SPIROCYCLIC INHIBITORS OF APOL1 AND METHODS OF USE THEREOF

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 the 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). JPEG2024544060000117.jpg5039

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 284,195, filed November 30, 2021, the contents of which are incorporated herein by reference in their entirety.

[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 genetic 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 global incidence of 0.2–1.1 / 100,000 / year. FSGS is a disease of podocytes (glomerular visceral epithelial cells) that causes proteinuria and progressive decline in kidney function. NDKD is a kidney disease associated with damage to the podocyte or glomerular vascular bed that is not caused by diabetes. NDKD is characterized by hypertension and progressive decline in kidney function. Human genetic analysis supports the causal role of G1 and G2 APOL1 variants in inducing kidney disease. Individuals with two APOL1 alleles are at increased risk for 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 distinct subgroups based on the underlying etiology. One homogeneous subgroup of FSGS is characterized by the presence of independent consensus sequence variants in the apolipoprotein L1 (APOL1) gene, termed "APOL1 risk alleles," designated G1 and G2. G1 encodes a correlated pair of nonsynonymous amino acid changes (S342G and I384M), G2 encodes a two-amino acid deletion (N388del:Y389del) near the C-terminus of the protein, and G0 is the ancestral (low-risk) allele. A distinct NDKD phenotype is also observed in patients with APOL1 genetic risk variants. In both APOL1-mediated FSGS and NDKD, patients with two risk alleles develop higher levels of proteinuria and more rapid loss of kidney function compared with patients with none or only one APOL1 genetic risk variant. Alternatively, AMKD can cause high levels of proteinuria and rapid loss of kidney function in patients with even one risk allele. See G. Vajgel et al., J. Rheumatol., November 2019, jrheum.190684.

[0005] APOL1 is a 44-kDa protein expressed only in humans, gorillas, and baboons. In humans, the APOL1 gene is expressed in multiple organs, including the liver and kidney. APOL1 is primarily produced by the liver and contains a signal peptide that allows it to be secreted 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 (TbBrucei). APOL1 is endocytosed by TbBrucei and transported to lysosomes. There, it inserts into the lysosomal membrane, forming a pore that results in the parasite's swelling and death.

[0006] Although the ability to lyse Tb brucei is common to all three APOL1 variants (G0, G1, and G2), the APOL1 G1 and G2 variants confer additional protection against parasite species that have evolved serum resistance-associated proteins (SRA) that inhibit APOL1 G0. APOL1 G1 and G2 variants also confer additional protection against trypanosome species that cause sleeping sickness. The G1 and G2 variants escape SRA inhibition, and G1 confers additional protection against Tb gambiense (which causes West African sleeping sickness), while G2 confers additional protection against Tb brucei (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, decreased renal function, podocyte abnormalities, and glomerular sclerosis. Consistent with these data, APOL1 G1 and G2 variants induce and accelerate the progression of FSGS in humans. Individuals with APOL1 risk alleles (i.e., homozygous or compound heterozygous for the APOL1 G1 or APOL1 G2 alleles) are at increased risk for developing FSGS and, if they do develop FSGS, are also at risk for rapid decline in renal function. Therefore, APOL1 inhibition may have a beneficial effect in individuals carrying APOL1 risk alleles.

[0008] Although normal plasma concentrations of APOL1 are relatively high and can vary by 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, APOL1 protein synthesis can be increased by approximately 200-fold by proinflammatory cytokines, such as interferon or tumor necrosis factor-α. In addition, several studies have shown that APOL1 protein forms pH-gated Na+ / K+ pores in the cell membrane, resulting in net intracellular K+ efflux and 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 for developing end-stage kidney disease (ESKD) and proteinuria-related complications, such as infection or thromboembolic events. There are no standardized treatment regimens or approved medications for FSGS or NDKD. Currently, FSGS and NDKD are managed with symptomatic treatment (including blood pressure control using renin-angiotensin system blockers), 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 renin-angiotensin system blockade.

[0011] Corticosteroids, alone or in combination with other immunosuppressants, have induced remission (e.g., remission of proteinuria in a minority of patients) in a minority of patients, but are associated with numerous side effects. However, even in patients who initially respond to corticosteroid and / or immunosuppressive treatment, remission is often short-lived. As a result, patients, particularly those of modern sub-Saharan African descent who carry two APOL1 risk alleles, experience rapid disease progression and end-stage renal disease (ESRD). Therefore, there is an unmet medical need for treatments for FSGS and NDKD. Specifically, given evidence that APOL1 plays a causative role in the induction and accelerated progression of renal disease, APOL1 inhibition should have a beneficial effect on patients with APOL1-mediated renal disease, particularly 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 tissue compared with adjacent tissue and is 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] G.Vajgel et al.,J.Rheumatol.,November 2019,jrheum.190684 [Non-patent document 2] Lin et al.,Cell Death and Disease(2021),12:760 Summary of the Invention [Means for solving the problem]

[0013] One aspect of the present disclosure provides at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, which can be used to treat diseases mediated by APOL1, such as FSGS and NDKD. For example, in some embodiments, the at least one compound is a compound represented by Formula I: [ka] wherein X, Y, Z, R1, R2, R3, ring A, and m are as defined in the embodiments disclosed herein.

[0014] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a compound represented by the following structural formula: [ka] tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is selected from 6-membered aryl and 6-membered heteroaryl groups; X is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Y is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Z is selected from a bond, —CH—, —NH—, —C(O)—, —S(O)—, and —O—, wherein: at least one of X and Y is selected from —CH— and —C(O)—; For each of X, Y, and Z, -CH2- or the hydrogen atom in each instance of -NH- is optionally replaced with R; R1, for each occurrence, is independently selected from halogen, -OH, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)ORc, -C(=O)N(Rc), and -OS(=O)2R groups; Rc, for each occurrence, is independently selected from hydrogen, C-C alkyl, and C-C haloalkyl; The 4- to 6-membered heterocyclyl of R1 contains one heteroatom selected from nitrogen and oxygen; the C1-C6 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, and a C1-C4 alkoxy group; The C1-C6 alkoxy of R1 is optionally substituted with 1 to 3 groups independently selected from -OH, cyano, and halogen groups; the C3-C6 carbocyclyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; The phenyl in R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; R2 is cyano, C1-C6 alkyl, —C(═O)O(C1-C4 alkyl), C2-C6 alkynyl, and [ka] is selected from the C1-C6 alkyl of R2 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl, C6 aryl, and 5- to 10-membered heteroaryl groups; Ring B is selected from C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl groups, and Ring B is optionally substituted with 1, 2, 3, 4, or 5 Ra groups; Ra, for each occurrence, is selected from the group consisting of halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, independently selected from -ORk, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -[O(CH2)q]rO(C1-C6 alkyl), -S(=O)pRk, -S(=O)pNRhRi, -C(=O)ORk, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl groups; The C1-C6 alkyl, C1-C6 alkoxy, and C2-C6 alkenyl of Ra are each independently selected from C6-C10 aryl (optionally substituted with 1 to 3 Rm groups), 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rm groups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rm groups), cyano, —C(═O)Rk, —C(═O)ORk, —C(═O)NRhRi, —NRhRi, —NRhC(═O)Rk, — optionally substituted with 1-3 groups independently selected from NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, -ORk, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -S(=O)pRk, -S(=O)pNRhRi, -O(C6 aryl) (optionally substituted with 1-3 Rm groups), and a C3-C6 carbocyclyl group (optionally substituted with 1-3 Rm groups); The C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, C1-C4 alkyl, -NRhRi, and -ORk groups; Rh, Ri, and Rj are each independently selected for each occurrence from hydrogen, C1-C4 alkyl, C6-C10 aryl, and C3-C6 cycloalkyl groups; the C1-C4 alkyl of any one of Rh, Ri, and Rj is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; Rk, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl; any one C1-C4 alkyl in Rk is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; Rm, for each occurrence, is independently selected from halogen, cyano, oxo, C-C alkyl, C-C alkoxy, -S(=O)pRk, and -ORk groups; the C1-C6 alkyl of Rm is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and —O(C1-C4 alkyl) groups; R3 is selected from C1-C6 alkyl, —C(═O)O(C1-C4 alkyl), C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl groups; the C1-C6 alkyl of R3 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; R3's C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl) (optionally substituted with —OH), —N(C1-C4 alkyl)2, C1-C5 alkyl (optionally substituted with —OH or —S(═O)2(C1-C4 alkyl)), C1-C4 alkoxy, —C(═O)NH2, —C(═O)NH(C1-C4 alkyl), —NHC(═O)(C1-C4 alkyl), —C(═O)(C1-C4 alkoxy), and —C(═O)N(C1-C4 alkyl)2 groups; m is an integer selected from 0, 1, 2, 3, 4, and 5; p, for each occurrence, is an integer independently selected from 1 and 2; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein q and r are integers independently selected from 1, 2, 3, and 4 for each occurrence.

[0015] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, ring A is phenyl; X is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Y is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Z is selected from a bond, —CH—, —NH—, —C(O)—, —S(O)—, and —O—, wherein: at least one of X and Y is selected from —CH— and —C(O)—; For each of X, Y, and Z, the hydrogen atom in each instance of -CH- or -NH- is optionally replaced with R; R1, for each occurrence, is independently selected from halogen, —OH, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, —C(═O)ORc, —C(═O)N(Rc), and —OS(═O)2R groups; Rc, for each occurrence, is independently selected from hydrogen, C-C alkyl, and C-C haloalkyl; the C1-C6 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, and a C1-C4 alkoxy group; The C1-C6 alkoxy of R1 is optionally substituted with 1 to 3 groups independently selected from -OH, cyano, and halogen groups; The phenyl in R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; R2 is C1-C6 alkyl and [ka] is selected from: the C1-C6 alkyl of R2 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl, C6 aryl, and 5- to 10-membered heteroaryl groups; Ring B is selected from a 3- to 12-membered heterocyclyl, C aryl, and a 5- to 10-membered heteroaryl group, and Ring B is optionally substituted with 1, 2, 3, 4, or 5 Ra groups; Ra, for each occurrence, is selected from the group consisting of halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, independently selected from -ORk, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -[O(CH2)q]rO(C1-C6 alkyl), -S(=O)pRk, -S(=O)pNRhRi, -C(=O)ORk, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl groups; The C1-C6 alkyl, C1-C6 alkoxy, and C2-C6 alkenyl of Ra are each independently selected from C6-C10 aryl (optionally substituted with 1 to 3 Rm groups), 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rm groups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rm groups), cyano, -C(=O)Rk, -C(=O)ORk, -C(=O)NRhRi, -NRh optionally substituted by 1 to 3 groups independently selected from Ri, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, -ORk, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -S(=O)pRk, -S(=O)pNRhRi, and a C-C carbocyclyl group (optionally substituted with 1 to 3 Rm groups); The C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, C1-C4 alkyl, -NRhRi, and -ORk groups; Rh, Ri, and Rj are each independently selected for each occurrence from hydrogen, C1-C4 alkyl, C6-C10 aryl, and C3-C6 cycloalkyl groups; the C1-C4 alkyl of any one of Rh, Ri, and Rj is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; Rk, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl; any one C1-C4 alkyl in Rk is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; Rm, for each occurrence, is independently selected from halogen, cyano, oxo, C-C alkyl, C-C alkoxy, -S(=O)pRk, and -ORk groups; the C1-C6 alkyl of Rm is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; R3 is selected from C1-C6 alkyl groups, wherein: the C1-C6 alkyl of R3 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; m is an integer selected from 0, 1, 2, and 3; p, for each occurrence, is an integer independently selected from 1 and 2; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein q and r are integers independently selected from 1, 2, 3, and 4 for each occurrence.

[0016] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, ring A is phenyl; X is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Y is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Z is selected from a bond, —CH—, —NH—, —C(O)—, —S(O)—, and —O—, wherein: at least one of X and Y is selected from —CH— and —C(O)—; For each of X, Y, and Z, the hydrogen atom in each instance of -CH- or -NH- is optionally replaced with R; R1, for each occurrence, is independently selected from halogen, -OH, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)ORc, -C(=O)N(Rc), and -OS(=O)2R groups; Rc, for each occurrence, is independently selected from hydrogen, C-C alkyl, and C-C haloalkyl; the C1-C6 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH groups; R2 is [ka] where: Ring B is selected from a 5-membered heterocyclyl and a 5-membered heteroaryl group, and Ring B is optionally substituted with 1 or 2 Ra groups; Ra, for each occurrence, is independently selected from a C-C alkyl group optionally substituted with one group independently selected from —S(═O)pRk groups; Rk, for each occurrence, is independently selected from a C1-C4 alkyl group; R3 is selected from C1-C3 alkyl groups; m is an integer selected from 0, 1, 2, and 3; p is an integer independently selected from 1 and 2 for each occurrence.

[0017] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, ring A is phenyl; X is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Y is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Z is selected from a bond, —CH—, —NH—, —C(O)—, —S(O)—, and —O—, wherein: at least one of X and Y is selected from —CH— and —C(O)—; For each of X, Y, and Z, the hydrogen atom in each instance of -CH- or -NH- is optionally replaced with R; R1, for each occurrence, is independently selected from halogen, -OH, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)ORc, -C(=O)N(Rc), and -OS(=O)2R groups; Rc, for each occurrence, is independently selected from hydrogen, C-C alkyl, and C-C haloalkyl; the C1-C6 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH groups; R2 is [ka] wherein: Ring B is selected from a pyrazole group and a triazole group, and Ring B is optionally substituted with one or two Ra groups, wherein Ra, for each occurrence, is independently selected from a C-C alkyl group optionally substituted with one group independently selected from —S(═O)pRk groups; Rk, for each occurrence, is independently selected from a C1-C4 alkyl group; R3 is methyl; m is an integer selected from 0, 1, 2, and 3; p is an integer independently selected from 1 and 2 for each occurrence.

[0018] In one aspect of the disclosure, the compound of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC is selected from compounds 1-42 and compounds I1-I36, whereby at least one compound, pharmaceutically acceptable salt, solvate, or deuterated derivative is selected from compounds 1-42 and compounds I1-I36, a pharmaceutically acceptable salt of any of those compounds, a solvate of any of the foregoing, and a deuterated derivative of any of the foregoing.

[0019] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions may comprise at least one compound selected from compounds 1-42 and compounds I1-I36, pharmaceutically acceptable salts of any of these compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. These compositions may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0020] Another aspect of the present disclosure provides a method of treating an APOL1-mediated disease, comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, VC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0021] Another aspect of the present disclosure provides a method of treating an APOL1-mediated cancer (e.g., pancreatic cancer), comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, VC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0022] Another aspect of the present disclosure provides a method of treating an 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 pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, VC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0023] 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 in a separate composition as at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the methods comprise administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, together with at least one additional active agent, either in the same pharmaceutical composition or in a separate composition.

[0024] Also provided is a method of inhibiting APOL1 comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, VC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method of inhibiting APOL1 comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. DETAILED DESCRIPTION OF THE INVENTION

[0025] definition The term "APOL1" as used herein means apolipoprotein L1 protein and the term "APOL1" means apolipoprotein L1 gene.

[0026] The term "APOL1-mediated disease" refers to a disease or condition associated with abnormal APOL1 (e.g., a particular APOL1 genetic 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.

[0027] The term "APOL1-mediated renal disease" refers to a disease or condition that impairs kidney function and can be caused by APOL1. In some embodiments, the APOL1-mediated renal disease is associated with a patient who has two APOL1 risk alleles, for example, who is 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, arteriosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1-mediated renal disease is chronic kidney disease or proteinuria.

[0028] As used herein, the term "FSGS" means focal segmental glomerulosclerosis, a disease of podocytes (glomerular visceral epithelial cells) that causes proteinuria and progressive decline in kidney function and is associated with two common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0029] The term "NDKD" as used herein means non-diabetic kidney disease characterized by severe hypertension and progressive decline in kidney function and associated with two common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0030] 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, in which the kidneys do not function sufficiently and the patient cannot survive without dialysis or a kidney transplant. In some embodiments, ESKD / ESRD is associated with two APOL1 risk alleles.

[0031] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having identical chemical structures, 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 among 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 shown also includes lesser amounts of isotopic substitutions having hydrogen atoms at one or more of the designated deuterium positions in the structure. The relative amounts 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 noted 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 substitution 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 compound.

[0032] 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 this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0033] The term "isotopically modified" refers to a species whose chemical structure differs from a reference compound only in its isotopic composition. Additionally, unless otherwise specified, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon by 13C or 14C are within the scope of this disclosure.

[0034] Unless otherwise indicated, structures depicted herein are also intended to include all isomeric forms of the structure, e.g., geometric (or conformational) isomers, such as racemic mixtures, cis / trans isomers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the present compounds are within the scope of this disclosure. Unless otherwise specified, all tautomeric forms of the compounds of this disclosure are within the scope of this disclosure.

[0035] 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 interchangeable by migration of atoms, e.g., hydrogen atoms, or groups, within the molecule.

[0036] "Stereoisomers" as used herein refers to enantiomers and diastereomers.

[0037] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ("D" or "2H"). 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 their 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 present 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).

[0038] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0039] As used herein, the term "alkyl" or "aliphatic" refers to 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-chain or unbranched. In some embodiments, an alkyl group is branched.

[0040] As used herein, the terms "cycloalkyl" and "cyclic alkyl" refer to a fully saturated monocyclic C hydrocarbon, or a spirocyclic, fused, or bridged bicyclic or tricyclic C hydrocarbon, wherein any individual ring within the bicyclic ring system has from 3 to 7 members. In some embodiments, a cycloalkyl is a C-C cycloalkyl. In some embodiments, a cycloalkyl is a C-C cycloalkyl. In some embodiments, a cycloalkyl is a C-C cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0041] As used herein, the term "carbocyclyl" or "cycloaliphatic" encompasses the terms "cycloalkyl" or "cyclic alkyl" and refers to a monocyclic C hydrocarbon, or a spirocyclic, fused, or bridged bicyclic or tricyclic C hydrocarbon, that is fully saturated or partially saturated to contain one or more saturated units, but is not aromatic, wherein any individual ring in the bicyclic ring system has 3 to 7 members. A bicyclic carbocyclyl includes a combination of a monocyclic carbocycle fused to a phenyl. In some embodiments, a carbocyclyl is a C-C carbocyclyl. In some embodiments, a carbocyclyl is a C-C carbocyclyl. In some embodiments, a carbocyclyl is a C-C carbocyclyl.

[0042] 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.

[0043] As used herein, the term "alkenyl" means 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.

[0044] As used herein, the terms "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" mean a non-aromatic (i.e., fully saturated or partially saturated because it contains one or more units of unsaturation, but not aromatic), monocyclic, or spirocyclic, fused, or bridged bicyclic or tricyclic ring system in which one or more ring members are independently selected heteroatoms. Bicyclic heterocyclyls include the following combinations of monocyclic rings: a monocyclic heteroaryl fused to a monocyclic heterocyclyl; a monocyclic heterocyclyl fused to another monocyclic heterocyclyl; a monocyclic heterocyclyl fused to a phenyl; a monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and a monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl.

[0045] In some embodiments, the heterocycle includes ring atoms substituted with one or more oxo groups (eg, C=O, S=O, or SO2 groups).

[0046] In some embodiments, a "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" group has 3 to 14 ring members, where one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3 to 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, and phosphorus. In some embodiments, a heterocycle has one heteroatom that is a nitrogen atom. In some embodiments, a heterocycle has one heteroatom that is an oxygen atom. In some embodiments, a heterocycle has two heteroatoms independently selected from nitrogen and oxygen. In some embodiments, a heterocycle has three heteroatoms independently selected from nitrogen and oxygen. In some embodiments, a 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.

[0047] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, for example, any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl)).

[0048] 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.

[0049] 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 connected 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.

[0050] As used herein, the terms "haloalkyl," "haloalkenyl," and "haloalkoxy" mean straight-chain or branched alkyl, alkenyl, or alkoxy, respectively, substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF, -CHF, -CF, -CF-, and perhaloalkyl, such as -CFCF. Non-limiting examples of haloalkoxy groups include -OCHF, -OCHF, -OCF, and -OCF.

[0051] The term "halogen" includes F, Cl, Br, and I, ie, fluoro, chloro, bromo, and iodo, respectively.

[0052] The term "aminoalkyl" refers to an alkyl group that is substituted with or contains an amino group.

[0053] As used herein, "amino" refers to a group that is a primary, secondary, or tertiary amine.

[0054] As used herein, a "carbonyl" group refers to C=O.

[0055] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0056] As used herein, a "hydroxy" group refers to an --OH group.

[0057] As used herein, a "thiol" group refers to -SH.

[0058] As used herein, "tert" and "t-" each refer to tertiary.

[0059] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system having delocalized pi orbitals consisting of [4n+2]p electrons, where n is an integer ranging from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0060] The term "aryl," used alone or as part of a larger moiety, as in "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 (C6) and naphthyl (C10) rings.

[0061] The term "heteroaryl," used alone or as part of a larger moiety, such as "heteroarylalkyl" or "heteroarylalkoxy," refers to a monocyclic, spirocyclic, fused, or bridged bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and 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, heteroaryl is a 3- to 12-membered heteroaryl. In some embodiments, heteroaryl is a 3- to 10-membered heteroaryl. In some embodiments, heteroaryl is a 3- to 8-membered heteroaryl. In some embodiments, heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, heteroaryl is a 5- to 8-membered heteroaryl. In some embodiments, heteroaryl is a 5- or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls include pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, and the like.

[0062] In some embodiments, the heteroaryl includes one or more ring atoms substituted with one or more oxo groups (e.g., C=O, S=O, or SO groups). Illustratively, a non-limiting example of a heteroaryl group is a benzo[d]oxazol-2(3H)-one group.

[0063] Non-limiting examples of useful protecting groups for nitrogen-containing groups such as amine groups include, for example, t-butylcarbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethylcarbamate (Fmoc), benzylcarbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide.Methods for adding (commonly referred to as "protecting") and removing (commonly referred to as "deprotecting") such amine protecting groups are well known in the art, and can be found, for example, in PJ 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 Jersey, 2014), which are incorporated herein by reference in their entirety.

[0064] Non-limiting examples of suitable solvents that may be used in the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CHCl), 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-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0065] Non-limiting examples of suitable bases that can be used in the present disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (KCO), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropyl-ethylamine (i-PrEtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH).

[0066] The present disclosure includes pharmaceutically acceptable salts of the disclosed compounds, which are 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.

[0067] 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 S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0068] Acids commonly employed to form pharmaceutically 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 pharmaceutically acceptable salts include 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. benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0069] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N(C1-4 alkyl)4 salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups 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.

[0070] The terms "patient" and "subject" are used interchangeably herein and refer to animals, including humans.

[0071] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of the compound for which it is administered that produces the desired effect (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 reduction in the progression of FSGS and / or NDKD, or reduction in the progression of symptoms of FSGS and / or NDKD). The exact amount of the effective dose will depend on the purpose of treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0072] As used herein, the term "treatment" and its cognate terms refer to the slowing or stopping of disease progression.As used herein, "treatment" and its cognate terms 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).The 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.

[0073] The terms "about" and "approximately," when used in reference to a dose, amount, or weight percent of a component of a composition or dosage form, include a particular dose, amount, or weight percent value, or a range of doses, amounts, or weight percent, that would be recognized by one of skill in the art as providing an equivalent pharmacological effect to that obtained from the particular dose, amount, or weight percent.

[0074] At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, can be administered, for example, once daily, twice daily, or three times daily, for the treatment of FSGS. In some embodiments, the compound of formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC is selected from compounds 1-42, and compounds I1-I36, tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, is administered once daily. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, is administered once daily.In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, is administered twice daily. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, is administered twice daily. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, is administered three times daily. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, is administered three times daily.

[0075] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, a tautomer thereof, a deuterated derivative of such a compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing is 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, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, is administered once daily, twice daily, or three times daily.

[0076] Those skilled in the art will recognize that when the amount of a compound is disclosed, the relative amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. The amounts of compounds, pharmaceutically 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 pharmaceutically acceptable salt selected from the compound of Formula I and its pharmaceutically acceptable salts" includes 1000 mg of the compound of Formula I and a pharmaceutically acceptable salt of the compound of Formula I at a concentration equivalent to 1000 mg of the compound of Formula I.

[0077] As used herein, the term "ambient conditions" means room temperature, outside air conditions, and uncontrolled humidity conditions.

