4-Phenyl-2-(1H-1,2,3-triazol-4-yl)piperidin-4-ol derivatives as inhibitors of APOL1 and methods of using same

Abstract

The present disclosure provides at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula (I), their tautomers, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, compositions comprising them, and methods of using them, including use in the treatment of APOL1-mediated diseases, including pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and / or non-diabetic kidney disease (NDKD). JPEG2024543934000186.jpg8951

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 284,166, filed November 30, 2021, U.S. Provisional Application No. 63 / 286,165, filed December 6, 2021, and U.S. Provisional Application No. 63 / 310,832, filed February 16, 2022, the contents of which are incorporated by reference herein in their entireties. [Background technology]

[0002] The present disclosure provides compounds that can inhibit apolipoprotein L1 (APOL1) and methods of using those compounds to treat APOL1-mediated diseases, such as pancreatic cancer, focal segmental glomerulosclerosis (FSGS) and / or non-diabetic kidney disease (NDKD). In some embodiments, FSGS and / or NDKD are associated with at least one of two common APOL1 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 the podocyte (the glomerular visceral epithelial cells) that causes proteinuria and progressive decline in kidney function. NDKD is a kidney disease with damage to the podocyte or glomerular vascular bed not caused by diabetes. NDKD is a disease characterized by hypertension and progressive decline in kidney function. Human genetic analysis supports a causal role for G1 and G2 APOL1 variants in inducing kidney disease. Individuals with two APOL1 alleles are at increased risk of developing end-stage kidney disease (ESKD), including primary (idiopathic) FSGS, human immunodeficiency virus (HIV)-associated FSGS, NDKD, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. See P. Dummer et al., Semin Nephrol. 35(3):222-236 (2015).

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

[0005] APOL1 is a 44 kDa protein that is expressed only in humans, gorillas, and baboons. In humans, the APOL1 gene is expressed in multiple organs, including the liver and kidney. APOL1 is produced primarily by the liver and contains a signal peptide that allows secretion into the bloodstream, where it circulates bound to a subset of high-density lipoproteins. APOL1 also contributes to defense against the invasive parasite Trypanosoma Brucei Brucei (TbBrucei). APOL1 is endocytosed by Tbbrucei and transported to lysosomes. There, it is inserted into the lysosomal membrane, forming a pore that results in the parasite's swelling and death.

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

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

[0008] Although normal plasma concentrations of APOL1 are relatively high and may vary at least 20-fold in humans, circulating APOL1 is not causally related to renal disease. However, renal APOL1 is thought to be responsible for the development of renal diseases, including FSGS and NDKD. Under certain circumstances, the synthesis of APOL1 protein can be increased by approximately 200-fold by proinflammatory cytokines, for example, interferon or tumor necrosis factor-α. In addition, several studies have shown that APOL1 protein forms pH-gated Na+ / K+ pores in cell membranes, resulting in a net extrusion of intracellular K+, ultimately activating local and systemic inflammatory responses, cell swelling, and death.

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

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

[0011] Corticosteroids, alone or in combination with other immunosuppressants, have induced remission in a small number of patients (e.g., remission of proteinuria in a small number of patients), but are also associated with numerous side effects. However, even in patients who initially respond to corticosteroid and / or immunosuppressive treatment, remission is often short-lived. As a result, patients, especially those of modern sub-Saharan African descent who carry two APOL1 risk alleles, rapidly progress to end-stage renal disease (ESRD). Thus, there is an unmet medical need for the treatment of FSGS and NDKD. Specifically, given the evidence that APOL1 plays a causative role in inducing and accelerating the progression of renal disease, inhibition of APOL1 should have a positive impact on patients with APOL1-mediated renal disease, especially those who carry two APOL1 risk alleles (i.e., homozygous or compound heterozygous for the G1 or G2 alleles). Furthermore, APOL1 is a gene that is aberrantly expressed in multiple cancers (Lin et al., Cell Death and Disease (2021), 12: 760). Recently, APOL1 has been found to be abnormally elevated in human pancreatic cancer tissues compared with adjacent tissues and has been associated with poor prognosis of 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 pharma- ceutically acceptable salt selected from compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, which can be used for the treatment of diseases mediated by APOL1, such as FSGS and NDKD.

[0014] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure is a compound represented by the following structural formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: X is a bond (i.e., X is absent) or is selected from -(CH)-, and -(CH)SO-; Ring A is selected from C6 cycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl groups; R1 is independently selected for each occurrence from halogen, -ORc, =O, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, -C(=O)N(Rc)2, -S-(cyclopropyl), and -SO2(Rc) groups; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R1 4-6 membered heterocyclyl contains one heteroatom selected from nitrogen and oxygen; The C1-C6 alkyl of R1 is optionally substituted with 1 to 6 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; R1 C3-C6 carbocyclyl is 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 Optionally substituted with 1 to 3 groups independently selected from -C(=O)N(C1-C4 alkyl) groups; The phenyl 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; or two R1 groups, together with the ring A atom connecting them, form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring; Each of the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 groups selected from halogen, —OH, and C1-C4 alkyl; 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, 5-10 membered heterocyclyl, C6 aryl, and 5-10 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 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); Each of the C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra is 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; 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, 5-10 membered heterocyclyl, and C3-C6 carbocyclyl; Any one of Rk's C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and -OH groups; Rm is independently selected for each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 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; R4 is hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)nC(=O)NRnRo, -NRnRo, -NRoC(=O)Rp, -NRnS(=O)pRp, -(CH2)nORp, -S(=O)pRp, -S(=O)pNRnRo, -OS(=O)pNRnRo, and -(CH2)nC(=O)ORp groups, Rn and Ro are each independently selected for each occurrence from hydrogen and a C1-C4 alkyl group; Rp, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R5 is selected from hydrogen and C1-C6 alkyl; m is an integer selected from 0, 1, 2, 3, 4, and 5; n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; q and r are each an integer independently selected from 1, 2, 3, and 4 for each occurrence.

[0015] In some embodiments, the variable X in the compound of formula I is a bond (ie, X is absent).

[0016] In some embodiments, compound I296 and compound 43a are excluded from Formula I.

[0017] In some embodiments, the compound of formula I is a compound represented by the following structural formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from C6 aryl, and 5- and 6-membered heteroaryl groups; R1 is, for each occurrence, independently selected from halogen, -OH, =O, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, -C(=O)N(Rc)2, and -SO2(Rc) groups; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R1 4-6 membered heterocyclyl 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; R1 C3-C6 carbocyclyl is 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 Optionally substituted with 1 to 3 groups independently selected from -C(=O)N(C1-C4 alkyl) groups; The phenyl 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; or two R1 groups, together with the ring A atom connecting them, form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring; Each of the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 groups selected from halogen, —OH, and C1-C4 alkyl; 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, 5-10 membered heterocyclyl, C6 aryl, and 5-10 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 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); Each of the C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra is 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; 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, 5-10 membered heterocyclyl, and C3-C6 carbocyclyl; Any one of Rk's C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and -OH groups; Rm is independently selected for each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 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; R4 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)nC(=O)NRnRo, -NRnRo, -NRoC(=O)Rp, -NRnS(=O)pRp, -(CH2)nORp, -S(=O)pRp, -S(=O)pNRnRo, -OS(=O)pNRnRo, and -(CH2)nC(=O)ORp groups, wherein Rn and Ro are each independently selected for each occurrence from hydrogen and a C1-C4 alkyl group; Rp, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R5 is selected from hydrogen and C1-C6 alkyl; m is an integer selected from 0, 1, 2, 3, 4, and 5; n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; q and r are each an integer independently selected from 1, 2, 3, and 4 for each occurrence.

[0018] In some embodiments, compound I296 and compound 43a are excluded from formula Ia.

[0019] Formula I also includes compounds of formula Ib, which have the structure: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from C6 aryl, and 5- and 6-membered heteroaryl groups; R1 is, for each occurrence, independently selected from halogen, -OH, =O, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, -C(=O)N(Rc)2, and -SO2(Rc) groups; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R1 4-6 membered heterocyclyl 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 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; or two R1 groups, together with the ring A atom connecting them, form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring; Each of the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 groups selected from halogen, —OH, and C1-C4 alkyl; 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, 5-10 membered heterocyclyl, C6 aryl, and 5-10 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 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); Each of the C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra is 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; 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, 5-10 membered heterocyclyl, and C3-C6 carbocyclyl; Any one of Rk's C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and -OH groups; Rm is independently selected for each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 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; R4 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)nC(=O)NRnRo, -NRnRo, -NRoC(=O)Rp, -NRnS(=O)pRp, -(CH2)nORp, -S(=O)pRp, -S(=O)pNRnRo, -OS(=O)pNRnRo, and -(CH2)nC(=O)ORp groups, wherein Rn and Ro are each independently selected for each occurrence from hydrogen and a C1-C4 alkyl group; Rp, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; m is an integer selected from 0, 1, 2, 3, 4, and 5; n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; q and r are each an integer independently selected from 1, 2, 3, and 4 for each occurrence.

[0020] In some embodiments, compound I296 and compound 43a are excluded from formula Ib.

[0021] Formula I also includes compounds of formula Ic, which have the structure: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from C6 aryl, and 5- and 6-membered heteroaryl groups; R1, for each occurrence, is independently selected from halogen, -OH, =O, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, and -C(=O)N(Rc)2 groups; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R1 4-6 membered heterocyclyl 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 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; 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, 5-10 membered heterocyclyl, C6 aryl, and 5-10 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 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); Each of the C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra is 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; 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, 5-10 membered heterocyclyl, and C3-C6 carbocyclyl; Any one of Rk's C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and -OH groups; Rm is independently selected for each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 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; R4 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)nC(=O)NRnRo, -NRnRo, -NRoC(=O)Rp, -NRnS(=O)pRp, -(CH2)nORp, -S(=O)pRp, -S(=O)pNRnRo, -OS(=O)pNRnRo, and -(CH2)nC(=O)ORp groups, wherein Rn and Ro are each independently selected for each occurrence from hydrogen and a C1-C4 alkyl group; Rp, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; m is an integer selected from 0, 1, 2, 3, 4, and 5; n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; q and r are each an integer independently selected from 1, 2, 3, and 4 for each occurrence.

[0022] In some embodiments, compound I296 and compound 43a are excluded from formula Ic.

[0023] In some embodiments, in the compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of formula Ic, Ring A is selected from C6 aryl and 5- and 6-membered heteroaryl groups; R1, for each occurrence, is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, and -C(=O)N(Rc)2 groups; R1 4-6 membered heterocyclyl contains one heteroatom selected from nitrogen and oxygen; R1 C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with 1 to 3 groups selected from -OH, cyano, and halogen groups; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R2 and R3 are each independently selected from a C1-C4 alkyl, a C3-C6 carbocyclic, and a 5-membered heteroaryl group; the 5-membered heteroaryl group is optionally substituted with 1 to 2 C1-C4 alkyl groups optionally substituted with -S(=O)2CH3; the C1-C4 alkyl group is optionally substituted with halogen and a C3-C6 carbocyclic group; R4 is -OH and -O(C1-C4 alkyl) groups; m is an integer selected from 0, 1, 2, 3, 4, and 5;

[0024] In some embodiments, in the compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of formula Ic, Ring A is selected from C6 aryl and 5- and 6-membered heteroaryl groups; R1, for each occurrence, is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3 cycloalkyl, and -C(=O)N(Rc)2 groups; R1 C1-C4 alkyl and C1-C4 alkoxy are optionally substituted with 1 to 3 groups selected from halogen; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R2 and R3 are each independently selected from a C1-C4 alkyl and a 5-membered heteroaryl group, the 5-membered heteroaryl group being optionally substituted with 1-2 C1-C4 alkyl groups optionally substituted with -S(=O)2CH3; R4 is -OH; m is an integer selected from 0, 1, and 2; In some embodiments, compound I296 and compound 43a are excluded from formula Ic.

[0025] In one embodiment of the disclosure, the compound of formula I is selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, whereby at least one compound, pharma- ceutically acceptable salt, solvate, or deuterated derivative is selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, a pharma- ceutically acceptable salt of any of those compounds, a solvate of any of the foregoing, and a deuterated derivative of any of the foregoing.

[0026] In some embodiments, the disclosure provides pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions may comprise at least one compound selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, pharma- ceutically acceptable salts of any of the foregoing, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. These compositions may further comprise at least one additional pharma- ceutically active ingredient and / or at least one carrier.

[0027] 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 pharma- ceutically acceptable salt selected from compounds of Formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt. In some embodiments, the methods include administering at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing.

[0028] 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 pharma- ceutically acceptable salt selected from compounds of Formulas I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt. In some embodiments, the methods include administering at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing.

[0029] 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 pharma- ceutically acceptable salt selected from compounds of Formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt. In some embodiments, the methods include administering at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing.

[0030] 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 pharma- ceutically acceptable salt selected from compounds of Formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the methods include administering at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, together with at least one additional active agent, either in the same pharmaceutical composition or in a separate composition.

[0031] Also provided is a method of inhibiting APOL1 comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of Formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt. In some embodiments, the method of inhibiting APOL1 comprises administering at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt. [Brief description of the drawings]

[0032] [Figure 1] FIG. 1 shows the XRPD diffractogram of Compound 16 Form A.

[0033] [Diagram 2] FIG. 2 shows the TGA of Compound 16 Form A.

[0034] [Diagram 3] FIG. 3 shows the DSC of Compound 16 Form A.

[0035] [Figure 4] FIG. 4 shows the 13C SSNMR spectrum of Compound 16 Form A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] definition The term "APOL1" as used herein means apolipoprotein L1 protein, and the term "APOL1" means apolipoprotein L1 gene.

[0037] 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 G2 allele. In some embodiments, the APOL1-mediated disease is associated with patients with one APOL1 risk allele.

[0038] The term "APOL1-mediated renal disease" refers to a disease or condition that impairs renal function and can be caused by APOL1. In some embodiments, APOL1-mediated renal disease is associated with a patient who has two APOL1 risk alleles, for example, homozygous or compound heterozygous for G1 allele or 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 renal disease. In some embodiments, the APOL1-mediated renal disease is chronic renal disease or proteinuria.

[0039] 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 renal function and is associated with two common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0040] The term "NDKD" as used herein means non-diabetic kidney disease characterized by severe hypertension and progressive decline in renal function and associated with two common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0041] 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., renal failure, where the kidneys do not function well enough that the patient cannot survive without dialysis or kidney transplantation. In some embodiments, ESKD / ESRD is associated with two APOL1 risk alleles.

[0042] The term "compound", when referring to a compound of the present disclosure, refers to a collection of molecules having the same chemical structure, unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic variations may exist between the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown also contains a lesser amount of isotopic substitutions having a hydrogen atom at one or more of the designated deuterium positions in the structure. The relative amount of such isotopic substitutions in the compounds of the present disclosure will depend on several factors, including the isotopic purity of the reagents used to make the compound, and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as described above, the relative amount of such isotopic substitutions overall will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitutions overall will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compounds.

[0043] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally," refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions. Combinations of substituents envisioned by the present disclosure are those that result in the formation of stable or chemically feasible compounds.

[0044] The term "isotopically modified" refers to a species whose chemical structure differs from the reference compound only in its isotopic composition.In addition, unless otherwise specified, the 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 this structure except for the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with 13C or 14C are within the scope of this disclosure.

[0045] Unless otherwise indicated, the structures depicted herein are also intended to include all isomeric forms of the structures, such as racemic mixtures, cis / trans isomers, (Z) and (E) double bond isomers, and geometric (or conformational) isomers, such as (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds are within the scope of the disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0046] The term "tautomer" as used herein refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchanged by migration of atoms, e.g., hydrogen atoms or groups, within the molecule.

[0047] As used herein, "stereoisomers" refers to enantiomers and diastereomers.

[0048] As used herein, a "deuterated derivative" refers to a compound that has the same chemical structure as a reference compound, but has 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 a synthesized compound depending on the source of the chemicals used in the synthesis. The concentration of naturally occurring stable hydrogen isotopes is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein, despite this variation. Thus, unless otherwise specified, when a "deuterated derivative" of a compound of the present disclosure is referred to, at least one hydrogen is replaced with deuterium well above its natural isotopic abundance (which is typically about 0.015%). In some embodiments, deuterated derivatives of the disclosure have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).

[0049] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0050] The term "alkyl" or "aliphatic" as used herein means a straight-chain (i.e., linear or unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated. Unless otherwise specified, an alkyl group contains 1-20 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-10 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1-8 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1-6 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-4 alkyl carbon atoms, in other embodiments, an alkyl group contains 1-3 alkyl carbon atoms, and in still other embodiments, an alkyl group contains 1 or 2 alkyl carbon atoms. In some embodiments, an alkyl group is linear or straight-chained or unbranched. In some embodiments, an alkyl group is branched.

[0051] As used herein, the terms "cycloalkyl" and "cyclic alkyl" refer to a fully saturated monocyclic C3-8 hydrocarbon, or a spirocyclic, fused, or bridged bicyclic or tricyclic C8-14 hydrocarbon, where any individual ring within the bicyclic ring system has 3 to 7 members. In some embodiments, a cycloalkyl is a C3-C12 cycloalkyl. In some embodiments, a cycloalkyl is a C3-C8 cycloalkyl. In some embodiments, a cycloalkyl is a C3-C6 cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0052] As used herein, the term "carbocyclyl" or "cycloaliphatic" encompasses the term "cycloalkyl" or "cyclic alkyl" and refers to a monocyclic C3-8 hydrocarbon, or a spirocyclic, fused, or bridged bicyclic or tricyclic C8-14 hydrocarbon, which is fully saturated or partially saturated to contain one or more saturated units, but is not aromatic, and any individual ring of the bicyclic ring system has 3 to 7 members. A bicyclic carbocyclyl includes a combination of a monocyclic carbon ring fused to a phenyl. In some embodiments, the carbocyclyl is a C3-C12 carbocyclyl. In some embodiments, the carbocyclyl is a C3-C10 carbocyclyl. In some embodiments, the carbocyclyl is a C3-C8 carbocyclyl.

[0053] 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.

[0054] As used herein, the term "alkenyl" refers to a straight-chain (i.e., linear or unbranched) or branched hydrocarbon chain containing one or more double bonds. In some embodiments, an alkenyl group is straight-chain. In some embodiments, an alkenyl group is branched.

