy and C 2 -C 8 Each alkenyl is cyano, -C(=O)R k , -C(=O)OR k , -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h C(=O)NRi R j , -NR h S(=O) p R k 、 -OR k , -[O(CH 2 ) q ] r OH, -OC(=O)R k , -OC(=O)OR k , -OC(=O)NR h R i , -SR k , -S(=O) p R k , -S(=O) p NR h R i , -[O(CH 2 ) q ] r O(C 1 -C 4 alkyl), -O-(C 6 aryl or 5-8 membered heteroaryl) (1-3 R m group), C 3 -C 6 Carbocyclyl (1 to 3 R m group), C 6 -C 10 Aryl (1 to 3 R m 5-10 membered heterocyclyl (1-3 R m aryl (optionally substituted with 1 to 3 R m is optionally substituted with 1 to 3 groups independently selected from the group consisting of aryl, aryloxy ...

[0100] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R a C 1 -C 8 Alkyl, C 1 -C 6 Haloalkyl, C 1-C 6 Alkoxy and C 2 -C 8 Each alkenyl is one to three -C(=O)NR h R i In some embodiments of Formula I, (ring A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h and R i are hydrogen and C for each occurrence, respectively. 1 -C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above), the variable R h and R i is hydrogen. In some embodiments of formula I, (ring A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h and R i is C 1 -C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above), the variable R h and R i One of them is hydrogen and the other is C 1 -C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h and R i One of them is hydrogen and the other is -CH 3 In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h and R iare -CH 3 It is.

[0101] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R a C 1 -C 8 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 2 -C 8 Each alkenyl is 1 to 3 -S(=O) p R k In some embodiments of Formula I, (ring A, R 1 , R 2 , and R 3 In some embodiments of Formula I (including the embodiment above defining 1 , R 2 , and R 3 In some embodiments of Formula I (including the embodiments defined above), the variable p is 2. 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R k is C 1 -C 6 In some embodiments of Formula I, (Rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R k is C 1 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R k is -CH 3 It is.

[0102] In some embodiments of formula I, (variable rings A, R1 , R 2 , and R 3 (including the embodiment defined above), R a C 3 -C 12 Carbocyclyl, 3-12 membered heterocyclyl, C 6 and C 10 Aryl and 5-10 membered heteroaryl are each selected from halogen, cyano, oxo, C 1 -C 6 Alkyl (1 to 3 R m group), -C(=O)R k , -C(=O)OR k , -NR h R i , -OR k , -S(=O) p R k , -S(=O) p NR h R i , C 6 Aryl (1 to 3 R m In some embodiments of Formula I, (rings A, R are optionally substituted with 1 to 3 groups independently selected from a 5- to 10-membered heterocyclyl group) and a 5- to 10-membered heterocyclyl group. 1 , R 2 , and R 3 (including the embodiment defined above), R a C 3 -C 12 The carbocyclyl, the 3- to 12-membered heterocyclyl, the C6 and C10 aryl, and the 5- to 10-membered heteroaryl are each optionally substituted with 1-3 oxo.

[0103] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h , R i , and R j are hydrogen, C, 1 -C 6 Alkyl, C 6 -C 10 Aryl, C 3 -C8 Carbocyclyl (1 to 3 R m aryl (optionally substituted with 1 to 3 R m R m The aryl groups are independently selected from the group (optionally substituted with aryl groups).

[0104] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h , R i , and R j are hydrogen and C for each occurrence, respectively. 1 -C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h , R i , and R j are hydrogen and C for each occurrence, respectively. 1 -C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h , R i , and R j Each of R is hydrogen. In some embodiments of Formula I, 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h , R i , and R j is C 1 -C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h , Ri , and R j One of them is hydrogen and the other two are C 1 -C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h , R i , and R j Two of them are hydrogen and the other one is C 1 -C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R h , R i , and R j are, for each occurrence, hydrogen and -CH 3 are independently selected from

[0105] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R h , R i , and R j Any one of C 1 -C 6 Alkyl is a halogen, cyano, -OH, C 1 -C 4 Alkoxy, -C(=O)NH(C 1 -C 4 Alkyl), C 3 -C 6 Carbocyclyl (1 to 3 R m aryl (optionally substituted with 1 to 3 R m R m is optionally substituted with 1 to 3 groups independently selected from the group

[0106] In some embodiments of formula I, (rings A, R1 , R 2 , and R 3 (including the embodiment described above that defines the variable R k For each occurrence, hydrogen, C 1 -C 6 Alkyl, benzyl, C 6 Aryl, C 3 -C 6 In some embodiments of Formula I, (Ring A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R k is C 1 -C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R k is C 1 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R k is -CH 3 It is.

[0107] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R k Any one of C 1 -C 6 Alkyl is halogen, cyano, -NH 2、 -OH, C 1 -C 4 Alkoxy, C 3 -C 6 Cycloalkyl (optionally substituted with 1 to 3 halogen groups), 5 to 10 membered heteroaryl (1 to 3 and 5-10 membered heterocyclyl (optionally substituted with 1-3 -OH groups).

[0108] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R k Any one of C 3 -C 6 Carbocyclyl, benzyl, and C 6 Aryl is halogen, cyano, oxo, -OH, -C(=O)NH 2 , -C(=O)N(CH 3 ) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl (optionally substituted with 1 to 3 halogen groups), C 6 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R k Any one of C 3 -C 6 Carbocyclyl, benzyl, and C 6 Each aryl is C 1 -C 6 Optionally substituted with alkyl, C 1 -C 6 The alkyl is optionally substituted with 1 to 3 -OH groups.

[0109] In some embodiments of formula I, (rings A, R1 , R 2 , and R 3 (including the embodiment defined above), R k Any one of the 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl is halogen, cyano, -C(=O)CH 3 , -NH 2 , -OH, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 3 -C 6 Cycloalkyl and C 1 -C 4 In some embodiments of Formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R k Any one of the 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl is C 1 -C 4 Optionally substituted with alkyl, C 1 -C 4 The alkyl is optionally substituted with 1 to 3 -OH groups.