[0078] Compounds and Compositions In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a compound represented by the following structural formula: [ka] tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is selected from 6-membered aryl and 6-membered heteroaryl groups; X is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Y is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Z is selected from a bond, —CH—, —NH—, —C(O)—, —S(O)—, and —O—, wherein: at least one of X and Y is selected from —CH— and —C(O)—; For each of X, Y, and Z, the hydrogen atom in each instance of -CH- or -NH- is optionally replaced with R; R1, for each occurrence, is independently selected from halogen, -OH, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)ORc, -C(=O)N(Rc), and -OS(=O)2R groups; Rc, for each occurrence, is independently selected from hydrogen, C-C alkyl, and C-C haloalkyl; The 4- to 6-membered heterocyclyl of R1 contains one heteroatom selected from nitrogen and oxygen; the C1-C6 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, and a C1-C4 alkoxy group; The C1-C6 alkoxy of R1 is optionally substituted with 1 to 3 groups independently selected from -OH, cyano, and halogen groups; the C3-C6 carbocyclyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; The phenyl in R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; R2 is cyano, C1-C6 alkyl, —C(═O)O(C1-C4 alkyl), C2-C6 alkynyl, and [ka] is selected from the C1-C6 alkyl of R2 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl, C6 aryl, and 5- to 10-membered heteroaryl groups; Ring B is selected from C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl groups, and Ring B is optionally substituted with 1, 2, 3, 4, or 5 Ra groups; Ra, for each occurrence, is selected from the group consisting of halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, independently selected from -ORk, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -[O(CH2)q]rO(C1-C6 alkyl), -S(=O)pRk, -S(=O)pNRhRi, -C(=O)ORk, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl groups; The C1-C6 alkyl, C1-C6 alkoxy, and C2-C6 alkenyl of Ra are each C6-C10 aryl (optionally substituted with 1 to 3 Rm groups), 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rm groups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rm groups), cyano, -C(=O)Rk, -C(=O)ORk, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, -ORk, -OC(=O)Rk, optionally substituted with 1-3 groups independently selected from -OC(=O)ORk, -OC(=O)NRhRi, -S(=O)pRk, -S(=O)pNRhRi, -O(C6 aryl) (optionally substituted with 1-3 Rm groups), and a C3-C6 carbocyclyl group (optionally substituted with 1-3 Rm groups); The C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, C1-C4 alkyl, -NRhRi, and -ORk groups; Rh, Ri, and Rj are each independently selected for each occurrence from hydrogen, C1-C4 alkyl, C6-C10 aryl, and C3-C6 cycloalkyl groups; the C1-C4 alkyl of any one of Rh, Ri, and Rj is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; Rk, for each occurrence, is selected from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl groups, wherein any one C1-C4 alkyl in Rk is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; Rm, for each occurrence, is independently selected from halogen, cyano, oxo, C-C alkyl, C-C alkoxy, -S(=O)pRk, and -ORk groups; the C1-C6 alkyl of Rm is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and —O(C1-C4 alkyl) groups; R3 is selected from C1-C6 alkyl, —C(═O)O(C1-C4 alkyl), C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl groups; the C1-C6 alkyl of R3 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; R3's C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl) (optionally substituted with —OH), —N(C1-C4 alkyl)2, C1-C5 alkyl (optionally substituted with —OH or —S(═O)2(C1-C4 alkyl)), C1-C4 alkoxy, —C(═O)NH2, —C(═O)NH(C1-C4 alkyl), —NHC(═O)(C1-C4 alkyl), —C(═O)(C1-C4 alkoxy), and —C(═O)N(C1-C4 alkyl)2 groups; m is an integer selected from 0, 1, 2, 3, 4, and 5; p, for each occurrence, is an integer independently selected from 1 and 2; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein q and r are integers independently selected from 1, 2, 3, and 4 for each occurrence.

[0079] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, m is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, m is 0, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, m is 1, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0080] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring A is phenyl, pyrimidinyl, or pyridinyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring A is phenyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring A is pyrimidinyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ring A is pyridinyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0081] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R2 is C1-C4 alkyl and [ka] is selected from the group The C1-C4 alkyl of R2 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, C1-C2 alkoxy, C3-C6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl groups, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0082] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R2 is C1-C2 alkyl and [ka] is selected from the group The C1-C2 alkyl of R2 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and a 5- to 6-membered heterocyclyl group, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0083] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R2 is -CH3 and [ka] All other variables selected from groups not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0084] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R2 is selected from -CH3, -CH2OH, and (tetrahydro-2H-pyran-4-yl)methyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0085] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring B is selected from cyclopropyl, 5- to 10-membered heterocyclyl, phenyl, and 5- to 9-membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 Ra groups, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0086] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring B is selected from cyclopropyl, a 5- to 10-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, phenyl, and a 5- to 9-membered heteroaryl containing 1-3 heteroatoms selected from N and O, each of which is optionally substituted with 1, 2, 3, 4, or 5 R groups, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0087] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring B is selected from cyclopropyl, a 5-membered heterocyclyl having 1-3 heteroatoms selected from N and O, a 6-membered heterocyclyl having 1-3 heteroatoms selected from N and O, a 9-membered heterocyclyl having 1-3 heteroatoms selected from N and O, a 10-membered heterocyclyl having 1-3 heteroatoms selected from N and O, phenyl, a 5-membered heteroaryl having 1-3 heteroatoms selected from N and O, a 6-membered heteroaryl having 1-3 heteroatoms selected from N and O, a 9-membered heteroaryl having 1-3 heteroatoms selected from N and O, each of which is optionally substituted with 1, 2, 3, 4, or 5 R groups; and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0088] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, Ring B is: [ka] each of which is optionally substituted with 1, 2, 3, 4, or 5 Ra groups, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0089] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, Ring B is: [ka] [ka] each of which is optionally substituted with 1, 2, 3, 4, or 5 Ra groups, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0090] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R2 is selected from -CH3 and Ring B, and Ring B is [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. [ka] and optionally substituted with one Ra group.

[0091] In some embodiments, in the disclosed compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, R3 is selected from C1-C4 alkyl, —C(═O)O(C1-C2 alkyl), C3-C6 cycloalkyl, and a 5- to 10-membered heterocyclyl group; the C1-C4 alkyl of R3 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and a C1-C2 alkoxy group; R3 C3-C6 cycloalkyl and 5-10 membered heterocyclyl are each optionally substituted with 1-3 groups independently selected from halogen, cyano, —OH, C1-C2 alkyl, and C1-C2 alkoxy groups; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0092] In some embodiments, in the disclosed compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, R3 is selected from C1-C2 alkyl, —C(═O)O(C1-C2 alkyl), cyclopropyl, cyclobutyl, and a 5- to 6-membered heterocyclyl group; the C1-C2 alkyl of R3 is optionally substituted with 1 to 3 groups independently selected from F, Cl, Br, cyano, —OH, and a C1-C2 alkoxy group; R3 cyclopropyl, cyclobutyl, and 5- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups independently selected from F, Cl, Br, cyano, —OH, C1-C2 alkyl, and C1-C2 alkoxy groups; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0093] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R3 is selected from -CH3, -CH2CH3, -CH2OH, -C(=O)OCH3, -CHOCH3, -CH(CH3)2, cyclopropyl, difluorocyclopropyl, and tetrahydro-2H-pyranyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0094] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R3 is -CH3, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0095] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R is, for each occurrence, independently selected from hydrogen, halogen, cyano, —OH, C-C alkyl, C-C alkoxy, —C(═O)N(R), and a C-C cycloalkyl group, wherein: Rc, for each occurrence, is independently selected from hydrogen and a C1-C2 alkyl group; the C1-C4 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and a C1-C2 alkoxy group; The C1-C4 alkoxy in R1 is optionally substituted with 1 to 3 independently selected halogen groups; the C3-C6 cycloalkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and a C1-C2 alkoxy group; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0096] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R is, for each occurrence, independently selected from hydrogen, halogen, cyano, —OH, C-C alkyl, C-C alkoxy, and C-C cycloalkyl; the C1-C4 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C2 alkoxy; The C1-C4 alkoxy in R1 is optionally substituted with 1 to 3 independently selected halogen groups; the C3-C6 cycloalkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C2 alkoxy; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0097] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R is, for each occurrence, independently selected from F, Cl, Br, C-C alkyl, and C-C cycloalkyl; the C1-C4 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; The C3-C6 cycloalkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0098] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R, for each occurrence, is independently selected from F, Cl, Br, C-C alkyl, C-C alkoxy, —C(═O)N(R), and a C-C cycloalkyl group, wherein: Rc, for each occurrence, is independently selected from hydrogen and a C1-C2 alkyl group; the C1-C4 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; The C1-C4 alkoxy in R1 is optionally substituted with 1 to 3 independently selected halogen groups; The C3-C6 cycloalkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0099] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R is, for each occurrence, independently selected from F, Cl, Br, C-C alkyl, and C-C cycloalkyl; the C1-C4 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; The C3-C6 cycloalkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0100] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R, for each occurrence, is independently selected from F, Cl, Br, C-C alkyl, C-C alkoxy, —C(═O)N(R), and a C-C cycloalkyl group, wherein: Rc, for each occurrence, is independently selected from hydrogen and a C1-C2 alkyl group; the C1-C4 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; The C1-C4 alkoxy in R1 is optionally substituted with 1 to 3 independently selected halogen groups; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0101] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R1, for each occurrence, is independently selected from Cl, Br, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH2CHF2, -CH2CH(CH3)2, difluorocyclobutyl, and cyclohexyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0102] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R1, for each occurrence, is independently selected from F, Cl, Br, -CH3, -CH(CH3)2, -CF3, -OCH3, -OCF3, -C(=O)N(CH3)2, and cyclopropyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0103] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R1 is Cl for each occurrence, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0104] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R is, for each occurrence, independently selected from halogen, —OH, and C-C alkyl; the C1-C4 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0105] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R is, for each occurrence, independently selected from F, Cl, Br, —OH, and C-C alkyl; the C1-C2 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from F, Cl, and —OH; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0106] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R1 is independently selected for each occurrence from F, —OH, —CH3, —CHF2, and —CH2OH, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0107] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ra is, for each occurrence, independently selected from halogen, cyano, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, —C(═O)NRhRi, —NRhRi, —NRhC(═O)Rk, —ORk, —[O(CH)q]rO(C-C6 alkyl), —S(═O)2Rk, —S(═O)2NRhRi, C-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl; the C1-C6 alkyl of Ra is optionally substituted with 1 to 3 groups independently selected from cyano, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, -ORk, -S(=O)2Rk, -S(=O)pNRhRi, and C3-C6 cycloalkyl; Each of the C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl in Ra is optionally substituted with 1 to 3 groups independently selected from halogen, C1-C2 alkyl, and -ORk; Rh, Ri, and Rj, for each occurrence, are each independently selected from hydrogen, C1-C2 alkyl, cyclopropyl, and cyclobutyl; C1-C2 alkyl of any one of Rh, Ri, and Rj is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; Rk, for each occurrence, is independently selected from hydrogen and C1-C4 alkyl; The C1-C4 alkyl of Rk is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; q and r are each an integer selected from 1, 2, and 3; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0108] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ra is, for each occurrence, independently selected from halogen, cyano, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, —C(═O)NRhRi, —NRhRi, —NRhC(═O)Rk, —ORk, —[O(CH)q]rO(C-C4 alkyl), —S(═O)2Rk, —S(═O)2NRhRi, cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl; The C1-C6 alkyl of Ra is optionally substituted with 1 to 3 groups independently selected from cyano, —C(═O)NRhRi, —NRhRi, —ORk, cyclopropyl, and cyclobutyl; Each of the cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl in Ra is optionally substituted with 1 to 3 groups independently selected from halogen, —CH3, —OH, and —OCH3; Rh and Ri are each independently selected for each occurrence from hydrogen, —CH3, cyclopropyl, and cyclobutyl; -CH3 of any one of Rh and Ri is optionally substituted with 1 to 3 groups independently selected from F, Cl, and -OH; Rk, for each occurrence, is independently selected from hydrogen and -CH3; -CH3 of Rk is optionally substituted with 1 to 3 groups independently selected from halogen and -OH; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0109] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ra, for each occurrence, is independently selected from F, Cl, Br, cyano, C-C alkyl, C-C alkoxy, C-C haloalkyl, —C(═O)NRhRi, —NRhRi, —NRhC(═O)Rk, —ORk, —[O(CH)q]rO(C-C2 alkyl), —S(═O)2Rk, —S(═O)2NRhRi, cyclopropyl, cyclobutyl, 5-membered heterocyclyl, phenyl, and 6-membered heteroaryl; The C1-C6 alkyl of Ra is optionally substituted with 1 to 3 groups independently selected from cyano, —C(═O)NRhRi, —ORk, and cyclopropyl; Each of the cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl in Ra is optionally substituted with 1 to 3 groups independently selected from halogen, —CH3, —OH, and —OCH3; Rh and Ri are each independently selected for each occurrence from hydrogen, —CH3, and cyclopropyl; -CH3 of any one of Rh and Ri is optionally substituted with 1 to 3 groups independently selected from F, Cl, and -OH; Rk, for each occurrence, is independently selected from hydrogen and -CH3; q and r are each integers independently selected from 1 and 2; All other variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0110] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ra is, for each occurrence, F, cyano, —OH, —CH, —CF, —CH(CH), —(CH)OH, —(CH)OCH, —CHCH(OH)CH, —CHC(CH)(CHOH), —OCH, —OCHCH, —[O(CH)]OCH, —CHC(═O)NHCH, —(CH)SOCH, —CHC(═O)N(CH), —CH(cyclopropyl), — All other variables independently selected from C(=O)NH2, -C(=O)NH(cyclopropyl), -NH2, -NHCH3, -N(CH3)2, -NHC(CH3)2CH2OH, -NHC(=O)CH3, -SO2CH3, -SON2NH2, cyclopropyl, 2-methoxyphenyl, N-methylpiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl, and tetrahydrothiophenyl 1,1-dioxide and not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0111] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Ra is independently selected for each occurrence from -CH3 and -(CH2)2SO2CH3, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0112] In some embodiments, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is represented by one of the following structural formulas: [ka] tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0113] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a compound represented by one of the following structural formulas: [ka] tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0114] In some embodiments, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is represented by one of the following structural formulas: [ka] tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0115] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a compound represented by one of the following structural formulas: [ka] tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0116] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a compound represented by one of the following structural formulas: [ka] tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: R1a is selected from hydrogen, halogen, -OH, and a phenyl group, wherein: The phenyl of R1a is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; R and R are each independently selected from hydrogen, halogen, —OH, cyano, C-C alkyl, C-C alkoxy, —C(═O)OR, —C(═O)N(R), and —OS(═O)R groups; Rc, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; The C1-C6 alkyl of R1b and / or R1c is optionally substituted with 1 to 3 groups independently selected from halogen and —OH groups; All variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0117] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a compound represented by one of the following structural formulas: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R1a is selected from hydrogen, phenyl, and a C(=O)N(Rc1)2 group; The phenyl of R1a is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; Rc1, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R1b and R1c are each independently selected from hydrogen and a halogen group; All variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0118] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a compound represented by one of the following structural formulas: [ka] tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: R1a and R1b are each independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 haloalkyl groups; All variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0119] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a compound represented by one of the following structural formulas: [ka] tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: R1a and R1b are each independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 haloalkyl groups; All variables not specifically defined in this embodiment are as defined in any one of the previous embodiments.

[0120] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a silicon derivative represented by one of the following structural formulas: [ka] tautomers thereof, silicon derivatives or deuterated derivatives of the tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein all variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0121] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a boron derivative represented by one of the following structural formulas: [ka] tautomers thereof, boron derivatives or deuterated derivatives of the tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein all variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0122] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is selected from compounds 1-42 shown in Table 1, tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. [ka] represents a bond between two atoms and indicates the location of mixed stereochemistry in 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 the molecule.

[0123] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is selected from compounds I1-I36 shown in Table 2, tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. [ka] represents a bond between two atoms and indicates the location of mixed stereochemistry in 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 the molecule. [Table 1-1] [Table 1-2] [Table 1-3] [Table 2-1] [Table 2-2] [Table 2-3]

[0124] Some embodiments of the present disclosure include derivatives of compounds 1-42 and compounds I1-I36, or compounds of formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the derivative is a silicon derivative in which at least one carbon atom of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, or compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with silicon. In some embodiments, the derivative is a boron derivative, in which at least one carbon atom of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, or compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with boron.In another embodiment, the derivative is a phosphorus derivative, in which at least one carbon atom of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, or a compound of formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, a tautomer thereof, a deuterated derivative of such a compound or tautomer, and a pharmaceutically acceptable salt of any of the foregoing, is replaced with phosphorus.

[0125] In some embodiments, the derivative is a silicon derivative in which one carbon atom of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, or compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with silicon or a silicon derivative (e.g., —Si(CH3)2— or —Si(OH)2—). The carbon substituted with silicon may be a non-aromatic carbon. In other embodiments, fluorine is replaced with a silicon derivative (e.g., —Si(CH3)3). In some embodiments, the silicon derivatives of the present invention may contain one or more hydrogen atoms replaced with deuterium. In some embodiments, the derivative is a silicon derivative of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, or a compound of formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, a tautomer thereof, a deuterated derivative of a compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein the silicon derivative can be silicon incorporated into a heterocycle.

[0126] In some embodiments, the derivative is a boron derivative in which one carbon atom of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, or compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with boron or a boron derivative.

[0127] In some embodiments, the derivative is a phosphorus derivative in which one carbon atom of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, or compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with phosphorus or a phosphorus derivative.

[0128] Another aspect of the disclosure provides pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of formulas selected from Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, as well as compounds 1-42 and compounds I1-I36, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, and compounds 1-42 and I1-I36, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered to a patient in need thereof.

[0129] The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the at least one pharmaceutically acceptable is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0130] It will also be understood that the pharmaceutical compositions of the present disclosure can be employed in combination therapy, i.e., the pharmaceutical compositions described herein can further comprise at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing can be administered as a separate composition simultaneously with, before, 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 pharmaceutically acceptable salt selected from Compounds 1-42 and Compounds I1-I36, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be administered as a separate composition simultaneously with, before, or after a composition comprising at least one other active therapeutic agent.

[0131] As mentioned above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier.The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles.As used herein, at least one pharmaceutically acceptable carrier includes any solvent, diluent, other liquid vehicle, dispersion aid, suspension aid, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder, and lubricant suitable for the specific dosage form desired.Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J. Swarbrick and JC B. Boylan, 1988 to 1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically 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), and the like. Examples of suitable carriers include, but are not limited to, cellulose acetate, sodium, 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, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0132] 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.

[0133] 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.

[0134] In some embodiments of the present disclosure, the compounds and pharmaceutical compositions described herein are used to treat pancreatic cancer. In some embodiments, the pancreatic cancer is mediated by APOL1.

[0135] In some embodiments, the methods of the disclosure comprise administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is selected from compounds 1-42 and compounds I1-I36, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the patient in need thereof carries the APOL1 gene variants G1;S342G:I384M, and G2:N388del:Y389del.