[0055] As used herein, the terms "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" mean a non-aromatic (i.e., fully saturated or partially saturated, but not aromatic, as it contains one or more units of unsaturation), monocyclic, or spirocyclic, fused, or bridged bicyclic or tricyclic ring system in which one or more ring members of the ring system are independently selected heteroatoms. Bicyclic heterocyclyls include the following combinations of monocyclic rings: monocyclic heteroaryl fused to a monocyclic heterocyclyl; monocyclic heterocyclyl fused to another monocyclic heterocyclyl; monocyclic heterocyclyl fused to a phenyl; monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl.

[0056] In some embodiments, the heterocycle includes one or more ring atoms substituted with an oxo group (eg, a C=O group, an S=O group, or an SO2 group, etc.).

[0057] In some embodiments, a "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has 3-14 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 3-7 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, each independently selected from nitrogen and oxygen. In some embodiments, a heterocycle has three heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, a heterocyclyl is a 3-12 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.

[0058] 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, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl)).

[0059] 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.

[0060] The term "alkoxy" or "thioalkyl" as used herein refers to an alkyl group, as previously defined, in which one carbon of the alkyl group is replaced by an oxygen ("alkoxy") or sulfur ("thioalkyl") atom, respectively, provided that the oxygen and sulfur atoms are linked between two carbon atoms. "Cyclic alkoxy" refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group but is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl.

[0061] As used herein, the terms "haloalkyl", "haloalkenyl", and "haloalkoxy" refer to straight or branched alkyl, alkenyl, or alkoxy, respectively, substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CF2-, and perhaloalkyl, such as -CF2CF3. Non-limiting examples of haloalkoxy groups include -OCHF2, -OCH2F, -OCF3, and -OCF2.

[0062] The term "halogen" includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.

[0063] The term "aminoalkyl" means an alkyl group that is substituted with or contains an amino group.

[0064] As used herein, "amino" refers to a group that is a primary, secondary, or tertiary amine.

[0065] As used herein, a "carbonyl" group refers to C=O.

[0066] As used herein, a "cyano" or "nitrile" group refers to --C.ident.N.

[0067] As used herein, a "hydroxy" group refers to an --OH group.

[0068] As used herein, a "thiol" group refers to -SH.

[0069] As used herein, "tert" and "t-" each refer to tertiary.

[0070] As used herein, an "aromatic group" or "aromatic ring" refers to a chemical group that contains a conjugated planar ring system having delocalized pi orbitals consisting of [4n+2]p orbital electrons, where n is an integer ranging from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0071] The term "aryl" used alone or as part of a larger moiety, such as "arylalkyl", "arylalkoxy", or "aryloxyalkyl", refers to a monocyclic, or spirocyclic, fused or bridged bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, in which all rings in the system are aromatic rings containing only carbon atoms, and in which each ring of a bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C6) and naphthyl (C10) rings.

[0072] The term "heteroaryl," used alone or as part of a larger moiety, such as "heteroarylalkyl" or "heteroarylalkoxy," refers to a monocyclic, or spirocyclic, fused, or bridged, bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and where each ring in the bicyclic and tricyclic ring systems contains 3 to 7 ring members. Bicyclic heteroaryls include the following combinations of monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl. In some embodiments, a heteroaryl group has one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group has one heteroatom. In some embodiments, a heteroaryl group has two heteroatoms. In some embodiments, a heteroaryl group is a monocyclic ring system having five ring members. In some embodiments, a heteroaryl group is a monocyclic ring system having six ring members. In some embodiments, the heteroaryl is a 3-12 membered heteroaryl. In some embodiments, the heteroaryl is a 3-10 membered heteroaryl. In some embodiments, the heteroaryl is a 3-8 membered heteroaryl. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-8 membered heteroaryl. In some embodiments, the heteroaryl is a 5 or 6 membered heteroaryl. Non-limiting examples of monocyclic heteroaryls include pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, and the like.

[0073] In some embodiments, a heteroaryl includes a ring atom substituted with one or more oxo groups (e.g., a C=O group, a S=O group, or a SO2 group, etc.). Illustratively, a non-limiting example of a heteroaryl group is a benzo[d]oxazol-2(3H)-one group.

[0074] Non-limiting examples of useful protecting groups for nitrogen-containing groups such as amine groups include, for example, t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide.Methods for adding (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.

[0075] 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" (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethylsulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0076] Non-limiting examples of suitable bases that may 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 (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropyl-ethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

[0077] The present disclosure includes specific substantially crystalline solid forms of the compounds of the present invention. As used herein, the terms "crystal form" and "form" refer interchangeably to a crystal structure (or polymorph) having a specific molecular packing arrangement in a crystal lattice. Crystal forms can be identified and distinguished from one another by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, solid state nuclear magnetic resonance (SSNMR), differential scanning calorimetry (DSC), infrared radiation (IR), and / or thermogravimetric analysis (TGA). Thus, as used herein, "crystal form [X] of compound [Y]" refers to a unique crystal form that can be identified and distinguished from other crystal forms of compound [Y] by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, SSNMR, differential scanning calorimetry (DSC), infrared radiation (IR), and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline form [X] of compound [Y] is characterized by an X-ray powder diffractogram having one or more signals at one or more specific two-theta values ​​(°2θ).

[0078] As used herein, the term "SSNMR" refers to solid-state nuclear magnetic resonance analytical characterization. SSNMR spectra can be recorded at ambient or non-ambient conditions (e.g., 275K) for any magnetically active isotope present in the sample. Common examples of active isotopes for small molecule active pharmaceutical ingredients include 1H, 2H, 13C, 19F, 31P, 15N, 14N, 35Cl, 11B, 7Li, 17O, 23Na, 79Br, and 195Pt.

[0079] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded under ambient conditions in a transmission or reflection geometry using a diffractometer.

[0080] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," and "XRPD pattern" refer interchangeably to an experimentally obtained pattern that plots signal position (on the abscissa) against signal intensity on the ordinate. For amorphous materials, the X-ray powder diffractogram may include one or more broad signals, and for crystalline materials, the X-ray powder diffractogram may include one or more signals, each identified by its angular value, measured in degrees 2θ (°2θ), depicted on the abscissa of the X-ray powder diffractogram, which may be expressed as "signal at ... °2θ," "signal at 2θ values ​​of ...," and / or "signal at at least ... 2θ values ​​selected from ...."

[0081] As used herein, a "signal" or "peak" refers to a point in an XRPD pattern or SSNMR spectrum where the intensity, measured in counts, is at a local maximum. Those skilled in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may not be apparent, for example, to the naked eye. Indeed, those skilled in the art will recognize that several art-recognized methods are capable and suitable for determining whether a signal is present in a pattern, such as, for example, Rietveld refinement.

[0082] As used herein, "signal at ...° 2θ", "signal at 2θ values ​​of ... [ ]", and / or "signal at at least ... 2θ values ​​selected from ..." refer to X-ray reflection positions measured and observed in an X-ray powder diffraction experiment (° 2θ).

[0083] The reproducibility of the angle values ​​is within a range of ±0.2°2θ, i.e., the angle values ​​can be at the recited angle value +0.2°2θ, angle value −0.2°2θ, or any value between those two end points (angle value +0.2°2θ and angle value −0.2°2θ).

[0084] As used herein, the terms "signal intensity" and "peak intensity" refer interchangeably to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect relative signal intensity or peak intensity include sample thickness and preferred orientation (e.g., crystalline particles are not randomly distributed).

[0085] The terms "X-ray powder diffractogram having signals at ... 2 theta values" and "X-ray powder diffractogram including signals at ... 2 theta values" are used interchangeably herein and refer to an XRPD pattern that includes X-ray reflection positions (°2θ) measured and observed in an X-ray powder diffraction experiment.

[0086] As used herein, an X-ray powder diffractogram is "substantially similar to that of a [particular] figure" if at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms overlap. In determining "substantial similarity," one of skill in the art will understand that there may be variations in intensity and / or signal positions in XRPD diffractograms even for the same crystalline form. Thus, one of skill in the art will understand that signal positions (in degrees two theta (°2θ) as referred to herein) in an XRPD diffractogram generally mean that the reported values ​​are ±0.2 degrees 2θ of the reported values, an art-recognized variance.

[0087] As used herein, a SSNMR spectrum is "substantially similar to that of a [particular] figure" if at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two spectra overlap. In determining "substantial similarity," one skilled in the art will understand that there may be variations in the intensity and / or signal positions of SSNMR spectra even for the same crystal type. Thus, one skilled in the art will understand that the signal positions in SSNMR spectra (ppm) referred to herein generally mean that the reported values ​​are ±0.2 ppm of the reported value, which is an art-recognized variance.

[0088] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry. A DSC curve is "substantially similar to that of a [particular] figure" if at least 90%, such as at least 95%, at least 98%, or at least 99% of the features in the two curves overlap. In determining "substantial similarity," one skilled in the art will understand that there may be variations in the intensity and / or peak (e.g., endothermic or exothermic) positions of DSC curves even for the same solid form.

[0089] As used herein, the term "TGA" refers to the analytical method of Thermo Gravimetric (or thermogravimetric) analysis. A TGA thermogram is "substantially similar to that of a [particular] figure" if at least 90%, such as at least 95%, at least 98%, or at least 99%, of the features in the two thermograms overlap. In determining "substantial similarity," one of skill in the art will understand that there may be variations in the intensities and / or peak (e.g., decomposition peak) positions of TGA thermograms even for the same solid form.

[0090] As used herein, the term "substantially crystalline" refers to a solid material that has few or no amorphous molecules. For example, a substantially crystalline substance has less than 15% amorphous molecules (e.g., less than 10% amorphous molecules, less than 5% amorphous molecules, or less than 2% amorphous molecules). It is also noted that the term "substantially crystalline" includes the descriptor "crystalline," which refers to a material that is 100% crystalline.

[0091] As used herein, a crystalline form is "substantially pure" when it comprises 90% or more by weight of the sum of all solid forms in a sample, as determined by methods in the art, such as, for example, quantitative XRPD. In some embodiments, a solid form is "substantially pure" when it comprises 95% or more by weight of the sum of all solid forms in a sample. In some embodiments, a solid form is "substantially pure" when it comprises 99% or more by weight of the sum of all solid forms in a sample.

[0092] The present disclosure includes pharma- ceutically acceptable salts of the disclosed compounds. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0093] 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 reaction, and the like, commensurate with a reasonable benefit / risk ratio. "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.

[0094] Acids commonly employed to form pharma- ceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharma- ceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-diate, hexyne-2,4-di ... Included are oates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharma- ceutically acceptable acid addition salts include those formed with mineral acids, such as hydrochloric acid and hydrobromic acid, and those formed with organic acids, such as maleic acid.

[0095] 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 group of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0096] The terms "patient" and "subject" are used interchangeably herein and refer to animals, including humans.

[0097] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of the compound for which it is administered to produce 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 can be ascertained by the skilled artisan using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0098] As used herein, the term "treatment" and its cognate terms refer to the slowing or stopping of disease progression.As used herein, the term "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 evaluated according to methods and techniques known in the art or subsequently developed.

[0099] The terms "about" and "approximately", when used in connection with 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 percents, that is recognized by a person skilled in the art as providing a pharmacological effect equivalent to that obtained from the particular dose, amount, or weight percent. The terms "about" and "approximately" may also refer to an acceptable error for a particular value determined by a person skilled in the art, which depends, in part, on how the value is measured or determined. In some embodiments, the terms "about" and "approximately" mean within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. As used herein, the symbol "~" appearing immediately before a numerical value has the same meaning as the terms "about" and "approximately".

[0100] At least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing, can be administered once a day, twice a day, or three times a day, for example, for the treatment of FSGS. In some embodiments, the compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b are selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing, is administered once daily. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing, is administered once daily.In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing, is administered twice daily. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing, is administered twice daily. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing, is administered three times daily. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing, is administered three times daily.

[0101] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of Formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing, is administered once a day, twice a day, or three times a day. In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing, is administered once a day, twice a day, or three times a day.

[0102] Those skilled in the art will recognize that when the amount of a compound is disclosed, the relative amount of the pharma- ceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. The amount of the compounds, pharma- ceutically acceptable salts, solvates, and deuterated derivatives disclosed herein is based on the free base form of the reference compound. For example, "1000 mg of at least one compound or pharma- ceutically acceptable salt selected from the compound of formula I and its pharma- ceutically acceptable salt" includes 1000 mg of the compound of formula I and a pharma- ceutically acceptable salt of the compound of formula I in a concentration equivalent to 1000 mg of the compound of formula I.

[0103] As used herein, the term "ambient conditions" refers to room temperature, outside air conditions, and uncontrolled humidity conditions.

[0104] Compounds and Compositions In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure is a compound represented by the following structural formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from C6 aryl, and 5- and 6-membered heteroaryl groups; R1 is independently selected for each occurrence from halogen, -OH, =O, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, -C(=O)N(Rc)2, and -SO2Rc groups; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R1 4-6 membered heterocyclyl 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; R1 C3-C6 carbocyclyl is 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 Optionally substituted with 1 to 3 groups independently selected from -C(=O)N(C1-C4 alkyl) groups; The phenyl 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; or two R1 groups, together with the ring A atom connecting them, form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring; Each of the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 groups selected from halogen, —OH, and C1-C4 alkyl; 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, 5-10 membered heterocyclyl, C6 aryl, and 5-10 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 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); Each of the C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra is 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; 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, 5-10 membered heterocyclyl, and C3-C6 carbocyclyl; Any one of Rk's C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and -OH groups; Rm is independently selected for each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 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; R4 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)nC(=O)NRnRo, -NRnRo, -NRoC(=O)Rp, -NRnS(=O)pRp, -(CH2)nORp, -S(=O)pRp, -S(=O)pNRnRo, -OS(=O)pNRnRo, and -(CH2)nC(=O)ORp groups, wherein Rn and Ro are each independently selected for each occurrence from hydrogen and a C1-C4 alkyl group; Rp, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R5 is selected from hydrogen and C1-C6 alkyl; m is an integer selected from 0, 1, 2, 3, 4, and 5; n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; q and r are each an integer independently selected from 1, 2, 3, and 4 for each occurrence.

[0105] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, R4 is -OH, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0106] In some embodiments, in the compounds of the present disclosure (i.e., compounds of any one of formulas I, Ia, Ib, and Ic), or tautomers, deuterated derivatives, or pharma- ceutically acceptable salts thereof, 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 the compounds of the present disclosure (i.e., compounds of any one of formulas I, Ia, Ib, and Ic), or tautomers, deuterated derivatives, or pharma-ceutically acceptable salts thereof, or tautomers, deuterated derivatives, or pharma-ceutically acceptable salts thereof, 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 the compounds of the present disclosure (i.e., compounds of any one of formulas I, Ia, Ib, and Ic), or tautomers, deuterated derivatives, or pharma-ceutically acceptable salts thereof, m is 1, 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 the compounds of the present disclosure (i.e., compounds of any one of formulas I, Ia, Ib, and Ic), or tautomers, deuterated derivatives, or pharma- ceutically acceptable salts, ring A is phenyl, thiophenyl, 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 the compounds of the present disclosure (i.e., compounds of any one of formulas I, Ia, Ib, and Ic), or tautomers, deuterated derivatives, or pharma-ceutically acceptable salts, 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 the compounds of the present disclosure (i.e., compounds of any one of formulas I, Ia, Ib, and Ic), or tautomers, deuterated derivatives, or pharma-ceutically acceptable salts, ring A is thiophenyl, 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 of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, Ring A is pyridinyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0108] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, 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.

[0109] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, 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.

[0110] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, 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 preceding embodiments.

[0111] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, 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.

[0112] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, ring B is selected from cyclopropyl, 5- to 10-membered heterocyclyl, phenyl, and 5- to 9-membered heteroaryl groups, 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.

[0113] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, 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 the preceding embodiments.

[0114] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, 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, a 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 the preceding embodiments.

[0115] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, Ring B is: [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0116] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, Ring B is: [ka] [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0117] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, 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.

[0118] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, R3 is selected from C1-C4 alkyl, —C(═O)O(C1-C2 alkyl), C3-C6 cycloalkyl, and a 5-10 membered heterocyclyl group; R3 C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, and C1-C2 alkoxy groups; 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 preceding embodiments.

[0119] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, R3 is selected from C1-C2 alkyl, —C(═O)O(C1-C2 alkyl), cyclopropyl, cyclobutyl, and a 5- to 6-membered heterocyclyl group; R3 C1-C2 alkyl 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 1-3 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 preceding embodiments.

[0120] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, R3 is selected from -CH3, -CH2CH3, -CH2OH, -C(=O)OCH3, -CH2OCH3, -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.

[0121] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, R3 is -CH3, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0122] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, R1, for each occurrence, is independently selected from hydrogen, halogen, cyano, -OH, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)N(Rc)2, and -SO2(Rc), and a C3-C6 cycloalkyl group; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 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 of 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; or two R1 groups, together with the ring A atom connecting them, form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring; Each of the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 groups selected from halogen, —OH, and C1-C4 alkyl; All other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0123] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, 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 of 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 preceding embodiments.

[0124] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, R1, for each occurrence, is independently selected from hydrogen, halogen, cyano, —OH, C1-C4 alkyl, C1-C4 alkoxy, and C3-C6 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 of 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 preceding embodiments.

[0125] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, R1, for each occurrence, is independently selected from F, Cl, Br, C1-C4 alkyl, and C3-C6 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 preceding embodiments.

[0126] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, R1, for each occurrence, is independently selected from F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy, —C(═O)N(Rc), 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 of 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 preceding embodiments.

[0127] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, R1, for each occurrence, is independently selected from F, Cl, Br, C1-C4 alkyl, and C3-C6 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 preceding embodiments.

[0128] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, R1, for each occurrence, is independently selected from F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy, —C(═O)N(Rc), 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 of 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 preceding embodiments.

[0129] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, 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.

[0130] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, 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.

[0131] In some embodiments, in a compound, tautomer, deuterated derivative, or pharma- ceutically 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.

[0132] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts of the present disclosure, R1, for each occurrence, is independently selected from halogen, -OH, and C1-C4 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.

[0133] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, R1, for each occurrence, is independently selected from F, Cl, Br, -OH, and C1-C2 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.

[0134] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, R1, for each occurrence, is independently selected 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.