[0110] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R m For each occurrence, halogen, cyano, oxo, -(CH 2 ) n C(=O)NH 2 , -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 Alkyl) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, -C(=O)R k , -S(=O)p R k , -OR k , C 3 -C 6 In some embodiments of Formula I, (Rings A, R 1 , R 2 , and R 3 (including the embodiment defined above), R m Any one of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy and 5-10 membered heterocyclyl are substituted with halogen, cyano, -OH, and C 1 -C 4 It is optionally substituted with 1 to 3 groups independently selected from alkoxy groups.

[0111] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R 4 teeth [ka] and ring B is [ka] Selected from R a is a halogen, C 1 -C 4 Alkyl, and C 1 -C 4 alkoxy.

[0112] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above that defines the variable R 4 teeth [ka] and ring B is [ka] Selected from R a does not exist.

[0113] In some embodiments of formula I, (rings A, R 1 , R 2 , and R 3 (including the embodiment described above), the variable R 4 teeth, [ka] is selected from.

[0114] In some embodiments of formula I, (rings A, R 1 , R 2 , R 3 and R 4 (including the embodiment described above that defines the variable R 5 is OH. In some embodiments of Formula I, (rings A, R 1 , R 2 , R 3 , and R 4 (including the embodiment described above that defines the variable R 5 is halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -(CH 2 ) n C(=O)NR n R o , -NR n R o , -NR o C(=O)R p , -NR n S(=O) p R p 、 -(CH 2 ) n OR p , -S(=O) p R p , -S(=O) p NR n R o , -OS(=O) p NR n Ro , and -(CH 2 ) n C(=O)OR p wherein the variable R n and R o are hydrogen and C for each occurrence, respectively. 1 -C 4 The variable R p For each occurrence, hydrogen, C 1 -C 4 Alkyl, and C 1 -C 4 haloalkyl groups are independently selected from the group consisting of haloalkyl groups.

[0115] In some embodiments of formula I, (rings A, R 1 , R 2 , R 3 and R 4 (including the embodiment described above that defines the variable R 5 is -(CH 2 ) n OR p In some embodiments of formula I, (rings A, R 1 , R 2 , R 3 and R 4 In some embodiments of Formula I (including the embodiments defined above), the variable n is 0. 1 , R 2 , R 3 and R 4 (including the embodiment described above that defines the variable R p is hydrogen.

[0116] In some embodiments of formula I, (rings A, R 1 , R 2 , R 3 , R 4 , and R 5 In some embodiments of Formula I (including the embodiment above defining R), the variable m is an integer selected from 0, 1, 2, 3, 4, and 5. 1 , R 2 , R 3 , R 4 , and R 5In some embodiments of Formula I (including the embodiment above defining R), the variable m is an integer selected from 0, 1, and 2. 1 , R 2 , R 3 , R 4 and R 5 In some embodiments of Formula I (including the embodiments defined above), the variable m is 0. 1 , R 2 , R 3 , R 4 and R 5 In some embodiments of Formula I (including the embodiments defined above), the variable m is 1. 1 , R 2 , R 3 , R 4 and R 5 (including the embodiment described above that defines

[0117] In some embodiments of formula I, (rings A, R 1 , R 2 , R 3 , R 4 , R 5 In some embodiments of Formula I (including the embodiments above defining rings A, R 1 , R 2 , R 3 , R 4 , R 5 , and the embodiments above defining m), where n is 0.

[0118] In some embodiments of formula I, (rings A, R 1 , R 2 , R 3 , R 4 , R 5 In some embodiments of formula I (including the embodiments above defining the variables A, R, m, and n), the variable p, for each occurrence, is an integer independently selected from 1 and 2. 1 , R 2 , R 3 , R 4 , R 5, m, and n), and p is 2.

[0119] In some embodiments of formula I, (rings A, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, and p), the variables q and r are integers independently selected from 0, 1, 2, and 3 for each occurrence.

[0120] In some embodiments of Formula I, R 2 and R 3 At least one of them is hydrogen and the other is C 1 -C 4 In these embodiments, the compound of formula I is a compound represented by the enantiomeric structures of formula IIa and formula IIb: [ka] and [ka] or a tautomer thereof, a deuterated derivative of said compound and tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein R 2 and R 3 is C 1 -C 4 alkyl group; rings A and R 1 , R 4 , and R 5 is as defined above for formula I.

[0121] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure is selected from compounds 1-26 shown in Table 1, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing. [ka] ) depicts a bond between two atoms and indicates the location of mixed stereochemistry for a collection of molecules such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. An asterisk (e.g., [ka] ) indicates a chiral position in a molecule.

[0122] In some embodiments of the invention, the compound of formula I is selected from the compounds shown in Table 1 below, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharma- ceutically acceptable salts of any of the foregoing. [Table 1-1] [Table 1-2] [Table 1-3]

[0123] Some embodiments of the present disclosure include derivatives of compounds 1-26, or compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the derivative is a silicon derivative in which at least one carbon atom in the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts selected from compounds 1-26, or compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing is replaced by silicon. In some embodiments, the derivative is a boron derivative in which at least one carbon atom in the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts selected from compounds 1-26, or compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing is replaced by boron. In another embodiment, the derivative is a phosphorus derivative, in which at least one carbon atom in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-26 or compounds of Formula I, IIa, IIb, tautomers thereof, deuterated derivatives of such compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, is replaced by phosphorus.

[0124] In some embodiments, the derivative is a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-26, or compounds of formulas I, IIa, and IIb, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, in which one carbon atom in the compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt is silicon or a silicon derivative (e.g., Si(CH 3 ) 2 - or -Si(OH) 2 -). The carbon substituted with silicon may be a non-aromatic carbon. In other embodiments, fluorine is a silicon derivative (e.g., -Si(CH3 ) 3 ) is substituted. In some embodiments, the silicon derivatives of the present disclosure may contain one or more hydrogen atoms replaced by deuterium. In some embodiments, the silicon derivatives of compounds 1-26, or compounds of formulas I, IIa, and IIb, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing, may have silicon incorporated into a heterocyclic ring.