[0136] Another aspect of the present disclosure provides a method for inhibiting APOL1 activity, comprising contacting the APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method for inhibiting APOL1 activity comprises contacting the APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-42 and compounds I1-I36, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0137] Non-limiting example embodiments Some embodiments of the present disclosure include, but are not limited to, the following. 1. A compound represented by the following structural formula: [ka] tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is selected from 6-membered aryl and 6-membered heteroaryl groups; X is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Y is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Z is selected from a bond, —CH—, —NH—, —C(O)—, —S(O)—, and —O—, wherein: at least one of X and Y is selected from —CH— and —C(O)—; For each of X, Y, and Z, the hydrogen atom in each instance of -CH- or -NH- is optionally replaced with R; R1, for each occurrence, is independently selected from halogen, -OH, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)ORc, -C(=O)N(Rc), and -OS(=O)2R groups; Rc, for each occurrence, is independently selected from hydrogen, C-C alkyl, and C-C haloalkyl; The 4- to 6-membered heterocyclyl of R1 contains one heteroatom selected from nitrogen and oxygen; the C1-C6 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, and a C1-C4 alkoxy group; The C1-C6 alkoxy of R1 is optionally substituted with 1 to 3 groups independently selected from -OH, cyano, and halogen groups; the C3-C6 carbocyclyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; The phenyl in R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; R2 is cyano, C1-C6 alkyl, —C(═O)O(C1-C4 alkyl), C2-C6 alkynyl, and [ka] is selected from the C1-C6 alkyl of R2 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl, C6 aryl, and 5- to 10-membered heteroaryl groups; Ring B is selected from C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl groups, and Ring B is optionally substituted with 1, 2, 3, 4, or 5 Ra groups; Ra, for each occurrence, is selected from the group consisting of halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, independently selected from -ORk, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -[O(CH2)q]rO(C1-C6 alkyl), -S(=O)pRk, -S(=O)pNRhRi, -C(=O)ORk, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl groups; The C1-C6 alkyl, C1-C6 alkoxy, and C2-C6 alkenyl of Ra are each independently selected from C6-C10 aryl (optionally substituted with 1 to 3 Rm groups), 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rm groups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rm groups), cyano, —C(═O)Rk, —C(═O)ORk, —C(═O)NRhRi, —NRhRi, —NRhC(═O)Rk, — optionally substituted with 1-3 groups independently selected from NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, -ORk, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -S(=O)pRk, -S(=O)pNRhRi, -O(C6 aryl) (optionally substituted with 1-3 Rm groups), and a C3-C6 carbocyclyl group (optionally substituted with 1-3 Rm groups); The C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, C1-C4 alkyl, -NRhRi, and -ORk groups; Rh, Ri, and Rj are each independently selected for each occurrence from hydrogen, C1-C4 alkyl, C6-C10 aryl, and C3-C6 cycloalkyl groups; the C1-C4 alkyl of any one of Rh, Ri, and Rj is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; Rk, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl; any one C1-C4 alkyl in Rk is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; Rm, for each occurrence, is independently selected from halogen, cyano, oxo, C-C alkyl, C-C alkoxy, -S(=O)pRk, and -ORk groups; the C1-C6 alkyl of Rm is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and —O(C1-C4 alkyl) groups; R3 is selected from C1-C6 alkyl, —C(═O)O(C1-C4 alkyl), C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl groups; the C1-C6 alkyl of R3 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; R3's C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl) (optionally substituted with —OH), —N(C1-C4 alkyl)2, C1-C5 alkyl (optionally substituted with —OH or —S(═O)2(C1-C4 alkyl)), C1-C4 alkoxy, —C(═O)NH2, —C(═O)NH(C1-C4 alkyl), —NHC(═O)(C1-C4 alkyl), —C(═O)(C1-C4 alkoxy), and —C(═O)N(C1-C4 alkyl)2 groups; m is an integer selected from 0, 1, 2, 3, 4, and 5; p, for each occurrence, is an integer independently selected from 1 and 2; A compound represented by the structural formula of Formula I, wherein q and r are, for each occurrence, integers independently selected from 1, 2, 3, and 4, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. 2. Ring A is selected from 6-membered aryl and 6-membered heteroaryl groups; X is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Y is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Z is selected from a bond, —CH—, —NH—, —C(O)—, —S(O)—, and —O—, wherein: at least one of X and Y is selected from —CH— and —C(O)—; For each of X, Y, and Z, the hydrogen atom in each instance of -CH- or -NH- is optionally replaced with R; R1, for each occurrence, is independently selected from halogen, —OH, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, —C(═O)ORc, —C(═O)N(Rc), and —OS(═O)2R groups; Rc, for each occurrence, is independently selected from hydrogen, C-C alkyl, and C-C haloalkyl; the C1-C6 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, and a C1-C4 alkoxy group; The C1-C6 alkoxy of R1 is optionally substituted with 1 to 3 groups independently selected from -OH, cyano, and halogen groups; The phenyl in R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; R2 is C1-C6 alkyl and [ka] is selected from: the C1-C6 alkyl of R2 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl, C6 aryl, and 5- to 10-membered heteroaryl groups; Ring B is selected from a 3- to 12-membered heterocyclyl, C aryl, and a 5- to 10-membered heteroaryl group, and Ring B is optionally substituted with 1, 2, 3, 4, or 5 Ra groups; Ra, for each occurrence, is selected from the group consisting of halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, independently selected from -ORk, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -[O(CH2)q]rO(C1-C6 alkyl), -S(=O)pRk, -S(=O)pNRhRi, -C(=O)ORk, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl groups; The C1-C6 alkyl, C1-C6 alkoxy, and C2-C6 alkenyl of Ra are each independently selected from C6-C10 aryl (optionally substituted with 1 to 3 Rm groups), 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rm groups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rm groups), cyano, -C(=O)Rk, -C(=O)ORk, -C(=O)NRhRi, -NRh optionally substituted by 1 to 3 groups independently selected from Ri, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, -ORk, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -S(=O)pRk, -S(=O)pNRhRi, and a C-C carbocyclyl group (optionally substituted with 1 to 3 Rm groups); The C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, C1-C4 alkyl, -NRhRi, and -ORk groups; Rh, Ri, and Rj are each independently selected for each occurrence from hydrogen, C1-C4 alkyl, C6-C10 aryl, and C3-C6 cycloalkyl groups; the C1-C4 alkyl of any one of Rh, Ri, and Rj is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; Rk, for each occurrence, is selected from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl groups, wherein any one C1-C4 alkyl in Rk is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; Rm, for each occurrence, is independently selected from halogen, cyano, oxo, C-C alkyl, C-C alkoxy, -S(=O)pRk, and -ORk groups; the C1-C6 alkyl of Rm is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; R3 is selected from C1-C6 alkyl groups, wherein: the C1-C6 alkyl of R3 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; m is an integer selected from 0, 1, 2, and 3; p, for each occurrence, is an integer independently selected from 1 and 2; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein q and r are, for each occurrence, integers independently selected from 1, 2, 3, and 4. 3. Ring A is selected from a 6-membered aryl and a 6-membered heteroaryl group; X is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Y is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Z is selected from a bond, —CH—, —NH—, —C(O)—, —S(O)—, and —O—, wherein: at least one of X and Y is selected from —CH— and —C(O)—; For each of X, Y, and Z, the hydrogen atom in each instance of -CH- or -NH- is optionally replaced with R; R1, for each occurrence, is independently selected from halogen, -OH, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)ORc, -C(=O)N(Rc), and -OS(=O)2R groups; Rc, for each occurrence, is independently selected from hydrogen, C-C alkyl, and C-C haloalkyl; the C1-C6 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH groups; R2 is [ka] wherein: Ring B is selected from a 5-membered heterocyclyl and a 5-membered heteroaryl group, and Ring B is optionally substituted with 1 or 2 Ra groups; Ra, for each occurrence, is independently selected from a C-C alkyl group optionally substituted with one group independently selected from —S(═O)pRk groups; Rk, for each occurrence, is independently selected from a C1-C4 alkyl group; R3 is selected from C1-C3 alkyl groups; m is an integer selected from 0, 1, 2, and 3; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1 or 2, wherein p, for each occurrence, is an integer independently selected from 1 and 2. 4. Ring A is selected from a 6-membered aryl and a 6-membered heteroaryl group; X is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Y is selected from —CH—, —C(O)—, —S(O)—, —NH—, and —O—; Z is selected from a bond, —CH—, —NH—, —C(O)—, —S(O)—, and —O—, wherein: at least one of X and Y is selected from —CH— and —C(O)—; For each of X, Y, and Z, the hydrogen atom in each instance of -CH- or -NH- is optionally replaced with R; R1, for each occurrence, is independently selected from halogen, -OH, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)ORc, -C(=O)N(Rc), and -OS(=O)2R groups; Rc, for each occurrence, is independently selected from hydrogen, C-C alkyl, and C-C haloalkyl; the C1-C6 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH groups; R2 is [ka] wherein: Ring B is selected from a pyrazole group and a triazole group, and Ring B is optionally substituted with one or two Ra groups, wherein Ra, for each occurrence, is independently selected from a C-C alkyl group optionally substituted with one group independently selected from —S(═O)pRk groups; Rk, for each occurrence, is independently selected from a C1-C4 alkyl group; R3 is methyl; m is an integer selected from 0, 1, 2, and 3; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-3, wherein p, for each occurrence, is an integer independently selected from 1 and 2. 5. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4, wherein Ring A is selected from phenyl, pyrimidinyl, and pyridinyl, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-4. 6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4, wherein ring A is phenyl, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-4. 7. R1, for each occurrence, is independently selected from hydrogen, halogen, cyano, —OH, C1-C4 alkyl, C1-C4 alkoxy, —C(═O)N(Rc)2, and a C3-C6 cycloalkyl group; Rc, for each occurrence, is independently selected from hydrogen and a C1-C2 alkyl group; the C1-C4 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and a C1-C2 alkoxy group; The C1-C4 alkoxy in R1 is optionally substituted with 1 to 3 independently selected halogen groups; the C3-C6 cycloalkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and a C1-C2 alkoxy group; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, 5, or 6, wherein all other variables not specifically defined in this embodiment are as defined in embodiment 1, 5, or 6. 8. R1, for each occurrence, is independently selected from F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy, —C(═O)N(Rc)2, and a C3-C6 cycloalkyl group; Rc, for each occurrence, is independently selected from hydrogen and a C1-C2 alkyl group; the C1-C4 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; The C1-C4 alkoxy in R1 is optionally substituted with 1 to 3 independently selected halogen groups; The C3-C6 cycloalkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, 5, or 6, wherein all other variables not specifically defined in this embodiment are as defined in embodiment 1, 5, or 6. 9. R1, for each occurrence, is independently selected from F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy, —C(═O)N(Rc)2, and a C3-C6 cycloalkyl group; Rc, for each occurrence, is independently selected from hydrogen and a C1-C2 alkyl group; the C1-C4 alkyl of R1 is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; The C1-C4 alkoxy in R1 is optionally substituted with 1 to 3 independently selected halogen groups; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, 5, or 6, wherein all other variables not specifically defined in this embodiment are as defined in embodiment 1, 5, or 6. 10. R1, for each occurrence, is independently selected from F, Cl, Br, -CH3, -CH(CH3)2, -CF3, -OCH3, -OCF3, -C(=O)N(CH3)2, and cyclopropyl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, 5, or 6, wherein all other variables not specifically defined in this embodiment are as defined in embodiment 1, 5, or 6. 11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-10, wherein m is 1, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-10. 12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-10, wherein m is 2, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-10. 13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 and 5-12, wherein ring B is selected from cyclopropyl, 5-10 membered heterocyclyl, phenyl, and 5-9 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 Ra groups, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 5-12. 14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 and 5-12, wherein ring B is selected from cyclopropyl, a 5-10 membered heterocyclyl containing 1-3 heteroatoms selected from N and O, phenyl, and a 5-9 membered heteroaryl containing 1-3 heteroatoms selected from N and O, each of which is optionally substituted with 1, 2, 3, 4, or 5 Ra groups, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 5-12. 15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 and 5-12, wherein ring B is selected from cyclopropyl, a 5-membered heterocyclyl having 1-3 heteroatoms selected from N and O, a 6-membered heterocyclyl having 1-3 heteroatoms selected from N and O, a 9-membered heterocyclyl having 1-3 heteroatoms selected from N and O, a 10-membered heterocyclyl having 1-3 heteroatoms selected from N and O, phenyl, a 5-membered heteroaryl having 1-3 heteroatoms selected from N and O, a 6-membered heteroaryl having 1-3 heteroatoms selected from N and O, a 9-membered heteroaryl having 1-3 heteroatoms selected from N and O, each of which is optionally substituted with 1, 2, 3, 4, or 5 Ra groups, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 5-12. 16. Ring B is [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 5-12. 17. Ring B is [ka] [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 5-12. 18. Ring B is [ka] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 and 5-12, optionally substituted with one Ra group, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 5-12. 19. Ra, for each occurrence, is independently selected from halogen, cyano, C1-C6 alkyl, C1-C4 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -ORk, -[O(CH2)q]rO(C1-C6 alkyl), -S(=O)2Rk, -S(=O)2NRhRi, C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl groups; the C1-C6 alkyl of Ra is optionally substituted with 1 to 3 groups independently selected from cyano, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, -ORk, -S(=O)2Rk, -S(=O)pNRhRi, and a C3-C6 cycloalkyl group; Each of the C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl of Ra is optionally substituted with 1 to 3 groups independently selected from halogen, C1-C2 alkyl, and -ORk groups; Rh, Ri, and Rj, for each occurrence, are each independently selected from hydrogen, C1-C2 alkyl, cyclopropyl, and cyclobutyl groups; C1-C2 alkyl of any one of Rh, Ri, and Rj is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; Rk, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; The C1-C4 alkyl of Rk is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; q and r are each an integer selected from 1, 2, and 3; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 13-18, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 13-18. 20. Ra, for each occurrence, is independently selected from halogen, cyano, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -ORk, -[O(CH2)q]rO(C1-C4 alkyl), -S(=O)2Rk, -S(=O)2NRhRi, cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl; The C1-C6 alkyl of Ra is optionally substituted with 1 to 3 groups independently selected from cyano, —C(═O)NRhRi, —S(═O)Rk, —NRhRi, —ORk, cyclopropyl, and cyclobutyl groups; Each of the cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl in Ra is optionally substituted with 1 to 3 groups independently selected from halogen, —CH3, —OH, and —OCH3; Rh and Ri are each independently selected for each occurrence from hydrogen, —CH3, cyclopropyl, and cyclobutyl groups; -CH3 of any one of Rh and Ri is optionally substituted with 1 to 3 groups independently selected from F, Cl, and -OH; Rk is, for each occurrence, independently selected from hydrogen and -CH3; -CH3 of Rk is optionally substituted with 1 to 3 groups independently selected from halogen and -OH; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 13-18, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 13-18. 21. Ra, for each occurrence, is independently selected from F, Cl, Br, cyano, C1-C6 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -ORk, -[O(CH2)q]rO(C1-C2 alkyl), -S(=O)2Rk, -S(=O)2NRhRi, cyclopropyl, cyclobutyl, 5-membered heterocyclyl, phenyl, and 6-membered heteroaryl groups; The C1-C6 alkyl of Ra is optionally substituted with 1 to 3 groups independently selected from cyano, —C(═O)NRhRi, —ORk, —S(═O)2Rk, and cyclopropyl; The cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl of Ra are each optionally substituted with 1 to 3 groups independently selected from halogen, —CH3, —OH, and —OCH3; Rh and Ri are each independently selected for each occurrence from hydrogen, —CH3, and cyclopropyl; -CH3 of any one of Rh and Ri is optionally substituted with 1 to 3 groups independently selected from F, Cl, and -OH; Rk, for each occurrence, is independently selected from hydrogen and -CH3; q and r are each integers independently selected from 1 and 2; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 13-18, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 13-18. 22. For each occurrence of Ra, F, cyano, -OH, -CH3, -CF3, -CH(CH3)2, -(CH2)2OH, -(CH2)2OCH3, -CH2CH(OH)C2H5, -CH2C(CH3)(CH2OH)2, -OCH3, -OCH2CH3, -O(CH2)2]2OCH3, -CH2C(=O)NHCH3, -(CH2)2SO2CH3, -CH2C(=O)N(CH3)2, -CH2(cyclopropyl), -C(=O)NH2, -C(=O)NH(cyclopropyl), -NH2, -NHCH3, -N(CH3)2, -NHC A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 13-18, independently selected from (CH3)2CH2OH, —NHC(═O)CH3, —SO2CH3, —SO2NH2, cyclopropyl, 2-methoxyphenyl, N-methylpiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl, and tetrahydrothiophenyl 1,1-dioxide, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 13-18. 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 13-18, wherein Ra, for each occurrence, is independently selected from -CH3, and -(CH2)2SO2CH3, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 13-18. 24. A compound is represented by the following structural formula: [ka] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein all variables not specifically defined in this embodiment are as defined in any one of embodiments 1-23. 25. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiments 1-24, wherein Z is selected from -CH2-, -NH-, -C(O)-, -S(O)2-, and -O-, and all other variables not specifically defined in this embodiment are as defined in embodiments 1-24. 26. A compound represented by any one of the following structural formulas: [ka] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein all variables not specifically defined in this embodiment are as defined in any one of embodiments 1-4. 27. A compound is represented by any one of the following structural formulas: [ka] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein all variables not specifically defined in this embodiment are as defined in any one of embodiments 1-4. 28. A compound is represented by any one of the following structural formulas: [ka] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein all variables not specifically defined in this embodiment are as defined in any one of embodiments 1-4. 29. A compound represented by any one of the following structural formulas: [ka] tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: R1a is selected from hydrogen, halogen, -OH, and a phenyl group, wherein: The phenyl of R1a is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; R and R are each independently selected from hydrogen, halogen, —OH, cyano, C-C alkyl, C-C alkoxy, —C(═O)OR, —C(═O)N(R), and —OS(═O)R groups; Rc, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; The C1-C6 alkyl of Rb1 and / or R1c is optionally substituted with 1 to 3 groups independently selected from halogen and —OH groups; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein all variables not specifically defined in this embodiment are as defined in any one of embodiments 1-4. 30. A compound represented by any one of the following structural formulas: [ka] tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: R1a is selected from hydrogen, phenyl, and a C(=O)N(Rc1)2 group; The phenyl of R1a is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; Rc1, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R1b and R1c are each independently selected from hydrogen and a halogen group; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein all variables not specifically defined in this embodiment are as defined in any one of embodiments 1-4. 31. A compound represented by any one of the following structural formulas: [ka] tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: R1a and R1b are each independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 haloalkyl groups; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein all variables not specifically defined in this embodiment are as defined in any one of embodiments 1-4. 32. A compound represented by any one of the following structural formulas: [ka] tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: R1a and R1b are each independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 haloalkyl groups; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein all variables not specifically defined in this embodiment are as defined in any one of embodiments 1-4. 33. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the compounds of Table 1, their tautomers, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 34. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the compounds of Table 2, their tautomers, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 35. A pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-34, and a pharmaceutically acceptable carrier. 36. A method for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 34, or a pharmaceutical composition according to embodiment 35. 37. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 34, or the pharmaceutical composition according to embodiment 35, for the manufacture of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 38. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 34, or a pharmaceutical composition according to embodiment 35, for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 39. A method for inhibiting APOL1 activity, comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 34, or the pharmaceutical composition of embodiment 35. 40. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 34, or a pharmaceutical composition according to embodiment 35, for the manufacture of a medicament for inhibiting APOL1 activity. 41. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 34, or a pharmaceutical composition according to embodiment 35, for use in inhibiting APOL1 activity. 42. A method for treating an APOL1-mediated disease, comprising administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 34, or a pharmaceutical composition according to embodiment 35. 43. The method of embodiment 42, wherein the APOL1-mediated disease is cancer. 44. The method of embodiment 42 or 43, wherein the APOL1-mediated disease is pancreatic cancer. 45. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 34, or a pharmaceutical composition according to embodiment 35, for the manufacture of a medicament for treating an APOL1-mediated disease. 46. ​​The use according to embodiment 45, wherein the APOL1-mediated disease is cancer. 47. The use according to embodiment 45 or 46, wherein the APOL1-mediated disease is pancreatic cancer. 48. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 34, or a pharmaceutical composition according to embodiment 35, for use in the treatment of an APOL1-mediated disease. 49. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt for use according to embodiment 48, wherein the APOL1-mediated disease is cancer. 50. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt for use according to embodiment 48 or embodiment 49, wherein the APOL1-mediated disease is pancreatic cancer. 51. A method for inhibiting APOL1 activity, comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 34, or the pharmaceutical composition of embodiment 35. 52. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 34, or a pharmaceutical composition according to embodiment 35, for the manufacture of a medicament for inhibiting APOL1 activity. 53. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 34, or a pharmaceutical composition according to embodiment 35, for use in inhibiting APOL1 activity. 54. A silicon derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-34. 55. A pharmaceutical composition comprising the silicon derivative according to embodiment 54. 56. A method for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising administering to a patient in need thereof the silicon derivative of embodiment 54 or the pharmaceutical composition of embodiment 55. 57. Use of the silicon derivative according to embodiment 54 or the pharmaceutical composition according to embodiment 55 for the manufacture of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 58. The silicon derivative according to embodiment 54 or the pharmaceutical composition according to embodiment 55 for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 59. A method for treating an APOL1 mediated disease, comprising administering to a patient in need thereof a silicon derivative according to embodiment 54 or a pharmaceutical composition according to embodiment 55. 60. The method of embodiment 59, wherein the APOL1-mediated disease is cancer. 61. The method of embodiment 59 or 60, wherein the APOL1-mediated disease is pancreatic cancer. 62. Use of a silicon derivative according to embodiment 54 or a pharmaceutical composition according to embodiment 55 for the manufacture of a medicament for the treatment of an APOL1-mediated disease. 63. The use according to embodiment 62, wherein the APOL1-mediated disease is cancer. 64. The use according to embodiment 62 or 63, wherein the APOL1-mediated disease is pancreatic cancer. 65. A silicon derivative according to embodiment 54 or a pharmaceutical composition according to embodiment 55 for use in the treatment of an APOL1 mediated disease. 66. The silicon derivative or pharmaceutical composition for use according to embodiment 65, wherein the APOL1-mediated disease is cancer. 67. The silicon derivative or pharmaceutical composition for use according to embodiment 65 or embodiment 66, wherein the APOL1-mediated disease is pancreatic cancer. 68. A boron derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-34. 69. A pharmaceutical composition comprising the boron derivative according to embodiment 68. 70. A method for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising administering to a patient in need thereof the boron derivative of embodiment 68 or the pharmaceutical composition of embodiment 69. 71. Use of the boron derivative according to embodiment 68 or the pharmaceutical composition according to embodiment 69 for the manufacture of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 72. The boron derivative according to embodiment 68 or the pharmaceutical composition according to embodiment 69 for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 73. A method for treating an APOL1 mediated disease, comprising administering to a patient in need thereof a boron derivative according to embodiment 68, or a pharmaceutical composition according to embodiment 69. 74. The method of embodiment 73, wherein the APOL1-mediated disease is cancer. 75. The method of embodiment 73 or 74, wherein the APOL1-mediated disease is pancreatic cancer. 76. Use of a boron derivative according to embodiment 68 or a pharmaceutical composition according to embodiment 69 for the manufacture of a medicament for treating an APOL1-mediated disease. 77. The use according to embodiment 76, wherein the APOL1-mediated disease is cancer. 78. The use according to embodiment 76 or 77, wherein the APOL1-mediated disease is pancreatic cancer. 79. A boron derivative according to embodiment 68 or a pharmaceutical composition according to embodiment 69 for use in the treatment of an APOL1 mediated disease. 80. The boron derivative or pharmaceutical composition for use according to embodiment 79, wherein the APOL1-mediated disease is cancer. 81. The boron derivative or pharmaceutical composition for use according to embodiment 79 or embodiment 80, wherein the APOL1-mediated disease is pancreatic cancer. 82. A phosphorus derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-34. 83. A pharmaceutical composition comprising a phosphorus derivative according to embodiment 82. 84. A method for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising administering to a patient in need thereof a phosphorus derivative according to embodiment 82 or a pharmaceutical composition according to embodiment 83. 85. Use of the phosphorus derivative according to embodiment 82 or the pharmaceutical composition according to embodiment 83 for the manufacture of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 86. The phosphorus derivative according to embodiment 82 or the pharmaceutical composition according to embodiment 83 for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 87. A method for treating an APOL1-mediated disease, comprising administering to a patient in need thereof a phosphorus derivative according to embodiment 82 or a pharmaceutical composition according to embodiment 83. 88. The method of embodiment 87, wherein the APOL1-mediated disease is cancer. 89. The method of embodiment 87 or 88, wherein the APOL1-mediated disease is pancreatic cancer. 90. Use of a phosphorus derivative according to embodiment 82 or a pharmaceutical composition according to embodiment 83 for the manufacture of a medicament for treating an APOL1-mediated disease. 91. The use according to embodiment 90, wherein the APOL1-mediated disease is cancer. 92. The use according to embodiment 90 or 91, wherein the APOL1-mediated disease is pancreatic cancer. 93. A phosphorus derivative according to embodiment 82 or a pharmaceutical composition according to embodiment 83 for use in the treatment of an APOL1-mediated disease. 94. The phosphorus derivative or pharmaceutical composition for use according to embodiment 93, wherein the APOL1-mediated disease is cancer. 95. The phosphorus derivative or pharmaceutical composition for use according to embodiment 93 or embodiment 94, wherein the APOL1-mediated disease is pancreatic cancer. [Example]

[0138] In order that the disclosure set forth herein may be more fully understood, the following examples are set forth, it being understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any manner.

[0139] The compounds of the invention can be made according to standard chemical practices or as described herein. The following abbreviations are used throughout the following synthetic schemes and in the descriptions for preparing a compound of Formula I, IA, IB, IC, ID, II, IIA, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, or IXC, compounds 1-42, and compounds I1-I36, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing: Abbreviation AIBN = azobisisobutyronitrile ARP = Assay Ready Plate BBBPY = 4,4'-di-tert-butyl-2,2'-dipyridyl BF3 = boron trifluoride BF3.OEt2 = boron trifluoride diethyl etherate Boc2O = di-tert-butyl dicarbonate CBzCl = benzyl chloroformate CDMT = 2-chloro-4,6-dimethoxy-1,3,5-triazine DAST = diethylaminosulfur trifluoride DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DCM = dichloromethane DIBAL-H = diisobutylaluminum hydride DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMAP = dimethylaminopyridine DMA = dimethylacetamide DME = dimethoxyethane DMEM = Dulbecco's Modified Eagle's Medium DMF = dimethylformamide DMPU = N,N'-dimethylpropylene urea DMSO = dimethyl sulfoxide DPPA = diphenylphosphoryl azide dppb = 1-4-bis[P(Ph)2]-butane EtOAc = ethyl acetate EtOH = ethanol Et2O = diethyl ether FBS = fetal bovine serum FLU = Fluorescence Unit HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphorus hexafluoride ion) HDMC = N-[(5-chloro-3-oxido-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-hexafluorophosphate methylmethanaminium HEPES = 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HBSS = Hank's Balanced Salt Solution IPA = Isopropyl alcohol Ir[df(CF3)ppy]2(dtbbpy)PF6 = phosphorus hexafluoride LDA = lithium diisopropylamide LED = Light Emitting Diode MeCN = acetonitrile MeI = methyl iodide MeOH = methanol MsOH = methanesulfonic acid MTBE or TBME = methyl tert-butyl ether n-BuLi = n-butyllithium NBS = n-bromosuccinimide NMM = N-methylmorpholine NMP = N-methylpyrrolidine PBS = phosphate-buffered saline Pd(dppf)2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(PPh3)2 = bis(triphenylphosphine) palladium(II) dichloride PP = Polypropylene PTSA = p-toluenesulfonic acid monohydrate T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TBAF = tetra-n-butylammonium fluoride TBSCl = tert-butyldimethylsilyl chloride TEA = triethylamine Tet = tetracycline TFA or TFAA = trifluoroacetic acid TfOH = triflic acid THF = tetrahydrofuran 2-Me-THF = 2-methyltetrahydrofuran THP = tetrahydropyran TMSCl = trimethylsilyl chloride TMSS = Tris(trimethylsilyl)silane

[0140] Example 1. Synthesis of Compounds All specific and generic compounds, and intermediates disclosed for making those compounds, are considered to be part of the disclosure disclosed herein.

[0141] Synthesis of starting materials The preparations describe synthetic routes to intermediates used in the synthesis of compounds 1 to 42. Similar preparations can be used to synthesize intermediates for preparing compounds I1 to I36.

[0142] Preparation S1 2-chloro-5-(2-hydroxyethyl)phenol (S1) [ka] Step 1. Synthesis of 2-chloro-5-(2-hydroxyethyl)phenol (C2) To a solution of 2-(4-chloro-3-methoxy-phenyl)acetic acid (690 mg, 3.44 mmol) in THF (6.8 mL) at 0 °C was added BH3-THF (6.8 mL, 6.80 mmol, 1 M in THF) dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction was cooled to 0 °C and slowly quenched with MeOH (6 mL). Gas evolution was observed. The reaction was concentrated in vacuo to give the title compound C2 (641 mg, 100%) as a colorless oil. The crude was used directly without further purification. LCMS m / z 170.0 [M-OH+H]+.

[0143] Step 2. Synthesis of 2-chloro-5-(2-hydroxyethyl)phenol (S1) To a solution of 2-chloro-5-(2-hydroxyethyl)phenol (715 mg, 3.83 mmol) in DCM (12.5 mL) was slowly added BBr3 (7.6 mL, 7.60 mmol, 1 M in heptane) at 0 °C. The resulting colorless solution was slowly warmed to room temperature and stirred for 4 h. The reaction was cooled to 0 °C and slowly quenched with HO. Some white solid precipitated and was isolated by filtration to give the desired product. The filtrate was extracted with DCM (x3), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give additional product as a white solid. The two batches were combined to give the title compound S1 (570 mg, 86%). 1H NMR(300MHz,Chloroform-d)δ7.26(d,J=2.0Hz,1H),6.91(d,J=2.0Hz,1H),6.78 -6.70(m,1H),5.48(s,1H),3.85(q,J=6.3Hz,2H),2.81(t,J=6.5Hz,2H),1.35(br s,1H).LCMSm / z154.0[M-OH]+.

[0144] Preparation S2 (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S2) [ka] Step 1. Synthesis of bis[(3-tert-butoxy-3-oxo-propanoyl)oxy]magnesium (C4) A solution of 3-tert-butoxy-3-oxo-propanoic acid (321.51 g, 1.907 mol) in THF (2 L) was cooled to 5 °C in an ice bath, and Mg(OEt) (111.33 g, 953.5 mmol) was added. The reaction was stirred at 0 °C for 30 minutes, the cooling bath was removed, and the mixture was stirred at room temperature overnight. The reaction was filtered over a plug of Celite®, and the plug was washed with additional THF. The clear, colorless filtrate was evaporated under vacuum to give a muddy solid. The solid was triturated with 1 L of diethyl ether and filtered. The filter cake was washed with EtO and dried under vacuum. The filtrate was evaporated again under vacuum, then triturated with a small amount of EtO and filtered to give a second crop of product. The crops were combined and dried under vacuum to give the title compound C4 (294.49 g, 90%) as a white solid. 1H NMR (300MHz, Methanol-d4) δ4.92 (s, 4H), 1.48 (s, 18H).

[0145] Step 2. Synthesis of tert-butyl (5S)-5-(tert-butoxycarbonylamino)-3-oxo-hexanoate (C6) To a solution of (3S)-3-(tert-butoxycarbonylamino)butanoic acid (170.15 g, 837.2 mmol) in THF (1.5 L) was added CDI (149.8 g, 923.8 mmol). The milky suspension cleared over the next few minutes. Gas evolution was observed. The reaction was stirred at room temperature for 3 hours. Bis[(3-tert-butoxy-3-oxo-propanoyl)oxy]magnesium (172.19 g, 502.6 mmol) was added. Another milky suspension formed, which cleared after stirring for 30 minutes. The reaction was stirred for 48 hours. The reaction was poured into 1.5 L of 1 N HCl and extracted with MTBE (1 L). The pH was confirmed to be approximately 3. The extract was washed with saturated NaHCO, dried over MgSO, filtered, and concentrated in vacuo to give the title compound C6 (248.5 g, 98.5%) as a colorless oil. H NMR (300 MHz, chloroform-d) δ 4.90 (d, J = 18.1 Hz, 1H), 4.04 (dt, J = 13.8, 6.6 Hz, 1H), 3.47–3.22 (m, 2H), 2.76 (qd, J = 17.0, 5.7 Hz, 2H), 1.48 (s, 9H), 1.44 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H).

[0146] Step 3. Synthesis of tert-butyl (2S,3R,6S)-6-methyl-2-(1-methyltriazol-4-yl)-4-oxo-piperidine-3-carboxylate (C8) To a solution of tert-butyl (5S)-5-(tert-butoxycarbonylamino)-3-oxo-hexanoate (248.5 g, 824.5 mmol) in DCM (1.5 L) was added TFA (240 mL, 3.115 mol) and the reaction was stirred overnight. The reaction was evaporated under vacuum at 25 °C. The remaining solid was triturated with 500 mL of pentane and filtered. The filter cake was washed with pentane to remove most of the solvent from the filter cake. The cake was returned to the reaction flask and dissolved in 1 L of DCM. 1-Methyltriazole-4-carbaldehyde (120.7 g, 1.086 mol) was added. The reaction was stirred overnight at room temperature. Brine (100 mL) was added, followed by 6 N NaOH until the aqueous layer remained alkaline when the funnel was shaken. The organic layer was isolated and the aqueous layer was extracted with DCM (1 L). The organic layers were combined, dried over MgSO4, and filtered through a plug of silica gel. The plug was eluted with 10% MeOH / EtOAc. The filtrate was evaporated in vacuo to give a solid, which was triturated with MTBE (500 mL) and filtered. The filter cake was washed with MTBE and dried in vacuo to give a second crop of product. The mother liquor from the trituration was concentrated. The precipitated solid was filtered to give a second crop of product. The crops were combined to give the title compound C8 (105.45 g, 43%) as a white solid. 1H NMR(300MHz,Chloroform-d)δ7.48(s,1H),4.52(d,J=11.0Hz,1H),4.09(s,3H),3.61(dd,J=11.0,1.0Hz,1H),3.21(ddd,J =11.7,6.1,2.9Hz,1H),2.55(dd,J=13.7,2.9Hz,1H),2.37-2.13(m,1H),1.98(s,1H),1.39(s,9H),1.29(d,J=6.3Hz,3H).