[0135] In some embodiments, in the compounds of the present disclosure (i.e., compounds of any one of formulas I, Ia, Ib, and Ic), or tautomers, deuterated derivatives, or pharma- ceutically acceptable salts, R1, for each occurrence, is independently selected from -SO2(Rc), where Rc is selected from hydrogen and a C1-C2 alkyl group, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. In some embodiments, Rc is selected from a C1-C2 alkyl group. In some embodiments, Rc is selected from a C1 alkyl group. In some embodiments, Rc is -CH3.

[0136] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, two R groups, taken together with the ring A atom connecting them, form a 5-6 membered cycloalkyl, 5-8 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl ring, each of which is optionally substituted with 1-4 groups selected from halogen, —OH, and C-C alkyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0137] In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or a pharma- ceutically acceptable salt, two R groups taken together are: [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0138] In some embodiments, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, two R groups, together with the ring A atom connecting them, are: [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0139] In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, 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(CH2)q]rO(C1-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, 5-10 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl of Ra is optionally substituted with 1-3 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.

[0140] In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, 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(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, -NRhRi, -ORk, cyclopropyl, and cyclobutyl; Each of the cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl of Ra is optionally substituted with 1-3 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 is independently selected for each occurrence 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.

[0141] In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, Ra is, for each occurrence, 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(CH2)q]rO(C1-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 of Ra is optionally substituted with 1-3 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 is independently selected for each occurrence from hydrogen and -CH3; q and r are each an integer 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.

[0142] In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, Ra is, for each occurrence, F, cyano, -OH, -CH, -CF, -CH(CH), -(CHOH, -(CH)OCH, -CHCH(OH)CH, -CHC(CH)(CHOH), -OCH, -OCHCH, -[O(CH)]OCH, -CHC(=O)NHCH, -(CHSOCH, -CHC(=O)N(CH )2, -CH2(cyclopropyl), -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 all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0143] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, Ra is independently selected for each occurrence from -CH and -(CH)SOCH, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0144] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, R5 is selected from hydrogen and C1-C4 alkyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0145] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, R5 is selected from hydrogen, methyl, and propyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0146] In some embodiments, in the compounds of the present disclosure (i.e., compounds of any one of formulas I, Ia, Ib, and Ic), or tautomers, deuterated derivatives, or pharma- ceutically acceptable salts, R5 is hydrogen, R1 is independently selected for each occurrence from -SO2(Rc), Rc is selected from hydrogen and a C1-C2 alkyl group, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. In some embodiments, Rc is selected from a C1-C2 alkyl group. In some embodiments, Rc is selected from a C1 alkyl group. In some embodiments, Rc is -CH3.

[0147] In some embodiments, in a compound of the present disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, R5 is hydrogen, and two R1 groups, together with the ring A atom connecting them, form a 5-6 membered cycloalkyl, 5-8 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl ring, each of which is optionally substituted with 1-4 groups selected from halogen, -OH, and C1-C4 alkyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0148] In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, R5 is hydrogen and two R1 groups taken together are: [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0149] In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulas I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, R5 is hydrogen and the two R1 groups, together with the ring A atom connecting them, are: [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0150] In some embodiments, the disclosed compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts are represented by one of the following structural formulas: [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. In some embodiments of Formulas Ic-1 through Ic-6, compound I296 and compound 43a are excluded.

[0151] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure is a compound represented by the following structural formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from C6 aryl, and 5- and 6-membered heteroaryl groups; R1, for each occurrence, is independently selected from halogen, -OH, =O, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, and -C(=O)N(Rc)2 groups; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R1 4-6 membered heterocyclyl 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; R1 C3-C6 carbocyclyl is 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 Optionally substituted with 1 to 3 groups independently selected from -C(=O)N(C1-C4 alkyl) groups; The phenyl 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; 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, 5-10 membered heterocyclyl, C6 aryl, and 5-10 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 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); Each of the C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra is 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; 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, 5-10 membered heterocyclyl, and C3-C6 carbocyclyl; Any one of Rk's C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and -OH groups; Rm is independently selected for each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 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; R4 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)nC(=O)NRnRo, -NRnRo, -NRoC(=O)Rp, -NRnS(=O)pRp, -(CH2)nORp, -S(=O)pRp, -S(=O)pNRnRo, -OS(=O)pNRnRo, and -(CH2)nC(=O)ORp groups, wherein Rn and Ro are each independently selected for each occurrence from hydrogen and a C1-C4 alkyl group; Rp, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; m is an integer selected from 0, 1, 2, 3, 4, and 5; n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; q and r are each an integer independently selected from 1, 2, 3, and 4 for each occurrence. In some embodiments, compound I296 and compound 43a are excluded from formula II.

[0152] In some embodiments, in a compound of formula II, or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, R4 is -OH, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0153] In some embodiments, in a compound of Formula II, or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, 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.

[0154] In some embodiments, in a compound of Formula II, or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, Ring A is phenyl, thiophenyl, or pyridinyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0155] In some embodiments, in the compound of Formula II, or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, R is selected from a C alkyl group, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0156] In some embodiments, in the compound of Formula II, or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt thereof, R3 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.

[0157] In some embodiments, in the compound of formula II, or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, R3 is -CH3; R2 is selected from -CH3 and Ring B, Ring B is [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0158] In some embodiments, in the compound of formula II, or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, R3 is -CH3; R2 is selected from -CH3 and Ring B, Ring B is [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments.

[0159] In some embodiments, in the compound of formula II, or a tautomer, deuterated derivative, or pharma- ceutically acceptable salt, Ring A is selected from C6 aryl and 5- and 6-membered heteroaryl groups; R1, for each occurrence, is independently selected from halogen, C1-4 alkyl, C1-4 alkoxy, C3 cycloalkyl, and -C(=O)N(Rc)2 groups; The C1-4 alkyl and C1-4 alkoxy groups are optionally substituted with 1 to 3 groups selected from halogen; Rc, for each occurrence, is independently selected from hydrogen and a C alkyl group; R2 is selected from C1-4 alkyl and 5-membered heteroaryl groups, the 5-membered heteroaryl group being optionally substituted with 1-2 C1-4 alkyl groups optionally substituted with -S(=O)2CH3; R3 is selected from C1-4 alkyl groups; m is an integer selected from 0, 1, and 2;

[0160] In some embodiments, the compound of formula II, or a tautomer, deuterated derivative, or a pharma- ceutically acceptable salt, is represented by one of the following structural formulas: [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. In some embodiments of Formulas II-1-II-6, compound I296 and compound 43a are excluded.

[0161] In some embodiments, the compound of formula II-6 is selected from the compounds of formula II-6a and formula II-6b: [ka] wherein R1a and R1b are independently selected from halogen, H, C1-C4 alkyl, and C1-C4 haloalkyl groups; R1c is selected from halogen, H, CH3, -OH, and CH3OH; R2 in formula II-6a is defined as for formula II.

[0162] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure is selected from compounds 1-29 shown in Table 1, compounds I5-I295 shown in Table 2, compounds 30-44 shown in Table 3, and compounds 45-68 shown in Table 4, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharma- ceutically acceptable salts of any of the foregoing. [ka] represents a bond between two atoms and indicates the location of mixed stereochemistry for a set of molecules such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. Similarly, chiral centers (e.g., [ka] and [ka] where RW, RX, RY, and RZ are different) [ka] represents the location of mixed stereochemistry for a set of molecules. [Table 1-1] [Table 1-2] [Table 2-1]

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 3

Table 4-1

Table 4-2

[0163] Some embodiments of the disclosure include derivatives of compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, or compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the derivative is a silicon derivative in which at least one carbon atom of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, or compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of such compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, is replaced by silicon. In some embodiments, the derivative is a silicon derivative in which at least one halogen atom (e.g., fluorine) of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, or compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of such compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, is replaced by a silicon derivative (e.g., —Si(CH3)3).In some embodiments, the derivative is a boron derivative in which at least one carbon atom of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, or compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of such compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, is replaced by boron. In other embodiments, the derivative is a phosphorus derivative in which at least one carbon atom of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, or compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of such compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, is replaced by phosphorus.

[0164] In some embodiments, the derivative is a silicon derivative in which at least one carbon atom of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, or compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, is replaced by silicon or a silicon derivative (e.g., -Si(CH3)2- or -Si(OH)2-). The carbon replaced by silicon may be a non-aromatic carbon. In other embodiments, the fluorine is replaced by a silicon derivative (e.g., -Si(CH3)3). In some embodiments, the silicon derivatives of the present invention may include one or more hydrogen atoms replaced by deuterium. In some embodiments, the silicon derivatives of the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, or compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing, may incorporate silicon in a heterocyclic ring.

[0165] In some embodiments, the derivative is a boron derivative in which one carbon atom of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, or compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of such compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, is replaced by boron or a boron derivative.

[0166] In some embodiments, the derivative is a phosphorus derivative in which one carbon atom of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, or compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of such compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, are replaced by phosphorus or a phosphorus derivative.

[0167] Another aspect of the present disclosure provides pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of formulas selected from Formulas I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, as well as compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of such compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from Formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, as well as compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of such compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, is administered to a patient in need thereof.

[0168] The pharmaceutical composition may further comprise at least one pharma- ceutically acceptable carrier. In some embodiments, the at least one pharma- ceutically acceptable carrier is selected from a pharma- ceutically acceptable vehicle and a pharma- ceutically acceptable adjuvant. In some embodiments, the at least one pharma- ceutically acceptable is selected from a pharma- ceutically acceptable filler, a disintegrant, a surfactant, a binder, and a lubricant.

[0169] It will also be understood that the pharmaceutical compositions of the present disclosure may be employed in combination therapy, i.e., the pharmaceutical compositions described herein may further comprise at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutical acceptable salt selected from the compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, their tautomers, deuterated derivatives of the compounds or tautomers, and pharma- ceutical acceptable salts of any of the foregoing, may be administered as a separate composition, simultaneously with, prior to, or after a composition comprising at least one other active therapeutic agent. In some embodiments, a pharmaceutical composition comprising at least one compound, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, can be administered as a separate composition, simultaneously with, prior to, or subsequent to a composition comprising at least one other active therapeutic agent.

[0170] As mentioned above, the pharmaceutical composition disclosed herein may optionally further comprise at least one pharma- ceutically acceptable carrier. At least one pharma- ceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, at least one pharma- ceutically acceptable carrier includes any solvent, diluent, other liquid vehicle, dispersing aid, suspending 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 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 undesirable 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 pharma- ceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), saturated vegetable fatty acids, partial glyceride mixtures of water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxymethylcellulose sodium, cellulose acetate, cellulose acetate esters ... Examples of suitable carriers include, but are not limited to, cellulose acetate, ethylcellulose, ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, releasing agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] In some embodiments, the disclosed methods include administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt is selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the patient in need thereof carries the APOL1 gene variants: G1;S342G:I384M, and G2:N388del:Y389del.

[0175] Another aspect of the disclosure provides a method of inhibiting APOL1 activity comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of Formulas I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing. In some embodiments, the method of inhibiting APOL1 activity comprises contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing.

[0176] solid form Some embodiments of the present disclosure provide a solid form of compound 16. In some embodiments, the solid form of compound 16 is Form A. In some embodiments of the present disclosure, Form A of compound 16 is substantially pure. In some embodiments of the present disclosure, Form A of compound 16 is substantially crystalline.

[0177] In some embodiments, Form A of Compound 16 is characterized by an X-ray powder diffractogram that includes signals at °2θ values ​​selected from 19.9±0.2°2θ, 20.0±0.2°2θ, and 10.9±0.2°2θ. In some embodiments, Form A of Compound 16 is characterized by an X-ray powder diffractogram that includes two or more signals at 19.9±0.2°2θ, 20.0±0.2°2θ, and 10.9±0.2°2θ. In some embodiments, Form A of Compound 16 is characterized by an X-ray powder diffractogram that includes signals at 19.9±0.2°2θ, 20.0±0.2°2θ, and 10.9±0.2°2θ.

[0178] In some embodiments, Compound 16 Form A has any of the following properties: 10.9±0.2°2θ, 14.1±0.2°2θ, 15.4±0.2°2θ, 16.1±0.2°2θ, 17.5±0.2°2θ, 18.2±0.2°2θ, 19.3±0.2°2θ, 19.9±0.2°2θ, 20.0±0.2°2θ, 20.5±0.2°2θ, 20.6±0.2°2θ, 20.8 ... ±0.2°2θ, 21.4±0.2°2θ, 21.7±0.2°2θ, 22.8±0.2°2θ, 23.3±0.2°2θ, 23.8±0.2°2θ, 26.1±0.2°2θ, and 26.2±0.2°2θ. In some embodiments, Compound 16 Form A has any of the following properties: 10.9±0.2°2θ, 14.1±0.2°2θ, 15.4±0.2°2θ, 16.1±0.2°2θ, 17.5±0.2°2θ, 18.2±0.2°2θ, 19.3±0.2°2θ, 19.9±0.2°2θ, 20.0±0.2°2θ, 20.5±0.2°2θ, 20.6±0.2°2θ, 20.8 ... 20.6±0.2°2θ, 21.4±0.2°2θ, 21.7±0.2°2θ, 22.8±0.2°2θ, 23.3±0.2°2θ, 23.8±0.2°2θ, 26.1±0.2°2θ, and 26.2±0.2°2θ. In some embodiments, Compound 16 Form A has any of the following properties: 10.9±0.2°2θ, 14.1±0.2°2θ, 15.4±0.2°2θ, 16.1±0.2°2θ, 17.5±0.2°2θ, 18.2±0.2°2θ, 19.3±0.2°2θ, 19.9±0.2°2θ, 20.0±0.2°2θ, 20.5±0.2°2θ, 20.6±0.2°2θ, 20.8 ... ±0.2°2θ, 21.4±0.2°2θ, 21.7±0.2°2θ, 22.8±0.2°2θ, 23.3±0.2°2θ, 23.8±0.2°2θ, 26.1±0.2°2θ, and 26.2±0.2°2θ.In some embodiments, Compound 16 Form A has any of the following properties: 10.9±0.2°2θ, 14.1±0.2°2θ, 15.4±0.2°2θ, 16.1±0.2°2θ, 17.5±0.2°2θ, 18.2±0.2°2θ, 19.3±0.2°2θ, 19.9±0.2°2θ, 20.0±0.2°2θ, 20.5±0.2°2θ, 20.6±0.2°2θ, 20.8 ... 20.6±0.2°2θ, 21.4±0.2°2θ, 21.7±0.2°2θ, 22.8±0.2°2θ, 23.3±0.2°2θ, 23.8±0.2°2θ, 26.1±0.2°2θ, and 26.2±0.2°2θ. In some embodiments, Compound 16 Form A has any of the following properties: 10.9±0.2°2θ, 14.1±0.2°2θ, 15.4±0.2°2θ, 16.1±0.2°2θ, 17.5±0.2°2θ, 18.2±0.2°2θ, 19.3±0.2°2θ, 19.9±0.2°2θ, 20.0±0.2°2θ, 20.5±0.2°2θ, 20.6±0.2°2θ, 20.8 ... 20.6±0.2°2θ, 21.4±0.2°2θ, 21.7±0.2°2θ, 22.8±0.2°2θ, 23.3±0.2°2θ, 23.8±0.2°2θ, 26.1±0.2°2θ, and 26.2±0.2°2θ. In some embodiments, Compound 16 Form A has any of the following properties: 10.9±0.2°2θ, 14.1±0.2°2θ, 15.4±0.2°2θ, 16.1±0.2°2θ, 17.5±0.2°2θ, 18.2±0.2°2θ, 19.3±0.2°2θ, 19.9±0.2°2θ, 20.0±0.2°2θ, 20.5±0.2°2θ, 20.6±0.2°2θ, 20.8 ... 20.6±0.2°2θ, 21.4±0.2°2θ, 21.7±0.2°2θ, 22.8±0.2°2θ, 23.3±0.2°2θ, 23.8±0.2°2θ, 26.1±0.2°2θ, and 26.2±0.2°2θ.In some embodiments, Compound 16 Form A has any of the following properties: 10.9±0.2°2θ, 14.1±0.2°2θ, 15.4±0.2°2θ, 16.1±0.2°2θ, 17.5±0.2°2θ, 18.2±0.2°2θ, 19.3±0.2°2θ, 19.9±0.2°2θ, 20.0±0.2°2θ, 20.5±0.2°2θ, 20.6±0.2°2θ, 20.8 ... ±0.2°2θ, 21.4±0.2°2θ, 21.7±0.2°2θ, 22.8±0.2°2θ, 23.3±0.2°2θ, 23.8±0.2°2θ, 26.1±0.2°2θ, and 26.2±0.2°2θ. In some embodiments, Form A of Compound 16 is characterized by an X-ray powder diffractogram including signals at 10.9±0.2°2θ, 14.1±0.2°2θ, 15.4±0.2°2θ, 16.1±0.2°2θ, 17.5±0.2°2θ, 18.2±0.2°2θ, 19.3±0.2°2θ, 19.9±0.2°2θ, 20.0±0.2°2θ, 20.5±0.2°2θ, 20.6±0.2°2θ, 21.4±0.2°2θ, 21.7±0.2°2θ, 22.8±0.2°2θ, 23.3±0.2°2θ, 23.8±0.2°2θ, 26.1±0.2°2θ, and 26.2±0.2°2θ.

[0179] In some embodiments, Form A of Compound 16 is characterized by an X-ray powder diffractogram substantially similar to FIG.

[0180] In some embodiments, Form A of Compound 16 is characterized by thermogravimetric analysis showing minimal weight loss from ambient temperature to 250° C. In some embodiments, Form A of Compound 16 is characterized by a TGA thermogram substantially similar to FIG.

[0181] In some embodiments, Form A of Compound 16 is characterized by differential scanning calorimetry analysis exhibiting a single endothermic peak at 147° C. In some embodiments, Form A of Compound 16 is characterized by a DSC thermogram substantially similar to FIG.