[0125] In some embodiments, the derivative is a boron derivative, in which one carbon atom in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-26 or compounds of Formula I, IIa, IIb, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing is replaced by boron or a boron derivative.

[0126] In some embodiments, the derivative is a phosphorus derivative, in which one carbon atom in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-26 or compounds of Formula I, IIa, IIb, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, is replaced by phosphorus or a phosphorus derivative.

[0127] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of formulas selected from Formula I, IIa, and IIb, and compounds 1-26, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from Formula I, IIa, IIb, compounds 1-26, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing is administered to a patient in need thereof.

[0128] The pharmaceutical composition may further comprise at least one pharma- ceutically acceptable carrier. In some embodiments, the at least one pharma- ceutically acceptable carrier is selected from a pharma- ceutically acceptable vehicle and a pharma- ceutically acceptable adjuvant. In some embodiments, the at least one pharma- ceutically acceptable is selected from a pharma- ceutically acceptable filler, a disintegrant, a surfactant, a binder, and a lubricant.

[0129] It will also be understood that the pharmaceutical compositions of the present disclosure may be employed in combination therapy, i.e., the pharmaceutical compositions described herein may further comprise at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative of the compound or tautomer selected from compounds of formula I, IIa, and IIb, their tautomers, deuterated derivatives, or pharma- ceutically acceptable salts, and any of the foregoing, may be administered as a separate composition, either simultaneously with, prior to, or after a composition comprising at least one other active therapeutic agent. In some embodiments, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-26, their tautomers, deuterated derivative of the compound or tautomer, and any of the foregoing, may be administered as a separate composition, either simultaneously with, prior to, or after a composition comprising at least one other active therapeutic agent.

[0130] As mentioned above, the pharmaceutical composition disclosed herein may optionally further comprise at least one pharma- ceutically acceptable carrier. The at least one pharma- ceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, the at least one pharma- ceutically acceptable carrier includes any solvent, diluent, other liquid vehicle, dispersing aid, suspending aid, surface active agent, isotonicity agent, thickener, emulsifier, preservative, solid binder, and lubricant suitable for the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21 stedition, 2,005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988 to 1999, Marcel Dekker, New York, disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except where any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharma- ceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), saturated vegetable fatty acids, partial glyceride mixtures of water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxymethylcellulose sodium, cellulose acetate, cellulose acetate esters ... Examples of suitable carriers include, but are not limited to, cellulose acetate, ethylcellulose, ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavors, fragrances, preservatives, and antioxidants. Uses of the Compounds and Compositions

[0131] In some embodiments of the present disclosure, the compounds and pharmaceutical compositions described herein are used to treat FSGS and / or NDKD. In some embodiments, FSGS is mediated by APOL1. In some embodiments, NDKD is mediated by APOL1.

[0132] In some embodiments of the present disclosure, the compounds and pharmaceutical compositions described herein are used to treat cancer. In some embodiments, the cancer is mediated by APOL1.

[0133] In some embodiments of the present disclosure, the compounds and pharmaceutical compositions described herein are used to treat pancreatic cancer, which in some embodiments is mediated by APOL1.

[0134] In some embodiments, the methods of the disclosure include administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt is selected from compounds 1-26, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the patient in need thereof carries an APOL1 gene mutation, i.e., G1; S342G:I384M, and G2: N388del:Y389del.

[0135] Another aspect of the present disclosure provides a method of inhibiting APOL1 activity comprising contacting APOL1 with at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, IIa, and IIb, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the method of inhibiting APOL1 activity comprises contacting the APOL1 with at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-26, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. EXAMPLES

[0136] In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the disclosure in any manner.

[0137] The compounds of the present disclosure may be made according to standard chemical practices or as described herein. The following abbreviations are used throughout the following synthetic schemes and descriptions for preparing the compounds of formula I, IIa, and IIb, compounds 1-26, their tautomers, deuterated derivatives of the compounds and tautomers, and pharma- ceutically acceptable salts of any of the foregoing:

[0138] Abbreviation n-BuLi = n-butyllithium DCM = dichloromethane DMF = Dimethylformamide DMSO = dimethyl sulfoxide EtOAc = ethyl acetate Et 3 N = triethylamine HPLC = High Performance Liquid Chromatography KI = Potassium iodide K 2 CO 3 = Potassium carbonate LaCl 3 (LiCl) 2 = Lanthanum(III) chloride bis(lithium chloride) complex LCMS = Liquid Chromatography Mass Spectrometry MeCN = acetonitrile MeOH = methanol NaHCO 3 = Sodium bicarbonate Na 2 SO 4 = Sodium sulfate NH 4 Cl = ammonium chloride NMR = nuclear magnetic resonance PMB-Cl = p-Methoxybenzyl chloride, 4-Methoxybenzyl chloride rt = room temperature SFC = Supercritical Fluid Chromatography SiO 2 = Silicon dioxide tet = tetracycline THF = Tetrahydrofuran

[0139] Example 1. Synthesis of Compounds All specific and generic compounds, as well as intermediates disclosed for making those compounds, are considered to be part of the present disclosure disclosed herein.

[0140] compound 1 5-[[(2S,4R)-4-hydroxy-2-methyl-4-(m-tolyl)-1-piperidyl]methyl]-1,3-dimethyl-benzimidazol-2-one (1) [ka]

[0141] Step 1. Synthesis of 1,3-dimethyl-5-[[(2S)-2-methyl-4-oxo-1-piperidyl]methyl]benzimidazol-2-one (C1) A solution of 5-(chloromethyl)-1,3-dimethyl-benzimidazol-2-one (S1) (5.5 g, 22.2 mmol) in DMF (15 mL) was added with (2S)-2-methylpiperidin-4-one (S2) (7.5 g, 59.9 mmol) and K 2 CO 3(15.3 g, 110 mmol) and KI (365 mg, 2.2 mmol) were added at room temperature and the reaction mixture was allowed to warm to 80° C. and stirred at 80° C. for 16 h. At this point, the reaction mixture was poured into ice-cold water (500 mL), extracted with ethyl acetate (3×200 mL), washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (100-200 silica gel, eluted with 5% DCM in methanol). Fractions containing the product were pooled and concentrated to give the title compound C1 (1.2 g, 16%) as a yellow gum. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.12 (s, 1H), 7.09 (m, 2H), 3.93-3.90 (m, 1H), 3.93 (s, 1H), 3.55-3.51 (m, 1H), 3.35-3.30 (m, 6H), 3.01-2.99 (m, 1H), 2.88-2.74 (m, 1H), 2.56-2.51 (m, 1H), 2.49 (m, 1H), 2.30-2.27 (m, 1H), 2.18-2.14 (m, 1H), 1.08 (s, 3H).