[0147] Step 4. Synthesis of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S2) To a solution of tert-butyl (2S,3R,6S)-6-methyl-2-(1-methyltriazol-4-yl)-4-oxo-piperidine-3-carboxylate (70.59 g, 239.8 mmol) in DCM (750 mL) was added MsOH (62 mL, 955.4 mmol), and the reaction was heated to reflux for 6 hours. The reaction was cooled to room temperature and then poured into a separatory funnel. Brine (100 mL) was added, followed by shaking and 6N NaOH was added until the aqueous layer remained alkaline. The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 500 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound S2 (43.74 g, 94%) as a pale yellow solid. 1H NMR(300MHz,Chloroform-d)δ7.46(s,1H),4.20(dd,J=10.1,5.1Hz,1H),4.06(s,3H),3.11(dqd,J=12.3,6.2 ,3.0Hz,1H),2.73-2.48(m,2H),2.40(ddd,J=14.1,3.0,1.5Hz,1H),2.25-2.00(m,2H),1.23(d,J=6.2Hz,3H).

[0148] Preparation S3 2-Methyl-6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)piperidin-4-one (S3) [ka] Step 1. Synthesis of (3S)-3-(tert-butoxycarbonylamino)butanoic acid (C10) To a solution of (3S)-3-aminobutanoic acid (100 g, 969.7 mmol) in dioxane (600 mL) was added aqueous NaOH (950 mL of 1 M, 950.0 mmol) over 15 minutes, followed by the addition of BocO (300 g, 1.375 mol). The reaction mixture was stirred at room temperature for 12 hours. The reaction was partitioned between MTBE (1 L) and water (300 mL). The layers were separated, and the aqueous layer was extracted again with MTBE (500 mL). The aqueous layer was then acidified with 1N HCl to pH = 2 and extracted with DCM (3 x 600 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated in vacuo to provide the title compound C10 (176 g, 89%) as a white solid. 1H NMR (300MHz, Chloroform-d) δ4.92(s,1H),4.04(s,1H),2.56(dd,J=5.5,2.9Hz,2H),1.44(s,9H),1.25(d,J=6.8Hz,3H).

[0149] Step 2. Synthesis of tert-butyl N-[(1S)-3-[methoxy(methyl)amino]-1-methyl-3-oxo-propyl]carbamate (C11) To a solution of (3S)-3-(tert-butoxycarbonylamino)butanoic acid (160 g, 787.3 mmol) in DCM (1.5 L) was added N-methoxymethanamine (hydrochloride) (81 g, 830.4 mmol), followed by DIPEA (560 mL, 3.215 mol) over 10 min. The reaction mixture was cooled to 0 °C, and T3P (600 g of 50% w / w in EtOAc, 942.9 mmol) was added over 45 min. After the addition, the cooling bath was removed, and the reaction was stirred at room temperature for 1 h. The reaction mixture was cooled to 10 °C, 1 N aqueous NaOH (700 mL) was added, and the solution was stirred for 15 min. The organic phase was separated, washed with saturated aqueous ammonium chloride (200 mL) and brine (200 mL), dried, filtered through a silica gel plug, and concentrated in vacuo to give the title compound C11 (180 g, 93%) as a clear, colorless, viscous oil. 1H NMR (300 MHz, Chloroform-d) δ 5.30 (s, 1H), 4.06 (ddd, J = 14.3, 9.7, 6.0 Hz, 1H), 3.68 (s, 3H), 3.17 (s, 3H), 2.71 (dd, J = 15.6, 5.2 Hz, 1H), 2.54 (dd, J = 15.7, 5.7 Hz, 1H), 1.43 (s, 9H), 1.24 (d, J = 6.8 Hz, 3H).

[0150] Step 3. Synthesis of tert-butyl N-[(1S)-1-methyl-3-oxo-butyl]carbamate (C12) To a solution of tert-butyl N-[(1S)-3-[methoxy(methyl)amino]-1-methyl-3-oxo-propyl]carbamate (220 g, 893.2 mmol) in THF (4 L) at 0 °C was added iodine(methyl)magnesium (900 mL of 3 M, 2.700 mol) over 40 min. The resulting reaction mixture was stirred at 0 °C for 4 h. The reaction was quenched with saturated ammonium chloride solution (2 L), followed by MTBE (1 L) and water (2 L). The mixture was stirred for 30 min, and the organic layer was separated. The aqueous layer was extracted with MTBE (1 L), and the combined organic layer was washed with saturated ammonium chloride solution (1 L), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0–70% EtOAc in heptane) afforded the title compound C12 (115 g, 64%) as a white solid. 1H NMR(300MHz,Chloroform-d)δ4.83(s,1H),4.12-3.87(m,1H),2.69(dd,J=16.5,5.2Hz,1H), 2.63-2.47(m,1H),2.15(d,J=2.3Hz,3H),1.43(d,J=2.4Hz,9H),1.20(dd,J=6.8,2.4Hz,3H).

[0151] Step 4. Synthesis of (4S)-4-aminopentan-2-one (hydrochloride) (C13) To a solution of tert-butyl N-[(1S)-1-methyl-3-oxo-butyl]carbamate (16.3 g, 80.18 mmol) in MeOH (30 mL) was added hydrogen chloride (50 mL of 4 M in dioxane, 200.0 mmol) over 3 minutes. The reaction was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was co-evaporated with EtOH (2 x 30 mL) and dried under vacuum to give the title compound C13 (12 g, 98%) as a pink viscous oil. 1H NMR(300MHz,Chloroform-d)δ8.06(s,3H),3.48(d,J=6.8Hz,1H),2.88(dd,J=18 .0,5.8Hz,1H),2.75(dd,J=18.0,7.2Hz,1H),2.13(s,3H),1.17(d,J=6.6Hz,3H).

[0152] Step 5. Synthesis of 2-methyl-6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)piperidin-4-one (S3) To a mixture of (4S)-4-aminopentan-2-one (hydrochloride) (580 mg, 4.088 mmol) in EtOH (13 mL), 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (760 mg, 3.758 mmol), L-proline (94 mg, 0.8165 mmol), magnesium sulfate (600 mg, 4.985 mmol), and TEA (600 μL, 4.305 mmol) were added. The reaction mixture was stirred at room temperature overnight. TLC indicated an incomplete reaction, so additional 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (150 mg, 0.74 mmol) was added and the reaction was stirred overnight. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was quenched with saturated sodium bicarbonate solution and extracted with DCM (x3). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-60% of 20% MeOH / DCM in DCM) to give the title compound S3 (500 mg, 38%) in a 7:1 cis / trans ratio. Furthermore, the ER at the stereocenter from C13 was lost by approximately 85%. 1H NMR(300MHz,Chloroform-d)δ7.58(s,1H),7.53(s,1H),4.60(t,J=6.3Hz,2H),4.00(dd,J=11.6,3.3Hz,1H),3.65(t,J=6.2Hz,2H), 3.10(dqd,J=12.1,6.0,2.9Hz,1H),2.58-2.51(m,4H),2.48-2.37(m,2H),2.17(dd,J=14.1,11.6Hz,1H),1.26(d,J=6.1Hz,3H)(cis isomer).

[0153] Compounds 1 and 2 (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-ol (1) and (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-8-ol (2) [ka] To a solution of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (125 mg, 0.64 mmol) and 2-chloro-5-(2-hydroxyethyl)phenol (122 mg, 0.71 mmol) in dioxane (3.2 mL) was added triflic acid (285 μL, 3.221 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for 5 h. Volatiles were removed, and the crude material was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 micron), Gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give the major regioisomer 1 (175 mg, 53%) and the minor regioisomer 2 as trifluoroacetate salts (39 mg, 12%) in a ca. 4:1 ratio. The absolute stereochemistry was confirmed by extensive NMR analysis.

[0154] Characteristic analysis data of compound 1: 1H NMR(300MHz,Methanol-d4)δ8.05(s,1H),7.16(s,1H),6.71(s,1H),4.85(s,1H),4.13(s,3H),3.95(t,J=5.5Hz,2H),3.82(s,1H),2. 76(t,J=5.5Hz,2H),2.39(d,J=8.9Hz,2H),2.23(d,J=14.6Hz,1H),2.00-1.85(m,1H),1.40(d,J=6.6Hz,3H).LCMSm / z349.23[M+H]+.

[0155] Characteristic analysis data of compound 2: 1H NMR(300MHz,Methanol-d4)δ8.04(s,1H),7.21(d,J=8.2Hz,1H),6.77-6.65(m, 1H),4.88-4.98(m,1H),4.12(s,3H),3.94(t,J=5.5Hz,2H),3.86(ddd,J=12.6,6 .5,3.2Hz,1H),3.43-3.24(m,1H),2.94-2.76(m,3H),2.22(dt,J=14.5,2.8Hz, 1H),2.06(dt,J=14.5,2.8Hz,1H),1.40(d,J=6.6Hz,3H).LCMSm / z349.0[M+H]+.

[0156] Compounds 3 and 4 7-chloro-2'-methyl-6'-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-ol (3) and 7-chloro-2'-methyl-6'-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)spiro[isochroman-1,4'-piperidin]-8-ol (4) [ka] Compounds 3 and 4 were prepared from S1 and S3 according to the method described for compounds 1 and 2. The reaction was purified by reverse-phase HPLC (method: C18 Waters Sunfire column (30×150 mm, 5 micron), gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give the major regioisomer 3 (155 mg, 57%) and the minor regioisomer 4 as trifluoroacetate salts (25.8 mg, 9.6%) in a ratio of approximately 6:1.

[0157] Characteristic analysis data of compound 3: 1H NMR(300MHz,Methanol-d4)δ7.93(s,1H),7.73(s,1H),7.19(s,1H),6.71(s,1 H),4.76-4.60(m,3H),3.93(t,J=5.5Hz,2H),3.77(s,1H),3.70(t,J=6.3Hz,2H ),2.84(s,3H),2.75(t,J=5.5Hz,2H),2.35-2.26(m,2H),2.20(d,J=14.7Hz,1H ),1.87(dd,J=14.7,12.2Hz,1H),1.37(d,J=6.6Hz,3H).LCMSm / z440.0[M+H]+.

[0158] Characteristic analysis data of compound 4: 1H NMR(300MHz,Methanol-d4)δ7.90(s,1H),7.71(s,1H),7.22(d,J=8.2Hz,1H),6.73(d,J =8.3Hz,1H),4.74(dd,J=12.8,3.0Hz,1H),4.65(t,J=6.3Hz,2H),3.91(t,J=5.4Hz,2H) ,3.86-3.75(m,1H),3.70(t,J=6.3Hz,2H),3.26-3.16(m,1H),2.87-2.73(m,6H),2.15( dd,J=14.5,2.9Hz,1H),2.10-1.98(m,1H),1.37(d,J=6.6Hz,3H).LCMSm / z440.0[M+H]+.

[0159] Compounds 5 and 6 (1S,2'S,6'S)-6-Methoxy-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine] (5) and (1S,2'S,6'S)-8-Methoxy-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine] (6) [ka] Compounds 5 and 6 were prepared from commercially available 2-(3-methoxyphenyl)ethan-1-ol (C15) and S2 according to the method described for compounds 1 and 2. The reaction was purified by reverse-phase HPLC (method: C18 Waters Sunfire column (30 x 150 mm, 5 microns), gradient: MeCN in HO containing 0.2% formic acid) to give the major regioisomer 5 (39 mg, 40%) and the minor regioisomer 6 as formate salts (8 mg, 8%) in a ratio of approximately 5:1. The absolute stereochemistry was assigned analogously to compounds 1 and 2.

[0160] Characteristic analysis data of compound 5: 1H NMR(300MHz,Methanol-d4)δ8.33(s,1H),8.04(s,1H),7.12(d,J=8.7Hz,1H),6.82(dd,J=8.7,2.7Hz,1H ),6.75-6.68(m,1H),4.87(dd,J=12.1,3.5Hz,1H),4.12(s,3H),3.96(t,J=5.5Hz,2H),3.90-3.76(m,1H) ,3.77(s,3H),2.83(t,J=5.5Hz,2H),2.46(dd,J=14.7,12.1Hz,1H),2.34(ddd,J=14.7,3.6,2.2Hz,1H),2 .20(dt,J=14.6,2.8Hz,1H),1.98(dd,J=14.7,12.1Hz,1H),1.39(d,J=6.6Hz,3H).LCMSm / z328.4[M+H]+.

[0161] Characteristic analysis data of compound 6: 1H NMR(300MHz,Methanol-d4)δ8.49(s,1H),8.02(s,1H),7.20(dd,J=8.3,7.6Hz,1H),6.89(dd,J =8.3,1.1Hz,1H),6.79(dd,J=7.6,1.1Hz,1H),4.90(d,J=3.3Hz,1H),4.12(s,3H),3.98-3.74(m ,6H),3.19(dd,J=14.5,12.7Hz,1H),2.83(t,J=5.5Hz,2H),2.79-2.62(m,1H),2.19(ddd,J=14 .5,3.3,2.5Hz,1H),2.02(dt,J=14.5,2.8Hz,1H),1.38(d,J=6.6Hz,3H).LCMSm / z328.4[M+H]+.

[0162] Compounds 7 and 8 (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-ol (7) and (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-8-ol (8). [ka] Compounds 7 and 8 were prepared from commercially available 3-(2-hydroxyethyl)phenol (C16) and S2 according to the method described for compounds 1 and 2. The reaction was purified by reverse-phase HPLC (method: C18 Waters Sunfire column (30 x 150 mm, 5 microns), gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give the major regioisomer 7 (17.7 mg, 63%) and the minor regioisomer 8 as trifluoroacetate salts (4.7 mg, 16.7%) in a ratio of approximately 4:1. The absolute stereochemistry was assigned analogously to compounds 1 and 2.

[0163] Characterization data of compound 7: 1H NMR(400MHz,Methanol-d4)δ8.03(s,1H),7.02(d,J=8.6Hz,1H),6.72-6.65(m,1 H),6.57(d,J=2.5Hz,1H),4.89(s,1H),4.12(s,3H),3.95(t,J=5.5Hz,2H),3.81( s,1H),2.77(t,J=5.5Hz,2H),2.48-2.38(m,1H),2.35(d,J=14.7Hz,1H),2.19(d ,J=14.7Hz,1H),2.02-1.90(m,1H),1.39(d,J=6.6Hz,3H).LCMSm / z314.4[M+H]+.

[0164] Characteristic analysis data of compound 8: 1H NMR(400MHz,Methanol-d4)δ8.01(s,1H),7.02(t,J=7.8Hz,1H),6.66(d,J=7 .9Hz,2H),4.91(s,1H),4.12(s,3H),3.93(t,J=5.5Hz,2H),3.83(s,1H),3.38 (d,J=13.7Hz,1H),2.97-2.86(m,1H),2.81(t,J=5.4Hz,2H),2.20(d,J=14.7 Hz,1H),2.03(d,J=14.7Hz,1H),1.39(d,J=6.6Hz,3H).LCMSm / z314.4[M+H]+.

[0165] compound 9 (2'S,6'S)-6-Bromo-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine] (9) [ka] To a solution of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (500 mg, 2.574 mmol) and commercially available 2-(3-bromophenyl)ethanol (517.5 mg, 350.1 μL, 2.574 mmol) in dioxane (15 mL) was added triflic acid (1.93 g, 1.139 mL, 12.87 mmol) dropwise. The resulting solution was heated at 100 °C overnight. The reaction was cooled to room temperature and quenched with saturated NaHCO solution. The mixture was extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0–20% MeOH in DCM) to give the title product 9 (72 mg, 28.7%), contaminated with approximately 13% of an unknown isomer. 1H NMR (300MHz,Methanol-d4)δ7.85(s,1H),7.39-7.25(m,2H),7.13(d,J=8.4Hz,1H),4.43(dd,J=11.8,2.8Hz,1H),4.08(d,J=0.7Hz,3H),4.01-3.87(m,3H) ),2.81(t,J=5.5Hz,2H),2.21(dt,J=13.9,2.6Hz,1H),2.04-1.91(m,2H),1 .61(dd,J=13.9,11.5Hz,1H),1.17(t,J=6.2Hz,3H).LCMSm / z377.3[M+H]+.

[0166] Preparation S4 (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-yl trifluoromethanesulfonate (S4) [ka] To a suspension of (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-ol (247 mg, 0.71 mmol), 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1 g, 2.80 mmol), and tetrabutylammonium hydrogen sulfate (244 mg, 0.72 mmol) in DCM (8 mL) was added an aqueous solution of NaOH (2.8 mL, 7.0 mmol, 2.5 M). The mixture was stirred vigorously at room temperature overnight. The reaction was diluted with water. The organic layer was separated, and the aqueous layer was extracted with MTBE (x2). The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography (0-20% MeOH in DCM) to give the title compound S4 as a white solid (202 mg, 59%). LCMS m / z 481.0 [M+H]+.

[0167] compound 10 (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine] (10) [ka] To a solution of (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-yl]trifluoromethanesulfonate (28 mg, 0.058 mmol) in DMF (0.58 mL) was added Pd(dppf)Cl (4.8 mg, 0.0059 mmol) and EtN (24 μL, 0.17 mmol), followed by formic acid (4.5 μL, 0.12 mmol). The resulting red solution was heated at 60 °C for 6 h. The reaction was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO with 0.1% trifluoroacetic acid) to give the title compound 10 as the trifluoroacetate salt (24.9 mg, 94%). 1H NMR(300MHz,Methanol-d4)δ8.05(s,1H),7.32-7.11(m,3H),4.95-4.80(m,1H),4.12(s,3H),3.99(t,J=5.5Hz,2H),3.84(s,1H), 2.84(t,J=5.5Hz,2H),2.49-2.39(m,2H),2.27(d,J=14.5Hz,1H),2.05-1.87(m,1H),1.41(d,J=6.6Hz,3H).LCMSm / z332.8[M+H]+.

[0168] compound 11 (1S,2'S,6'S)-2'-Methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine]-7-carbonitrile (11) [ka] A 1-dram vial was charged with (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[isochroman-1,4'-piperidine] (15 mg, 0.045 mmol), XPhos Pd G3 (4 mg, 0.005 mmol), Zn(CN)2 (11 mg, 0.094 mmol), and Zn powder (1 mg, 0.015 mmol). The vial was capped and purged with N2 (x3), then DMA (0.5 mL) was added. The resulting dark orange solution was heated at 120 °C overnight. The reaction was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30x150 mm, 5 microns). Gradient: MeCN in HO with 0.1% trifluoroacetic acid) to give the title compound 11 as the trifluoroacetate salt (19.7 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ 9.31 (d, J = 10.6 Hz, 1H), 8.78 (d, J = 11.0 Hz, 1H), 8.21 (s, 1H), 7.66 (dd, J = 8.0, 1.6 Hz, 1H), 7.57 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 4.66 (t, J = 11.1 Hz, 1H), 4.04 (s, 3H). 3.90(t,J=5.4Hz,2H),3.50-3.70(m,1H),2.85(t,J=5.4Hz,2H),2.2.41-2.45(m,1H),2.28(d ,J=14.2Hz,1H),2.05(dt,J=26.4,14.1Hz,2H),1.23(d,J=14.8Hz,3H).LCMSm / z323.4[M+H]+.

[0169] compound 12 (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine] (12) [ka] To a solution of (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[isochroman-1,4'-piperidine] (15 mg, 0.045 mmol) in MeOH (0.5 mL) was added 5% Pd / C (19 mg, 0.008927 mmol). The reaction was bubbled with H for 1 minute and then stirred under an atmosphere of H (1 atm) overnight. The reaction was diluted with MeOH and filtered. The filtrate was concentrated in vacuo, and the crude material was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid) to give the title compound 12 as the trifluoroacetic acid salt (19.7 mg, 81%). 1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.96(d,J=11.4Hz,1H),8.24(s,1H),7.35-7.06(m,4H),4.72(t,J=11.2Hz,1H),4.08(s,3H),3.93(t,J=5.4Hz, 2H),3.63(s,1H),2.80(t,J=5.5Hz,2H),2.42(q,J=13.5Hz,1H),2.28(d,J =14.4Hz,1H),2.18-1.87(m,2H),1.36-1.22(m,3H).LCMSm / z298.4[M+H]+.

[0170] compound 13 (1S,2'S,6'S)-7-Ethyl-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine] (13) [ka] Step 1. Synthesis of (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-7-vinylspiro[isochroman-1,4'-piperidine] (C18) A 2-dram vial was charged with (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[isochroman-1,4'-piperidine] (30 mg, 0.090 mmol), potassium vinyltrifluoroborate (18 mg, 0.13 mmol), di-μ-chloro-bis-[5-hydroxy-2-[1-(hydroxyimino-κN)-ethyl]-phenyl-κC]-palladium(II) dimer (Najera catalyst) (2.6 mg, 0.0045 mmol), 1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphane (5.6 mg, 0.0089 mmol), and cesium carbonate (88 mg, 0.27 mmol). The vial was capped and purged with N (x3). DMF was added and the mixture was heated at 120° C. overnight. The reaction was quenched with saturated NaHCO and brine and extracted with EtOAc (×3). The combined organic extracts were dried over NaSO, filtered, and concentrated in vacuo. The crude was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30×150 mm, 5 micron). Gradient: MeCN in H0 with 0.1% trifluoroacetic acid) to give the title compound C18 as the trifluoroacetic acid salt (14.4 mg, 32%). LCMS m / z 325.0 [M+H].

[0171] Step 2. Synthesis of (1S,2'S,6'S)-7-ethyl-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine] (13) To a solution of (1S,2'S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)-7-vinyl-spiro[isochroman-1,4'-piperidine] (trifluoroacetate) (14.4 mg, 0.044 mmol) in MeOH (1 mL) was added 10 wt% Pd / C (22 mg, 0.0087 mmol). The mixture was bubbled with H for 2 minutes and then stirred overnight at room temperature under an atmosphere of H (1 atm). The reaction was diluted with MeOH and filtered. The filtrate was concentrated in vacuo, and the crude was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O containing 0.1% trifluoroacetic acid) to give the title compound 13 as the trifluoroacetate salt (2.0 mg, 9%). 1H NMR(400MHz,DMSO-d6)δ9.32(d,J=10.2Hz,1H),8.93(s,1H),8.24(s,1H),7.04(d ,J=28.6Hz,3H),4.71(t,J=11.2Hz,1H),4.08(s,3H),3.90(t,J=5.4Hz,2H),3.62( s,1H),2.74(q,J=9.1,7.2Hz,2H),2.65-2.38(m,3H),2.29(t,J=15.8Hz,1H),2.13 -1.94(m,2H),1.29(d,J=6.5Hz,3H),1.18(t,J=7.6Hz,3H).LCMSm / z326.4[M+H]+.

[0172] compound 14 (1S,2'S,6'S)-2'-Methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-yl trifluoromethanesulfonate (14) [ka] Compound 14 was prepared from compound 7 according to the method described for compound S4. The reaction was purified by silica gel chromatography (0-20% MeOH in DCM) to give the title compound 14 as a white solid (338 mg, 67%). 1H NMR(400MHz,Methanol-d4)δ7.84(s,1H),7.39(d,J=8.7Hz,1H),7.23-7.17(m,1 H),7.15(d,J=2.6Hz,1H),4.40(dd,J=11.7,2.7Hz,1H),4.08(s,3H),3.97(t,J=5 .5Hz,2H),3.34(s,1H),2.88(t,J=5.5Hz,2H),2.27-2.19(m,1H),2.02-1.91(m, 2H),1.61(dd,J=13.8,11.5Hz,1H),1.17(d,J=6.5Hz,3H).LCMSm / z446.4[M+H]+.

[0173] compound 15 (1S,2'S,6'S)-6-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine] (15) [ka] A 1-dram vial was charged with (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-yl trifluoromethanesulfonate (25 mg, 0.056 mmol), tBuBrettPhos Pd G3 (4.8 mg, 0.0056 mmol), tBuBrettPhos (5.5 mg, 0.011 mmol), potassium chloride (8.4 mg, 0.11 mmol), and potassium fluoride (1.5 mg, 0.026 mmol). The vial was capped and purged with N2 (x3). Dioxane (0.5 mL) was added, and the mixture was heated at 130 °C overnight. The reaction was cooled to room temperature, filtered, and purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30x150 mm, 5 micron). Gradient: MeCN in HO with 0.1% trifluoroacetic acid) to give the title compound 15 as the trifluoroacetate salt (7.5 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.94 (d, J = 11.2 Hz, 1H), 8.22 (s, 1H), 7.36 (dd, J = 8.4, 2.3 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4.71 (t, J = 11.0 Hz, 1H), 4.0 8(s,3H),3.91(t,J=5.4Hz,2H),3.62(s,1H),2.81(t,J=5.5Hz,2H),2.46-2.22(m,2H), 2.12(d,J=14.2Hz,1H),2.05-1.88(m,1H),1.28(d,J=6.5Hz,3H).LCMSm / z332.8[M+H]+.

[0174] compound 16 (1S,2'S,6'S)-2',6-dimethyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine] (16) [ka] A 1-dram vial was charged with (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-yl trifluoromethanesulfonate (25 mg, 0.056 mmol) and Pd(PPh3)4 (13.1 mg, 0.011 mmol). The vial was capped and purged with N2 (x3). THF (0.5 mL) was added, followed by AlMe3 (70 μL, 0.14 mmol, 2 M in heptane). The reaction was heated at reflux overnight. The reaction was cooled to room temperature and then slowly quenched with MeOH. The volatiles were removed and the crude material was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30x150 mm, 5 micron). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give the title compound 16 as the trifluoroacetic acid salt (9.6 mg, 38%). 1H NMR(400MHz,DMSO-d6)δ9.28(d,J=10.6Hz,1H),8.93(d,J=11.2Hz,1H),8.21 (s,1H),7.14-6.87(m,3H),4.71(s,1H),4.08(s,3H),3.90(t,J=5.4Hz,2H), 3.60(s,1H),2.74(q,J=7.5,6.5Hz,2H),2.38(d,J=13.0Hz,2H),2.26(s,3H) ,2.03(dd,J=37.9,13.6Hz,2H),1.28(d,J=6.5Hz,3H).LCMSm / z312.4[M+H]+.