[0182] In some embodiments, Form A of Compound 16 is characterized by solid-state NMR. In some embodiments, Form A of Compound 16 is characterized by a C SSNMR spectrum comprising one or more signals selected from 153.5±0.2 ppm, 151.5±0.2 ppm, 126.9±0.2 ppm, 125.1±0.2 ppm, 123.9±0.2 ppm, 122.1±0.2 ppm, 73.6±0.2 ppm, 49.9±0.2 ppm, 47.2±0.2 ppm, 37.2±0.2 ppm, and 23.0±0.2 ppm. In some embodiments, Form A of compound 16 is characterized by a 13C SSNMR spectrum comprising two or more signals selected from 153.5±0.2 ppm, 151.5±0.2 ppm, 126.9±0.2 ppm, 125.1±0.2 ppm, 123.9±0.2 ppm, 122.1±0.2 ppm, 73.6±0.2 ppm, 49.9±0.2 ppm, 47.2±0.2 ppm, 37.2±0.2 ppm, and 23.0±0.2 ppm. In some embodiments, Form A of compound 16 is characterized by a 13C SSNMR spectrum comprising three or more signals selected from 153.5±0.2 ppm, 151.5±0.2 ppm, 126.9±0.2 ppm, 125.1±0.2 ppm, 123.9±0.2 ppm, 122.1±0.2 ppm, 73.6±0.2 ppm, 49.9±0.2 ppm, 47.2±0.2 ppm, 37.2±0.2 ppm, and 23.0±0.2 ppm. In some embodiments, Form A of compound 16 is characterized by a C SSNMR spectrum comprising four or more signals selected from 153.5±0.2 ppm, 151.5±0.2 ppm, 126.9±0.2 ppm, 125.1±0.2 ppm, 123.9±0.2 ppm, 122.1±0.2 ppm, 73.6±0.2 ppm, 49.9±0.2 ppm, 47.2±0.2 ppm, 37.2±0.2 ppm, and 23.0±0.2 ppm.In some embodiments, Form A of compound 16 is characterized by a C SSNMR spectrum comprising five or more signals selected from 153.5±0.2 ppm, 151.5±0.2 ppm, 125.9±0.2 ppm, 126.1±0.2 ppm, 123.9±0.2 ppm, 122.1±0.2 ppm, 73.6±0.2 ppm, 49.9±0.2 ppm, 47.2±0.2 ppm, 37.2±0.2 ppm, and 23.0±0.2 ppm. In some embodiments, Form A of compound 16 is characterized by a C SSNMR spectrum containing six or more signals selected from 153.5±0.2 ppm, 151.5±0.2 ppm, 125.9±0.2 ppm, 126.1±0.2 ppm, 123.9±0.2 ppm, 122.1±0.2 ppm, 73.6±0.2 ppm, 49.9±0.2 ppm, 47.2±0.2 ppm, 37.2±0.2 ppm, and 23.0±0.2 ppm.

[0183] In some embodiments, Form A of compound 16 is characterized by a 13C NMR spectrum substantially similar to FIG.

[0184] In some embodiments, Form A of compound 16 is characterized by a 19F SSNMR spectrum comprising a signal at -58.0±0.2 ppm.

[0185] In some embodiments, Form A of compound 16 is characterized by a unit cell having an orthorhombic crystal system, a P212121 space group, and dimensions measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å). [Table 5]

[0186] In some embodiments, Form A of compound 16 is characterized by a unit cell having an orthorhombic crystal system, a P212121 space group, and dimensions measured at 298 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å). [Table 6]

[0187] Another embodiment of the present disclosure provides a method for making crystalline Compound 16 Form A by crystallizing Compound 16 in MTBE, filtering the crystallized compound, and drying under vacuum at 60° C. overnight to obtain Compound 16 Form A.

[0188] 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 formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: X is a bond (i.e., X is absent) or is selected from -(CH)-, and -(CH)SO-; Ring A is selected from C6 cycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl groups; R1 is independently selected for each occurrence from halogen, -ORc, =O, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, -C(=O)N(Rc)2, -S-(cyclopropyl), and -SO2(Rc) groups; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R1 4-6 membered heterocyclyl contains one heteroatom selected from nitrogen and oxygen; The C1-C6 alkyl of R1 is optionally substituted with 1 to 6 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 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; or two R1 groups, together with the ring A atom connecting them, form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring; Each of the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 groups selected from halogen, —OH, and C1-C4 alkyl; 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, 5-10 membered heterocyclyl, C6 aryl, and 5-10 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 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); Each of the C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra is 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; 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, 5-10 membered heterocyclyl, and C3-C6 carbocyclyl; Any one of Rk's C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and -OH groups; Rm is independently selected for each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 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; R4 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)nC(=O)NRnRo, -NRnRo, -NRoC(=O)Rp, -NRnS(=O)pRp, -(CH2)nORp, -S(=O)pRp, -S(=O)pNRnRo, -OS(=O)pNRnRo, and -(CH2)nC(=O)ORp groups, wherein Rn and Ro are each independently selected for each occurrence from hydrogen and a C1-C4 alkyl group; Rp, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R5 is selected from hydrogen and C1-C6 alkyl; m is an integer selected from 0, 1, 2, 3, 4, and 5; n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; and q and r are, for each occurrence, integers independently selected from 1, 2, 3, and 4; a compound, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing. 1a. A compound represented by the following structural formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from C6 aryl, and 5- and 6-membered heteroaryl groups; R1 is, for each occurrence, independently selected from halogen, -OH, =O, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, -C(=O)N(Rc)2, and -SO2(Rc) groups; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R1 4-6 membered heterocyclyl 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 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; or two R1 groups, together with the ring A atom connecting them, form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring; The 5-6 membered cycloalkyl, 5-8 membered heterocyclyl, 5-6 membered aryl, and 5-6 membered heteroaryl are each optionally substituted with 1-4 groups selected from halogen, -OH, and C1-C4 alkyl, and R2 is selected from 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, 5-10 membered heterocyclyl, C6 aryl, and 5-10 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 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); Each of the C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra is 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; 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, 5-10 membered heterocyclyl, and C3-C6 carbocyclyl; Any one of Rk's C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and -OH groups; Rm is independently selected for each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 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; R4 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)nC(=O)NRnRo, -NRnRo, -NRoC(=O)Rp, -NRnS(=O)pRp, -(CH2)nORp, -S(=O)pRp, -S(=O)pNRnRo, -OS(=O)pNRnRo, and -(CH2)nC(=O)ORp groups, wherein Rn and Ro are each independently selected for each occurrence from hydrogen and a C1-C4 alkyl group; Rp, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; R5 is selected from hydrogen and C1-C6 alkyl; m is an integer selected from 0, 1, 2, 3, 4, and 5; n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; and q and r are, for each occurrence, integers independently selected from 1, 2, 3, and 4; a compound, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing. 1b. A compound represented by the following structural formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from C6 aryl, and 5- and 6-membered heteroaryl groups; R1 is, for each occurrence, independently selected from halogen, -OH, =O, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, -C(=O)N(Rc)2, and -SO2(Rc) groups; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R1 4-6 membered heterocyclyl 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 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; or two R1 groups, together with the ring A atom connecting them, form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring; Each of the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 groups selected from halogen, —OH, and C1-C4 alkyl; 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, 5-10 membered heterocyclyl, C6 aryl, and 5-10 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 halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkenyl, independently selected from C1-C6 haloalkoxy, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk, -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); Each of the C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra is 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; 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, 5-10 membered heterocyclyl, and C3-C6 carbocyclyl; Any one of Rk's C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and -OH groups; Rm is independently selected for each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 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; R4 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)nC(=O)NRnRo, -NRnRo, -NRoC(=O)Rp, -NRnS(=O)pRp, -(CH2)nORp, -S(=O)pRp, -S(=O)pNRnRo, -OS(=O)pNRnRo, and -(CH2)nC(=O)ORp groups, wherein Rn and Ro are each independently selected for each occurrence from hydrogen and a C1-C4 alkyl group; Rp, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; m is an integer selected from 0, 1, 2, 3, 4, and 5; n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; and q and r are, for each occurrence, integers independently selected from 1, 2, 3, and 4; a compound, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing. 1c. A compound represented by the following structural formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from C6 aryl, and 5- and 6-membered heteroaryl groups; R1, for each occurrence, is independently selected from halogen, -OH, =O, cyano, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, and -C(=O)N(Rc)2 groups; Rc, for each occurrence, is independently selected from hydrogen and a C1-C4 alkyl group; R1 4-6 membered heterocyclyl 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 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; 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, 5-10 membered heterocyclyl, C6 aryl, and 5-10 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 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); Each of the C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra is 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; 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, 5-10 membered heterocyclyl, and C3-C6 carbocyclyl; Any one of Rk's C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and -OH groups; Rm is independently selected for each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 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; R4 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)nC(=O)NRnRo, -NRnRo, -NRoC(=O)Rp, -NRnS(=O)pRp, -(CH2)nORp, -S(=O)pRp, -S(=O)pNRnRo, -OS(=O)pNRnRo, and -(CH2)nC(=O)ORp groups, wherein Rn and Ro are each independently selected for each occurrence from hydrogen and a C1-C4 alkyl group; Rp, for each occurrence, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; m is an integer selected from 0, 1, 2, 3, 4, and 5; n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; and q and r are, for each occurrence, integers independently selected from 1, 2, 3, and 4; a compound, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing. 2. A compound represented by the following structural formula: [ka] A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of the foregoing, wherein R1, R2, R3, R4, Ring A, and m are defined as described in any one of embodiments 1-1b. 3. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1-2, wherein R4 is -OH, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-2. 4. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-3, wherein R3 is selected from a C1-C4 alkyl group, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-3. 5. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1-4, wherein R3 is -CH3, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-4. 6. 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; The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-5, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-5. 7. R2 is -CH3 and [ka] is selected from the group The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-6, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-6. 8. The compound has the following structural formula: [ka] is represented by one of The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any of the foregoing, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-7. 9. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 8, wherein ring B is selected from cyclopropyl, 5-10 membered heterocyclyl, phenyl, and 5-9 membered heteroaryl groups, 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 1-8. 10. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 8, wherein ring B is selected from cyclopropyl, 5-10 membered heterocyclyl containing 1-3 heteroatoms selected from N and O, phenyl, and 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 1-8. 11. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of embodiment 8, wherein ring B is selected from cyclopropyl, a 5-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, a 6-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, a 9-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, a 10-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, a 5-membered heteroaryl containing 1-3 heteroatoms selected from N and O, a 6-membered heteroaryl containing 1-3 heteroatoms selected from N and O, a 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 1-8. 12. Ring B is [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-8. 13. Ring B is [ka] [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-8. 14. Ring B is optionally substituted with one Ra group. [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-8. 15. 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, 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 of 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 pharma- ceutically acceptable salt of any one of embodiments 1-14, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-14. 16. 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, 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 of 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 pharma- ceutically acceptable salt of any one of embodiments 1-15, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-15. 17. 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, 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 of R1 is optionally substituted with 1 to 3 independently selected halogen groups; The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-16, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-16. 18. R1 is, for each occurrence, 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 pharma- ceutically acceptable salt of any one of embodiments 1-17, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-17. 18a. R1, for each occurrence, is independently selected from a -SO2(Rc) group, and Rc is independently selected from a C1-C4 alkyl group; The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-14, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-14. 18b. R1, for each occurrence, is independently selected from a -SO2(Rc) group, and Rc is independently selected from a C1 alkyl group; The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-14, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-14. 18c. two R1 groups, together with the ring A atom connecting them, form a 5-6 membered cycloalkyl, 5-8 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl ring; Each of the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl is optionally substituted with 1 to 4 groups selected from halogen, —OH, and C1-C4 alkyl; The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1, 1a-1, 1a-2, and 2-14, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-14. 18d. Two R1 groups, together with the ring A atom connecting them, [ka] forming a group selected from The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-14, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-14. 19. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-18, wherein m is 1, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-18. 20. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-18, wherein m is 2, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-18. 21. Ra is, for each occurrence, 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, 5-10 membered heterocyclyl, phenyl, and 5-8 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, 5-10 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl of Ra is optionally substituted with 1-3 groups independently selected from halogen, C1-C2 alkyl, and -ORk groups; Rh, Ri, and Rj are each independently selected for each occurrence 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 pharma- ceutically acceptable salt of any one of embodiments 1-20, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-20. 22. Ra is, for each occurrence, 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)2Rk, -NRhRi, -ORk, cyclopropyl, and cyclobutyl groups; Each of the cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl of Ra is optionally substituted with 1-3 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 independently selected for each occurrence 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 pharma- ceutically acceptable salt of any one of embodiments 1-21, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-21. 23. Ra is, for each occurrence, 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; Each of the cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl of Ra is optionally substituted with 1-3 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 is independently selected for each occurrence from hydrogen and -CH3; q and r are each an integer independently selected from 1 and 2; The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-22, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-22. 24. 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, -N A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1-23, wherein each of the compounds is independently selected from HC(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 1-23. 25. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1-24, 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 1-24. 26. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-25, wherein Ring A is selected from phenyl, thiophenyl, and pyridinyl, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-25. 27. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1-26, wherein ring A is phenyl, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1-26. 27a. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of embodiments 1 and 2 to 27, wherein R5 is selected from hydrogen, methyl, and propyl, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 2 to 27. 27b. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1 and 2 to 27a, wherein R5 is hydrogen, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 2 to 27a. 28. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from the compounds of Table 1, their tautomers, deuterated derivatives of those compounds and tautomers, and pharma- ceutically acceptable salts of any of the foregoing. 28a. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from the compounds of Table 2, their tautomers, deuterated derivatives of those compounds and tautomers, and pharma- ceutically acceptable salts of any of the foregoing. 28b. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from the compounds of Table 3, their tautomers, deuterated derivatives of those compounds and tautomers, and pharma- ceutically acceptable salts of any of the foregoing. 29. A pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1-28b, and a pharma- ceutically acceptable carrier. 30. 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 according to any one of embodiments 1 to 28b, or a pharmaceutical composition according to embodiment 29. 31. Use of at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1 to 28b, or a pharmaceutical composition according to embodiment 29, for the manufacture of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 32. At least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1-28b, or a pharmaceutical composition according to embodiment 29, for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 33. A method for inhibiting APOL1 activity, comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1 to 28b, or a pharmaceutical composition according to embodiment 29. 34. Use of at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1 to 28b, or a pharmaceutical composition according to embodiment 29, for the manufacture of a medicament for inhibiting APOL1 activity. 35. At least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1 to 28b, or a pharmaceutical composition according to embodiment 29, for use in inhibiting APOL1 activity. 36. A method for treating an APOL1 mediated disease, comprising administering to a patient in need thereof at least one compound according to any one of embodiments 1 to 28b, or a pharmaceutical composition according to embodiment 29. 37. The method of embodiment 36, wherein the APOL1 mediated disease is cancer. 38. The method of embodiment 36 or 37, wherein the APOL1 mediated disease is pancreatic cancer. 39. Use of at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1 to 28b, or a pharmaceutical composition according to embodiment 29, for the manufacture of a medicament for treating an APOL1 mediated disease. 40. The use according to embodiment 39, wherein the APOL1 mediated disease is cancer. 41. The use according to embodiment 39 or 40, wherein the APOL1 mediated disease is pancreatic cancer. 42. At least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1 to 28b, or a pharmaceutical composition according to embodiment 29, for use in the treatment of an APOL1 mediated disease. 43. At least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt for use according to embodiment 42, wherein the APOL1 mediated disease is cancer. 44. At least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt for use according to embodiment 42 or embodiment 43, wherein the APOL1 mediated disease is pancreatic cancer. 45. A method for inhibiting APOL1 activity, comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1-28b, or a pharmaceutical composition according to embodiment 29. 46. ​​Use of at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1 to 28b, or a pharmaceutical composition according to embodiment 29, for the manufacture of a medicament for inhibiting APOL1 activity. 47. At least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1 to 28b, or a pharmaceutical composition according to embodiment 29, for use in inhibiting APOL1 activity. 48. A silicon derivative of at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1-28b. 49. A pharmaceutical composition comprising the silicon derivative according to embodiment 48. 50. A method for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising administering to a patient in need thereof a silicon derivative according to embodiment 48 or a pharmaceutical composition according to embodiment 49. 51. Use of the silicon derivative according to embodiment 48 or the pharmaceutical composition according to embodiment 49 for the manufacture of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 52. The silicon derivative according to embodiment 48 or the pharmaceutical composition according to embodiment 49 for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 53. A method for treating an APOL1 mediated disease, comprising administering to a patient in need thereof a silicon derivative as defined in embodiment 48 or a pharmaceutical composition as defined in embodiment 49. 54. The method of embodiment 53, wherein the APOL1 mediated disease is cancer. 55. The method of embodiment 53 or 54, wherein the APOL1 mediated disease is pancreatic cancer. 56. Use of a silicon derivative according to embodiment 48 or a pharmaceutical composition according to embodiment 49 for the manufacture of a medicament for the treatment of an APOL1 mediated disease. 57. The use according to embodiment 56, wherein the APOL1 mediated disease is cancer. 58. The use according to embodiment 56 or 57, wherein the APOL1 mediated disease is pancreatic cancer. 59. A silicon derivative according to embodiment 48 or a pharmaceutical composition according to embodiment 49 for use in the treatment of an APOL1 mediated disease. 60. The silicon derivative or pharmaceutical composition for use according to embodiment 59, wherein the APOL1 mediated disease is cancer. 61. The silicon derivative or pharmaceutical composition for use according to embodiment 59 or embodiment 60, wherein the APOL1 mediated disease is pancreatic cancer. 62. A boron derivative of at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1-28b. 63. A pharmaceutical composition comprising the boron derivative according to embodiment 62. 64. A method for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising administering to a patient in need thereof a boron derivative according to embodiment 62, or a pharmaceutical composition according to embodiment 63. 65. Use of the boron derivative according to embodiment 62, or the pharmaceutical composition according to embodiment 63, for the manufacture of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 66. The boron derivative according to embodiment 62, or the pharmaceutical composition according to embodiment 63, for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 67. A method for treating an APOL1 mediated disease, comprising administering to a patient in need thereof a boron derivative as defined in embodiment 62, or a pharmaceutical composition as defined in embodiment 63. 68. The method of embodiment 67, wherein the APOL1 mediated disease is cancer. 69. The method of embodiment 67 or 68, wherein the APOL1 mediated disease is pancreatic cancer. 70. Use of a boron derivative as defined in embodiment 62 or a pharmaceutical composition as defined in embodiment 63 for the manufacture of a medicament for the treatment of an APOL1 mediated disease. 71. The use according to embodiment 70, wherein the APOL1 mediated disease is cancer. 72. The use according to embodiment 70 or 71, wherein the APOL1 mediated disease is pancreatic cancer. 73. A boron derivative according to embodiment 62 or a pharmaceutical composition according to embodiment 63 for use in the treatment of an APOL1 mediated disease. 74. The boron derivative or pharmaceutical composition for use according to embodiment 73, wherein the APOL1 mediated disease is cancer. 75. The boron derivative or pharmaceutical composition for use according to embodiment 73 or embodiment 74, wherein the APOL1 mediated disease is pancreatic cancer. 76. A phosphorus derivative of at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of embodiments 1-28b. 77. A pharmaceutical composition comprising a phosphorus derivative according to embodiment 76. 78. 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 76 or a pharmaceutical composition according to embodiment 77. 79. Use of a phosphorus derivative according to embodiment 76, or a pharmaceutical composition according to embodiment 77, for the manufacture of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 80. A phosphorus derivative according to embodiment 76 or a pharmaceutical composition according to embodiment 77 for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 81. A method for treating an APOL1 mediated disease, comprising administering to a patient in need thereof a phosphorus derivative according to embodiment 76 or a pharmaceutical composition according to embodiment 77. 82. The method of embodiment 81, wherein the APOL1 mediated disease is cancer. 83. The method of embodiment 81 or 82, wherein the APOL1 mediated disease is pancreatic cancer. 84. Use of a phosphorus derivative according to embodiment 76 or a pharmaceutical composition according to embodiment 77 for the manufacture of a medicament for treating an APOL1 mediated disease. 85. The use according to embodiment 84, wherein the APOL1 mediated disease is cancer. 86. The use according to embodiment 84 or 85, wherein the APOL1 mediated disease is pancreatic cancer. 87. A phosphorus derivative according to embodiment 76 or a pharmaceutical composition according to embodiment 77 for use in the treatment of an APOL1 mediated disease. 88. The phosphorus derivative or pharmaceutical composition for use according to embodiment 87, wherein the APOL1 mediated disease is cancer. 89. The phosphorus derivative or pharmaceutical composition for use according to embodiment 87 or embodiment 88, wherein the APOL1 mediated disease is pancreatic cancer. 90. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to embodiment 1, wherein the variable X is a bond (i.e., X is absent). 91. A compound represented by the following formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: R1a and R1b are independently selected from halogen, H, C1-C4 alkyl, and C1-C4 haloalkyl groups; R1c is selected from halogen, H, CH3, -OH, and CH3OH; 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, 5-10 membered heterocyclyl, C6 aryl, and 5-10 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 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); Each of the C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C10 aryl, and 5- to 10-membered heteroaryl of Ra is 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; 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, 5-10 membered heterocyclyl, and C3-C6 carbocyclyl; Any one of Rk's C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and -OH groups; Rm is independently selected for each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S(=O)pRk, and -ORk groups; A compound, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein 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. 92. A compound represented by the following formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein: R1a and R1b are independently selected from halogen, H, C1-C4 alkyl, and C1-C4 haloalkyl groups; A compound, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, wherein R1c is selected from halogen, H, CH3, -OH, and CH3OH. 93. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to embodiment 91 or embodiment 92. 94. A method for treating an APOL1 mediated disease, comprising administering to a patient in need thereof a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to embodiment 91 or embodiment 92, or a pharmaceutical composition according to embodiment 93. 95. The method of embodiment 94, wherein the APOL1 mediated disease is cancer. 96. The method of embodiment 94 or 95, wherein the APOL1 mediated disease is pancreatic cancer. 97. A method for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising administering to a patient in need thereof a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to embodiment 91 or embodiment 92, or a pharmaceutical composition according to embodiment 93. 98. Use of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to embodiment 91 or embodiment 92, or a pharmaceutical composition according to embodiment 93, for the manufacture of a medicament for treating an APOL1-mediated disease. 99. The use according to embodiment 98, wherein the APOL1 mediated disease is cancer. 100. The use according to embodiment 98 or 99, wherein the APOL1 mediated disease is pancreatic cancer. 101. Use of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to embodiment 91 or embodiment 92, or a pharmaceutical composition according to embodiment 93, for the manufacture of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 102. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to embodiment 91 or embodiment 92, or a pharmaceutical composition according to embodiment 93, for use in the treatment of an APOL1 mediated disease. 103. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to embodiment 91 or embodiment 92, or a pharmaceutical composition according to embodiment 93, for use in the treatment of APOL1-mediated cancer. 104. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to embodiment 91 or embodiment 92, or a pharmaceutical composition according to embodiment 93, for use in the treatment of APOL1-mediated pancreatic cancer. 105. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to embodiment 91 or embodiment 92, or a pharmaceutical composition according to embodiment 93, for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. EXAMPLES