[0142] Step 2. Synthesis of 5-[[(2S,4R)-4-hydroxy-2-methyl-4-(m-tolyl)-1-piperidyl]methyl]-1,3-dimethyl-benzimidazol-2-one (1) To a solution of 1-bromo-3-methyl-benzene (C2) (300 mg, 1.7 mmol) and C1 (500 mg, 1.6 mmol) in THF (10 mL) was added n-BuLi (1.4 mL of 2.5 M, 3.5 mmol) at −78° C. The reaction temperature was allowed to warm to room temperature over 2 h. At this point, the reaction mixture was diluted with saturated NH 4 Quench with Cl solution, extract with EtOAc (2×80 mL), wash the combined organics with brine (40 mL), and 2 SO 4The mixture was dried at 40° C. and the solvent was evaporated to give the crude. The crude compound was purified by preparative HPLC (Mobile phase A: 10 mM ammonium bicarbonate (Aq), Mobile phase B: acetonitrile, Column: Xbridge C18, 250 mm×19 mm×5 μm, Flow rate: 14 ml / min, 15-98% MeCN in water, Room temperature). The combined fractions were concentrated under reduced pressure and purified by preparative SFC (Chiralpak(c) IC, 250 mm×30 mm×5 μm, Mobile phase: 45% 30 mM ammonia in methanol, 65% carbon dioxide, 70 mL / min, 100.0 bar, 30° C.). The fractions containing the product were pooled and concentrated to give the title compound 1 (25 mg, 4%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.28-7.24 (m, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.059-6.99 (m, 4H), 4.76 (s, 1H), 3.85 (d, J = 13.2 Hz, 1H), 3.32 (s, 6H), 3.20 (d, J = 13.2 Hz, 1H),2.73-2.69 (m, 1H), 2.60-2.51 (m, 1H), 2.30 (s, 3H), 2.24-2.20 (m, 1H), 2.11-2.07 (m, 1H), 2.03-1.98 (m, 1H), 1.63-1.58 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H). LCMS m / z 380.2 [M+H] + .

[0143] Compounds 2-16 were prepared in a similar manner to compound 1 using appropriately selected 2-(R)-methylpiperidone or 2-(S)-methylpiperidone starting materials as reagent S2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0144] compound 16 (2S,4R)-4-(3-chlorophenyl)-1-[[1-(1,1-dioxothiolan-3-yl)pyrazol-4-yl]methyl]-2-methyl-piperidin-4-ol (16) [ka]

[0145] Step 1. Synthesis of (2S)-1-[(4-methoxyphenyl)methyl]-2-piperidin-4-one (C15) To a solution of (2S)-2-methylpiperidin-4-one hydrochloride salt S3 (6.8 g, 45 mmol) in DMF (50 mL) was added PMB-Cl (8.6284 g, 7.5 mL, 54 mmol), followed by K 2 CO 3 (34.9 g, 247.5 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 h. At this point, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product (12 g). The crude compound was purified by column chromatography (SiO 2、 The crude product was purified by elution with 30-40% ethyl acetate in hexanes). Fractions containing the product were pooled and concentrated to give the title compound C15 (7 g, 67%) as a brown gum. 1 H NMR (300 MHz, DMSO-d 6 ): 7.26 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 3.83-3.76 (m, 1H), 3.73 (s, 3H), 3.69-3.45 (m, 1H), 2.99-2.85 (m, 2H), 2.55-2.44 (m, 2H), 2.35-2.10 (m, 3H), 1.06 (d, J = 6.9 Hz, 3H). LCMS m / z 234.39 [M+H] + .

[0146] Step 2. Synthesis of (2S,4R)-4-(3-chlorophenyl)-1-[(4-methoxyphenyl)methyl]-2-methyl-piperidin-4-ol (C16) To a solution of magnesium (1.6 g, 64.5 mmol) in THF (70 mL) was added 1,2-dibromoethane (50 mg, 0.26 mmol) followed by 1-bromo-3-chloro-benzene (C4) (13.1 g, 10 mL, 67.2 mmol) in THF (70 mL) at room temperature for 75 min. The reaction was cooled to 0° C. at which point a solution of lanthanum(III) chloride bis(lithium chloride) complex in THF (57 mL of 0.6 M, 34.200 mmol) was added over 15 min and allowed to stir at 0° C. for 30 min. A solution of C15 (7 g, 26.1 mmol) in THF (70 mL) was added to the reaction mixture at 0° C. and the reaction was stirred for 1 h. At this point, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2×500 mL), and the combined organic layers were dried over sodium sulfate, filtered, and evaporated in vacuo to give the crude mixture. 2 The residue was purified by column chromatography using 10% MeOH in DCM (eluted with DCM to 10% MeOH in DCM). Fractions containing the product were pooled and concentrated to give the title compound C16 (3 g, 25%) as a brown gum. 1 H NMR (400 MHz, DMSO-d 6) : δ 7.50-7.49 (m, 1H), 7.41-7.38 (m, 1H), 7.32 (t, J =7.6 Hz, 1H), 7.26-7.21 (m, 3H), 6.87 (d, J = 8.8 Hz, 2H), 4.93 (s, 1H), 4.0 (d, J =13.2 Hz, 1H), 3.73 (s, 3H), 3.07 (d, J = 13.2 Hz, 1H), 2.67-2.65 (m, 1H), 2.52-2.49 (m, 1H), 2.40-2.34 (m, 1H), 1.84-1.76 (m, 1H), 1.62-1.60 (m, 2H), 1.49-1.46 (m, 1H), 1.12 (d, J = 6.0 Hz, 3H), LCMS m / z 346.47 [M+H] + .