[0175] compound 17 (1S,2'S,6'S)-6-Ethyl-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine] (17) [ka] A 1-dram vial was charged with (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-yl trifluoromethanesulfonate (25 mg, 0.056 mmol) and Pd(PPh3)4 (13.1 mg, 0.011 mmol). The vial was capped and purged with N2 (x3). THF (0.5 mL) was added, followed by AlEt3 (75 μL, 0.5571 mmol, 25 wt% in toluene). The reaction was heated at reflux overnight. The reaction was cooled to room temperature and then slowly quenched with MeOH. The volatiles were removed and the crude material was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30x150 mm, 5 micron). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give the title compound 17 as the trifluoroacetic acid salt (17.3 mg, 69%). 1H NMR(400MHz,DMSO-d6)δ9.28(d,J=9.7Hz,1H),8.92(d,J=11.0Hz,1H),8.23(s, 1H),7.18-6.91(m,3H),4.71(t,J=11.4Hz,1H),4.09(d,J=2.6Hz,3H),3.91(t, J=5.4Hz,2H),3.55(s,1H),2.83-2.62(m,2H),2.55-2.45(m,3H),2.30-1.89(m ,3H),1.28(d,J=6.5Hz,3H),1.16(td,J=7.6,2.0Hz,3H).LCMSm / z326.4[M+H]+.

[0176] compound 18 (1S,2'S,6'S)-6-Isopropyl-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine] (18) [ka] An oven-dried 1-dram vial was charged with (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-yl trifluoromethanesulfonate (30 mg, 0.064 mmol) and Pd(dppf)Cl2 (5.2 mg, 0.0064 mmol). The vial was capped and purged with N2 (x3). THF (0.5 mL) was added, followed by i-PrMgCl (96 μL, 0.19 mmol, 2 M in THF). The reaction was heated at 50 °C for 3.5 h. The reaction was cooled to room temperature and then slowly quenched with MeOH. The volatiles were removed and the crude material was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30x150 mm, 5 micron). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give the title compound 18 as the trifluoroacetic acid salt (15.9 mg, 49%). 1H NMR(400MHz,Methanol-d4)δ8.03(s,1H),7.12(s,2H),7.03(s,1H),4.93-4.8 5(m,1H),4.12(s,3H),3.97(t,J=5.5Hz,2H),3.83(s,1H),2.92-2.80(m,3H), 2.46(dd,J=14.6,12.2Hz,1H),2.41-2.33(m,1H),2.26-2.18(m,1H),2.05-1. 93(m,1H),1.40(d,J=6.6Hz,3H),1.22(d,J=6.9Hz,6H).LCMSm / z340.4[M+H]+.

[0177] compound 19 Methyl (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine]-6-carboxylate (19) [ka] To a solution of (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-yl trifluoromethanesulfonate (300 mg, 0.67 mmol) in MeOH (6 mL) in a 100-mL pressure tube, Pd(dppf)Cl (55 mg, 0.067 mmol) and DIPEA (328 μL, 1.88 mmol) were added. The tube was purged sequentially with N (x3) and CO (x3) and then heated at 80 °C under a CO (50 psi) atmosphere for 48 h. The reaction was cooled to room temperature and the volatiles were removed. The crude product was purified by silica gel chromatography (0–20% MeOH in DCM) to give the title compound 19 (200 mg, 76%). 1H NMR(300MHz,Methanol-d4)δ7.93-7.73(m,3H),7.35(d,J=8.2Hz,1H),4.52(dd, J=11.8,3.0Hz,1H),4.09(s,3H),3.98(t,J=5.5Hz,2H),3.89(s,3H),3.45(ddd,J =11.6,6.5,2.7Hz,1H),2.89(t,J=5.5Hz,2H),2.33-2.20(m,1H),2.18-1.97(m, 2H),1.72(dd,J=14.0,11.6Hz,1H),1.23(d,J=6.5Hz,3H).LCMSm / z357.2[M+H]+.

[0178] compound 20 2-((1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-yl)propan-2-ol (20) [ka] An oven-dried 2-dram vial was charged with methyl (1S,2'S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[isochroman-1,4'-piperidine]-6-carboxylate (43 mg, 0.12 mmol) and THF (1 mL). The resulting solution was cooled to -78 °C, and MeLi-LiBr (322 μL, 0.48 mmol, 1.5 M in EtO) was slowly added. The reaction was stirred at the same temperature for 50 minutes, then quenched with saturated NaHCO and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30x150 mm, 5 micron). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give the title compound 20 as the trifluoroacetic acid salt (1.2 mg, 3%). 1H NMR(300MHz,Methanol-d4)δ8.01(s,1H),7.36(d,J=8.3Hz,1H),7.28(s,1H),7.16(d,J=8.3Hz,1H),4.81(s,1H),4.11(s,3H),3.98(t,J=5.4Hz,2H),3.7 8(s,1H),2.86(t,J=5.4Hz,2H),2.52-2.27(m,2H),2.19(d,J=14.9Hz,1H),2 .04-1.88(m,1H),1.50(s,6H),1.38(d,J=6.6Hz,3H).LCMSm / z356.5[M+H]+.

[0179] compound 21 (1S,2'S,6'S)-2'-Methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidine]-6-carbonitrile (21) [ka] Compound 21 was prepared from compound 14 according to the method described for compound 11. The reaction was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30x150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give the title compound 21 as the trifluoroacetate salt (23.3 mg, 26%). H NMR (400 MHz, Methanol-d) δ 8.04 (d, J = 1.5 Hz, 1H), 7.66-7.57 (m, 2H), 7.41 (dd, J = 8.2, 2.1 Hz, 1H), 4.91 (dd, J = 12.3, 3.7 Hz, 1H), 4.12 (s, 3H), 4.02 (t, J = 5.5 Hz, 2H), 3.85 (s, 1H). ),2.93(d,J=11.1Hz,1H),2.93(s,1H),2.57-2.46(m,1H),2.42(d,J=13.9Hz,1H),2.28 (d,J=14.7Hz,1H),2.02(t,J=13.5Hz,1H),1.41(d,J=6.6Hz,3H).LCMSm / z323.4[M+H]+.

[0180] compound 22 ((1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-yl)methanol (22) [ka] To a solution of (1S,2'S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[isochroman-1,4'-piperidine]-6-carboxylate (20 mg, 0.056 mmol) in THF (0.5 mL) was added LiBH (2.5 mg, 0.1148 mmol). The mixture was heated at reflux for 2 h. The reaction was cooled to room temperature and quenched with EtOAc. Volatiles were removed, and the crude material was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in HO with 0.1% trifluoroacetic acid) to give the title compound 22 as the trifluoroacetic acid salt (14.7 mg, 75%). 1H NMR(300MHz,Methanol-d4)δ8.04(s,1H),7.35-7.12(m,3H),4.90-4.80(m,1H),4.57(s,2H),4.12(s,3H),3.99(t,J=5.4Hz,2H),3.87(s,1H), 2.86(t,J=5.5Hz,2H),2.57-2.30(m,2H),2.23(d,J=14.7Hz,1H),2.01(dd,J=14.7,12.1Hz,1H),1.40(d,J=6.6Hz,3H).LCMSm / z328.4[M+H]+.

[0181] Preparation S5 (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-1'-(2,2,2-trifluoroacetyl)spiro[isochroman-1,4'-piperidin]-6-yl trifluoromethanesulfonate (S5) [ka] To a solution of [(1S,2'S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-yl]trifluoromethanesulfonate (529 mg, 1.185 mmol) in DCM (6 mL) was added DIPEA (268 μL, 1.539 mmol). The resulting solution was cooled to 0 °C, and (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (181 μL, 1.302 mmol) was added dropwise over 15 minutes. The reaction was stirred at the same temperature for 2 hours. The reaction was quenched with saturated NH4Cl solution and then extracted with DCM (x3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography (0-100% EtOAc in heptane) to give the title compound S5 as a white solid (632 mg, 98%). LCMS m / z 543.2 [M+H]+.

[0182] Preparation S6 2,2,2-trifluoro-1-((1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)spiro[isochroman-1,4'-piperidin]-1'-yl)ethan-1-one (S6) [ka] Step 1. Synthesis of ((1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-1'-(2,2,2-trifluoroacetyl)spiro[isochroman-1,4'-piperidin]-6-yl)boronic acid (C19) A 2-dram vial was charged with (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-1'-(2,2,2-trifluoroacetyl)spiro[isochroman-1,4'-piperidin]-6-yl]trifluoromethanesulfonate (120 mg, 0.22 mmol), tetrahydroxydiboron (40 mg, 0.45 mmol), KOAc (65 mg, 0.66 mmol), and Pd(dppf)Cl (18 mg, 0.022 mmol). The vial was capped and purged with N (x3), then MeOH (1 mL) was added. The reaction was heated at 40 °C overnight. The reaction was cooled to room temperature, quenched with water, and extracted with DCM (x3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography (0-20% MeOH in DCM) to give the title compound C19 as a brown solid (90.3 mg, 93%). LCMS m / z 439.3 [M+H]+.

[0183] Step 2. Synthesis of 2,2,2-trifluoro-1-((1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)spiro[isochroman-1,4'-piperidin]-1'-yl)ethan-1-one (S6) A 1-dram vial was charged with ((1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-1'-(2,2,2-trifluoroacetyl)spiro[isochroman-1,4'-piperidin]-6-yl)boronic acid (1020 mg, 2.328 mmol), CuOAc (71 mg, 0.579 mmol), and 5-(trifluoromethyl)dibenzothiophen-5-ium trifluoromethanesulfonate (1.50 mg, 3.728 mmol). The vial was capped and purged with N2 (x3), then DMA (6 mL) was added, followed by collidine (616 μL, 4.661 mmol). The resulting dark green solution was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography (0-100% EtOAc in heptane) to give the title compound S6 as a white solid (578 mg, 54%). LCMS m / z 463.2 [M+H]+.

[0184] compound 23 (1S,2'S,6'S)-2'-Methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)spiro[isochroman-1,4'-piperidine] (23) [ka] To a solution of 2,2,2-trifluoro-1-[(1S,2'S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)-6-(trifluoromethyl)spiro[isochroman-1,4'-piperidin]-1'-yl]ethanone (52 mg, 0.11 mmol) in MeOH (1 mL) was added 6 M aqueous NaOH (225 μL, 1.35 mmol). The reaction was heated at 60° C. for 1 h and then cooled to room temperature. Volatiles were removed and the crude material was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in HO with 0.1% trifluoroacetic acid) to give the title compound 23 as the trifluoroacetate salt (13.2 mg, 21%). NMR(400MHz,Methanol-d4)δ8.05(s,1H),7.56(d,J=8.3Hz,1H),7.51(s,1H),7.42 (d,J=8.2Hz,1H),4.97-4.88(m,1H),4.12(d,J=1.6Hz,3H),4.03(t,J=5.5Hz,2H),3 .86(s,1H),2.95(t,J=5.5Hz,2H),2.49(dt,J=29.7,14.6Hz,2H),2.29(d,J=14.8H z,1H),2.04(dd,J=14.8,12.2Hz,1H),1.42(d,J=6.4Hz,3H).LCMSm / z366.4[M+H]+.

[0185] compound 24 7-Chloro-2'-methyl-6'-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)spiro[isochroman-1,4'-piperidine] (24) [ka] Step 1. Synthesis of 7-chloro-2'-methyl-6'-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)spiro[isochroman-1,4'-piperidin]-6-yl trifluoromethanesulfonate (C20) Compound C20 was prepared from compound 3 according to the method described for compound S4. The reaction was purified by silica gel chromatography (0-20% MeOH in DCM) to give the title compound C20 as a white solid (111 mg, 72%). LCMS m / z 571.1 [M+H]+.

[0186] Step 2. Synthesis of 7-chloro-2'-methyl-6'-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)spiro[isochroman-1,4'-piperidine] (24) Compound 24 was prepared from compound C20 according to the method described for compound 10. The reaction was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30x150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give the title compound 24 as the trifluoroacetic acid salt (16.6 mg, 77%). 1H NMR(300MHz,Methanol-d4)δ7.94(s,1H),7.73(s,1H),7.31-7.15(m,3H),4.78-4.69(m,1H),4.66(t,J=6.3Hz,2H),3.97(t,J=5.5Hz,2H),3.81(s, 1H),3.71(t,J=6.3Hz,2H),2.85(s,5H),2.40-2.30(m,2H),2.24(d,J=14. 9Hz,1H),1.99-1.83(m,1H),1.38(d,J=6.6Hz,3H).LCMSm / z424.0[M+H]+.

[0187] Compounds 25 and 26 (Method A) (1S,2'S,4S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-ol (25) and (1S,2'S,4R,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-ol (26) [ka] Step 1. Synthesis of (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-one (C21) To a solution of (1S,2'S,6'S)-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[isochroman-1,4'-piperidine] (hydrochloride) (29.8 mg, 0.081 mmol) in MeCN (0.15 mL) and HO (0.45 mL) was added ammonium hydrogen sulfate (65 mg, 0.28 mmol) and Cu(OAc) (4.5 mg, 0.025 mmol). The resulting pale blue solution was stirred at 50 °C overnight. The reaction was quenched with saturated NaHCO solution and brine and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated in vacuo to give the title compound C21. The crude was used directly without further purification. LCMS m / z 349.0 [M+H].

[0188] Step 2. Synthesis of (1S,2'S,4S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-ol (25) and (1S,2'S,4R,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-ol (26) To a solution of (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-one (28 mg, 0.081 mmol) in MeOH (1.5 mL) was added NaBH (3.0 mg, 0.079 mmol). The reaction was stirred at room temperature for 15 minutes. EtOAc was added and stirred for 10 minutes, then the volatiles were removed. The crude product was purified by chiral SFC separation (column: Daicel Chiralpak AD-H, 10 x 250 mm, mobile phase: 40% ethanol (5 mM ammonia), 60% CO. Flow rate: 15 mL / min, isocratic) to give diastereomer 25 (1.0 mg, 3%) and diastereomer 26 (1.2 mg, 4%). The absolute stereochemistry was assigned by comparison with an authentic sample obtained from the asymmetric reduction of the ketone intermediate (Method B).

[0189] Characteristic analysis data of compound 25: 1H NMR(400MHz,Methanol-d4)δ7.83(s,1H),7.46(d,J=2.1Hz,1H),7.29(dd,J=8.4,2.2Hz,1H),7.22(d,J=8. 4Hz,1H),4.55(t,J=4.8Hz,1H),4.37(dd,J=11.9,2.7Hz,1H),4.08(s,3H),4.01(dd,J=11.7,4.0Hz,1H),3. 75(dd,J=11.8,5.8Hz,1H),3.40-3.30(m,1H),2.17(dt,J=13.8,2.5Hz,1H),2.06(dt,J=14.1,2.6Hz,1H), 1.89(dd,J=13.7,11.9Hz,1H),1.58(dd,J=13.8,11.5Hz,1H),1.17(d,J=6.4Hz,3H).LCMSm / z348.8[M+H]+.

[0190] Characteristic analysis data of compound 26: 1H NMR(300MHz,Methanol-d4)δ7.84(s,1H),7.46(d,J=2.2Hz,1H),7.33-7.17(m,2H),4.56( dd,J=5.9,4.1Hz,1H),4.40(dd,J=11.7,2.7Hz,1H),4.08(s,3H),4.01(dd,J=11.8,4.1Hz ,1H),3.75(dd,J=11.8,6.0Hz,1H),3.60(q,J=7.1Hz,1H),2.29(dt,J=13.7,2.6Hz,1H),2 .01-1.86(m,2H),1.53(dd,J=13.8,11.4Hz,1H),1.23-1.08(m,3H).LCMSm / z348.8[M+H]+.

[0191] Alternative Preparation of Compound 25 (Method B) (1S,2'S,4S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-ol (25) [ka] Step 1. Synthesis of 1-((1S,2'S,6'S)-6-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-1'-yl)-2,2,2-trifluoroethan-1-one (C22) A pressure tube was charged with [(1S,2'S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)-1'-(2,2,2-trifluoroacetyl)spiro[isochroman-1,4'-piperidin]-6-yl]trifluoromethanesulfonate (4 g, 7.005 mmol), tBuBrettPhos Pd G2 (630 mg, 0.737 mmol), potassium chloride (1.35 g, 18.11 mmol), and potassium fluoride (270 mg, 4.647 mmol). The tube was capped and purged with N2 (x3), then dioxane (36 mL) was added. The tube was sealed and heated at 130 °C behind a blast shield for 24 h. The reaction was cooled to room temperature, quenched with water and brine (1 / 1), and then extracted with DCM (x3). The combined organic extracts were concentrated in vacuo, and the crude material was purified by silica gel chromatography (0-40% EtOAc in heptane) to afford the title compound C22 as a light brown foamy solid (2.0 mg, 63%). 1H NMR(300MHz,Chloroform-d)δ7.53(s,1H),7.23-7.11(m,1H),7.01(d,J=2.1Hz,1H),5.53(s,1H),4.35(q,J=7.2Hz,1H),4.04(s,3H),3.78(t,J=5.6H) z,2H),3.22(dd,J=14.6,6.4Hz,1H),2.72(q,J=5.3Hz,2H),2.44(dd,J=14. 6,8.3Hz,1H),2.22-1.95(m,1H),1.34-1.10(m,5H).LCMSm / z429.1[M+H]+.

[0192] Step 2. Synthesis of (1S,2'S,6'S)-6-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-1'-(2,2,2-trifluoroacetyl)spiro[isochroman-1,4'-piperidin]-4-one (C23) To a solution of 1-[(1S,2'S,6'S)-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[isochroman-1,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone (2.96 g, 6.902 mmol) in MeCN (100 mL) was added cobalt acetate tetrahydrate (90 mg, 0.361 mmol) and N-hydroxyphthalimide (2.9 g, 17.78 mmol). HO (1.6 mL, 15.66 mmol, 30% w / w) was slowly added. The reaction was heated at 50 °C for 5 h, during which time additional HO (1.6 mL, 15.66 mmol, 30% w / w) and cobalt acetate tetrahydrate (90 mg, 0.361 mmol) were added every hour. The reaction was cooled to room temperature and then quenched with saturated NaSO solution and saturated NaHCO solution. The reaction was extracted with DCM (x3). The combined organic extracts were concentrated in vacuo. The crude material was purified by silica gel chromatography (0 to 50% EtOAc in heptane) to afford the title compound C23 as a white solid (916 mg, 29%). 1H NMR(300MHz,Chloroform-d)δ8.00(s,1H),7.67-7.58(m,3H),5.65(s,2H),4.49-4.33(m,3H),4.13(s,3H), 3.47(dd,J=15.0,5.3Hz,1H),2.67(dd,J=15.1,8.7Hz,1H),2.23(s,2H),1.25(s,3H).LCMSm / z443.1[M+H]+.

[0193] Step 3. Synthesis of 1-((1S,2'S,4S,6'S)-6-chloro-4-hydroxy-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-1'-yl)-2,2,2-trifluoroethan-1-one (C24) To a 100-mL three-necked RBF, 1,2,3,4,5-pentamethylcyclopentane, rhodium tetrachloride (8.2 mg, 0.013 mmol), and N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-4-methyl-benzenesulfonamide (12 mg, 0.0327 mmol) were added, followed by MeCN (7 mL). The mixture was stirred at room temperature for 20 minutes, and then TEA (605 μL, 4.341 mmol) and formic acid (410 μL, 10.87 mmol) (a 5:2 commercial solution from Oakwood) were added. The reaction mixture immediately turned bright orange, and some effervescence was observed. The mixture was cooled to −15 °C in an acetone / dry ice bath. To a separate flask was added (1S,2'S,6'S)-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)-1'-(2,2,2-trifluoroacetyl)spiro[isochroman-1,4'-piperidin]-4-one (910 mg, 1.973 mmol), MeCN (7 mL), and DCM (3 mL). The mixture was cooled to -15 °C to form a slurry and then added to the first flask. The reaction was stirred while maintaining the internal temperature between -5 °C and -25 °C for 5 h. The reaction was quenched with saturated NaHCO3 solution and then extracted with DCM (x2). The combined organic extracts were concentrated in vacuo. The crude product was purified by silica gel chromatography (0-50% EtOAc in heptane) to afford the title compound C24 as an off-white foamy solid (766 mg, 84%). 1H NMR(300MHz,Chloroform-d)δ7.60(s,2H),7.43(s,1H),7.34(d,J=7.8Hz,1H),5.58(s,1H),4.60-4.43(m,2H),4.11(s,3H),3.96(dd,J=12.1,3.2Hz, 1H),3.80(dd,J=12.1,4.4Hz,1H),3.20(dd,J=15.1,6.1Hz,1H),2.58(d,J =11.7Hz,1H),2.38-2.17(m,3H),1.53-0.83(m,3H).LCMSm / z444.1[M+H]+.

[0194] Note that the stereochemistry of the alcohol C24 was assigned based on literature understanding of reductions using this catalyst and complex system. (See: New Chiral Rhodium and Iridium Complexes with Chiral Diamine Ligands for Asymmetric Transfer Hydrogenation of Aromatic Ketones. Kunihiko Murata, Takao Ikariya, and Ryoji Noyori. The Journal of Organic Chemistry 1999 64(7), 2186-2187.)

[0195] Step 4. Synthesis of (1S,2'S,4S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-ol (25) To a solution of 1-[(1S,2'S,4S,6'S)-6-chloro-4-hydroxy-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[isochroman-1,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone (760 mg, 1.642 mmol) in MeOH (9 mL) was added NaOH (3 mL, 18.00 mmol, 6 M in HO). The reaction was heated at 60°C for 1.5 hours. The reaction was cooled to room temperature and then diluted with water. The pH was adjusted to 11 by the addition of saturated NH4Cl solution. MeOH was removed in vacuo, and the remaining aqueous solution was extracted with MTBE (x3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound 25 (560 mg, 97%) as a white solid. 1H NMR(400MHz,Methanol-d4)δ7.83(s,1H),7.46(d,J=2.1Hz,1H),7.29(dd,J=8.4,2.2Hz,1H),7.22(d,J=8. 4Hz,1H),4.55(t,J=4.8Hz,1H),4.37(dd,J=11.9,2.7Hz,1H),4.08(s,3H),4.01(dd,J=11.7,4.0Hz,1H),3. 75 (dd, J = 11.8, 5.8 Hz, 1H), 3.40-3.30 (m, 1H), 2.17 (dt, J = 13.8, 2.5 Hz, 1H), 2.06 (dt, J = 14.1, 2.6 Hz, 1H), 1.89 (dd, J = 13.7, 11.9 Hz, 1H), 1.58 (dd, J = 13.8, 11.5 Hz, 1H), 1.17 (d, J = 6.4 Hz, 3H). LCMS m / z 349.1 [M+H]+. SFC showed >99% de novo.

[0196] Compounds 27 and 28 (1S,2'S,4S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)spiro[isochroman-1,4'-piperidin]-4-ol (27) and (1S,2'S,4R,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)spiro[isochroman-1,4'-piperidin]-4-ol (28) [ka] Step 1. Synthesis of (1S,2'S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-1'-(2,2,2-trifluoroacetyl)-6-(trifluoromethyl)spiro[isochroman-1,4'-piperidin]-4-one (C25) Compound C25 was prepared from compound S6 according to the method described for compound C23. The reaction was purified by silica gel chromatography (0-50% EtOAc in heptane) to give the title compound C25 (1032 mg, 80% purity, 34% yield) as a white solid. LCMS m / z 477.0 [M+H]+.

[0197] Step 2. Synthesis of 2,2,2-trifluoro-1-((1S,2'S,4S,6'S)-4-hydroxy-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)spiro[isochroman-1,4'-piperidin]-1'-yl)ethan-1-one (C26) Compound C26 was prepared from compound C25 according to the method described for compound C24. The reaction was purified by silica gel chromatography (0-100% EtOAc in heptane) to give the title compound C26 (211 mg, 25% yield) as a pale yellow oil. SFC analysis showed a 9:1 dr. LCMS m / z 479.0 [M+H]+.

[0198] Step 3. Synthesis of (1S,2'S,4S,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)spiro[isochroman-1,4'-piperidin]-4-ol (27) and (1S,2'S,4R,6'S)-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)spiro[isochroman-1,4'-piperidin]-4-ol (28) Compounds 27 and 28 were prepared from compound C26 according to the method described for compound 25. The reaction was purified by chiral SFC separation (column: Daicel Chiralpak® AD-H, 20×250 mm, mobile phase: 10% MeOH (5 mM ammonia), 90% CO. Flow rate: 80 mL / min, isocratic) to give the major diastereomer 27 (93.6 mg, 55.3%) and the minor diastereomer 28 (9.4 mg, 2.7%).

[0199] 27 feature analysis data: 1H NMR(300MHz,Methanol-d4)δ7.84(s,1H),7.78(s,1H),7.58(d,J=8.3Hz,1H),7 .44(d,J=8.3Hz,1H),4.64(t,J=4.9Hz,1H),4.40(d,J=11.1Hz,1H),4.08(s,4H) ,3.79(dd,J=11.8,5.8Hz,1H),3.40-3.30(m,1H),2.20(d,J=13.8Hz,1H),2.10 (d,J=13.9Hz,1H),2.03-1.84(m,1H),1.71-1.53(m,1H),1.19(d,J=6.5Hz,3H). 19F NMR (282 MHz, methanol-d4) δ -64.13. LCMS m / z 382.4 [M+H]+.

[0200] 28 feature analysis data: 1H NMR(300MHz,Chloroform-d)δ7.75(s,1H),7.56(d,J=8.3Hz,1H),7.47(s,1H),7.35(d,J=8.1Hz,1H),4.65(s,1H),4.55(dd,J=11.3,2.7Hz,1H),4. 11-4.01(m,4H),3.92(dd,J=12.2,4.4Hz,1H),3.31(d,J=28.9Hz,1H),2. 12(dt,J=39.4,13.8Hz,3H),1.60-1.38(m,3H),1.17(d,J=6.3Hz,3H).19F NMR (282 MHz, chloroform-d) δ -62.63. LCMS m / z 382.4 [M+H]+.

[0201] Compounds 29 and 30 (mixture of diastereomers) (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-ol (29) and (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-ol (30) [ka] Step 1. Synthesis of (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-one (C27) Compound C27 was prepared from compound 10 according to the method described for compound C21. The crude was used directly without further purification. LCMS m / z 347.2 [M+H]+.