[0189] In order that the disclosure set forth herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only, and should not be construed as limiting the disclosure in any manner.

[0190] The compounds of the present invention can be made according to standard chemical practices or as described herein. Throughout the following synthetic schemes and in the description of preparing compounds of formula I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a, and II-6b, compounds 1-29, compounds I5-I295, compounds 30-44, and compounds 45-68, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of any of the foregoing, the following abbreviations are used: Abbreviation AIBN = azobisisobutyronitrile ARP = Assay Ready Plates 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'-Dimethylpropyleneurea 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-butyl lithium 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 Pd2dba3 = Tris(dibenzylideneacetone)dipalladium PP = Polypropylene psig=pounds per square inch gauge PTSA = p-toluenesulfonic acid monohydrate rt=room temperature SFC = Supercritical Fluid Chromatography 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 TBME = methyl tert-butyl ether 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

[0191] Example 1. Synthesis of Compounds All specific and generic compounds, as well as intermediates disclosed for making those compounds, are considered to be part of the disclosure disclosed herein.

[0192] Synthesis of starting materials In the preparation, synthetic routes to intermediates used in the synthesis of compounds 1-29, compounds I5-I295, compound I296, compounds 30-44, and compounds 45-68 are described.

[0193] General scheme In some embodiments, the process for preparing a compound of formula I includes the reactions depicted in Schemes 1-10. In the following schemes, A is CH or N, and R1, R2, and R3 are as defined above.

[0194] Scheme 1 shows a process for preparing a compound of formula 1-2 from piperidinone S1. Piperidinone S1 can be optionally substituted with a protecting group reagent, such as allyl bromide, to provide a protected piperidinone, represented by S2. A suitable aryl halide is treated with hexyllithium in a solvent, such as THF, which is then combined with S2 to form a compound represented by formula 1-1. The allyl group is subsequently deprotected to provide a compound represented by formula 1-2. Scheme 1 Representative scheme using n-hexyllithium to form aryllithium 0 nucleophiles for 1,2-addition [ka]

[0195] Scheme 2 shows an alternative process for preparing compounds of formula 2-2 from protected piperidinone S2. A suitable aryl halide is treated with t-butyllithium in a solvent such as THF, which is then combined with S2 to form a compound of formula 2-1. The allyl group is subsequently deprotected to give compounds of formula 2-2. Scheme 2 Representative scheme using tert-butyllithium to form aryllithium nucleophiles for 1,2-addition [ka]

[0196] Scheme 3 shows an alternative process for preparing compounds of formula 3-2 from protected piperidinone S2. A suitable aryl halide is treated with n-butyllithium in a solvent such as THF, which is then combined with S2 to form a compound of formula 3-1. The allyl group is subsequently deprotected to give compounds of formula 3-2. Scheme 3 Representative scheme using n-butyllithium to form aryllithium nucleophiles for 1,2-addition [ka]

[0197] Scheme 4 shows an alternative process for preparing compounds of formula 4-2 from protected piperidinone S2. A suitable aryl halide is treated with s-butyllithium in a solvent such as THF, which is then combined with S2 to form compounds of formula 4-1. The allyl group is subsequently deprotected to give compounds of formula 4-2. Scheme 4 Representative scheme for forming aryllithium nucleophiles for 1,2-addition using sec-butyllithium [ka]

[0198] Scheme 5 shows an alternative process for preparing compounds of formula 5-2 from protected piperidinone S2. A suitable aryl aryl ethylate reagent in a solvent such as THF is combined with S2 to form compounds of formula 5-1. The allyl group is subsequently deprotected to give compounds of formula 5-2. Scheme 5 Representative scheme of 1,2-addition to aryllithium nucleophiles using phenyllithium [ka]

[0199] Scheme 6 shows an alternative process for preparing compounds of formula 6-2 from protected piperidinone S2. In some embodiments, an appropriate aryl Grignard reagent (ArMgX), prepared by treatment of an appropriate aryl halide with magnesium in a solvent such as THF, is then combined with S2 to form a compound of formula 6-1. The allyl group is subsequently deprotected to give compounds of formula 6-2. Scheme 6 Representative scheme for 1,2-addition using arylmagnesium bromide nucleophiles [ka]

[0200] Scheme 7 shows an alternative process for the preparation of compounds of formula 7-2 from protected piperidinone S2. A suitable aryl halide can be treated with iPrMgCl-LiCl in a solvent such as THF and then combined with S2 to form compounds of formula 7-1, followed by deprotection of the allyl group to provide compounds of formula 7-2. Scheme 7 Representative scheme for the generation and addition of arylmagnesium halide nucleophiles [ka]

[0201] Scheme 8 shows an alternative process for preparing compounds of formula 8-2 from protected piperidinone S2. In some embodiments, the appropriate aryl Grignard reagent (ArMgX), prepared by treatment of an appropriate aryl halide with magnesium in a solvent such as THF, is then combined with LaCl3-2LiCl and S2 to form compounds of formula 8-1. The allyl group is subsequently deprotected to give compounds of formula 8-2. Scheme 8 Representative scheme using arylmagnesium halide Grignard reagents with LaCl3-2LiCl as nucleophile [ka]

[0202] Scheme 8a shows an alternative process for preparing a compound of formula 16 from a piperidinone of formula S1. Note that this chemical reaction proceeds without an N-protecting group. In some embodiments, a suitable aryl Grignard reagent (ArMgX), prepared by treatment of a suitable aryl halide with magnesium in a solvent such as THF or 2-MeTHF, is then combined with S1 to form a compound represented by formula 16. Scheme 8a Representative scheme for the generation and addition of arylmagnesium halide nucleophiles [ka]

[0203] Scheme 9 shows an alternative process for preparing a compound of formula 9-6 from an N-protected beta amino acid of formula 9-1. PG4 can be Boc or any suitable nitrogen protecting group. The dimagnesium salt of compound 9-2 can be coupled to a compound of formula 9-1 using a reagent such as CDI in a solvent such as THF. Condensation of a compound of formula 9-3 with an aldehyde of formula 9-4 gives a compound of formula 9-5. In some embodiments, the reaction can be carried out by treating a compound of formula 9-3 with an acid such as TFA in a solvent such as dichloromethane, followed by addition of an aldehyde of formula 9-4. A compound of formula 9-6 can be prepared from a compound of formula 9-5 by treatment with an acid such as methanesulfonic acid in a solvent such as dichloromethane. The reaction can be carried out in the presence of heat (e.g., reflux conditions). Scheme 9 Representative scheme for the synthesis of 2,6-disubstituted piperidinones [ka]

[0204] Scheme 10 shows a process for preparing compounds of formula 10-3 from piperidinone 9-6. Piperidinone 9-6 can be optionally substituted with a protecting group reagent, such as allyl bromide, to provide protected piperidinones of formula 10-1. A suitable aryl halide, such as 1-iodo-4-(trifluoromethyl)benzene, is treated with hexyllithium in a solvent, such as THF, which is then combined with formula 10-1 to form compounds of formula 10-2. The allyl group is subsequently deprotected to provide compounds of formula 10-3. Scheme 10 General scheme for allyl protection, 1,2-addition, and deprotection [ka] Preparation S1 (2S,6S)-1-Allyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-4-one (S1) [ka]

[0205] Step 1. Synthesis of bis[(3-tert-butoxy-3-oxo-propanoyl)oxy]magnesium (C2) A solution of 3-tert-butoxy-3-oxo-propanoic acid (C1) (321.51 g, 1.907 mol) in THF (2 L) was cooled to 5° C. in an ice bath and Mg(OEt)2 (111.33 g, 953.5 mmol) was added. The reaction was stirred at 0° C. for 30 min, the cooling bath was removed and 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 damp solid. The solid was triturated with 1 L of diethyl ether and filtered. The filter cake was washed with Et2O and dried under vacuum. The filtrate was evaporated again under vacuum and then triturated with a small amount of Et2O and filtered to give a second crop of product. The crops were combined and dried in vacuo to give the title compound C2 (294.49 g, 90%) as a white solid. 1H NMR (300 MHz, Methanol-d4) δ 4.92 (s, 4H), 1.48 (s, 18H).

[0206] Step 2. Synthesis of (5S)-tert-butyl 5-(tert-butoxycarbonylamino)-3-oxo-hexanoate (C4) To a solution of (3S)-3-(tert-butoxycarbonylamino)butanoic acid (C3) (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 h. Bis[(3-tert-butoxy-3-oxo-propanoyl)oxy]magnesium (C2) (172.19 g, 502.6 mmol) was added. Another milky suspension formed and after stirring for 30 min cleared. The reaction was stirred for 48 h. The reaction was poured into 1.5 L of 1 M HCl and extracted with MTBE (1 L). The pH was confirmed to be approximately 3. The extract was washed with saturated NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound C4 (248.5 g, 99%) as a clear oil. 1H 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).

[0207] Step 3. Synthesis of tert-butyl (2S,3R,6S)-6-methyl-2-(1-methyltriazol-4-yl)-4-oxo-piperidine-3-carboxylate (C6) To a solution of (5S)-tert-butyl 5-(tert-butoxycarbonylamino)-3-oxo-hexanoate (C4) (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 6M 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 under vacuum to give a solid which was triturated with MTBE (500 mL) and filtered. The filter cake was washed with MTBE and dried under vacuum to give a 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 C6 (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).

[0208] Step 4. Synthesis of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S1) To a solution of (2S,3R,6S)-tert-butyl 6-methyl-2-(1-methyltriazol-4-yl)-4-oxo-piperidine-3-carboxylate (C6) (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 h. The reaction was cooled to room temperature and then poured into a separatory funnel. Brine (100 mL) was added, followed by 6M NaOH after shaking until the aqueous layer remained alkaline. The organic layer was separated and the aqueous layer was extracted with DCM (2x500 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo to give the title compound S1 (43.74 g, 94%) as an off-white 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).

[0209] Step 5. (2S,6S)-1-allyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-4-one (S2) To a suspension of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S1) (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 about 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 precipitation 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 S2 (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). Preparation S3 2-Methyl-6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)piperidin-4-one (S3) [ka]

[0210] Step 1. Synthesis of (3S)-3-(tert-butoxycarbonylamino)butanoic acid (C8) To a solution of (3S)-3-aminobutanoic acid (C7) (100 g, 969.7 mmol) in dioxane (600 mL) was added aqueous NaOH (950 mL of 1 M, 950.0 mmol) over 15 min, followed by Boc2O (300 g, 1.375 mol). The reaction mixture was stirred at room temperature for 12 h. 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 1 M HCl until pH = 2 and extracted with DCM (3 x 600 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound C8 (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).

[0211] Step 2. Synthesis of tert-butyl N-[(1S)-3-[methoxy(methyl)amino]-1-methyl-3-oxo-propyl]carbamate (C9) To a solution of (3S)-3-(tert-butoxycarbonylamino)butanoic acid (C8) (160 g, 787.3 mmol) in DCM (1.5 L) was added N-methoxymethanamine (hydrochloride salt) (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 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. and 1 M aqueous NaOH (700 mL) was added. 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 C9 (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).

[0212] Step 3. Synthesis of tert-butyl N-[(1S)-1-methyl-3-oxo-butyl]carbamate (C10) To a solution of tert-butyl N-[(1S)-3-[methoxy(methyl)amino]-1-methyl-3-oxo-propyl]carbamate (C9) (220 g, 893.2 mmol) in THF (4 L) at 0 °C was added iodo(methyl)magnesium (900 mL of 3 M, 2.7 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 under vacuum. Purification by silica gel chromatography (gradient: 0-70% EtOAc in heptane) afforded the title compound C10 (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).

[0213] Step 4. Synthesis of (4S)-4-aminopentan-2-one (hydrochloride) (S11) To a solution of tert-butyl N-[(1S)-1-methyl-3-oxo-butyl]carbamate (C10) (16.3 g, 80.2 mmol) in MeOH (30 mL) was added hydrogen chloride (50 mL of 4 M in dioxane, 200.0 mmol) over 3 min. The reaction was stirred at room temperature for 5 h and then concentrated under reduced pressure. The residue was coevaporated with EtOH (2×30 mL) and dried under vacuum to give the title compound C11 (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).

[0214] 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 salt) C11 (580 mg, 4.088 mmol) in EtOH (13 mL) was added 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). The reaction mixture was stirred at room temperature overnight. TLC indicated an incomplete reaction so additional 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (C12) (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 was purified by silica gel chromatography (0-60% of 20% MeOH / DCM in DCM) to give the title compound S3 (500 mg, 38%) as an orange oil in a 7:1 cis / trans ratio. Additionally, the enantiomeric ratio at the stereocenter from C11 was compromised to about 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).

[0215] compound 1 (2S,6R)-4-(3-chlorophenyl)-2,6-dimethyl-piperidin-4-ol) (1) [ka] A solution of bromo-(3-chlorophenyl)magnesium (3.2 mL of 0.5 M, 1.60 mmol) in THF was diluted with THF (4.8 mL) and then cooled to 0° C. To this solution was added (2S,6R)-2,6-dimethylpiperidin-4-one (C13) (100 mg, 0.786 mmol) as a solution in THF (2 mL) and the reaction was stirred at 0° C. for 1 h, then warmed to room temperature and stirred for 3 h. At this point, the mixture was quenched with water (5 mL) and diluted with DCM (5 mL). The aqueous layer was further extracted with DCM (3×5 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. The crude residue was purified by silica gel chromatography (gradient: 0-20% MeOH in DCM) to afford the title compound 1 as a ca. 3:1 mixture of diastereomers. The oil was then re-purified by silica gel chromatography (gradient: 0-20% MeOH in DCM) to give the purified title compound 1 (60.5 mg, 30%) as a yellow solid. 1H NMR (300 MHz, Chloroform-d) δ 7.70-7.14 (m, 4H), 3.22 (ddd, J=11.2, 6.1, 2.3 Hz, 2H), 1.80-1.68 (m, 2H), 1.64-1.48 (m, 2H), 1.13 (d, J=6.4 Hz, 6H). ESI-MS m / z calculated 239.1077, found 240.09 (M+H)+.