[0147] Step 3. Synthesis of (2S,4R)-4-(3-chlorophenyl)-2-methyl-piperidin-4-ol hydrochloride (C17) To a solution of C16 (6.4 g, 13.9 mmol) in DCM (140 mL) was added triethylamine (10 mL, 68.4 mmol) and 1-chloroethyl chloroformate (7 mL, 68.2 mmol) at -15°C. The reaction mixture was cooled to -15°C for 2 h. The reaction mixture was evaporated under vacuum to give a crude residue which was redissolved in MeOH (300 mL) and refluxed for 3 h. At this point, the reaction mixture was cooled to room temperature and evaporated under reduced pressure to give a crude brown residue. The crude compound was dissolved in DCM (400 mL) and K 2 CO 3 (30 g, 212.7 mmol) was added and stirred at room temperature for 1 h. The reaction was filtered and the filtrate was evaporated in vacuo to give a crude brown gum. The crude compound was purified by column chromatography (SiO 2 , eluted with 0-10% MeOH in DCM) to give a crude solid, which was recrystallized from MeCN (50 mL) to give the title compound C17 (1.4 g, 38%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6): δ 8.85 (brs, 2H), 7.50-7.49 (m, 1H), 7.43-7.32 (m, 3H), 5.60 (s, 1H), 3.48-3.44 (m, 1H), 3.32-3.18 (m, 2H), 2.21-2.13 (m, 1H), 2.01-1.95 (m, 1H), 1.81-1.72 (m, 2H), 1.25 (d, J = 6.8 Hz, 3H), LCMS m / z 226.11 [M+H] + .

[0148] Step 4. Synthesis of (2S,4R)-4-(3-chlorophenyl)-1-[[1-(1,1-dioxothiolan-3-yl)pyrazol-4-yl]methyl]-2-methyl-piperidin-4-ol (16) A solution of C17 (15 mg, 0.057 mmol) in DCM (1 mL) / Et 3 A solution of N (8 μL, 0.057 mmol) was added. To this slurry was added sodium triacetoxyborohydride (10 mg, 0.047 mmol) and the reaction was stirred overnight. At this point, the reaction was heated to 45° C. and stirred for 5 h. At this point, the reaction was passed through a phase separator and saturated NaHCO 3 (1 mL) and extracted with DCM (1 mL) then passed through a phase separator. The organics were concentrated under a stream of nitrogen. The concentrated crude residue was redissolved in DMSO (1 mL) for purification by reverse phase HPLC. Purification by (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 micron. Gradient: acetonitrile in water with 10 mM ammonium hydroxide) afforded the title compound 16 (5.1 mg, 20%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 7.79 (s, 1H), 7.50 - 7.44 (m, 2H), 7.41 - 7.29 (m, 2H), 7.25 (d, J = 7.8 Hz, 1H), 5.23 (p, J = 7.7 Hz, 1H), 4.90 (s, 1H), 3.72 (dd, J = 13.9, 9.8 Hz, 2H), 3.45 (d, J = 6.0 Hz, 3H), 3.25 (dt, J = 13.3, 8.1 Hz, 1H), 2.69 - 2.39 (m, 3H), 1.92 - 1.82 (m, 1H), 1.56 (p, J = 13.4 Hz, 3H), 1.10 (d, J = 6.1 Hz, 3H). *2H under DMSO. LCMS m / z 424.23 [M+H] + .

[0149] Compounds 17-26 were prepared following the method described for the preparation of compound 16. [Table 3-1] [Table 3-2] [Table 3-3]

[0150] Example 2. Assays for detecting and measuring the APOL1 inhibitor properties of compounds MultiTox-Fluor multiplex cytotoxicity assay The MultiTox-Fluor multiplex cytotoxicity assay is a single-reagent-addition, homogeneous fluorescent assay that simultaneously measures the number of live and dead cells in a culture well. The assay measures cell viability and cytotoxicity by detecting two distinct protease activities. Live cell protease activity is restricted to intact live cells and measured using a fluorogenic cell-permeant peptide glycyl-phenylalanylaminofluorocoumarin (GF-AFC) substrate. The substrate enters intact cells where it is cleaved to generate a fluorescent signal proportional to the number of live cells. This live cell protease activity marker becomes inactive upon loss of membrane integrity and leakage into the surrounding culture medium. A second cell-impermeant fluorescent peptide substrate (bis-AAF-R110 substrate) is used to measure dead cell proteases released from cells that have lost membrane integrity. The ratio of dead to live cells is used to normalize the data.

[0151] Briefly, tet-inducible transgenic APOL1 T-REx-HEK293 cell lines were incubated in duplicate with 50ng / mL tet in the presence of 3-(2-(4-fluorophenyl)-1H-indol-3-yl)-N-((3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl)propenamide 10.03, 3.24, 1.13, 0.356, 0.129, 0.042, 0.129, 0.0045, 0.0015, 0.0005μM in a humidified 37°C incubator for 24 hours to induce APOL1. MultiTox reagent was added to each well and placed back in the incubator for an additional 30 minutes. Plates were read on an EnVision plate reader. Dead to live cell ratio was used for normalization and data was imported, analyzed, and fitted using Genedata Screener (Basel, Switzerland) software. Data was normalized using percentages of control, no tet (100% viability), and 50 ng / mL tet treatment (0% viability) and fitted using Smart Fit. Reagents, methods, and a complete protocol for the MultiTox assay are described below. [Table 4] [Table 5]

[0152] Multiple toxicity assay protocols Human embryonic kidney (HEK293) cell lines G0 DC2.13, G1 DC3.25, and G2 DC4.44 containing the tet-inducible expression system (T-REx™, Invitrogen, Carlsbad, CA) and the adeno-associated virus site 1 pAAVS1-Puro-APOL1 G0 or pAAVS1-Puro-APOL1 G1 or pAAVS1-Puro-APOL1 G2 clones were grown at approximately 90% confluency in T-225 flasks in cell growth medium (DMEM solution, 10% Tet-free FBS, 2 mM L-glutamine, 100 units / mL penicillin-streptomycin, 5 μg / mL blasticidin S HCl, 1 μg / mL puromycin dihydrochloride). The cells were washed with DPBS and then trypsinized to dissociate from the flasks. The trypsin was quenched using medium, then the cells were pelleted at 200 g and resuspended in fresh cell assay medium (DMEM solution, 2% Tet-free FBS, 2 mM L-glutamine, 100 units / mL penicillin-streptomycin). Cells were counted and 1.17×10 6 The cells were diluted to 1000 cells / mL. 20 μL of cells (23,400 / well) were dispensed into each well of a 384-well poly-D-lysine coated plate using a Multidrop dispenser. The plate was then incubated at room temperature for 1 hour.