[0202] Step 2. Synthesis of (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-ol (29) and (1S,2'S,6'S)-7-chloro-2'-methyl-6'-(1-methyl-1H-1,2,3-triazol-4-yl)spiro[isochroman-1,4'-piperidin]-4-ol (30) Compounds 29 and 30 (a mixture of diastereomers) were prepared from compound C27 according to the method described for compounds 25 and 26. The reaction was purified by reverse-phase HPLC (method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give the title compounds as a mixture of trifluoroacetate salts (11.8 mg, 38%). The mixture was purified again by chiral SFC separation (column: Daicel Chiralpak AD-H, 10 x 250 mm, mobile phase: 40% isopropanol (5 mM ammonia), 60% CO. Flow rate: 15 mL / min, isocratic) to give diastereomer 29 (2.5 mg, 10%) and diastereomer 30 (3.0 mg, 13%).

[0203] Preparation S7 (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxylic acid (S7) [ka] Step 1. (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (C28) A 250 mL flask was charged with (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one S2 (2.02 g, 10.09 mmol), potassium carbonate (2.69 g, 19.46 mmol), and MeCN (20 mL). Bromomethylbenzene (1.4 mL, 11.77 mmol) was then added, and the resulting mixture was heated to 60 °C. After 5 h, the reaction flask was left at room temperature overnight. The reaction was quenched with saturated NaHCO3 solution and extracted with DCM (x4). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (column: 220 g column, gradient: 0 to 100% EtOAc in heptane) afforded (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one C28 (1.67 g, 58%). 1H NMR(300MHz,Chloroform-d)δ7.25-7.11(m,6H),4.33(dd,J=10.2,3.9Hz,1H),3.93(s,3H),3.81(s,2H),3.20(h,J =6.5Hz,1H),2.92(dd,J=15.0,10.2Hz,1H),2.69(dd,J=15.0,4.0Hz,1H),2.53-2.37(m,2H),1.13(d,J=6.4Hz,3H).

[0204] Step 2. (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carbonitrile (C29) An oven-dried 250-mL flask was charged with KOtBu (5.93 g, 52.85 mmol) and purged with nitrogen for 10 minutes. tBuOH (48 mL) and DME (8 mL) were added. To a separate 100-mL flask, (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one C28 (1.67 g, 5.873 mmol) and DME (10 mL) were added. The C28 solution was added to the KOtBu flask, and the resulting solution was stirred at room temperature for 1 hour. A solution of 1-(isocyanomethylsulfonyl)-4-methyl-benzene (2.22 g, 11.37 mmol) in DME (8 mL) was then added. The reaction mixture was heated at 85 °C for 3 hours and then cooled to room temperature. Water was added to the brown solution. The reaction mixture was then extracted with DCM (x4). The combined organic layers were washed with brine, and the aqueous layer was extracted with DCM (x2). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (column: 120 g column, gradient: 0 to 10% MeOH in DCM) afforded (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carbonitrile C29 (1.47 g, 76%). LCMS m / z 296.21 [M+H]+. The product contained a mixture of diastereomers with a 1.6:1 ratio based on the H NMR spectrum.

[0205] Step 3. (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxylic acid (S7) To a stirred solution of (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carbonitrile C29 (1.47 g, 4.479 mmol) in EtOH (18 mL) was added a solution of lithium hydroxide hydrate (1.895 g, 45.16 mmol) in water (18 mL) at room temperature. The reaction mixture was then heated to 100 °C. After 4 h, the reaction was cooled to room temperature, quenched with 6 M aqueous hydrogen chloride (7.8 mL 6 M, 46.80 mmol), and concentrated in vacuo to remove all solvent. Purification by silica gel chromatography (column: 80 g column, gradient: 0 to 10% MeOH in DCM) afforded (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxylic acid S7 (874 mg, 62%). 1H NMR(300MHz,Methanol-d4)δ8.08(s,1H),7.45-6.94(m,5H),4.98-4.76(m,1H),4.51-4.25(m,2H),4.13(s,3H), 3.79-3.47(m,1H),2.95-2.66(m,1H),2.50-2.12(m,3H),2.10-1.79(m,1H),1.56(s,3H).LCMSm / z315.21[M+H]+.

[0206] compound 31 (2'S,3R,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (31) [ka] Step 1. (2'S,3R,6'S)-5-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (C31) To a stirred solution of (2'S,3R,6'S)-1'-benzyl-5-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C30 (17 mg, 0.03060 mmol, prepared as described below) in EtOH (500 μL) and EtOAc (500 μL) was added 5% palladium on carbon (6 mg, 0.002819 mmol). The reaction flask was evacuated and refilled with H2 three times. The reaction mixture was then stirred under hydrogen balloon pressure. After 22 h, the reaction flask was evacuated and refilled with H2 three times. After 11 h, the reaction mixture was filtered through Celite®, and the solids were rinsed with EtOAc. The crude material was purified on a silica gel column and eluted with 0-12% MeOH in DCM to give (2'S,3R,6'S)-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C31 (3.8 mg, 29%). 1H NMR (300 MHz, Chloroform-d) δ 7.77-7.70 (m, 1H), 7.51 (s, 1H), 7.24-7.13 (m, 3H), 7.03 (td, J = 7.6, 1.1 Hz, 1H), 6.87-6.75 (m, 3H), 4.87 (s, 2H), 4.67 (dd, J = 12.4, 2.8 Hz, 1H). ,4.06(s,3H),3.76(s,3H),3.52(ddd,J=11.9,6.2,2.7Hz,1H),2.19(t,J=12.7Hz,1H ),1.92-1.76(m,2H),1.60-1.49(m,1H),1.17(d,J=6.2Hz,3H).LCMSm / z418.3[M+H]+. A chloro product was also isolated.

[0207] Step 2. (2'S,3R,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (31) To a 1-dram vial containing (2'S,3R,6'S)-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C31 (3.8 mg, 0.009 mmol) was added DCM (200 μL), followed by trifluoromethanesulfonic acid (13 μL, 0.1469 mmol). After 24 h, the reaction mixture was cooled to 0 °C, carefully quenched with saturated NaHCO solution, and extracted with DCM (×5). The combined organic layers were dried over NaSO, filtered, and concentrated. The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was purified on a silica gel column and eluted with 0–20% MeOH in DCM to give (2'S,3R,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one 31 (1.8 mg, 18%). 1H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 7.26 (dd, J = 15.5, 1.2 Hz, 1H), 7.05 (td, J = 7.6, 1.1 Hz, 1H), 6.93 (dt, J = 7.7, 0.8 Hz, 1H), 4.67 (d d,J=12.3,2.8Hz,1H),4.05(s,3H),3.61-3.48(m,1H),2.14(t,J=12.7Hz,1H),1.96-1. 75(m,2H),1.59(dt,J=13.1,2.4Hz,1H),1.17(d,J=6.1Hz,3H).LCMSm / z295.46[M+H]+.

[0208] compound 32 (2'S,3S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (32) [ka] (2'S,3S,6'S)-2'-Methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one 32 was prepared from (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C32 (4.5 mg, 0.009269 mmol, prepared as described below) according to the procedure for synthesizing compound 31. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30x150 mm, 5 microns). Gradient: MeCN in HO with 0.2% formic acid. The product was isolated as (2'S,3S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (formate salt) (3.6 mg, 97%). 1H NMR(300MHz,Methanol-d4)δ8.05(s,1H),7.27(t,J=7.7Hz,2H),7.09(t,J=7.5Hz,1H),6.94(d,J=7.7Hz,1H),5.41(dd,J=12.6,3.2Hz,1H),4.33(h,J=6). 9Hz,1H),4.12(s,3H),2.52(dd,J=14.7,12.7Hz,1H),2.25(dd,J=14.8,3.2H z,1H),2.06(d,J=8.2Hz,2H),1.40(d,J=6.5Hz,3H).LCMSm / z298.34[M+H]+.

[0209] compound 33 (2'S,3S,6'S)-2',6-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (33) [ka] Step 1. (2S,6S)-1-benzyl-N-(2-bromo-5-methyl-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide (C33) A 2-dram vial was charged with (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxylic acid S7 (98 mg, 0.3117 mmol), 2-bromo-5-methyl-aniline (64 mg, 0.3440 mmol), pyridine (80 μL, 0.9891 mmol), and EtOAc (1000 μL). Propylphosphonic anhydride solution (360 μL, 0.605 mmol, 50 wt % in EtOAc) was added. After 4 h, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (×4). The crude mixture was purified by silica gel chromatography using 0-100% EA in heptane to give (2S,6S)-1-benzyl-N-(2-bromo-5-methyl-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C33 (99 mg, 64%). NMR(300MHz,Chloroform-d)δ8.16(s,1H),7.59(s,1H),7.38(d,J=8.2Hz,1H),7.2 1(q,J=5.1Hz,5H),7.17-7.08(m,1H),6.79(d,J=8.5Hz,1H),3.96(dd,J=11.7,2.9 Hz,1H),3.88(s,3H),3.81-3.59(m,2H),2.68(s,1H),2.60-2.46(m,1H),2.31(s,3 H),2.20(s,1H),2.03-1.68(m,3H),1.17(d,J=6.1Hz,3H).LCMSm / z482.12[M+H]+.

[0210] Step 2. (2S,6S)-1-benzyl-N-(2-bromo-5-methyl-phenyl)-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide (C34) A 2-dram vial was charged with (2S,6S)-1-benzyl-N-(2-bromo-5-methyl-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C33 (99 mg, 0.2008 mmol) in THF (2 mL). The vial was cooled to 0 °C and treated with sodium hydride (12.7 mg, 0.3175 mmol, 60 wt%) at 0 °C. The vial was warmed to room temperature after 5 minutes. After 10 minutes, 1-(bromomethyl)-4-methoxy-benzene (35 μL, 0.2401 mmol) was added at room temperature. After 6 hours, additional NaH (4 mg, 0.1 mmol, 60 wt%) and 1-(bromomethyl)-4-methoxy-benzene (10 μL, 0.069 mmol) were added. After 2 h, the reaction was slowly quenched with saturated NaHCO3 solution and extracted with DCM (x3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was absorbed onto silica gel and purified with 0 to 100% EtOAc in heptane to give (2S,6S)-1-benzyl-N-(2-bromo-5-methyl-phenyl)-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C34 (106 mg, 85%). LCMS m / z 602.07 [M+H]+. 1H NMR spectrum indicated a ca. 1.34:1 mixture of diastereomers. The material was then heated to 80 °C for 3 h to remove residual EtOAc.

[0211] Step 3. (2'S,6'S)-1'-benzyl-1-[(4-methoxyphenyl)methyl]-2',6-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (C35) The reaction was set up in a N2-glove box. To an oven-dried 2-dram vial was added (2S,6S)-1-benzyl-N-(2-bromo-5-methyl-phenyl)-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C34 (105 mg, 0.1688 mmol), followed by BINAP Pd G3 (16 mg, 0.01612 mmol) and sodium t-butoxide (35 mg, 0.3642 mmol), followed by dioxane (1.5 mL). The vial was transferred to a fume hood and heated to 100 °C. After 14 h, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (x5). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified on a silica gel column and eluted with 0-100% EtOAc in heptane to give (2'S,6'S)-1'-benzyl-1-[(4-methoxyphenyl)methyl]-2',6-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C35 (80.9 mg, 87%). LCMS m / z 522.31 [M+H]+.

[0212] Step 4. (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2',6-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (C36) To a stirred solution of (2'S,6'S)-1'-benzyl-1-[(4-methoxyphenyl)methyl]-2',6-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C35 (80.9 mg, 0.1473 mmol) in EtOH (1.5 mL) and EtOAc (1.5 mL) was added palladium on carbon (Evonik Noblyst® P1090 5% Pd, 16 mg, 0.007517 mmol). The reaction flask was evacuated and refilled with H2 four times. The reaction mixture was then stirred under hydrogen balloon pressure. After 25 h, it was refilled with H2 and additional palladium (16 mg, 0.007517 mmol) was added. The reaction was left at room temperature for 24 h and then refilled with H2. After an additional 24 h, the reaction mixture was filtered through a plug of Celite®, washing with EtOAc. The filtrate was concentrated and purified by silica gel chromatography (Column: 12 g column, Gradient: 0-10% MeOH in DCM) to give two fractions.

[0213] (2'S,3R,6'S)-1-[(4-methoxyphenyl)methyl]-2',6-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indolin-3,4'-piperidin]-2-one C57 (19.4 mg, 31%). 1H NMR (300 MHz, Chloroform-d) δ 7.61 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.18 (d, J = 8.5 Hz, 2H), 6.83 (dd, J = 8.2, 3.4 Hz, 3H), 6.62 (s, 1H), 4.84 (s, 2H), 4.65 (dd, J = 12.4, 2.8 Hz, 1H), 4.05 (s, 3H), 3.76 (s, 3H), 3.50 (ddd, J = 12.0, 6.2, 2.9 Hz, 1H), 2.30 (s, 3H), 2.18 (t, J = 12.6 Hz, 1H), 1.94-1.76 (m, 2H), 1.53 (dt, J = 12.9, 2.4 Hz, 1H), 1.16 (d, J = 6.1 Hz, 3H). Based on the 1H NOESY, the relative stereochemistry is assigned as cis, with the major NOESY signal being between the oxindole CH and the two methine protons.

[0214] (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2',6-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indolin-3,4'-piperidin]-2-one C36 (34.8 mg, 55%). 1H NMR (300 MHz, chloroform-d) δ 7.44 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.91–6.78 (m, 3H), 6.54 (s, 1H), 4.99 (dd, J = 11.5, 3.1 Hz, 1H), 4.80 (s, 2H) ), 4.05(s, 3H), 3.97~3.79(m, 1H), 3.76(s, 3H), 2.28(s, 3H), 2.18~1.87(m, 2H ), 1.77(t, J=2.0Hz, 1H), 1.60(dd, J=13.6, 11.3Hz, 1H), 1.14(d, J=6.3Hz, 3H).

[0215] The product was assigned as trans based on the NMR assignment of the cis isomer.

[0216] Step 5. (2'S,3S,6'S)-2',6-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (33) To a 20-mL vial of (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2',6-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C36 (34.8 mg, 0.08064 mmol) in DCM (1.4 mL) was added trifluoromethanesulfonic acid (72 μL, 0.8137 mmol) at 0 °C. The vial was allowed to warm to room temperature after the acid addition. After 6 h, the reaction vial was cooled to 0 °C and carefully quenched with saturated NaHCO solution and extracted with DCM (x5). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was purified by silica gel column eluting with 0-20% MeOH in DCM to give (2'S,3S,6'S)-2',6-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one 33 (22.1 mg, 85%). 1H NMR(300MHz,Chloroform-d)δ8.68(s,1H),7.43(s,1H),7.05(d,J=7.6Hz,1H), 6.83(d,J=7.6Hz,1H),6.72(s,1H),4.96(dd,J=8.8,5.9Hz,1H),4.03(s,3H),3 .96-3.72(m,1H),2.32(s,3H),2.06-1.96(m,2H),1.77(dd,J=13.6,2.7Hz,1H) ,1.58(dd,J=13.6,11.4Hz,1H),1.13(d,J=6.3Hz,3H).LCMSm / z312.19[M+H]+.

[0217] compound 34 (2'S,3S,6'S)-2',5-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (34) [ka] Step 1. (2S,6S)-1-benzyl-N-(2-bromo-4-methyl-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide (C37) A 2-dram vial was charged with (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxylic acid S7 (82 mg, 0.2608 mmol), 2-bromo-4-methyl-aniline (53 mg, 0.2849 mmol), pyridine (64 μL, 0.7913 mmol), and EtOAc (800 μL). Propylphosphonic anhydride solution (300 μL, 0.504 mmol, 50 wt % in EtOAc) was added. After 6 h, the reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (×4). The crude mixture was purified by silica gel chromatography using 0-100% EtOAc in heptane to give (2S,6S)-1-benzyl-N-(2-bromo-4-methyl-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C37 (85 mg, 65%). 1H NMR (300 MHz, Chloroform-d) δ 8.14 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.41-7.32 (m, 1H), 7.25-7.17 (m, 5H), 7.17-7.02 (m, 2H), 3.95 (dd, J = 11.6, 2.8 Hz, 1H), 3.88 (s, 3H), 3.08 (s, 3H). .77-3.55(m,2H),2.67(t,J=7.5Hz,1H),2.52(tt,J=12.3,3.7Hz,1H),2.29(s,3H), 2.23-2.07(m,1H),2.02-1.70(m,3H),1.16(d,J=6.1Hz,3H).LCMSm / z482.26[M+H]+.

[0218] Step 2. (2S,6S)-1-benzyl-N-(2-bromo-4-methyl-phenyl)-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide (C38) A vial was charged with (2S,6S)-1-benzyl-N-(2-bromo-4-methyl-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C37 (85 mg, 0.1762 mmol) and THF (1.8 mL). The vial was cooled to 0 °C and treated with sodium hydride (14 mg, 0.3500 mmol, 60 wt%) at 0 °C. The vial was warmed to room temperature after 5 minutes. After 10 minutes, 1-(bromomethyl)-4-methoxy-benzene (39 μL, 0.2675 mmol) was added at room temperature. After 7 hours, the reaction was slowly quenched with saturated NaHCO solution and extracted with DCM (x3). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was absorbed onto silica gel and purified with 0 to 100% EtOAc in heptane to give (2S,6S)-1-benzyl-N-(2-bromo-4-methyl-phenyl)-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C38 (95 mg, 83%). LCMS m / z 602.25 [M+H]+. The material was then heated to 80°C under vacuum for 2 hours to remove residual EtOAc. 1H NMR indicated the product was a mixture of diastereomers in a 1.34:1 ratio.

[0219] Step 3. (2'S,6'S)-1'-benzyl-1-[(4-methoxyphenyl)methyl]-2',5-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (C39) The reaction was set up in a N2-glove box. To a 20 ml vial, (2S,6S)-1-benzyl-N-(2-bromo-4-methyl-phenyl)-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C38 (95 mg, 0.1463 mmol) was added, followed by BINAP Pd G3 46-2153 (7.3 mg, 0.007356 mmol) and sodium t-butoxide (28 mg, 0.2914 mmol). Finally, dioxane (1.3 mL) was added. The vial was transferred from the glove box to the bench and heated to 100 °C. After 15 h, the reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (x5). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified on a silica gel column, eluting with 0–100% EtOAc in heptane, to give (2′S,6′S)-1′-benzyl-1-[(4-methoxyphenyl)methyl]-2′,5-dimethyl-6′-(1-methyltriazol-4-yl)spiro[indoline-3,4′-piperidin]-2-one C39 (83.4 mg, 0.1071 mmol, 67% purity by H NMR) mixed with the starting material in a ratio of 1.44:1.0:1.18 (diastereomers 1 and 2 and starting material). The mixture was carried on to the next reaction.

[0220] Step 4. (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2',5-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (C40) To a stirred solution of (2'S,6'S)-1'-benzyl-1-[(4-methoxyphenyl)methyl]-2',5-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C39 (83.4 mg, 0.1071 mmol, 67% pure by H NMR) in EtOH (1 mL) and EtOAc (1 mL) was added palladium on carbon (Evonik Noblyst® P1090 5% Pd, 34.6 mg, 0.01626 mmol). The reaction flask was evacuated and refilled with H2 four times. The reaction mixture was then stirred under hydrogen balloon pressure. After 18 h, H2 was refilled and the reaction mixture was stirred at room temperature. After an additional 24 h, the reaction flask was evacuated and refilled with N2. The mixture was filtered through a plug of Celite® and washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography (column: 24 g column, gradient: 0-10% MeOH in DCM) to give two diastereomers. The trans isomer was isolated as the more polar fraction. (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2',5-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C40 (23.1 mg, 43%). 1H NMR(300MHz,Chloroform-d)δ7.51(s,1H),7.19(d,J=8.5Hz,2H),7.05(s,1H),6.94(d,J= 7.9Hz,1H),6.83(d,J=8.4Hz,2H),6.60(d,J=7.8Hz,1H),5.03(dd,J=11.7,2.9Hz,1H),4. 81(s,2H),4.06(s,3H),4.02-3.83(m,1H),3.76(s,3H),2.36(d,J=2.2Hz,3H),2.17(t,J= 12.7Hz, 1H), 1.99 (d, J = 17.5Hz, 1H), 1.71 (dt, J = 24.7, 13.1Hz, 2H), 1.18 (d, J = 6.3Hz, 3H).

[0221] NOTE: Stereochemistry was assigned by comparing the H NMR spectrum from the synthesis with a related analog (compound 33). The major H signal is the methine peak at approximately 4.5-5 ppm. The trans isomer exhibits a slight downfield shift (approximately 5.0 ppm), while the cis isomer exhibits a downfield shift (approximately 4.6 ppm).

[0222] Step 5. (2'S,3S,6'S)-2',5-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (34) To a 20-mL vial of (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2',5-dimethyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C40 (23.1 mg, 0.04978 mmol) in DCM (800 μL) was added trifluoromethanesulfonic acid (45 μL, 0.5085 mmol) at 0 °C. The vial was allowed to warm to room temperature after the acid was added. After 7 h, the reaction was cooled to 0 °C, carefully quenched with saturated NaHCO3 solution, and extracted with DCM (x5). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified on a silica gel column, eluting with 0–20% MeOH in DCM to give (2′S,3S,6′S)-2′,5-dimethyl-6′-(1-methyltriazol-4-yl)spiro[indoline-3,4′-piperidin]-2-one 34 (12.8 mg, 77%). 1H NMR(300MHz,Chloroform-d)δ7.85(s,1H),7.44(s,1H),6.99(d,J=10.1Hz,2H),6.75(d,J=7.7Hz,1H),4.95(dd,J=9.9,4.7Hz,1H),4.05(s,3H),3.82(ddd ,J=11.7,6.4,2.8Hz,1H),2.31(s,3H),2.15-1.99(m,2H),1.80(dd,J=13.7, 2.7Hz,1H),1.68-1.47(m,1H),1.14(d,J=6.3Hz,3H).LCMSm / z312.14[M+H]+.

[0223] compound 35 (2'S,3S,6'S)-5-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (35) [ka] Step 1. (2S,6S)-1-benzyl-N-(2-bromo-4-chloro-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide (C41) To a 20-mL vial was added (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxylic acid S7 (118 mg, 0.3753 mmol), DCM (1.5 mL), and oxalyl dichloride (380 μL of 2 M, 0.75 mmol), followed by dropwise addition of DMF. After 3 h, the reaction mixture was concentrated in vacuo.

[0224] The crude material was dissolved in 0.5 mL of pyridine and 2 mL of DCM. 2-Bromo-4-chloro-aniline (84.8 mg, 0.4107 mmol) was added at 0° C. After 14 h, the reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (x3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using 0-30% EtOAc in heptane to give (2S,6S)-1-benzyl-N-(2-bromo-4-chloro-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C41 (101 mg, 51%). 1H NMR(400MHz,Chloroform-d)δ8.29(d,J=9.0Hz,1H),7.59(s,1H),7.53(d,J=2.2Hz,1H),7.31-7. 27(m,1H),7.25-7.17(m,5H),7.15(d,J=6.6Hz,1H),3.95(dd,J=11.5,2.7Hz,1H),3.88(d,J=1.6 Hz,3H),3.76-3.60(m,2H),2.67(d,J=9.7Hz,1H),2.53(t,J=12.4Hz,1H),2.17(d,J=12.7Hz,1H) ,2.02-1.85(m,2H),1.79(q,J=12.2Hz,1H),1.17(dd,J=6.1,1.6Hz,3H).LCMSm / z502.24[M+H]+.

[0225] Step 2. (2S,6S)-1-benzyl-N-(2-bromo-4-chloro-phenyl)-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide (C42) To a 2-dram vial was added (2S,6S)-1-benzyl-N-(2-bromo-4-chloro-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C41 (98 mg, 0.1949 mmol) and THF (2 mL). The vial was cooled to 0 °C and treated with sodium hydride (12 mg, 0.30 mmol, 60 wt%) at 0 °C. The vial was allowed to warm to room temperature. After 10 min, 1-(bromomethyl)-4-methoxy-benzene (34 μL, 0.2332 mmol) was added. After 20 h, the reaction was slowly quenched with saturated NaHCO solution and extracted with DCM (x3). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was absorbed onto SiO2 and purified with 0-100% EtOAc in heptane to give (2S,6S)-1-benzyl-N-(2-bromo-4-chloro-phenyl)-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C42 (102 mg, 78%). 1H NMR (400 MHz, Chloroform-d) δ 7.70 (dd, J = 2.3, 1.2 Hz, 1H), 7.23-6.94 (m, 9H), 6.88-6.69 (m, 2H), 6.60 (dd, J = 26.5, 8.4 Hz, 1H), 5.53 (dd, J = 14.2, 6.0 Hz, 1H), 3.93-3.86 (m, 1H), 3.84 (d, J = 2.5 Hz, 3H), 3.77 (d, J = 9.5 Hz, 3H), 3.71-3.47 (m, 3H), 2.46-2.23 (m, 1H), 2.12 (td, J = 14.2, 13.0, 9.8 Hz, 1H), 2.02-1.63 (m, 3H), 1.03 (dd, J = 28.9, 6.1 Hz, 3H). LCMS m / z 622.32 [M+H]+. 1H NMR spectrum indicated a ca. 1.3:1 mixture of diastereomers.

[0226] Step 3. (2'S,3S,6'S) and (2'S,3R,6'S)-1'-benzyl-5-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (C43 and C30) To a 20 mL vial was added (2S,6S)-1-benzyl-N-(2-bromo-4-chloro-phenyl)-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C42 (102 mg, 0.1354 mmol), followed by BINAP Pd G3 (17 mg, 0.01713 mmol) and sodium t-butoxide (49 mg, 0.5099 mmol). The vial was purged with N2 for 15 minutes, followed by the addition of dioxane (1.5 mL). The vial was heated to 100 °C for 12 hours. The reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (x3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified on a silica gel column, eluting with 0-100% EtOAc in heptane to give two fractions.