[0216] compound 2 4-(3-chlorophenyl)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]piperidin-4-ol (2) [ka] Compound 2 was prepared from compound S3 following the method described for compound 1. The reaction was purified by silica gel chromatography (gradient: 0-20% MeOH in DCM) followed by reverse-phase HPLC (method: Waters XSelect CSH C18 OBD preparative column; 30×150 mm, 5 micron. Gradient: acetonitrile in water with 0.1% trifluoroacetic acid) to give the title compound 2 (2.0 mg, 2%) as a yellow solid. 1H NMR (300 MHz, Methanol-d4) δ 7.74 (s, 1H), 7.62 (s, 1H), 7.56 (t, J=2.0 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.50-7.13 (m, 2H), 4.60 (t, J=6.5 Hz, 2H), 4.32 (dd, J=11.4, 3.4 Hz ,1H),3.67(t,J=6.5Hz,2H),3.47-3.34(m,1H),2.73(s,3H),2.07-1.86(m,2H),1.8 4-1.59(m,2H),1.19(d,J=6.4Hz,3H).ESI-MSm / z calculated value 397.12268, actual value 398.26(M+H)+.

[0217] compound 3 (2S,4R,6S)-4-(3-chlorophenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol) (3) [ka] Compound 3 was prepared from compound S1 according to the method described for compound 1. The reaction mixture was purified by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD Prep column; 30×150 mm, 5 microns. Gradient: acetonitrile in water with 10 mM ammonium hydroxide) to give the title compound 3 (2 mg, 1%) as a yellow solid. 1H NMR(300MHz,Methanol-d4)δ7.85(s,1H),7.62-7.50(m,2H),7.46-7.28(m,2H),4.10(s,3H),3.84(dd,J=12.3,2.4Hz,1H),2.85-2.73(m,2H),2. 55(dt,J=13.4,2.5Hz,1H),1.98-1.84(m,1H),1.60(dd,J=13.4,11.8Hz,1H),1.19(d,J=6.3Hz,3H).ESI-MSm / z calculated value 306.12473, measured value 307.32(M+H)+.

[0218] compound 4 (2S,4S,6S)-4-(4-chlorophenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (4) [ka] To a mixture of compound S2 (100 mg, 0.4268 mmol) in THF (2 mL) was added a solution of bromo-(4-chlorophenyl)magnesium (1 mL of 1 M, 1.000 mmol) in diethyl ether at −20° C. (1:15). After addition, a UPLC was obtained which indicated complete conversion. The mixture was quenched with saturated aqueous ammonium chloride solution and then warmed to room temperature. The suspension was diluted with water (1 mL) and ethyl acetate (4 mL). The aqueous layer was washed with additional ethyl acetate (2×2 mL) and the combined organic layers were passed through a phase separator, concentrated, diluted to a minimum in DCM, and loaded onto a silica gel column for purification (gradient: 0-10% MeOH in DCM) to give the intermediate.

[0219] In an inert glovebox, to a mixture of Pd2(dba)3 (4 mg, 0.004368 mmol) and dppb (5 mg, 0.01172 mmol) in THF (0.5 mL) was added 2-sulfanylbenzoic acid (30 mg, 0.1946 mmol). The mixture was stirred under argon for 10 minutes (9:30). At this point, to the mixture was added the intermediate (60 mg, 0.1730 mmol) in THF (1 mL) and the reaction was stirred at room temperature for 20 minutes. At this point, the reaction was diluted with TBME (6 mL) and 1 M HCl (5 mL). The layers were mixed, the organic layer was removed and extracted with 1 M HCl (5 mL). The organic layer was removed and the combined aqueous layers were filtered through a 0.45 micron filter, washed with additional TBME (5 mL) and the pH was adjusted to pH 11 with a combination of saturated aqueous sodium bicarbonate and 6 M NaOH. The cloudy mixture was then extracted with DCM (3×5 mL) and the combined organic layers were passed through a phase separator and concentrated to give the title compound 4 (37.5 mg, 65%) as a pale yellow oil. 1H NMR(300MHz,Chloroform-d)δ7.50-7.43(m,2H),7.41(s,1H),7.32-7.26(m,2H ),4.51(dd,J=9.6,4.8Hz,1H),4.03(s,3H),3.79-3.68(m,1H),3.38(dtd,J=12 .6,6.3,2.7Hz,1H),2.07-1.92(m,2H),1.88-1.75(m,2H),1.59(dd,J=13.6,11 .2Hz,1H),1.14(d,J=6.3Hz,3H).ESI-MSm / z calculated value 306.12473, actual value 307.15(M+H)+.

[0220] compound 5 (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-4-(p-tolyl)piperidin-4-ol (5) [ka] Compound S2 (20 mg, 0.08536 mmol) was diluted with a solution of chlorolithium in THF, trichlorolanthanum (145 μL of 0.6 M, 0.0870 mmol) and cooled to −20 °C. At this point, bromo(p-tolyl)magnesium (200 μL of 1 M, 0.200 mmol) was added at −20 °C (1:15). After the addition, a UPLC was obtained which indicated complete conversion. The mixture was quenched with saturated aqueous ammonium chloride solution (2 mL) and ethyl acetate (2 mL) and then allowed to warm to room temperature. The aqueous layer was extracted with additional ethyl acetate (2 × 2 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was used in the next step without further purification.

[0221] The crude mixture was diluted with THF (0.2 mL) and 2-sulfanylbenzoic acid (14 mg, 0.09080 mmol) was added. Inside an inert glovebox, a solution of dppb (2 mg, 0.004690 mmol) and Pd2(dba)3 (2 mg, 0.002184 mmol) in THF (0.2 mL) was prepared and after 5 min of mixing, the light brown mixture was added to the intermediate mixture and the formed solution was stirred for 5 min. At this point, the reaction was diluted with ethyl acetate (1 mL) and 1 M TFA (2 × 0.75 mL). The aqueous layers were combined and purified by reverse phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30 × 150 mm, 5 micron. Gradient: 5 to 98% acetonitrile in water with 0.1% trifluoroacetic acid). The title compound 5 (8.3 mg, 24%) was isolated as a clear amorphous solid. 1H NMR (400MHz, DMSO-d6) δ9.27(s, 1H), 8.89(s, 1H), 8.24(s, 1H), 7.38(d, J=8.0Hz, 2H), 7.19(d, J=7.9Hz, 2H), 5.65(s, 1H), 4.79(d, J=10.9 Hz, 1H), 4.09(s, 3H), 3.72(s, 1H), 2.40(t, J=13.3Hz, 1H), 2.29(s, 3H), 2.07(d, J=13.9Hz, 1H), 2.03-1.85(m, 2H), 1.28(d, J=6.5Hz, 3H).

[0222] ESI-MS m / z calculated 286.17935, found 287.36 (M+H)+.

[0223] compound 6 (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-4-(m-tolyl)piperidin-4-ol (6) [ka] Compound 6 was synthesized from compound S2 according to the method described for compound 5 and purified by reverse phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30×150 mm, 5 microns. Gradient: 5-98% acetonitrile in water with 0.1% trifluoroacetic acid) to give the title compound 6 (8.3 mg, 24%) as a white solid. NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.88(s,1H),8.24(s,1H),7.30(d,J=10.4Hz ,3H),7.10(t,J=4.1Hz,1H),5.67(s,1H),4.81(d,J=11.7Hz,1H),4.09(s,3H),3.7 2(s,1H),2.42(t,J=13.4Hz,1H),2.33(s,3H),2.13-2.00(m,1H),1.93(dd,J=27.8 ,13.0Hz,2H),1.29(d,J=6.5Hz,3H).ESI-MSm / z calculated value 286.17935, actual value 287.32(M+H)+.

[0224] compound 7 (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-4-(phenyl)piperidin-4-ol (7) [ka] Compound 7 was synthesized from compound S2 according to the method described for compound 5 and purified by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30 × 150 mm, 5 microns. Gradient: 5 to 98% acetonitrile in water with 0.1% trifluoroacetic acid) to give the title compound 7 (8.9 mg, 25%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.91 (s, 1H), 8.25 (s, 1H), 7.50 (d, J = 7.7 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 7.3 Hz, 1H), 5.72 (s, 1H), 4.82 (s, 1H), 4.09 (s, 3H), 3.74(s,1H),2.43(t,J=13.3Hz,1H),2.09(d,J=14.1Hz,1H),2.05-1.95(m,1H),1.91 (d,J=14.0Hz,1H),1.29(d,J=6.5Hz,3H).ESI-MSm / z calculated value 272.1637, actual value 273.32(M+H)+.

[0225] compound 8 (2S,4S,6S)-4-(4-isopropylphenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (8) [ka] i. To a solution of compound S2 (80 mg, 0.3414 mmol) in THF (0.4 mL), a solution of chlorolithium in THF; lanthanum trichloride (580 μL of 0.6 M, 0.3480 mmol) was added and the mixture was cooled to −20° C. At this point, bromo-(4-isopropylphenyl)magnesium (1.2 mL of 0.5 M, 0.6000 mmol) was added at −20° C. After 10 min, the mixture was quenched with saturated aqueous ammonium chloride (0.1 mL) and then warmed to room temperature. The suspension was diluted with water (2 mL) and EtOAc (2 mL), extracted with EtOAc (2×2 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a crude residue.

[0226] ii. The crude mixture was diluted with THF (0.4 mL) and 2-sulfanylbenzoic acid (56 mg, 0.3632 mmol) was added. In a glove box, a solution of dppb (4 mg, 0.009379 mmol) and Pd2(dba)3 (4 mg, 0.004368 mmol) was prepared and after 30 min of mixing, the light brown mixture was added to the intermediate solution. The mixture was stirred. After 30 min, complete conversion was observed. The mixture was diluted with TBME (5 mL) followed by 1 M HCl (2 x 5 mL). The aqueous layers were removed and combined, then the pH was adjusted with aqueous NaOH (6 M, 1.7 mL) followed by saturated aqueous ammonium chloride to obtain a pH of approximately 9. The mixture was diluted and extracted with TBME (3×10 mL) and the combined organic layers were filtered through a phase separator and concentrated to a crude residue which was purified by reverse phase HPLC (Method: Waters XBridge Prep C8 column, 30×150 mm, 5 micron. Gradient: 5-98% acetonitrile in water with 10 mM ammonium hydroxide) to give the title compound 8 (23 mg, 21%) as a white solid. 1H NMR(400MHz,Chloroform-d)δ7.49-7.38(m,3H),7.23(d,J=8.3Hz,2H),4.53(p,J=7.0Hz,1H),4.05(s,3H),3.47-3.34(m,1H),2.90(hept,J= 6.9Hz,1H),2.11-2.05(m,2H),1.89-1.63(m,3H),1.25(d,J=7.0Hz,6H),1.16(d,J=6.3Hz,3H).ESI-MSm / z calculated value 314.21066, actual value 315.32(M+H)+.

[0227] compound 9 (2S,4S,6S)-4-(3-chloro-4-fluoro-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (9) [ka] i. A mixture of 4-bromo-2-chloro-1-fluoro-benzene (54 mg, 0.258 mmol) was diluted with THF (0.25 mL). To the mixture cooled to -20°C was added Turbo Grignard (200 μL of 1.3 M, 0.260 mmol). The mixture was stirred for 30 minutes (11:00), at which point a solution of compound S2 (20 mg, 0.0854 mmol) in THF (0.25 mL) was added and the reaction was stirred for 45 minutes. At this point, saturated aqueous ammonium chloride was added and the mixture was diluted with ethyl acetate (2 mL) and separated. The aqueous layer was extracted with additional ethyl acetate (2 mL) and the combined organic layers were passed through a phase separator, concentrated, and used directly in the next step.

[0228] ii. A mixture of Pd2(dba)3 (2 mg, 0.00218 mmol) and 4-diphenylphosphanylbutyl(diphenyl)phosphane (2 mg, 0.00469 mmol) in THF (0.25 mL) was stirred at room temperature under argon for 15 min. At this point, a solution of the intermediate from step i, (2S,4S,6S)-1-allyl-4-(3-chloro-4-fluorophenyl)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-4-ol, and 2-sulfanylbenzoic acid (15 mg, 0.0973 mmol) in THF (0.25 mL) was added and the mixture was stirred for 10 min. The reaction was extracted with 1 M HCl (2 x 750 μL) and directly purified by reverse phase HPLC. (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: 5-98% acetonitrile in water with 5 mM hydrochloric acid.) The title compound 9 was isolated as a white solid. (7.6mg, 23%)1H NMR (300MHz, methanol-d4) δ8.08(s, 1H), 7.68(dd, J=7.1, 2.4Hz, 1H), 7.50(ddd, J=8.7, 4.5, 2.4Hz, 1H), 7.27(t, J=8.9Hz, 1H), 4.96(dd, J=12.5 , 3.1Hz, 1H), 4.13(s, 3H), 3.98~3.81(m, 1H), 2.51(dd, J=14.5, 12.5Hz, 1H), 2.23(d, J=14.3Hz, 1H), 2.08~1.97(m, 2H), 1.42(d, J=6.6Hz, 3H). ESI-MS m / z calculated 324.11533, found 325.34 (M+H)+.

[0229] compound 10 (2S,4S,6S)-4-(3-chloro-4-fluoro-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (10) [ka] i. A mixture of 1-bromo-3-chloro-5-fluoro-benzene (67 mg, 0.320 mmol) was diluted with THF (0.25 mL). To the mixture cooled to -20°C was added turbo Grignard (250 μL of 1.3 M, 0.325 mmol) followed by diglyme (50 μL, 0.349 mmol). The mixture was stirred for 30 minutes, at which point a solution of compound S2 (25 mg, 0.107 mmol) in THF (0.25 mL) was added and the reaction was stirred for 45 minutes. At this point, saturated aqueous ammonium chloride was added and the mixture was diluted with ethyl acetate (2 mL) and separated. The aqueous layer was extracted with additional ethyl acetate (2 mL) and the combined organic layers were passed through a phase separator, concentrated, and used directly in the next step.

[0230] ii. A mixture of Pd2(dba)3 (2.5 mg, 0.00273 mmol) and 4-diphenylphosphanylbutyl(diphenyl)phosphane (2.5 mg, 0.00586 mmol) in THF (0.25 mL) was stirred at room temperature under argon for 15 min. At this point, the intermediate and 2-sulfanylbenzoic acid (18 mg, 0.117 mmol) in THF (0.25 mL) were added and the mixture was stirred for 10 min. The reaction was extracted with 1 M HCl (2×750 μL) and purified directly by reverse phase HPLC. (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: acetonitrile in water with 5 mM hydrochloric acid.) The title compound 10 was isolated as a white solid (17 mg, 43%). 1H NMR(300MHz,Methanol-d4)δ8.08(s,1H),7.68(dd,J=7.1,2.4Hz,1H),7.50(ddd,J =8.7,4.5,2.4Hz,1H),7.27(t,J=8.9Hz,1H),4.96(dd,J=12.5,3.1Hz,1H),4.13(s ,3H),3.98-3.81(m,1H),2.51(dd,J=14.5,12.5Hz,1H),2.23(d,J=14.3Hz,1H),2. 08-1.97(m,2H),1.42(d,J=6.6Hz,3H).ESI-MSm / z calculated value 324.781, actual value 325.29(M+H)+.

[0231] compound 11 (2S,4S,6S)-4-(3-fluoro-4-methyl-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (11) [ka] Compound 11 was synthesized from compound S2 following the method described for compound 10. Purification by reverse phase HPLC (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: 5-98% acetonitrile in water with 5 mM hydrochloric acid) afforded the title compound 11 (18.3 mg, 50%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ9.46-9.18(m,2H),8.32(s,1H),7.30(t,J=8.0Hz,1H) ,7.27-7.14(m,2H),5.80(s,1H),4.77(t,J=11.2Hz,1H),4.09(s,3H),3.70(s ,1H),2.46(s,1H),2.22(d,J=1.7Hz,3H),2.08(t,J=13.3Hz,2H),1.88(d,J=1 4.1Hz,1H),1.31(d,J=6.4Hz,3H).ESI-MSm / z calculated value 304.363, actual value 305.34(M+H)+.

[0232] compound 12 (2S,4S,6S)-4-(4-fluoro-3-methyl-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (12) [ka] Compound 12 was synthesized from compound S2 according to the method described for compound 10. Purification by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30×150 mm, 5 microns. Gradient: acetonitrile in water with 5 mM hydrochloric acid) afforded the title compound 12 (4.6 mg, 12%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ9.37(s,2H),8.34(s,1H),7.43-7.31(m,2H),7.31-7.05(m,2H),5.71(s,1H),4.76(t,J=11.2Hz,1H),4.09(s,3H),3.69 (s,1H),2.25(d,J=1.9Hz,3H),2.08(t,J=15.7Hz,2H),1.88(d,J=13.9Hz,1H),1.31(d,J=6.4Hz,3H).ESI-MSm / z calculated value 304.363, measured value 305.34(M+H)+.

[0233] compound 13 (2S,4S,6S)-4-(4-fluoro-3-methyl-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (13) [ka] Compound 13 was synthesized from compound S2 following the method described for compound 10. Purification by reverse phase HPLC (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: 5-98% acetonitrile in water with 5 mM hydrochloric acid) afforded the title compound 13 (23 mg, 59%) as a white solid. 1H NMR(300MHz,Methanol-d4)δ8.12(s,1H),7.54-7.41(m,2H),7.36(dd,J=8.5,2.2Hz,1H),4.97(dd,J=12.5,3.1Hz,1H),4.13(s,3H),3.97-3.82(m ,1H),2.55(dd,J=14.5,12.6Hz,1H),2.22(d,J=13.8Hz,1H),2.11-2.01(m,2H),1.43(d,J=6.6Hz,3H).ESI-MSm / z calculated value 324.781, measured value 325.29(M+H)+.

[0234] compound 14 (2S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-4-[5-(trifluoromethyl)-3-thienyl]piperidin-4-ol (14) [ka] Compound 14 was synthesized from compound S2 following the method described for compound 10. Purification by reverse phase HPLC (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: acetonitrile in water with 5 mM hydrochloric acid) afforded the title compound 14 (21 mg, 51%) as a white solid. ESI-MS m / z calculated 346.371, found 347.28 (M+H)+.