[0153] Tetracycline is required to induce APOL1 expression. 1 mg / mL tet stock in water was diluted to 250 ng / mL (5x) in cell assay medium. 60 μL of cell assay medium (no tet control) was dispensed into columns 1 and 24, and 60 μL of 5Xtet in a 384-PP-round bottom plate was dispensed into columns 2-23 with a Multidrop dispenser.

[0154] Assay-ready plates from the Global Compound Archive were ordered using the template 384_APOL1Cell_DR10n2_50μM_v3. Compounds were dispensed at 200nL in DMSO. The final top concentration was 10μM, and for the MultiTox assay, 10-point 3-fold dilutions were performed in duplicate.

[0155] 20 μL was transferred from the 5Xtet plate to the ARP and mixed, then 5 μL of 5Xtet plus compound was transferred to the cell plate and mixed using a Bravo. The cell plate was incubated at 37° C. in a humidified 5% CO 2 Place in incubator for 24 hours.

[0156] The MultiTox-Fluor Multiplex Cytotoxicity Assay was performed according to the manufacturer's protocol. After incubating cells with tet and compounds for 24 hours, 25 μL of 1× MultiTox reagent was added to each well using a Multidrop dispenser and the plate was placed on a plate shaker (600 rpm) for 2 minutes, then briefly centrifuged and returned to a 37° C. incubator for 30 minutes. Cell viability (excitation: 400 nm, emission: 486 nm) and cytotoxicity (excitation: 485 nm, emission: 535 nm) were read using an EnVision plate reader. The ratio of dead cells (cytotoxicity) to live cells (viability) was reported. Data was exported and analyzed in Genedata. Data was normalized using percentages of control, no tet (100% viability), and 50 ng / mL tet treatment (0% viability) and fitted using the Smart Fit setting in Genedata.

[0157] Efficacy data for compounds 1-26 The compounds of formula I are useful as inhibitors of APOL1 activity. Table 6 below shows the IC values ​​of compounds 1-26 using the above procedure. 50 The above procedure may be used to determine the potency of any compound of formula I. In Table 6 below, the following meanings apply: IP 50 (i.e., IC of cell proliferation50 ), "+++" means ≦100 nM, "++" means 100 nM-500 nM, and "+" means >500-5000 nM. ND = not determined. [Table 6]

[0158] Other embodiments The present disclosure provides only non-limiting, exemplary embodiments of the disclosed subject matter. Those skilled in the art will readily recognize from this disclosure and the following claims that various changes, modifications, and variations can be made without departing from the spirit and scope of the present disclosure, as defined in the following claims.