[0227] (2'S,3S,6'S)-1'-Benzyl-5-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C43 (14.9 mg, 20%). 1H NMR (300 MHz, Chloroform-d) δ 7.33-7.23 (m, 6H), 7.23-7.14 (m, 3H), 7.11 (dd, J = 8.3, 2.1 Hz, 1H), 6.91-6.76 (m, 2H), 6.62 (d, J = 8.3 Hz, 1H), 4.95 (dd, J = 12.0, 2.9 Hz, 1H), 4.91-4.66 (m, 2H), 3.89 (s, 3H). ,3.85(d,J=8.8Hz,2H),3.79(s,3H),3.78-3.69(m,1H),2.33(dd,J=13.8,12.0Hz,1H),1.96(ddd,J =13.7,5.8,2.6Hz,2H),1.75(dt,J=13.7,2.8Hz,1H),1.09(d,J=6.3Hz,3H).LCMSm / z542.39[M+H]+.

[0228] (2'S,3R,6'S)-1'-Benzyl-5-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C30 (17.2 mg, 14%, purity 59%). LCMS m / z 542.43 [M+H]+.

[0229] Step 4. (2'S,3S,6'S)-5-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (C44) To a stirred solution of (2'S,3S,6'S)-1'-benzyl-5-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C43 (14.9 mg, 0.02682 mmol) in EtOH (400 μL) and EtOAc (400 μL) was added 5% palladium on carbon (5.3 mg, 0.002490 mmol). The reaction flask was evacuated and refilled with H 3 three times. The reaction mixture was then stirred under hydrogen balloon pressure. After 48 h, the reaction flask was evacuated and refilled with H 3 three times. After 6 h, the reaction mixture was filtered through Celite®, and the solids were rinsed with EtOAc. The crude material was purified on a silica gel column and eluted with 0-10% MeOH in DCM to give (2'S,3S,6'S)-5-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C44 (5.9 mg, 48%). 1H NMR (300 MHz, Chloroform-d) δ 7.48 (s, 1H), 7.22-7.13 (m, 3H), 7.10 (dd, J = 8.3, 2.1 Hz, 1H), 6.89-6.78 (m, 2H), 6.62 (d, J = 8.3 Hz, 1H), 5.00 (dd, J = 10.7, 3.8 Hz, 1H), 4.81 (d, J = 2.3 Hz). z, 2H), 4.06 (s, 3H), 3.96-3.80 (m, 1H), 3.77 (s, 3H), 2.18-1.89 (m, 2H), 1.80 (dd, J = 2.9, 1.4 Hz, 1H), 1.60 (dd, J = 13.6, 11.3 Hz, 1H), 1.16 (d, J = 6.3 Hz, 3H). LCMS m / z 452.28 [M+H]+. The dehalogenated product was also isolated.

[0230] NOTE: Stereochemistry was assigned by comparing the H NMR spectrum from the synthesis with a related analog (compound 33). The major H signal is the methine peak at approximately 4.5-5 ppm. The trans isomer exhibits a slight downfield shift (approximately 5.0 ppm), while the cis isomer exhibits a downfield shift (approximately 4.6 ppm).

[0231] Step 5. (2'S,3S,6'S)-5-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (35) To a 1-dram vial containing (2'S,3S,6'S)-5-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C44 (5.9 mg, 0.01281 mmol) in DCM (150 μL) was added trifluoromethanesulfonic acid (12 μL, 0.1356 mmol) (Caution: Exothermic). After 3 h, the reaction was cooled to 0 °C, carefully quenched with saturated NaHCO solution, and extracted with DCM (x4). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was purified on a silica gel column, eluting with 0–20% MeOH in DCM to give (2′S,3S,6′S)-5-chloro-2′-methyl-6′-(1-methyltriazol-4-yl)spiro[indoline-3,4′-piperidin]-2-one 35 (4.3 mg, 97%). 1H NMR(300MHz,Chloroform-d)δ7.91(s,1H),7.49(s,1H),7.24-7.15(m,2H),6.82(d,J=8.8Hz,1H),4.96(dd,J=9.0,5.6Hz,1H),4.08(s,3H),3.83(dqd, J=12.6,6.2,2.7Hz,1H),2.18-1.95(m,2H),1.84(dt,J=13.9,1.7Hz,1H),1 .60(dd,J=13.6,11.4Hz,1H),1.17(d,J=6.4Hz,3H).LCMSm / z332.21[M+H]+.

[0232] compound 36 (2'S,3S,6'S)-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (36) [ka] Step 1. (2S,6S)-1-benzyl-N-(2-bromo-5-chloro-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide (C45) A 20 mL vial was charged with (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxylic acid S7 (120 mg, 0.3817 mmol), 2-bromo-5-chloroaniline (86.5 mg, 0.4190 mmol), pyridine (100 μL, 1.236 mmol), and EtOAc (1.5 mL). Propylphosphonic anhydride solution (480 mg, 0.7543 mmol, 50 wt % in EtOAc) was added. After 3 h, the reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (x3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using 0-100% EtOAc in heptane to afford (2S,6S)-1-benzyl-N-(2-bromo-5-chloro-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C45 (135.5 mg, 69%). 1H NMR(300MHz,Chloroform-d)δ8.44(d,J=2.5Hz,1H),7.64(s,1H),7.43(d,J=8.6H z,1H),7.24-7.10(m,6H),6.96(dd,J=8.6,2.5Hz,1H),3.96(dd,J=11.6,2.8Hz,1 H),3.89(s,3H),3.81-3.63(m,2H),2.68(s,1H),2.61-2.44(m,1H),2.16(dd,J=1 3.0,3.1Hz,1H),2.08-1.71(m,3H),1.18(d,J=6.1Hz,3H).LCMSm / z502.2[M+H]+.

[0233] Step 2. (2S,6S)-1-benzyl-N-(2-bromo-5-chloro-phenyl)-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide (C46) A solution of (2S,6S)-1-benzyl-N-(2-bromo-5-chloro-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C45 (135 mg, 0.2632 mmol) in THF (3.70 mL) was cooled to 0 °C in a vial and treated with sodium hydride (16.6 mg, 0.4150 mmol, 60 wt%). After 10 min, 1-(bromomethyl)-4-methoxy-benzene (46 μL, 0.3155 mmol) was added at 0 °C. The reaction was allowed to warm to room temperature after 10 min. After 15 h, the reaction was slowly quenched with saturated NaHCO solution and extracted with DCM (x4). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The crude material was absorbed onto silica gel and purified with 0 to 100% EtOAc in heptane to afford (2S,6S)-1-benzyl-N-(2-bromo-5-chloro-phenyl)-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C46 (151 mg, 88%). NMR(300MHz,Chloroform-d)δ7.63(d,J=8.6Hz,1H),7.32-6.95(m,9H),6.85-6.66(m,3H),5.4 5(d,J=14.2Hz,1H),3.99(d,J=14.2Hz,1H),3.85(d,J=1.0Hz,3H),3.79(d,J=6.4Hz,3H),3.72 −3.61 (m, 1H), 3.58 (d, J = 2.3 Hz, 2H), 2.36 (dddd, J = 29.7, 11.1, 5.5, 2.5 Hz, 1H), 2.26-2.07 (m, 1H), 2.03-1.86 (m, 1H), 1.86-1.46 (m, 3H), 1.06 (dd, J = 13.7, 6.1 Hz, 3H). LCMS m / z 622.1 [M+H]+. 1H NMR spectrum indicated a ca. 1:1 mixture of diastereomers.

[0234] Step 3. (2'S,6'S)-1'-benzyl-6-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (C47) The reaction was set up in a N2-glove box. To an oven-dried 2-dram vial was added (2S,6S)-1-benzyl-N-(2-bromo-5-chloro-phenyl)-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C46 (66 mg, 0.1009 mmol), followed by BINAP Pd G3 (10 mg, 0.01008 mmol), sodium t-butoxide (29 mg, 0.3018 mmol), and dioxane (1.1 mL). The vial was transferred to a fume hood and heated to 100 °C. After 5 h, the reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (x5). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified on a 40 g silica gel column and eluted with 0 to 100% EtOAc in heptane to give (2'S,6'S)-1'-benzyl-6-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C47 (35.4 mg, 29%). LCMS m / z 542.16 [M+H]+. 1H NMR indicated it contained a mixture of two diastereomers.

[0235] Step 4. (2'S,3S,6'S)-6-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one and (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (C48 and C32) To a stirred solution of (2'S,6'S)-1'-benzyl-6-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C47 (35 mg, 0.065 mmol) was added palladium on carbon (Evonik Noblyst® P1090 5% Pd, 12.4 mg) in EtOH (250 μL) and EtOAc (250 μL). The reaction flask was evacuated and refilled with H2 four times. The reaction mixture was then stirred under hydrogen balloon pressure. After 48 h, the reaction mixture was filtered through a plug of Celite® and washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography (column: 12 g column, gradient: 0 to 10% MeOH in DCM) to give four fractions containing two diastereomeric products and the dehalogenated product. The desired trans product was isolated as the third and fourth fractions:

[0236] (2'S,3S,6'S)-6-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C48 (4.9 mg, 17%). 1H NMR(300MHz,Chloroform-d)δ7.48(s,1H),7.19(d,J=8.5Hz,2H),7.12(d,J=7.9Hz,1H),7.00(dd,J=7.9,1.8Hz,1H),6.86(d,J=8.4Hz,2H),6.70(d,J=1.8H) z,1H),5.00(dd,J=11.6,3.1Hz,1H),4.80(s,2H),4.06(s,3H),3.94-3.80(m, 1H),3.78(s,3H),2.17-1.95(m,2H),1.82-1.56(m,2H),1.17(d,J=6.3Hz,3H).

[0237] (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C32 (4.5 mg, 12%). 1H NMR(300MHz,Chloroform-d)δ7.52(s,1H),7.21(d,J=8.2Hz,3H),7.15(t,J=7.6Hz,1H),7.07-6.97(m,1H),6.84(d,J=8.3Hz,2H),6.72(d,J=7.7Hz,1H), 5.04(dd,J=11.8,2.9Hz,1H),4.83(s,2H),4.06(s,3H),4.00-3.83(m,1H),3 .77(s,3H),2.19(t,J=12.7Hz,2H),1.84-1.67(m,2H),1.19(d,J=6.3Hz,3H).

[0238] NOTE: Stereochemistry was assigned by comparing the H NMR spectrum from the synthesis with a related analog (compound 33). The major H signal is the methine peak at approximately 4.5-5 ppm. The trans isomer exhibits a slight downfield shift (approximately 5.0 ppm), while the cis isomer exhibits a downfield shift (approximately 4.6 ppm).

[0239] Step 5. (2'S,3S,6'S)-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one (36) To a 1-dram vial containing (2'S,3S,6'S)-6-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[indoline-3,4'-piperidin]-2-one C48 (4.9 mg, 0.01084 mmol) (E35207-226-F3) in DCM (300 μL) was added trifluoromethanesulfonic acid (10 μL, 0.1130 mmol) at 0 °C (Caution: Exothermic). The vial was allowed to warm to room temperature after the acid was added. After 5 h, the reaction was cooled to 0 °C, carefully quenched with saturated NaHCO solution, and extracted with DCM (x5). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified on two 4 g silica gel columns, eluting with 0–20% MeOH in DCM to give (2′S,3S,6′S)-6-chloro-2′-methyl-6′-(1-methyltriazol-4-yl)spiro[indoline-3,4′-piperidin]-2-one 36 (3.8 mg, 99%). 1H NMR(300MHz,Chloroform-d)δ7.93(s,1H),7.45(s,1H),7.10(d,J=8.0Hz,1H),7. 01(dd,J=8.0,1.8Hz,1H),6.88(d,J=1.8Hz,1H),4.93(dd,J=8.6,6.0Hz,1H),4.05 (s,3H),3.80(ddd,J=11.4,6.1,2.6Hz,1H),2.13-2.01(m,2H),1.81(d,J=2.7Hz, 1H),1.57(dd,J=13.6,11.4Hz,1H),1.15(d,J=6.3Hz,3H).LCMSm / z332.12[M+H]+.

[0240] compound 37 (2'S,3S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)-5-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one (37) [ka] Step 1. (2S,6S)-1-benzyl-N-[2-bromo-4-(trifluoromethyl)phenyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide (C49) A 20-mL scintillation vial was charged with (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxylic acid S7 (76 mg, 0.2417 mmol), 2-bromo-4-(trifluoromethyl)aniline (66 mg, 0.2750 mmol), pyridine (64 μL, 0.7913 mmol), and EtOAc (1000 μL). Propylphosphonic anhydride solution (270 μL, 0.46 mmol, 50 wt % in EtOAc) was added last. After 23 h, the reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (×4). The crude mixture was purified by silica gel chromatography using 0-100% EtOAc in heptane to afford (2S,6S)-1-benzyl-N-[2-bromo-4-(trifluoromethyl)phenyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C49 (100 mg, 76%). 1H NMR(300MHz,Chloroform-d)δ8.54(d,J=8.7Hz,1H),7.82(d,J=2.8Hz,2H),7.58(d,J=8.7Hz,1H),7.34-7.00(m,5H),4.07-3.94(m,1H),3.91(s,3H),3.8 2-3.64(m,2H),2.70(d,J=7.7Hz,1H),2.58(td,J=12.4,6.1Hz,1H),2.29-2. 10(m,1H),2.05-1.72(m,3H),1.20(d,J=6.0Hz,3H).LCMSm / z536.04[M+H]+.

[0241] Step 2. (2S,6S)-1-benzyl-N-[2-bromo-4-(trifluoromethyl)phenyl]-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide (C50) A solution of (2S,6S)-1-benzyl-N-[2-bromo-4-(trifluoromethyl)phenyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C49 (100 mg, 0.1864 mmol) in THF (1.5 mL) was cooled to 0 °C in a vial and treated with sodium hydride (16 mg, 0.40 mmol, 60 wt%). The vial was warmed to room temperature after 5 min. After an additional 10 min, 1-(bromomethyl)-4-methoxy-benzene (41 μL, 0.2812 mmol) was added at room temperature. After 6 h, additional 1-(bromomethyl)-4-methoxy-benzene (10 μL, 0.069 mmol) was added. After an additional 1 h, the reaction was slowly quenched with saturated NaHCO3 solution and extracted with EtOAc (x4). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was absorbed onto silica gel and purified with 0 to 100% EtOAc in heptane to give (2S,6S)-1-benzyl-N-[2-bromo-4-(trifluoromethyl)phenyl]-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C50 (37.2 mg, 27%). LCMS m / z 656.17 [M+H]+. The material was then heated to 80 °C for 2 h to remove residual EtOAc. 1H NMR indicated the product consisted of a mixture of diastereomers in a 1.3:1 ratio.

[0242] Step 3. (2'S,3S,6'S)-1'-benzyl-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)-5-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one (C51) The reaction was set up in a N2-glovebox. To a 2-dram vial was added (2S,6S)-1-benzyl-N-[2-bromo-4-(trifluoromethyl)phenyl]-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C50 (37.2 mg, 0.05103 mmol), followed by BINAP Pd G3 (5.1 mg, 0.005139 mmol) and sodium t-butoxide (11.2 mg, 0.1165 mmol). Finally, dioxane (500 μL) was added. The vial was transferred from the glovebox to the bench and heated to 100 °C. After 16 h, the reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (x5). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified on a silica gel column, eluting with 0 to 100% EtOAc in heptane, to give two diastereomers. The trans isomer was isolated as the less polar fraction and was also the major product. (2'S,3S,6'S)-1'-benzyl-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)-5-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one C51 (22.5 mg, 77%). 1H NMR(300MHz,Chloroform-d)δ7.48(s,1H),7.41(d,J=8.3Hz,1H),7.30-7.01(m,8H),6.84(d,J=8.1Hz,2H),6.76(d,J=8.2Hz,1H),5.04-4.76(m,3H) ,3.85(d,J=15.0Hz,5H),3.77(t,J=1.1Hz,4H),2.34(t,J=12.9Hz,1H),1. 99(q,J=15.2,14.1Hz,2H),1.74(d,J=13.7Hz,1H),1.08(d,J=6.2Hz,3H).

[0243] Step 4. (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)-5-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one (C52) To a stirred solution of (2'S,3S,6'S)-1'-benzyl-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)-5-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one C51 (22.5 mg, 0.0391 mmol) in EtOH (450 μL) and EtOAc (450 μL) was added palladium on carbon (Evonik Noblyst® P1090 5% Pd, 13 mg, 0.006108 mmol). The reaction flask was evacuated and refilled with H2 four times. The reaction mixture was then stirred under hydrogen balloon pressure. After 17 h, the reaction flask was evacuated and refilled with N2, and the reaction mixture was then filtered through a plug of Celite® and washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography (column: 12 g column, gradient: 0-12% MeOH in DCM) to afford (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)-5-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one C52 (17.1 mg, 87%). NMR(300MHz,Chloroform-d)δ7.48(s,1H),7.46-7.34(m,2H),7.19(d,J=8.1Hz,2H),6.85 (d,J=8.2Hz,2H),6.77(d,J=8.1Hz,1H),5.00(dd,J=11.2,3.4Hz,1H),4.85(s,2H),4.06(d ,J=1.4Hz,3H),3.87(t,J=8.9Hz,1H),3.77(t,J=1.3Hz,3H),2.38-1.93(m,2H),1.79(dd, J=13.6,2.3Hz,1H),1.61(d,J=12.7Hz,1H),1.17(d,J=6.3Hz,3H).LCMSm / z486.17[M+H]+.

[0244] Step 5. (2'S,3S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)-5-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one (37) To a 20-mL vial containing (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)-5-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one C52 (17.1 mg, 0.03397 mmol) in DCM (500 μL) was added trifluoromethanesulfonic acid (31 μL, 0.3503 mmol) at 0 °C. The vial was allowed to warm to room temperature after the acid addition. After 5 h, the reaction was cooled to 0 °C, carefully quenched with saturated NaHCO solution, and extracted with DCM (×5). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was purified on a silica gel column, eluting with 0-20% MeOH in DCM to give (2'S,3S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)-5-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one 37 (12.3 mg, 97%). NMR (300MHz, CDCl3) δ8.83(s, 1H), 7.47(d, J=8.8Hz, 3H), 6.97(d, J=8.0Hz, 1H), 4.96(t, J=7.3Hz, 1H), 4.05(s, 3H), 3.94~3.69(m, 1H), 2.07(d, J=7.4Hz, 2H), 1.82(d, J=13.3Hz, 1H), 1.70~1.54(m, 1H), 1.16(d, J=6.2Hz, 3H). LCMSm / z366.1[M+H]+.

[0245] compound 38 (2'S,3S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)-6-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one (38) [ka] Step 1. (2S,6S)-1-benzyl-N-[2-bromo-5-(trifluoromethyl)phenyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide (C53) A 2-dram vial was charged with (2S,6S)-1-benzyl-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxylic acid S7 (85 mg, 0.2704 mmol), 2-bromo-5-(trifluoromethyl)aniline (44 μL, 0.3071 mmol), pyridine (70 μL, 0.8655 mmol), and EtOAc (900 μL). Propylphosphonic anhydride solution (310 μL, 0.52 mmol, 50 wt % in EtOAc) was added. After 24 h, the reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (×4). The crude mixture was purified by silica gel chromatography using 0-100% EtOAc in heptane to give (2S,6S)-1-benzyl-N-[2-bromo-5-(trifluoromethyl)phenyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C53 (105 mg, 71%). LCMS m / z 536.04 [M+H]+.

[0246] Step 2. (2S,6S)-1-benzyl-N-[2-bromo-5-(trifluoromethyl)phenyl]-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide (C54) To a vial was added (2S,6S)-1-benzyl-N-[2-bromo-5-(trifluoromethyl)phenyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C53 (105 mg, 0.1958 mmol) in THF (2.2 mL). The vial was cooled to 0 °C and treated with sodium hydride (16 mg, 0.4000 mmol, 60 wt%) at 0 °C. The vial was warmed to room temperature after 5 min. After an additional 10 min, 1-(bromomethyl)-4-methoxy-benzene (44 μL, 0.3018 mmol) was added at room temperature. After 4 h, the reaction was slowly quenched with saturated NaHCO solution and extracted with DCM (×3). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was absorbed onto silica gel and purified with 0 to 100% EtOAc in heptane to give (2S,6S)-1-benzyl-N-[2-bromo-5-(trifluoromethyl)phenyl]-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C54 (106 mg, 78%). LCMS m / z 656.12 [M+H]+. The material was then heated to 80°C for 2 hours to remove residual EtOAc. 1H NMR indicated the product consisted of a mixture of diastereomers in a 1.3:1 ratio.

[0247] Step 3. (2'S,6'S)-1'-benzyl-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)-6-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one (C55) The reaction was set up in a N2-glove box. To a 20 mL vial, (2S,6S)-1-benzyl-N-[2-bromo-5-(trifluoromethyl)phenyl]-N-[(4-methoxyphenyl)methyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidine-4-carboxamide C54 (105 mg, 0.1599 mmol) was added, followed by BINAP Pd G3 (16 mg, 0.01612 mmol) and sodium t-butoxide (35 mg, 0.3642 mmol). Finally, dioxane (1.5 mL) was added. The vial was transferred from the glove box to the bench and heated to 100 °C. After 17 h, the reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (x5). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified on a silica gel column, eluting with 0 to 100% EtOAc in heptane, to give (2'S,6'S)-1'-benzyl-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)-6-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one C55 (92.3 mg, 93%). LCMS m / z 576.19 [M+H]+. Based on F NMR, the diastereomeric ratio is 2.7:1. Based on H NMR, the isolated product also contained approximately 7% BINAP-related impurities.

[0248] Step 4. (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)-6-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one (C56) To a stirred solution of (2'S,6'S)-1'-benzyl-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)-6-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one C55 (92.3 mg, 0.1491 mmol) in EtOH (1.6 mL) and EtOAc (1.6 mL) was added palladium on carbon (Evonik Noblyst® P1090 5% Pd, 47.5 mg, 0.02232 mmol). The reaction flask was evacuated and refilled with H2 four times. The reaction mixture was then stirred under hydrogen balloon pressure. After 3 h, H2 was refilled and the reaction was left at room temperature for 62 h. The reaction mixture was filtered through a plug of Celite® and washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography (column: 12 g column, gradient: 0–12% MeOH in DCM) to give two fractions, the more polar fraction was isolated as (2′S,3S,6′S)-1-[(4-methoxyphenyl)methyl]-2′-methyl-6′-(1-methyltriazol-4-yl)-6-(trifluoromethyl)spiro[indoline-3,4′-piperidin]-2-one C56 (44.6 mg, 60%). 1H NMR(300MHz,Chloroform-d)δ7.45(s,1H),7.30(s,2H),7.21(d,J=8.2Hz,2H),6. 92(s,1H),6.90-6.79(m,2H),5.11-4.91(m,1H),4.84(s,2H),4.05(d,J=1.7Hz,3H ),3.98-3.78(m,1H),3.77(d,J=1.5Hz,3H),2.21-1.83(m,3H),1.76(dd,J=13.5, 2.5Hz,1H),1.61(t,J=12.4Hz,1H),1.16(d,J=6.3Hz,3H).LCMSm / z486.13[M+H]+.

[0249] NOTE: Stereochemistry was assigned by comparing the H NMR spectrum from the synthesis with a related analog (compound 33). The major H signal is the methine peak at approximately 4.5-5 ppm. The trans isomer exhibits a slight downfield shift (approximately 5.0 ppm), while the cis isomer exhibits a downfield shift (approximately 4.6 ppm).

[0250] Step 5. (2'S,3S,6'S)-2'-methyl-6'-(1-methyltriazol-4-yl)-6-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one (38) To a 20-mL vial containing (2'S,3S,6'S)-1-[(4-methoxyphenyl)methyl]-2'-methyl-6'-(1-methyltriazol-4-yl)-6-(trifluoromethyl)spiro[indoline-3,4'-piperidin]-2-one C56 (44.6 mg, 0.09186 mmol) in DCM (1.5 mL) was added trifluoromethanesulfonic acid (83 μL, 0.9380 mmol) at 0 °C. The vial was allowed to warm to room temperature after the acid addition. After 6 h, the reaction was cooled to 0 °C, carefully quenched with saturated NaHCO solution, and extracted with DCM (x5). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was purified on a silica gel column, eluting with 0–20% MeOH in DCM to give (2′S,3S,6′S)-2′-methyl-6′-(1-methyltriazol-4-yl)-6-(trifluoromethyl)spiro[indoline-3,4′-piperidin]-2-one 38 (28.0 mg, 81%). 1H NMR(300MHz,Chloroform-d)δ8.99(s,1H),7.46(s,1H),7.30(d,J=2.7Hz,2H),7.12(s,1H),4.97(dd,J=9.1,5.5Hz,1H),4.05(d,J=1.4Hz) ,3H),3.93-3.71(m,1H),2.22-1.99(m,2H),1.81(d,J=13.7Hz,1H),1.61(t,J=12.4Hz,1H),1.15(d,J=6.2Hz,3H).LCMSm / z366.14[M+H]+.

[0251] Preparation S8 (2S,6S)-1-Allyl-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S8) [ka] To a suspension of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S2) (10.0 g, 50.5 mmol) and K2CO3 (8.0 g, 57.9 mmol) in MeCN (100 mL) was added allyl bromide (5.5 mL, 63.6 mmol), and the mixture was heated to 40 °C and stirred for 18 h. The suspension was then filtered, rinsed with MeCN, and concentrated to approximately 3 volumes. The mixture was diluted with TBME / EtOAc / DCM 1:1:1 (300 mL) and water (250 mL). The aqueous layer was extracted with DCM (2 x 150 mL). The combined organic layers were washed with saturated brine (250 mL), dried over MgSO4, filtered, and concentrated. The mixture was suspended in TBME (180 mL) and refluxed. Upon reflux, complete dissolution into a yellow solution was observed. The mixture was removed from the bath and stirred. After approximately 5 minutes, significant precipitation was observed. At this point, the mixture was cooled in an ice bath for 10 minutes, filtered, and rinsed with TBME (2 x 15 mL). Dissolution was observed, and subsequent rinses were performed using heptane (3 x 20 mL). The addition of heptane caused a significant amount of precipitate in the mother liquor, which was filtered and rinsed with heptane (3 x 10 mL) to give a second crop. The crops were combined to give the title compound S8 (2S,6S)-1-allyl-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (8.42 g, 71%) as an off-white solid. 1H NMR(300MHz,Chloroform-d)δ7.48(s,1H),5.91(ddt,J=16.9,11.1,6.4Hz,1H),5.13(t ,J=14.6Hz,2H),4.23(dd,J=10.9,3.8Hz,1H),4.12(d,J=1.3Hz,3H),3.44(dd,J=16.0, 6.8Hz,1H),3.17(dd,J=16.0,6.3Hz,1H),3.06(dt,J=10.5,5.4Hz,1H),2.88(dd,J=14. 6,10.9Hz,1H),2.59(dd,J=14.8,3.7Hz,1H),2.53-2.34(m,2H),1.27(d,J=6.2Hz,3H).