[0235] compound 15 (2S,4S,6S)-4-(4-fluorophenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (15) [ka] Compound 15 was synthesized from compound S2 following the method described for compound 10. Purification by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30 x 150 mm, 5 microns. Gradient: 5-98% acetonitrile in water with 5 mM hydrochloric acid) afforded the title compound 15 (17 mg, 46%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.47 (d, J = 10.1 Hz, 1H), 9.18 (d, J = 10.2 Hz, 1H), 8.28 (s, 1H), 7.79-7.61 (m, 1H), 7.36 (dt, J = 11.0, 5.4 Hz, 1H), 7.30-7.08 (m, 2H), 6.02 (s, 1H), 4.82 (t, J = 11.4 Hz, 1H). ,4.09(s,3H),3.75(s,1H),2.70(t,J=13.3Hz,1H),2.24(t,J=13.1Hz,1H),2.10(d,J=14.0Hz, 1H), 1.91(d,J=13.9Hz,1H),1.30(d,J=6.5Hz,3H).ESI-MSm / z calculated value 290.336, actual value 291.34(M+H)+.

[0236] compound 16 (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-4-[4-(trifluoromethyl)phenyl]piperidin-4-ol (16) [ka] Step i: A solution of 1-bromo-4-(trifluoromethyl)benzene (600 μL, 4.285 mmol) in THF (10 mL) was cooled to −78° C. At this point, a solution of tBuLi in pentane (5 mL of 1.7 M, 8.500 mmol) was added dropwise over 20 min, and the yellow suspension was stirred at this temperature for 30 min. At this point, a solution of compound S2 in THF (5 mL of 0.427 M, 2.135 mmol) was added dropwise over 20 min. After 30 min, the reaction was quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL) and water (10 mL). The aqueous layer was extracted with additional ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The crude material was minimally dissolved in DCM and loaded onto a silica gel column for purification (gradient: 0-10% MeOH in DCM). Fractions containing the product were pooled and concentrated. This sequence was repeated two more times and combined for the next step, giving a yield of approximately 60% per reaction.

[0237] Alternative preparation of step i [ka] To a suspension of magnesium (1.712 g, 70.44 mmol) in THF (100 mL) under nitrogen atmosphere, a drop of 1,2-dibromoethane was added followed by 1-bromo-4-(trifluoromethyl)benzene (14.88 g, 66.13 mmol). The mixture was sonicated for 5 min and stirred at ambient temperature for 1 h. The solution was cooled to −10° C. to −15° C. via a salt-ice bath and diglyme (3.123 mL, 21.81 mmol) was added followed by dropwise addition of a THF solution of (2S,6S)-1-allyl-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (49.98 mL of 0.427 M, 21.34 mmol). Stirring was continued for 45 min. The mixture was quenched with water (50 mL), the pH adjusted to pH 9 with ammonium chloride (50 mL), extracted with ether (2×100 mL), and the organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. The concentrate was minimally diluted in DCM and loaded onto a silica gel column for purification (gradient: 0-10% MeOH in DCM). Fractions containing the product were pooled and concentrated to give (2S,4S,6S)-1-allyl-2-methyl-6-(1-methyltriazol-4-yl)-4-[4-(trifluoromethyl)phenyl]piperidin-4-ol (4.350 g, 51%) ESI-MS m / z calculated 380.1824, found 381.2 (M+H)+ as an off-white solid, which was used in the next step.

[0238] Step ii: To the intermediate (1.756 g, 4.496 mmol) diluted in THF (5 mL) was added 2-sulfanylbenzoic acid (740 mg, 4.607 mmol). In an inert glovebox, a solution of dppb (20 mg, 0.04690 mmol) and Pd2(dba)3 (20 mg, 0.02184 mmol) in THF (5 mL) was prepared and after 10 min of mixing, the light brown solution was added to the previous mixture. The newly formed brown solution was stirred for 35 min. At this point, the mixture was diluted with TBME (30 mL) followed by 1 M HCl (2×20 mL). The aqueous layers were removed and combined, then the pH was adjusted with aqueous NaOH (7.4 mL of 6 M, 44.40 mmol) followed by about 1 mL of saturated aqueous ammonium chloride to obtain a pH of about 9. The mixture was diluted and extracted with TBME (3×20 mL), and the combined organic layers were dried with brine (20 mL) and pH adjusted to pH ∼9 with saturated aqueous ammonium chloride. The organic layers were dried over magnesium sulfate, MP-TMT resin (350 mg, 0.66 mmol / g) was added to the suspension, and the suspension was stirred for 2 h, then filtered and concentrated. The foam was diluted with 30 mL of TBME, and a solution of HCl in dioxane (1.2 mL of 4 M, 4.800 mmol) was added dropwise to the yellow solution, resulting in immediate loss of color in the mixture and a white precipitate. The suspension was stirred for 3 min, then filtered, rinsed with additional TBME, and dried at 70° C. for 3 days to give the title compound 16 (1.463 g, 84%) as an off-white solid. 1H NMR(300MHz,Methanol-d4)δ7.85(s,1H),7.72(d,J=8.3Hz,2H),7.64(d,J=8.3Hz,2H),4.49(dd,J=9.1,5.5Hz,1H),4.08(s,3H),3.40(dtd,J=12.9,6. 5,2.9Hz,1H),2.14-2.02(m,2H),1.86-1.76(m,1H),1.67(dd,J=13.6,11.2 Hz,1H),1.19(d,J=6.4Hz,3H).ESI-MSm / z calculated value 340.1511, actual value 341.14(M+H)+.

[0239] Preparation and Characterization of Compound 16 Form A: To (2S,4S,6S)-1-allyl-2-methyl-6-(1-methyltriazol-4-yl)-4-[4-(trifluoromethyl)phenyl]piperidin-4-ol (1.534 g, 3.928 mmol) diluted in THF (4.365 mL) was added 2-sulfanylbenzoic acid (646.0 mg, 4.022 mmol). In an inert glove box, a solution of dppb (17.47 mg, 0.04096 mmol) and Pd2dba3 (17.47 mg, 0.01908 mmol) in THF (4.365 mL) was prepared, and after 10 min of mixing, the light brown solution was added to the previous mixture. The newly formed brown solution was stirred for 35 min. At this point, the mixture was diluted with TBME (30 mL) followed by 1 N HCl (2 x 20 mL). The aqueous layers were removed and combined, then the pH was adjusted with aqueous NaOH (6.463 mL of 6 M, 38.78 mmol), followed by approximately 1 mL of saturated aqueous ammonium chloride to obtain a pH of approximately 9. The mixture was diluted and extracted with TBME (3×20 mL) and the combined organic layers were dried with brine (10 mL), which was pH adjusted to approximately pH 9 with saturated aqueous ammonium chloride. The organic layer was dried over magnesium sulfate, filtered through a pad of Florisil, and spun slowly, allowing crystallization to occur into a dense white solid.

[0240] The material was diluted with MTBE, homogenized, and then slowly concentrated while a dense white solid was observed to precipitate out of solution. The resulting white solid was dried overnight at 60° C. in a vacuum oven.

[0241] X-ray powder diffraction X-ray powder diffraction (XRPD) diffractograms of compound 16 form A were acquired in transmission mode at room temperature using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 3D Medipix-3 detector (Malvern PANalytical Inc, Westborough, MA). The X-ray generator was operated with copper radiation (1.54060 Å) at a voltage of 45 kV and a current of 40 mA. Powder samples were placed on a 96-well sample holder with mylar film and loaded into the instrument. Samples were scanned over the range of about 3° to about 40° 2θ with a step size of 0.0131303° and 49 seconds per step. The results are shown in Figure 1 and in the table below. [Table 7]

[0242] Thermogravimetric analysis (TGA): Thermogravimetric analysis of compound 16 Form A was measured using a TA5500 Discovery TGA. Samples weighing approximately 1-10 mg were placed in open platinum pans. The program was set to heat from ambient temperature to 350° C. at a heating rate of 10° C. / min with a nitrogen purge. The TGA thermogram shows minimal weight loss from ambient to 250° C. The TGA thermogram is shown in FIG. 2.

[0243] Differential Scanning Calorimetry (DSC): DSC analysis of compound 16 form A was measured using a TA Instruments TA2500 DSC. Samples weighing 1-10 mg were weighed into aluminum crimp-sealed pans with small holes. The pans were placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a nitrogen flow was passed through the cell. The program was set to a heating rate of 10° C. per minute and the temperature was increased to 250° C. The thermogram (FIG. 3) shows a single endothermic peak at 147° C.

[0244] Solid-state NMR A Bruker-Biospin 400 MHz wide-angle spectrometer equipped with a Bruker-Biospin 4 mm HFX probe was used. Samples were packed into a 4 mm ZrO2 rotor and spun under magic angle spinning (MAS) conditions with the spinning speed typically set at 12.5 kHz. Proton relaxation times were measured using a 1H MAS T1 saturation recovery relaxation experiment to set the probe recycle delay for the 13C cross-polarization (CP) MAS experiments. Fluorine relaxation times were measured using a 19F MAS T1 saturation recovery relaxation experiment to set the probe recycle delay for the 19F MAS experiments. The CP contact time for the carbon CPMAS experiments was set to 2 ms. CP proton pulses with linear ramps (50%-100%) were used. The carbon Hartmann-Hahn match was optimized with an external reference sample (glycine). Carbon and fluorine spectra were recorded with proton decoupling using a TPPM15 decoupling sequence with a field strength of approximately 100 kHz. The results are shown in Figure 4 (13C CPMAS) and in the table below. [Table 8] [Table 9]

[0245] Single crystal clarification Single crystals with the form A structure of compound 16 were grown from DVS cycling experiments at room temperature (25±2°C) from 0%-95%-0% relative humidity. X-ray diffraction data were acquired at 100K on a Bruker diffractometer equipped with Cu Kα radiation (λ=1.54178 Å) and a CMOS detector. The structure was solved and refined using the SHELX program (Sheldrick, GM, ActaCryst., (2008) A64, 112-122) and the results are summarized below. [Table 10] [Table 11]

[0246] compound 17 (2S,4S,6S)-4-(6-chloro-3-pyridyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (17) [ka] Step i: A mixture of 5-bromo-2-chloro-pyridine (38 mg, 0.198 mmol) in THF (0.2 mL) was cooled to -78 °C. At this point, hexyllithium (85 μL of 2.3 M, 0.196 mmol) was added and the mixture was stirred at this temperature for 15 min. The reaction turned blue within 5 min. At this point, a THF solution of compound S2 (0.2 mL of 0.5 M, 0.100 mmol) was added over 30 s. After 5 min, the mixture was diluted with saturated aqueous ammonium chloride (2 mL) and ethyl acetate (2 mL). The aqueous layer was extracted with additional ethyl acetate (2 x 2 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated, diluted to a minimum in DCM, loaded onto a silica gel column and purified (0-10% MeOH in DCM). Two spots were isolated, corresponding to the major and minor diastereomers. The fractions containing the product were pooled and concentrated.

[0247] Step ii: The intermediate was diluted with THF (250 μL) and 2-sulfanylbenzoic acid (17 mg, 0.110 mmol) was added. In a glove box, a solution of dppb (2 mg, 0.00469 mmol) and Pd2(dba)3 (2 mg, 0.00218 mmol) in THF (250 μL) was prepared and after 5 min of mixing, the light brown mixture was added to the intermediate solution. The mixture was stirred (8:20). After 5 min, complete conversion was observed. The mixture was diluted and partitioned with 1 M HCl (2×750 μL). The combined aqueous layers were pH adjusted with saturated aqueous sodium bicarbonate (1 mL) followed by extraction with DCM (3×5 mL). The organic layer was passed through a phase separator and concentrated to give the title compound, affording title compound 17 (7.6 mg, 16%) as a white solid. 1H NMR(300MHz,Methanol-d4)δ8.55(d,J=2.6Hz,1H),8.06(s,1H),7.98(dd,J=8.4,2.7Hz,1H),7.50(d,J=8.4Hz,1H),4.99(d,J=12.5Hz,1H),4.13( s,3H),3.94(s,1H),2.58-2.45(m,1H),2.29(d,J=14.9Hz,1H),2.20-1.9 7(m,2H),1.43(d,J=6.6Hz,3H).ESI-MSm / z calculated value 307.12, actual value 308.32(M+H)+.

[0248] compound 18 (2S,4S,6S)-4-(5-chloro-2-pyridyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (18) [ka] Compound 18 was synthesized from compound S2 according to the method described for compound 17. Purification by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30×150 mm, 5 microns. Gradient: acetonitrile in water with 0.1% trifluoroacetic acid) afforded the title compound 18 (3.1 mg, 5%) as a clear oil. 1H NMR(300MHz,Methanol-d4)δ8.54(s,1H),8.04(s,1H),7.89(d,J=8.9Hz,1H),7.75(d,J=8.7Hz,1H),4.95(d,J=15.1Hz,1H),4.12(s,3H),3.89(s,1H), 2.79-2.66(m,1H),2.35-2.22(m,1H),2.17(d,J=14.9Hz,1H),1.99(d,J=13 .7Hz,1H),1.41(d,J=6.5Hz,3H).ESI-MSm / z calculated value 307.12, actual value 308.36(M+H)+.

[0249] compound 19 (2S,4S,6S)-4-(4-chloro-3-methoxy-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (19) [ka] Compound 19 was synthesized from compound S2 following the method described for compound 17. Purification by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: 5-98% acetonitrile in water with 0.1% trifluoroacetic acid) afforded the title compound 19 (3.8 mg, 8%) as a clear oil. 1H NMR(300MHz,Methanol-d4)δ8.06(s,1H),7.37(d,J=8.2Hz,1H),7.26(s,1H),7.05(d,J=8.5Hz,1H),4.97(d,J=12.3Hz,1H),4.13(s,3H),3.9 2(s,4H),2.57-2.45(m,1H),2.24(d,J=14.5Hz,1H),2.05(d,J=10.6Hz,2H),1.42(d,J=6.6Hz,3H).ESI-MSm / z calculated value 336.135, actual value 337.30(M+H)+.

[0250] compound 20 (2S,4S,6S)-4-(4-chloro-2-methoxy-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (20) [ka] Compound 20 was synthesized from compound S2 according to the method described for compound 17. Purification by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30×150 mm, 5 microns. Gradient: acetonitrile in water with 0.1% trifluoroacetic acid) afforded the title compound 20 (7.3 mg, 16%) as a clear oil. 1H NMR(300MHz,Methanol-d4)δ8.03(s,1H),7.59(d,J=8.4Hz,1H),7.07(d,J=1.8Hz,1H),7.04-6.94(m,1H),4.96(d,J=12.7Hz,1H),4.12(s,3H),3. 90(s,4H),3.03(s,1H),2.65-2.52(m,1H),2.03(s,1H),1.88(d,J=14.4H z,1H),1.39(d,J=6.8Hz,3H).ESI-MSm / z calculated value 336.135, actual value 337.35(M+H)+.

[0251] compound 21 (2S,4S,6S)-4-(4-chloro-2-methyl-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (21) [ka] Compound 21 was synthesized from compound S2 following the method described for compound 17. Purification by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: 5-98% acetonitrile in water with 0.1% trifluoroacetic acid) afforded the title compound 21 (3.8 mg, 9%) as a clear oil. 1H NMR(300MHz,Methanol-d4)δ8.08(s,1H),7.42(d,J=8.5Hz,1H),7.23(s,1H),7.19(d,J=8.6Hz,1H),5.05-4.97(m,1H),4.14(s,3H),3.96(s,1H),2.6 3(s,3H),2.48(dd,J=21.7,13.0Hz,2H),2.29(d,J=14.3Hz,1H),2.10-1.9 7(m,1H),1.42(d,J=6.6Hz,3H).ESI-MSm / z calculated value 320.140, actual value 321.32(M+H)+.

[0252] compound 22 (2S,4S,6S)-4-(4-chloro-2-fluoro-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (22) [ka] Compound 22 was synthesized from compound S2 following the method described for compound 17. Purification by reverse phase HPLC (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: 5-98% acetonitrile in water with 0.1% trifluoroacetic acid) afforded the title compound 22 (5.7 mg, 12%) as a clear oil. 1H NMR(300MHz,Methanol-d4)δ8.04(s,1H),7.69(t,J=8.6Hz,1H),7.34(s,2H),4.99(d,J=12.2Hz,1H),4.12(s,3H),3.92(s,1H),2.84-2.72( m,1H),2.38-2.26(m,1H),2.20(d,J=14.5Hz,1H),2.03(d,J=14.6Hz,1H),1.40(d,J=6.6Hz,3H).ESI-MSm / z calculated value 324.115, actual value 325.29(M+H)+.

[0253] compound 23 (2S,4S,6S)-4-[4-chloro-3-(trifluoromethoxy)phenyl]-2-methyl- 6-(1-Methyltriazol-4-yl)piperidin-4-ol (23) [ka] Compound 23 was synthesized from compound S2 following the method described for compound 17. Purification by reverse phase HPLC (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: 5-98% acetonitrile in water with 0.1% trifluoroacetic acid) afforded the title compound 23 (22.3 mg, 44%) as a white solid. 1H NMR(300MHz,Methanol-d4)δ8.06(s,1H),7.64(s,1H),7.62(d,J=8.7Hz,1H),7 .52(dd,J=8.6,2.1Hz,1H),4.98(dd,J=12.4,3.1Hz,1H),4.13(s,3H),3.90(p, J=7.0,6.5Hz,1H),2.52(dd,J=14.4,12.6Hz,1H),2.23(d,J=14.6Hz,1H),2.11 -1.94(m,2H),1.42(d,J=6.6Hz,3H).ESI-MSm / z calculated value 390.107, actual value 391.22(M+H)+.

[0254] compound 24 2-Chloro-5-[(2S,4S,6S)-4-hydroxy-2-methyl-6-(1-methyltriazol-4-yl)-4-piperidyl]-N,N-dimethyl-benzamide (24) [ka] Compound 24 was synthesized from compound S2 following the method described for compound 17. Purification by reverse phase HPLC (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: 5-98% acetonitrile in water with 0.1% trifluoroacetic acid) afforded the title compound 24 (3 mg, 6%) as a clear oil. 1H NMR(300MHz,Methanol-d4)δ8.05(s,1H),7.59(s,1H),7.52(d,J=8.3Hz,2H),4.97(d,J=15.8Hz,1H),4.13(s,3H),3.95-3.89(m,1H),3. 13(s,3H),2.89(s,3H),2.50(s,1H),2.21(s,1H),2.06(d,J=5.7Hz,2H),1.41(d,J=6.6Hz,3H).ESI-MSm / z calculated value 377.162, measured value 378.3(M+H)+.