Claims

1. A compound represented by the following structural formula: 【Chemistry 27】 a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring A is C ６ aryl, and 5- to 12-membered heterocyclyl, and 5- and 12-membered heteroaryl groups; R １ For each occurrence, halogen, —OH, cyano, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ independently selected from carbocyclyl, and 4- to 6-membered heterocyclyl; R １ wherein said 4- to 6-membered heterocyclyl contains one heteroatom selected from nitrogen and oxygen; R １ The above C １ -C ６ The alkyl is selected from halogen, cyano, —OH, and C １ -C ４ optionally substituted with 1 to 3 groups independently selected from alkoxy groups; R １ The above C １ -C ６ the alkoxy is optionally substituted with 1 to 3 groups independently selected from —OH, cyano, and halogen groups; R １ The above C ３ -C ６ Carbocyclyl is halogen, cyano, —OH, —NH ２ , —NH(C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , C １ -C ４ Alkyl, and C １ -C ４ optionally substituted with 1 to 3 groups independently selected from alkoxy; R ２ and R ３ One of them is hydrogen and the other is C １ -C ４ alkyl groups, R ４ But C １ -C ６ alkyl, and 【Chemistry 28】 is selected from the group R ４ The above C １ -C ６ Alkyl is halogen, cyano, —OH, —NH ２ , —NH(C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , C １ -C ４ Alkoxy, C ３ -C ６ Carbocyclyl, C ６ Aryl, —O—(C ６ aryl), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein R ４ The above C １ ~C ６ The C of alkyl ６ Aryl and —O—(C ６ aryl) groups each containing halogen and C １ ~C ４ optionally substituted with 1 to 3 groups independently selected from haloalkyl groups; R ４ wherein the ring B is C ３ -C １２ Carbocyclyl, 3- to 12-membered heterocyclyl, C ６ and C １０ aryl, and 5- to 10-membered heteroaryl groups, and Ring B is selected from 1, 2, 3, 4, or 5 R ａ optionally substituted with a group, R ａ For each occurrence, halogen, cyano, oxo, C １ -C ８ Alkyl, C １ -C ６ Haloalkyl, C ２ -C ８ Alkenyl, C １ -C ６ Haloalkenyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, C ３ -C １２ Carbocyclyl, C ６ and C １０ Aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, —C(═O)NR ｈ R ｉ , -C(=O)OR ｋ , -C(=O)(C １ -C ４ alkylene) OR ｋ , -C(=O)R ｋ , -C(=O)(C １ -C ４ alkylene)S(=O) ｐ R ｋ , -C(=O)(C １ -C ４ alkylene)S(=O) ｐ NR ｈ R ｉ , -C(=O)(C １ -C ４ alkylene)NR ｉ S (= O) ｐ R ｋ , -C(=O)(C １ -C ４ alkylene)NR ｈ C(=O)R ｋ , -C(=O)C(=O)R ｋ , -NR ｈ R ｉ , —NH(CH2) ｑ CHR ｈ R ｉ , -NH(CH ２ ) ｑ NR ｈ R ｉ , -NR ｈ C(=O)R ｋ , -NR ｈ C(=O)OR ｋ , -NR ｈ C(=O)(C １ -C ４ alkylene) OR ｋ , -NR ｈ C(=O)O(C １ -C ４ alkylene) R ｋ , -NR ｈ C(=O)NR ｉ R ｊ , -NR ｈ C(=O)(C １ -C ４ alkylene)NR ｉ S (= O) ｐ R ｋ , -NR ｈ S (= O) ｐ R ｋ , -NR ｈ C(=O)(C １ -C ４ alkylene)S(=O) ｐ R ｋ , -NR ｈ S (= O) ｐ (C １ -C ４ alkylene)C(=O)OR ｋ , -NR ｈ C(=O)[O(CH ２ ) ｑ ] ｒ OC(=O)NR ｈ R ｉ (CH ２ ) ｑ [O(CH ２ ) ｑ ] ｒ (C １ -C ６ alkyl) (1 to 3 R ｍ group), —NR ｈ C(=O)(C １ -C ６ alkylene) [O(CH ２ ) ｑ ] ｒ OC(=O)NR ｈ R ｉ (CH ２ ) ｑ [O(CH ２ ) ｑ ] ｒ (C １ -C ６ alkyl) (1 to 3 R ｍ optionally substituted with a -OR group; ｋ , —OC(═O)R ｋ , -OC(=O)OR ｋ , -OC(=O)NR ｈ R ｉ , -[O(CH ２ ) ｑ ] ｒ O (C １ -C ６ alkyl), -S(=O) ｐ R ｋ , and -S(=O) ｐ NR ｈ R ｉ is independently selected from the group R ａ -C(=O)(C １ -C ４ alkylene)S(=O) ｐ R ｋ The C in each of １ -C ４ alkylene, -C(=O)(C １ -C ４ alkylene) OR ｋ , -C(=O)(C １ -C ４ alkylene)S(=O) ｐ NR ｈ R ｉ , -C(=O)(C １ -C ４ alkylene)NR ｉ S (= O) ｐ R ｋ , -C(=O)(C １ -C ４ alkylene)NR ｈ C(=O)R ｋ , -NR ｈ C(=O)O(C １ -C ４ alkylene) R ｋ , -NR ｈ C(=O)(C １ -C ４ alkylene) OR ｋ , -NR ｈ S (= O) ｐ (C １ -C ４ alkylene)C(=O)OR ｋ , and -NR ｈ C(=O)(C １ -C ４ alkylene)NR ｉ S (= O) ｐ R ｋ is optionally substituted with 1 to 3 groups independently selected from —OH; R ａ The above C １ -C ８ alkyl, the C １ -C ６ haloalkyl, the C １ -C ６ Alkoxy, and Said C ２ -C ８ Each alkenyl is selected from cyano, —C(═O)R ｋ , -C(=O)OR ｋ , —C(═O)NR ｈ R ｉ , -NR ｈ R ｉ , -NR ｈ C(=O)R ｋ , -NR ｈ C(=O)OR ｋ , -NR ｈ C(=O)NR ｉ R ｊ , -NR ｈ S (= O) ｐ R ｋ , -OR ｋ , -[O(CH ２ ) ｑ ] ｒ OH, -OC(=O)R ｋ , -OC(=O)OR ｋ , -OC(=O)NR ｈ R ｉ , -SR ｋ , -S(=O) ｐ R ｋ , -S(=O) ｐ NR ｈ R ｉ , -[O(CH ２ ) ｑ ] ｒ O (C １ -C ４ alkyl), —O—(C ６ aryl or 5- to 8-membered heteroaryl) (1 to 3 R ｍ optionally substituted with a group), C ３ -C ６ Carbocyclyl (1 to 3 R ｍ optionally substituted with a group), C ６ ~C １０ Aryl (1 to 3 R ｍ group), 5- to 10-membered heterocyclyl (1-3 R ｍ and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 R ｍ optionally substituted with 1 to 3 groups independently selected from the group The C of Ra ３ -C １２ carbocyclyl, the 3- to 12-membered heterocyclyl, C ６ and C １０ The aryl and the 5- to 10-membered heteroaryl are each selected from halogen, cyano, oxo, C １ -C ６ Alkyl (1 to 3 R ｍ optionally substituted with a —C(═O)R group, ｋ , -C(=O)OR ｋ , -NR ｈ R ｉ , -OR ｋ , -S(=O) ｐ R ｋ , -S(=O) ｐ NR ｈ R ｉ , C ６ Aryl (1 to 3 R ｍ and 5- to 10-membered heterocyclyl groups, wherein R ｈ , R ｉ , and R ｊ are, for each occurrence, hydrogen, C, １ -C ６ Alkyl, C ６ -C １０ Aryl, C ３ -C ８ Carbocyclyl (1 to 3 R ｍ aryl (optionally substituted with 1 to 3 R ｍ and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 R ｍ and optionally substituted with a group, wherein R ｈ , R ｉ , and R ｊ Any one of the C １ -C ６ Alkyl is halogen, cyano, —OH, C １ -C ４ Alkoxy, -C(=O)NH(C １ -C ４ alkyl), C ３ -C ６ Carbocyclyl (1 to 3 R ｍ aryl (optionally substituted with 1 to 3 R ｍ and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 R ｍ optionally substituted with 1 to 3 groups independently selected from the group R ｋ For each occurrence, hydrogen, C １ -C ６ Alkyl, benzyl, C ６ Aryl, C ３ -C ６ independently selected from carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein R ｋ Any one of the C １ -C ６ The alkyl is halogen, cyano, -NH ２ , -OH, C １ -C ４ Alkoxy, C ３ -C ６ Cycloalkyl (optionally substituted with 1 to 3 halogen groups), 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 —OH groups), and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 —OH groups). optionally substituted with 1 to 5 groups independently selected from the group: R ｋ Any one of the C ３ -C ６ Carbocyclyl, benzyl, and C ６ Aryl is independently halogen, cyano, oxo, —OH, —C(═O)NH ２ , -C(=O)N(CH ３ ) ２ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C ３ -C ６ cycloalkyl (optionally substituted with 1 to 3 halogen groups), C ６ optionally substituted with 1 to 3 groups independently selected from aryl (optionally substituted with 1 to 3 halogen groups), and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 halogen groups); Said C １ -C ４ the alkyl is optionally substituted with 1 to 3 —OH groups; R ｋ wherein the 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl are each selected from halogen, cyano, —C(═O)CH ３ , -NH ２ , -OH, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C ６ Cycloalkyl, and C １ -C ４ optionally substituted with 1 to 3 groups independently selected from alkoxy groups; Said C １ -C ４ the alkyl is optionally substituted with 1 to 3 —OH groups; R ｍ For each occurrence, halogen, cyano, oxo, -(CH ２ ) ｎ C(=O)NH ２ , -NH ２ , —NH(C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, —C(═O)R ｋ ,- S (= O) ｐ R ｋ , -OR ｋ , C ３ -C ６ independently selected from cycloalkyl, and 5- to 10-membered heterocyclyl groups; R ｍ Any one of the C １ -C ６ alkyl, the C １ -C ６ Alkoxy, and the 5- to 10-membered heterocyclyl is selected from halogen, cyano, —OH, C １ -C ４ optionally substituted with 1 to 3 groups independently selected from alkoxy groups; R ５ is —OH, n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; A compound wherein q and r, for each occurrence, are each an integer independently selected from 0, 1, 2, and 3.