[0252] Compounds 39 and 40 (2'S,6'S)-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide-diastereomer-1 (39) and (2'S,6'S)-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide-diastereomer-2 (40) [ka] Step 1. Synthesis of (2S,6S)-1-allyl-4-[4-chloro-2-(dimethoxymethyl)phenyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (C59) To a solution of 1-bromo-4-chloro-2-(dimethoxymethyl)benzene C58 (1.38 g, 4.937 mmol) in THF (12 mL) was added n-BuLi (2.8 mL 1.6 M, 4.480 mmol) under argon at −78° C. The mixture was stirred at −78° C. for 45 minutes, after which a solution of (2S,6S)-1-allyl-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one S8 (415 mg, 1.736 mmol) in THF (6 mL) was added. The reaction was stirred at −78° C. for 90 minutes and then warmed to 0° C. After 40 minutes at 0° C., the reaction was quenched with saturated aqueous ammonium chloride (100 mL), extracted with DCM (3×75 mL), dried over NaSO, passed through a phase separator, and concentrated in vacuo. The resulting crude residue was used in the next step without further purification.

[0253] Step 2. Synthesis of (2'S,6'S)-1'-allyl-6-chloro-1-methoxy-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine] (C60) The crude residue of C59 from step 1 was dissolved in MeOH (40 mL) and treated with 4-methylbenzenesulfonic acid (aqueous (1)) (986 mg, 5.184 mmol). The mixture was stirred at room temperature for 16 h. The reaction was then concentrated to approximately half its volume under a stream of N2, then quenched with saturated aqueous sodium bicarbonate (50 mL), extracted with DCM (3 x 50 mL), dried over Na2SO4, passed through a phase separator, and then concentrated in vacuo to give the crude residue, which was used in the next step without further purification.

[0254] Step 3. Synthesis of (2'S,6'S)-1'-allyl-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C61) The crude residue C60 from step 2 was dissolved in DCM (16 mL), cooled to -20 °C, and trimethylsilylformonitrile (1.45 mL, 10.87 mmol) and diethyloxonio(trifluoro)boranide (450 μL, 3.646 mmol) were added. The reaction was stirred at -20 °C for 30 min, at which point it was warmed to 0 °C and stirred for 120 min. The reaction was quenched with DCM and MeOH, followed by 50 mL of 1 N NaOH. The aqueous layer was extracted with DCM (x3), passed through a phase separator, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent: MeOH in DCM) to give partially purified C61, which was used in the next step without further purification.

[0255] Step 4. Synthesis of (2'S,6'S)-1'-allyl-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (C62) The residue from step 3, C61, was dissolved in THF (20 mL) and HO (20 mL). LiOH (84 mg, 3.508 mmol) was added. The reaction was stirred overnight at room temperature, then quenched with 1:1 saturated NH4Cl:brine and DCM and extracted with DCM (x3). The pooled organics were passed through a phase separator and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluent: MeOH in DCM) to give partially purified C62, which was used in the next step without further purification.

[0256] Step 5. Synthesis of (2'S,6'S)-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide-diastereomer-1 (39) and (2'S,6'S)-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide-diastereomer-2 (40) A mixture of 4-diphenylphosphanylbutyl(diphenyl)phosphane (35 mg, 0.08207 mmol) and Pd2(dba)3 (34.5 mg, 0.03768 mmol) in THF (4 mL) was stirred for 30 minutes. To this mixture was added 2-sulfanylbenzoic acid (316.4 mg, 2.052 mmol) and a solution of partially purified (2'S,6'S)-1'-allyl-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (C62) from Step 4 in THF (8 mL). The mixture was stirred under argon for 30 minutes. The reaction was diluted with TBME (40 mL) and 0.5 N HCl (40 mL). The layers were mixed, the organic layer removed, and extracted with 1N HCl (20 mL). The organic layer was removed, and the combined aqueous layers were filtered through a 0.45 micron filter and washed with additional TBME (20 mL). The pH was adjusted to pH 11 with 6N NaOH. The cloudy mixture was then extracted with DCM (3 x 50 mL), and the combined organic layers were passed through a phase separator and concentrated. The resulting crude residue was purified by reverse-phase HPLC. Method: Waters XBridge Prep C8 column; 30 x 150 mm, 5 microns. Gradient: Aqueous acetonitrile plus 10 mM ammonium hydroxide solution gave (2'S,6'S)-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide-diastereomer-1 (53.3 mg, 8% over 5 steps) (39). LCMSm / z362.19[M+1]+, 1H NMR (300MHz, chloroform-d) δ7.62(s, 1H), 7.42(s, 1H), 7.30(dd, J=8.1, 1.9Hz, 1H), 7.03(d, J=8.0Hz, 1H), 6.68(d, J=4.0Hz, 1H), 5.86(d , J=4.0Hz, 1H), 5.47(s, 1H), 4.46(dd, J=11.7, 2.8Hz, 1H), 4.05(s, 3H), 3.44~3.32(m, 1H), 2.19~1.63(m, 4H), 1.20(d, J=6.2Hz, 3H).(2'S,6'S)-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide-diastereomer-2 (40) (92.7 mg, 14% over 5 steps) LCMS m / z 362.19 [M+1]+; 1H NMR (300 MHz, chloroform-d) δ 7.62 (d, J = 1.7 Hz, 1H), 7.52–6.96 (m, 3H), 6.74 (d, J = 4.0 Hz, 1H), 5.81–5.59 (m, 1H), 5.47 (d, J = 4.5 Hz, 1H), 4.51 (dd, J = 10.5, 4.3 Hz, 1H), 4.06 (d, J = 5.2 Hz, 3H), 3.45–3.26 (m, 1H), 2.36–1.37 (m, 4H), 1.23–1.09 (m, 3H).

[0257] Compounds 41 and 42 (2'S,6'S)-5-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide diastereomer 1 (41) and (2'S,6'S)-5-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide diastereomer 2 (42) [ka] Step 1. Synthesis of (2S,6S)-1-allyl-4-[4-chloro-2-(dimethoxymethyl)phenyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (C64) To a solution of 2-bromo-4-chloro-1-(dimethoxymethyl)benzene C63 (333 mg, 1.191 mmol) in THF (3 mL) was added n-BuLi (700 μL of 1.6 M, 1.120 mmol) under argon at −78° C. The reaction was stirred at −78° C. for 45 minutes, after which a solution of (2S,6S)-1-allyl-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one S8 (101 mg, 0.4225 mmol) in THF (1.5 mL) was added. The reaction was stirred at −78° C. for 60 minutes and then warmed to 0° C. After 60 minutes at 0° C., the reaction was quenched with saturated aqueous ammonium chloride (75 mL), extracted with DCM (3×50 mL), dried over NaSO, passed through a phase separator, and concentrated in vacuo. The resulting crude residue, (2S,6S)-1-allyl-4-[4-chloro-2-(dimethoxymethyl)phenyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (C64), was used in the next reaction without further purification.

[0258] Step 2. Synthesis of (2'S,6'S)-1'-allyl-6-chloro-1-methoxy-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine] (C65) The crude residue of C64 from step 1 was dissolved in MeOH (10 mL) and treated with 4-methylbenzenesulfonic acid (water (1)) (240 mg, 1.262 mmol). The mixture was stirred at room temperature for 16 h, then concentrated to approximately half its volume under a stream of N, quenched with saturated aqueous sodium bicarbonate (50 mL), extracted with DCM (3 x 50 mL), dried over NaSO, passed through a phase separator, and then concentrated in vacuo to give the crude residue (2'S,6'S)-1'-allyl-6-chloro-1-methoxy-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine] (C65), which was used in the next reaction without further purification.

[0259] Step 3. Synthesis of (2'S,6'S)-1'-allyl-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C66) The crude residue C65 from step 2 was dissolved in DCM (4 mL), cooled to -25 °C, and trimethylsilylformonitrile (350 μL, 2.625 mmol) and diethyloxonio(trifluoro)boranide (110 μL, 0.8913 mmol) were added. The reaction was stirred for 30 min, at which point it was warmed to 0 °C and stirred for 120 min. The reaction was then quenched with DCM and MeOH, followed by 50 mL of 1 N NaOH. The aqueous layer was extracted with DCM (x3), passed through a phase separator, and concentrated in vacuo. The crude residue was partially purified by silica gel chromatography (eluent: MeOH in DCM) to give impure (2'S,6'S)-1'-allyl-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C66), which was used in the next step without further purification.

[0260] Step 4. Synthesis of (2'S,6'S)-1'-allyl-6-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (C67) The partially purified residue C66 from step 3 was dissolved in THF (5 mL) and HO (5 mL) and LiOH (23 mg, 0.9604 mmol) were added. The reaction was stirred overnight at room temperature. The reaction was quenched with 1:1 saturated NH4Cl:brine and DCM and extracted with DCM (x3). The pooled organics were passed through a phase separator and concentrated in vacuo. The resulting crude residue was partially purified by silica gel chromatography (eluent: MeOH in DCM) to give impure (2'S,6'S)-1'-allyl-5-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (C67), which was used in the next step without further purification. Yield: 123 mg (50% purity, 36%). LCMS m / z 402.28[M+1]+.

[0261] Step 5. Synthesis of (2'S,6'S)-5-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide diastereomer 1 (41) and (2'S,6'S)-5-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide diastereomer 2 (42) A mixture of 4-diphenylphosphanylbutyl(diphenyl)phosphane (12.6 mg, 0.02954 mmol) and Pd2(dba)3 (12 mg, 0.01310 mmol) in THF (1 mL) was aged for 30 minutes and then added to a solution of 2-sulfanylbenzoic acid (77 mg, 0.4994 mmol) from Step 4 and partially purified (2'S,6'S)-1'-allyl-5-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (C67) in THF (2 mL). The mixture was stirred under argon for 30 minutes. The reaction was diluted with TBME (10 mL) and 0.5 N HCl (10 mL). The layers were mixed, and the organic layer was removed and extracted with 1 N HCl (5 mL). The organic layer was removed, and the combined aqueous layers were filtered through a 0.45 micron filter and washed with TBME (5 mL). The pH was adjusted to pH 11 with 6N NaOH. The cloudy mixture was then extracted with DCM (3 x 5 mL), and the combined organic layers were passed through a phase separator and concentrated in vacuo. The resulting crude residue was purified by reverse-phase HPLC. Method: Waters XBridge Prep C8 column; 30 x 150 mm, 5 microns. Gradient: Aqueous acetonitrile plus 10 mM ammonium hydroxide solution gave (2'S,6'S)-5-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (24 mg, 15% over 5 steps) (41). LCMSm / z362.32[M+1]+, 1H NMR (300MHz, chloroform-d) δ7.61~7.49(m, 2H), 7.30(dd, J=8.1, 1.9Hz, 1H), 7.10(d, J=1.8Hz, 1H), 6.71(s, 1H), 5.50(s, 1H), 5.39(s, 1H), 4. 60~4.45(m, 1H), 4.08(s, 3H), 3.49~3.30(m, 1H), 2.16~2.07(m, 2H), 1.83(d, J=13.5Hz, 1H), 1.50(d, J=12.9Hz, 1H), 1.18(d, J=6.3Hz, 3H).and (2'S,6'S)-5-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (20.6 mg, 13% over 5 steps) (42). LCMS m / z 362.32 [M+1]+, 1H NMR (300 MHz, chloroform-d) δ 7.57 (d, J = 8.2 Hz, 1H), 7.48 (s, 1H), 7.30 (dd, J = 8.2 Hz, 1.9 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.67 (s, 1H), 5.48 (s, 1H), 5.44 (s, 1H), 4.51 (d, J = 11.4 Hz, 1H), 4.06 (s, 3H), 3.53–3.34 (m, 1H), 2.13–2.01 (m, 1H), 1.94 (t, J = 14.0 Hz, 1H), 1.88–1.75 (m, 2H), 1.23 (d, J = 6.5 Hz, 3H). Example 2. Assays for detecting and measuring the APOL1 inhibitor properties of compounds

[0262] 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. Data are normalized using the ratio of dead to live cells.

[0263] Briefly, the tet-inducible transgenic APOL1 T-REx-HEK293 cell line was incubated in duplicate with 50 ng / 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, or 0.0005 μM) in a humidified 37°C incubator for 24 hours to induce APOL1. MultiTox reagent was added to each well and returned to the incubator for an additional 30 minutes. Plates were read on an EnVision plate reader. The ratio of dead to live cells was used for normalization, and data were imported, analyzed, and fitted using Genedata Screener (Basel, Switzerland) software. Data were normalized using the percentages for control, no Tet (100% viability), and 50 ng / mL Tet treatment (0% viability) and fitted using Smart Fit. The reagents, methods, and complete protocol for the MultiTox assay are described below. [Table 3] [Table 4]

[0264] Multi-Tox Assay Protocol 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, pAAVS1-Puro-APOL1 G1, or pAAVS1-Puro-APOL1 G2 clones were grown in T-225 flasks at approximately 90% confluency in cell growth medium (DMEM, 10% Tet-free FBS, 2 mM L-glutamine, 100 units / mL penicillin-streptomycin, 5 μg / mL blasticidin S HCl, 1 μg / mL puromycin dihydrochloride). Cells were washed with DPBS and then trypsinized to dissociate from the flasks. The trypsin was quenched using culture medium, and the cells were then pelleted at 200 g and resuspended in fresh cell assay medium (DMEM, 2% Tet-free FBS, 2 mM L-glutamine, 100 units / mL penicillin-streptomycin). The cells were counted and diluted to 1.17 x 106 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.

[0265] Tetracycline is required to induce APOL1 expression. A 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 5x Tet in a 384-PP-round-bottom plate was dispensed into columns 2-23 using a Multidrop dispenser.

[0266] Assay-ready plates from the Global Compound Archive were ordered using the template 384_APOL1Cell_DR10n2_50uM_v3. Compounds were dispensed at 200nL in DMSO. The final top concentration was 10µM, and 10-point 3-fold dilutions were performed in duplicate for the MultiTox assay.

[0267] 20 μL was transferred from the 5Xtet plate to the ARP and mixed, then 5 μL of 5Xtet and compound was transferred to the cell plate and mixed using a Bravo. The cell plate was placed in a humidified 37°C 5% CO2 incubator for 24 hours.

[0268] The MultiTox-Fluor multiplex cytotoxicity assay was performed according to the manufacturer's protocol. After incubating cells with tet and compound for 24 hours, 25 μL of 1x MultiTox reagent was added to each well using a Multidrop dispenser. 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 were exported and analyzed in Genedata. Data were normalized using percentages for control, no tet (100% viability), and 50 ng / mL tet treatment (0% viability) and fitted using Genedata's Smart Fit setting.

[0269] Efficacy data for compounds 1-42 Compounds of Formula I are useful as inhibitors of APOL1 activity. Table 5 below sets forth the IC50s of compounds 1-42 using the above procedure. The potencies of compounds I1-I36 may also be determined using the above procedure. In Table 5 below, the following meanings apply: For IP50 (i.e., IC50 for cell proliferation), "+++" means ≦50 nM, "++" means 50 nM to 500 nM, and "+" means ≧500 nM. ND = not determined. [Table 5]

[0270] 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 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: 【Chemical 88】 tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is selected from 6-membered aryl and 6-membered heteroaryl groups; X is -CH ２ -, -C(O)-, -S(O) ２ -, -NH-, and -O-; Y is -CH ２ -, -C(O)-, -S(O) ２ -, -NH-, and -O-; Z is a bond, —CH ２ -, -NH-, -C(O)-, -S(O) ２ -, and -O-, wherein At least one of X and Y is —CH ２ - and -C(O)-; For each of X, Y, and Z, —CH ２ The hydrogen atom in each instance of - or -NH- is １ optionally substituted with R １ is, for each occurrence, halogen, —OH, cyano, phenyl, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Carbocyclyl, 4- to 6-membered heterocyclyl, —C(═O)OR ｃ , -C(=O)N(R ｃ ) ２ , and -OS(=O) ２ R ｃ are independently selected from the group R ｃ For each occurrence, hydrogen, C １ -C ４ Alkyl, and C １ -C ４ haloalkyl groups, 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 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 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, 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 optionally substituted with 1 to 3 groups independently selected from the group R １ The phenyl may be selected from 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 optionally substituted with 1 to 3 groups independently selected from the group R ２ but, 【Chemistry 89】 and Ring B is a 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, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkenyl, C １ -C ６ Haloalkoxy, —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 , —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 , -S(=O) ｐ NR ｈ R ｉ , -C(=O)OR ｋ , C ３ -C １２ Carbocyclyl, 3- to 12-membered heterocyclyl, C ６ and C １０ aryl, and 5- to 10-membered heteroaryl groups; R ａ The above C １ -C ６ Alkyl, C １ -C ６ Alkoxy, and the C ２ -C ６ Each alkenyl is C ６ -C １０ Aryl (1 to 3 R ｍ group), 5- to 10-membered heterocyclyl (1-3 R ｍ aryl (optionally substituted with 1 to 3 R ｍ group), 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 , —OC(═O)R ｋ , -OC(=O)OR ｋ , -OC(=O)NR ｈ R ｉ , -S(=O) ｐ R ｋ , -S(=O) ｐ NR ｈ R ｉ , -O(C ６ aryl) (1 to 3 R ｍ group), and C ３ -C ６ Carbocyclyl group (1 to 3 R ｍ optionally substituted with 1 to 3 groups independently selected from R ａ The above C ３ -C １２ carbocyclyl, the 3- to 12-membered heterocyclyl, the C ６ and C １０ The aryl and the 5- to 10-membered heteroaryl are each selected from halogen, cyano, C １ -C ４ Alkyl, —NR ｈ R ｉ , and -OR ｋ optionally substituted with 1 to 3 groups independently selected from the group R ｈ , R ｉ , and R ｊ are hydrogen, C, １ -C ４ Alkyl, C ６ -C １０ Aryl, and C ３ -C ６ cycloalkyl groups, R ｈ , R ｉ , and R ｊ Any one of the C １ -C ４ the alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; R ｋ For each occurrence, hydrogen, C １ -C ４ Alkyl, 5- to 10-membered heterocyclyl, and C ３ -C ６ carbocyclyl groups, wherein R ｋ Any one of the C １ -C ４ the alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH groups; R ｍ For each occurrence, halogen, cyano, oxo, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, —S(═O) ｐ R ｋ , and -OR ｋ are independently selected from the group R ｍ The above C １ -C ６ The alkyl is selected from halogen, cyano, —OH, and —O(C １ -C ４ optionally substituted with 1 to 3 groups independently selected from alkyl groups; R ３ But C １ -C ６ Alkyl, —C(═O)O(C １ -C ４ alkyl), C ３ -C １２ Carbocyclyl, 3- to 12-membered heterocyclyl, C ６ and C １０ aryl, and 5- to 10-membered heteroaryl groups; R ３ 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(═O)NH ２ , -C(=O)NH(C １ -C ４ alkyl), and —C(═O)N(C １ -C ４ alkyl) ２ optionally substituted with 1 to 3 groups independently selected from the group R ３ The above C ３ -C １２ carbocyclyl, the 3- to 12-membered heterocyclyl, the C ６ and C １０ The aryl and the 5- to 10-membered heteroaryl are each selected from halogen, cyano, —OH, —NH ２ , —NH(C １ -C ４ alkyl) (optionally substituted with —OH), —N(C １ -C ４ alkyl) ２ , C １ -C ５ Alkyl (-OH or -S(=O) ２ (C １ -C ４ alkyl), C １ -C ４ Alkoxy, —C(═O)NH ２ , -C(=O)NH(C １ -C ４ alkyl), -NHC(=O)(C １ -C ４ alkyl), -C(=O)(C １ -C ４ alkoxy), and —C(═O)N(C １ -C ４ alkyl) ２ optionally substituted with 1 to 3 groups independently selected from the group m is an integer selected from 0, 1, 2, 3, 4, and 5; p, for each occurrence, is an integer independently selected from 1 and 2; A compound represented by the structural formula of Formula I, wherein q and r are, for each occurrence, integers independently selected from 1, 2, 3, and 4, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

2. Ring A is selected from 6-membered aryl and 6-membered heteroaryl groups; X is -CH ２ -, -C(O)-, -S(O) ２ -, -NH-, and -O-; Y is -CH ２ -, -C(O)-, -S(O) ２ -, -NH-, and -O-; Z is a bond, —CH ２ -, -NH-, -C(O)-, -S(O) ２ -, and -O-, wherein At least one of X and Y is —CH ２ - and -C(O)-; For each of X, Y, and Z, —CH ２ The hydrogen atom in each instance of - or -NH- is １ optionally substituted with R １ For each occurrence, halogen, —OH, cyano, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, —C(═O)OR ｃ , -C(=O)N(R ｃ ) ２ , and -OS(=O) ２ R ｃ are independently selected from the group R ｃ For each occurrence, hydrogen, C １ -C ４ Alkyl, and C １ -C ４ haloalkyl groups, R １ The above C １ -C ６ the alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH groups; R ２ teeth, 【Chemistry 91】 where: Ring B is selected from 5-membered heterocyclyl and 5-membered heteroaryl groups, and Ring B is selected from 1 or 2 R ａ optionally substituted with a group, R ａ For each occurrence, -S(=O) ｐ R ｋ C optionally substituted with one group independently selected from the group １ -C ６ independently selected from alkyl groups, R ｋ For each occurrence, C １ -C ４ independently selected from alkyl groups, R ３ is C １ -C ３ alkyl groups, m is an integer selected from 0, 1, 2, and 3; 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein p, for each occurrence, is an integer independently selected from 1 and 2.

3. Ring A is selected from 6-membered aryl and 6-membered heteroaryl groups; X is -CH ２ -, -C(O)-, -S(O) ２ -, -NH-, and -O-; Y is -CH ２ -, -C(O)-, -S(O) ２ -, -NH-, and -O-; Z is a bond, —CH ２ -, -NH-, -C(O)-, -S(O) ２ -, and -O-, wherein At least one of X and Y is —CH ２ - and -C(O)-; For each of X, Y, and Z, —CH ２ The hydrogen atom in each instance of - or -NH- is １ optionally substituted with R １ For each occurrence, halogen, —OH, cyano, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, —C(═O)OR ｃ , -C(=O)N(R ｃ ) ２ , and -OS(=O) ２ R ｃ are independently selected from the group R ｃ For each occurrence, hydrogen, C １ -C ４ Alkyl, and C １ -C ４ haloalkyl groups, R １ The above C １ -C ６ the alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH groups; R ２ teeth, 【Chemistry 92】 where: Ring B is selected from a pyrazole group and a triazole group, and Ring B is selected from one or two R ａ and optionally substituted with a group, wherein R ａ For each occurrence, -S(=O) ｐ R ｋ C optionally substituted with one group independently selected from the group １ -C ６ independently selected from alkyl groups, R ｋ For each occurrence, C １ -C ４ independently selected from alkyl groups, R ３ is methyl, m is an integer selected from 0, 1, 2, and 3; 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein p, for each occurrence, is an integer independently selected from 1 and 2.

4. 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein Ring A is phenyl.

5. R １ For each occurrence, F, Cl, Br, -CH ３ , -CH(CH ３ ) ２ , -CF ３ , -OCH ３ , -OCF ３ , -C(=O)N(CH ３ ) ２ 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein:

6. 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein m is 1 or 2.

7. Ring B is selected from 5- to 10-membered heterocyclyl, phenyl, and 5- to 9-membered heteroaryl groups, each of which contains 1, 2, 3, 4, or 5 R ａ 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, optionally substituted with a group.

8. Ring B is 【Chemical 95】 and one R ａ 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, optionally substituted with a group.

9. R ａ For each occurrence, -CH ３ , and -(CH ２ ) ２ SO ２ CH ３ 9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 8, independently selected from:

10. The compound has the following structural formula: 【Chemistry 96】 or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

11. (1) The compound is represented by one of the following structural formulas: 【Chemistry 100】 tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: R １ａ is selected from hydrogen, halogen, —OH, and a phenyl group, wherein: R １ａ The phenyl may be selected from 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 optionally substituted with 1 to 3 groups independently selected from the group R １ｂ and R １ｃ are hydrogen, halogen, —OH, cyano, and C １ -C ４ Alkyl, C １ -C ４ Alkoxy, —C(═O)OR ｃ , -C(=O)N(R ｃ ) ２ , and -OS(=O) ２ R ｃ are independently selected from the group R ｃ For each occurrence, hydrogen, C １ -C ４ Alkyl, and C １ -C ４ haloalkyl groups, R １ｂ and / or R １ｃ The above C １ -C ６ The alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH groups; (2) The compound is represented by one of the following structural formulas: 【Chemistry 101】 tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: R 1a is selected from hydrogen, phenyl, and a C(═O)N(R c1 ) 2 group; said phenyl of R 1a is optionally substituted with 1 to 3 groups independently selected from 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 groups; R c1 , for each occurrence, is independently selected from hydrogen and a C 1 -C 4 alkyl group; R 1b and R 1c are each independently selected from hydrogen and halogen groups; or (3) The compound is represented by one of the following structural formulas: 【Chemical Engineering 102】 tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein:

2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein R 1a and R 1b are each independently selected from hydrogen, halogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl groups. 【Request Item 12】 【Chemistry 104】 【Chemistry 105】 【Chemistry 106】 【Chemistry 107】 Compounds selected from: their tautomers, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

13. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 12 and a pharmaceutically acceptable carrier.

14. A composition for treating an APOL1-mediated disease, comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of claims 1 to 12.

15. A composition for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of claims 1 to 12.

16. 13. Use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 12 in the manufacture of a medicament for treating an APOL1 mediated disease.

17. Use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 12 in the manufacture of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease.

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