2. Ring A is C ６ aryl, and 5- to 12-membered heterocyclyl; R １ For each occurrence, halogen, C １ -C ６ alkyl (optionally substituted with 1 to 3 groups independently selected from halogen), and C ３ -C ６ cycloalkyl groups, R ２ and R ３ One of them is hydrogen and the other is C １ -C ４ alkyl groups, R ４ but 【Chemistry 29】 is selected from the group Ring B is C ３ -C １２ cycloalkyl, 3- to 12-membered heterocyclyl, C ６ aryl, and 5- to 10-membered heteroaryl groups, and ring B is selected from 1, 2, or 3 R ａ optionally substituted with a group, Each R ａ But, oxo, C １ -C ８ Alkyl (-C(=O)NR ｈ R ｉ , -NR ｈ R ｉ , and -S(=O) ｐ R ｋ optionally substituted with 1 to 3 groups independently selected from １ -C ６ Haloalkyl, C ２ -C ８ Alkenyl, C １ -C ６ Haloalkenyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, C ３ -C １２ Carbocyclyl, C ６ and C １０ aryl, 3- to 12-membered heterocyclyl (optionally substituted with 1 to 3 oxo groups), 5- to 10-membered heteroaryl (halogen and C ６ aryl (optionally substituted with 1 to 3 groups independently selected from the group consisting of aryl (optionally substituted with 1 to 3 halogen groups), —C(═O)NR ｈ R ｉ , and —C(═O)OR ｋ are independently selected from R ｈ , R ｉ , and R ｋ is as defined in claim 1, R ５ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein is -OH.

3. R ２ and R ３ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein one of is hydrogen and the other is methyl.

4. The compound is represented by one of the following structural formulas IIa and IIb: 【Transformation 30】 and 【Chemistry 31】 In the formula, R ２ and R ３ But C １ -C ４ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein:

5. R ２ and R ３ 5. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 4, wherein each is methyl.

6. Ring A is C ６ 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein:

7. Each R １ is halogen and C １ -C ６ 10. The compound of claim 1, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein: R is an integer from 1 to 3; R is an integer from 1 to 3; and R is an integer from 1 to 3.

8. R ４ but, 【Chemistry 32】 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1 selected from:

9. Ring B is a 3- to 12-membered heterocyclyl, C ６ aryl, and 5- to 10-membered heteroaryl groups, and ring B is selected from 1, 2, or 3 R ａ 9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 8, optionally substituted with a group.

10. Ring B is 【Transformation 33】 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 9 selected from:

11. Each R ａ But halogen, oxo, C １ -C ８ Alkyl, C １ -C ６ haloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and —C(═O)NR ｈ R ｉ are independently selected from the group R ａ The above C １ -C ８ Alkyl and the C １ -C ６ Each haloalkyl is —C(═O)NR ｈ R ｉ group, -NR ｈ R ｉ group, and —S(═O) ｐ R ｋ optionally substituted with 1 to 3 groups independently selected from the group R ａ wherein said 3- to 12-membered heterocyclyl is optionally substituted with 1 to 3 oxo groups; R ａ wherein the 5- to 10-membered heteroaryl is selected from the group consisting of halogen and C ６ aryl (optionally substituted with 1 to 3 halogen groups) groups, wherein R ｈ , R ｉ and R ｊ are, for each occurrence, hydrogen and C １ -C ６ independently selected from alkyl groups, R ｋ But for each occurrence, C １ -C ６ 9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 8, wherein:

12. R ４ but 【Transformation 34】 wherein ring B is 【Chemistry 35】 wherein R ａ is absent or halogen, C １ -C ４ Alkyl, and C １ -C ４ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein the compound is selected from alkoxy.

13. R ４ but, 【Transformation 36】 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1 selected from: 【Request Item 14】 【Chemistry 101】 【Chemical Engineering 102】 【Chemistry 103】 or a tautomer thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

15. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 14.

16. Use of a compound according to any one of claims 1 to 14 in the manufacture of a medicament for treating an ApoL1 mediated disease.

17. Use of a compound according to any one of claims 1 to 14 in the manufacture of a pharmaceutical for treating focal segmental glomerulosclerosis (FSGS) and / or non-diabetic kidney disease (NDKD).

18. A composition for use in the treatment of an APOL1-mediated disease, comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 14.

19. A composition for use in the treatment of focal segmental glomerulosclerosis (FSGS) and / or non-diabetic kidney disease (NDKD), comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 14.

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