[0255] compound 25 (2S,4S,6S)-4-[3-fluoro-4-(trifluoromethyl)phenyl]-2-methyl-6- (1-Methyltriazol-4-yl)piperidin-4-ol (25) [ka] Compound 25 was synthesized from compound S2 following the method described for compound 17. Purification by reverse phase HPLC (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: 5-98% acetonitrile in water with 0.1% trifluoroacetic acid) afforded the title compound 25 (8.4 mg, 17%) as a white solid. 1H NMR(300MHz,Methanol-d4)δ8.06(s,1H),7.74(t,J=8.0Hz,1H),7.58-7.49(m,2H),5.03-4.95(m,1H),4.13(s,3H),3.92(dd,J=10.9,5.9H z,1H),2.58-2.47(m,1H),2.24(d,J=14.2Hz,1H),2.06(d,J=10.4Hz,2H),1.42(d,J=6.6Hz,3H).ESI-MSm / z calculated value 358.142, actual value 359.29(M+H)+.

[0256] compound 26 (2S,4S,6S)-4-(4-chloro-3-methyl-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (26) [ka] Compound 26 was synthesized from compound S2 following the method described for compound 17. Purification by reverse phase HPLC (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: 5-98% acetonitrile in water with 0.1% trifluoroacetic acid) afforded the title compound 26 (12.6 mg, 28%) as a white solid. 1H NMR(300MHz,Methanol-d4)δ8.06(s,1H),7.47(d,J=1.8Hz,1H),7.35(d,J=4.2Hz,2H),4.96(dd,J=12.4,3.1Hz,1H),4.13(s,3H),3.91(dt,J=11.3,5.6H z,1H),2.55-2.41(m,1H),2.40(s,3H),2.22(d,J=14.6Hz,1H),2.03(d,J=10 .8Hz,2H),1.41(d,J=6.6Hz,3H).ESI-MSm / z calculated value 320.140, actual value 321.28(M+H)+.

[0257] compound 27 (2S,4R,6S)-4-(4-bromophenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (27) [ka] Step i: A mixture of 1,4-dibromobenzene (120.8 mg, 0.512 mmol) in THF (800 μL) was cooled to −78° C. At this point, butyllithium (260 μL of 1.6 M, 0.416 mmol) was added dropwise and the mixture was stirred at −78° C. for 15 minutes. At this point, a solution of compound S2 (80 mg, 0.3414 mmol) in THF (800 μL) was added dropwise and the reaction was stirred for 15 minutes. The mixture was diluted with saturated aqueous ammonium chloride (10 mL), water (10 mL), and ethyl acetate (10 mL). The aqueous layer was extracted with additional ethyl acetate (2×10 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to a crude residue.

[0258] Step ii: The intermediate was diluted with THF (400 μL) and 2-sulfanylbenzoic acid (56 mg, 0.363 mmol) was added. In an inert glove box, a solution of dppb (4 mg, 0.00938 mmol) and Pd2(dba)3 (4 mg, 0.00437 mmol) in THF (400 μL) was prepared and after 30 min of mixing, the light brown mixture was added to the intermediate solution. The mixture was stirred. After 30 min, UPLC showed complete conversion. The mixture was diluted with TBME (5 mL) followed by 1 M HCl (2×5 mL). The aqueous layers were removed and combined, then the pH was adjusted with aqueous NaOH (6 M, 1.7 mL) followed by saturated aqueous ammonium chloride to obtain a pH of approximately 9. The mixture was diluted and extracted with TBME (3×10 mL) and the combined organic layers were filtered through a phase separator and concentrated to a crude residue which was purified by reverse phase HPLC (Method: Waters XBridge Prep C8 column, 30×150 mm, 5 micron. Gradient: 5-98% acetonitrile in water with 10 mM ammonium hydroxide) to give the title compound 27 (16.6 mg, 14%) as a white solid. 1H NMR(400MHz,Chloroform-d)δ7.55-7.41(m,5H),4.07(s,3H),3.98(dd,J=12.0,2.6Hz,1H),2.90-2.80(m,1H),2.79-2.72(m,1H) ,2.51-2.43(m,1H),2.01(t,J=12.4Hz,1H),1.73-1.57(m,1H),1.17(d,J=6.1Hz,3H).ESI-MSm / z calculated value 350.0742, measured value 351.17(M+H)+.

[0259] compound 28 (2S,4R,6S)-4-(4-bromophenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (28) [ka] Step i: A mixture of 4-bromo-2-methoxy-1-(trifluoromethyl)benzene (220 mg, 0.863 mmol) in THF (1000 μL) was cooled to −78° C. At this point, sec-butyllithium (600 μL of 1.4 M, 0.840 mmol) was added and the mixture was stirred at this temperature for 40 min. At this point, a solution of compound S2 (100 mg, 0.427 mmol) in THF (1,000 μL) was added over 30 s. The mixture was then stirred for 2 min before being quenched with 2 mL of saturated aqueous ammonium chloride and ethyl acetate (4 mL). The aqueous layer was extracted with additional ethyl acetate (2×4 mL) and the combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, filtered, and concentrated. The mixture was minimally diluted with DCM and loaded onto a silica gel column for purification (gradient: 0-8% MeOH in DCM). Fractions containing product were pooled and concentrated, revealing that the purity was only about 80% with the remainder being starting material. The mixture was redissolved in DCM and loaded onto another silica gel column for purification (0-6% MeOH in DCM). Fractions containing product were pooled and concentrated.

[0260] Step ii: In an inert glovebox, a solution of dppb (2 mg, 0.004690 mmol) and Pd2(dba)3 (2 mg, 0.002184 mmol) in THF (0.5 mL) was prepared and after mixing for 5 min, the light brown mixture was added to a solution of the intermediate and 2-sulfanylbenzoic acid (15 mg, 0.09729 mmol) in THF (0.5 mL). The mixture was stirred for 5 min. At this point, the mixture was diluted with TBME (2 mL) and extracted with 1 M HCl (2×1 mL), which was then pH adjusted to pH>10 and then extracted with DCM (2 mL). The organic layer was passed through a phase separator, concentrated to a minimum volume, and then diluted in DCM for silica gel purification (gradient: 0-10% MeOH in DCM). Fractions containing the product were pooled and concentrated to give the title compound 28 (26 mg, 14%) as a white solid. 1H NMR(300MHz,Methanol-d4)δ7.87(s,1H),7.53(d,J=8.1Hz,1H),7.35(s,1H),7.18(d,J= 8.2Hz,1H),4.51(dd,J=10.9,3.8Hz,1H),4.08(d,J=1.5Hz,3H),3.93(d,J=1.5Hz,3H),3 .43(ddd,J=12.5,6.5,3.3Hz,1H),2.19-2.01(m,2H),1.81(dd,J=13.6,2.4Hz,1H),1.70 (dd,J=13.4,11.4Hz,1H),1.23-1.15(m,3H).ESI-MSm / z calculated value 370.162, actual value 371.14(M+H)+.

[0261] compound 29 (2S,4S,6S)-4-(4-cyclopropylphenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (29) [ka] Step i: A mixture of 1-bromo-4-cyclopropyl-benzene (120 mg, 0.609 mmol) in THF (800 μL) was cooled to −78° C. At this point, butyllithium (260 μL of 1.6 M, 0.416 mmol) was added dropwise and the mixture was stirred at −78° C. for 10 minutes. To the reaction was added LaCl3·LiCl (580 μL of 0.6 M, 0.348 mmol) and the reaction was stirred for 5 minutes. At this point, a solution of compound S2 (80 mg, 0.341 mmol) in THF (800 μL) was added dropwise. The mixture was diluted with saturated aqueous ammonium chloride (10 mL), water (10 mL), and ethyl acetate (10 mL). The aqueous layer was extracted with additional ethyl acetate (2×10 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated.

[0262] Step ii: The intermediate was diluted with THF (400 μL) and 2-sulfanylbenzoic acid (55 mg, 0.357 mmol) was added. In a glove box, a solution of dppb (4 mg, 0.00938 mmol) and Pd2(dba)3 (4 mg, 0.00437 mmol) in THF (400 μL) was prepared and after 30 min of mixing, the light brown mixture was added to the intermediate solution. The mixture was stirred for 30 min. The mixture was diluted with TBME (5 mL) followed by 1 M HCl (2×5 mL). The aqueous layers were removed and combined, then the pH was adjusted with aqueous NaOH (6 N, 1.7 mL) followed by saturated aqueous ammonium chloride to obtain a pH of about 9. The mixture was diluted and extracted with TBME (3×10 mL) and the combined organic layers were filtered through a phase separator and concentrated to a crude residue which was purified by reverse phase HPLC (Method: Waters XBridge Prep C8 column, 30×150 mm, 5 micron. Gradient: 5-98% acetonitrile in water with 10 mM ammonium hydroxide) to give the title compound 29 (19.4 mg, 18%) as a white solid. 1H NMR(400MHz,Chloroform-d)δ7.47(s,1H),7.45-7.38(m,2H),7.07(d,J=8.0Hz,2H),4.54(dd,J=10.7,3.8Hz,1H),4.06(d,J=1.1Hz,3H),3.43(s, 1H),2.19-1.99(m,2H),1.97-1.68(m,4H),1.18(d,J=6.3Hz,3H),1.01-0 .92(m,2H),0.75-0.61(m,2H).ESI-MSm / z calculated value 312.195, actual value 313.33(M+H)+.

[0263] compound 30 4-[(2S,4S,6S)-4-Hydroxy-2-methyl-6-(1-methyltriazol-4-yl)-4-piperidyl]benzonitrile (30) [ka] To a mixture of Mg (17 mg, 699 μmol), LiCl (430 uL of 0.5 M in THF) in THF (500 μL) was added dropwise 1,2-dibromoethane followed by 4-bromobenzonitrile (117 mg, 643 μmol). The mixture was stirred at room temperature for 1 h and then heated to 40° C. After 1 h, the formed solution was cooled to −20° C. in a dry ice / acetone bath and a solution of (2S,6S)-1-allyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-4-one S2 (50 mg, 213 μmol) in THF (500 μL) was added. After 5 min, the reaction was quenched with saturated aqueous ammonium chloride (2 mL) and diluted with TBME (5 mL) and water (3 mL). The organic layer was passed through a phase separator, concentrated, and diluted with DMSO (1 mL). Purification by reverse phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O with 0.2% formic acid. Fractions containing pure product were pooled, concentrated, and diluted with THF (500 μL), at which point 2-sulfanylbenzoic acid (32.9 mg, 0.213 mmol) was added and the mixture was evacuated and backfilled with nitrogen (3x). In an inert glovebox, a solution of Pd2dba3 (1 mg, 107 μmol) and DPPB (1 mg, 213 μmol) in THF (500 μL) was prepared and the mixture was stirred for approximately 5 minutes until nearly homogeneous and tan in color. At this point, a solution of the tertiary alcohol and 2-sulfanylbenzoic acid in THF (500 μL) was evacuated and backfilled with nitrogen three times, then stirred at room temperature. At this point, the catalyst solution was added and the mixture was continued to stir under nitrogen. After 1 h, the mixture was diluted with TBME (1 mL), extracted with 1 M HCl (2×1 mL), and the aqueous layer was washed with TBME (2×1 mL). The combined aqueous layers were pH adjusted to pH 9 using 6 M NaOH and saturated aqueous ammonium chloride as needed. The cloudy aqueous layer was extracted with TBME (2×1 mL), and the combined organic layers were washed with brine (1 mL), dried over magnesium sulfate, passed through a Florisil cartridge, and washed with methanol (2×1 mL). The combined organics were concentrated to give the title compound 30 (2.9 mg, 4%) as a white solid.1H NMR(300MHz,Methanol-d4)δ7.84(s,1H),7.72(s,4H),4.47(dd,J=9.2,5.3Hz,1H),4.08(s,3H),3.45-3.35(m,1H), 2.10-1.96(m,2H),1.81-1.72(m,1H),1.64(dd,J=13.6,11.2Hz,1H),1.17(d,J=6.4Hz,3H).LCMSm / z298.08[M+H]+.

[0264] compound 31 (2S,4S,6S)-4-(2,2-dimethyl-3H-benzofuran-6-yl)-2-methyl-6- (1-Methyltriazol-4-yl)piperidin-4-ol (31) [ka] Compound 31 was synthesized from compound S2 using the appropriate aryl halide according to the method described for compound 30. Title compound 31 (8.7 mg, 11%) was isolated as a white solid. 1H NMR (300 MHz, Methanol-d4) δ 7.83 (s, 1H), 7.13-7.05 (m, 1H), 6.95 (dd, J = 7.8, 1.7 Hz, 1H), 6.85 (d, J = 1.6 Hz, 1H), 4.45 (dd, J = 8.5, 6.1 Hz, 1H), 4.08 (s, 3H), 3.41-3.36 (m, 1H), 3. .34(s,1H),2.98(d,J=1.1Hz,2H),2.06-1.98(m,2H),1.78(dd,J=13.4,2.5Hz,1H),1.6 1(dd,J=13.7,11.3Hz,1H),1.42(s,6H),1.16(d,J=6.4Hz,3H).LCMSm / z343.13[M+H]+.

[0265] compound 32 (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-4-spiro [Chroman-4,1'-cyclopropane]-7-yl-piperidin-4-ol (32) [ka] Compound 32 was synthesized from compound S2 following the method described for compound 30 using the appropriate aryl halide. Title compound 32 (14.5 mg, 19%) was isolated as a white solid. 1H NMR (300 MHz, Methanol-d4) δ 7.82 (s, 1H), 6.94 (dd, J = 8.1, 2.0 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 4.44 (dd, J = 9.4, 5.3 Hz, 1H), 4.28-4.15 (m, 2H), 4.07 (s, 3H), 3.41-3.35 (m ,1H),2.06-1.90(m,2H),1.87-1.80(m,2H),1.77(dt,J=13.8,2.3Hz,1H),1.58(dd,J=13.7,11 .3Hz,1H),1.16(d,J=6.4Hz,3H),1.05-0.98(m,2H),0.88-0.77(m,2H).LCMSm / z355.14[M+H]+.

[0266] compound 33 (2S,4S,6S)-4-[4-chloro-3-(trifluoromethyl)phenyl]-2-methyl-6- (1-Methyltriazol-4-yl)piperidin-4-ol (33) [ka] Compound 33 was synthesized from compound S2 with the appropriate aryl halide according to the method described for compound 30, with the final step workup and isolation modified as follows: The reaction mixture was diluted with TBME (500 μL) and extracted with 1 M HCl (3×500 μL). The combined aqueous layers were submitted for reverse phase purification to isolate the final product (Method: C18 Waters Sunfire column (30×150 mm, 5 micron). Gradient: MeCN in H2O with 0.2% formic acid). The fractions were concentrated to give the title compound 33 (formate salt) (2.9 mg, 4%) as a white solid. 1H NMR (300MHz, methanol-d4) δ8.06(s, 1H), 7.99(d, J=2.3Hz, 1H), 7.78(dd, J=8.5, 2.3Hz, 1H), 7.67(d, J=8.5Hz, 1H), 4.95(d, J=3.1Hz, 1H) , 4.15(s, 3H), 3.87(dt, J=11.2, 5.8Hz, 1H), 2.48(t, J=13.4Hz, 1H), 2.23(d, J=14.0Hz, 1H), 2.14~1.95(m, 2H), 1.41(d, J=6.6Hz, 3H). LCMSm / z375.25[M+H]+.

[0267] compound 34 (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-4-[3-methyl-4- (Trifluoromethyl)phenyl]piperidin-4-ol (34) [ka] Compound 34 was synthesized from compound S2 using the appropriate aryl halide with modification from compound 33 according to the method described for compound 30. The fractions were concentrated to give the title compound 34 (formate salt) (19.7 mg, 23%) as a white solid. 1H NMR (300MHz, methanol-d4) δ8.06(s, 1H), 7.68(d, J=8.3Hz, 1H), 7.58(s, 1H), 7.53(d, J=8.1Hz, 1H), 4.95(dd, J=12.3, 3.1Hz, 1H), 4.15(s, 3H) , 3.90(dd, J=10.3, 5.8Hz, 1H), 2.56~2.51(m, 3H), 2.51~2.42(m, 1H), 2.23(d, J=14.0Hz, 1H), 2.04(d, J=10.0Hz, 2H), 1.42(d, J=6.6Hz, 3H). LCMSm / z355.28[M+H]+.

[0268] compound 35 (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-4-[2-(trifluoromethyl)-4-pyridyl]piperidin-4-ol (35) [ka] Compound 35 was synthesized from compound S2 using the appropriate aryl halide with modification from compound 33 according to the method described for compound 30. The fractions were concentrated to give the title compound 35 (16.9 mg, 23%) as a white solid. 1H NMR (300MHz, methanol-d4) δ8.77(d, J=5.2Hz, 1H), 8.17(s, 1H), 8.03(dd, J=1.8, 0.8Hz, 1H), 7.84(dd, J=5.1, 1.8Hz, 1H), 5.04(dd, J=12.6, 3.1Hz, 1 H), 4.16(s, 3H), 3.98(ddd, J=11.0, 6.5, 4.1Hz, 1H), 2.66(dd, J=14.5, 12.5Hz, 1H), 2.31~2.22(m, 1H), 2.22~2.02(m, 2H), 1.47(d, J=6.6Hz, 3H). LCMSm / z342.31[M+H]+.

[0269] compound 36 (2S,4S,6S)-4-[3-chloro-4-(trifluoromethyl)phenyl]-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (36) [ka] Compound 35 was synthesized from compound S2 using the appropriate aryl halide with modification from compound 33 according to the method described for compound 30. The fractions were concentrated to give the title compound 36 (19.7 mg, 24%) as a white solid. 1H NMR(300MHz,Methanol-d4)δ8.11(s,1H),7.88-7.80(m,2H),7.67(d,J=8.3Hz,1H),5.02(dd,J=12.4,3.1Hz,1H),4.16(s,3H),4. 02-3.83(m,1H),2.65-2.48(m,1H),2.27(d,J=14.0Hz,1H),2.10(d,J=8.3Hz,2H),1.45(d,J=6.6Hz,3H).LCMSm / z375.29[M+H]+.

[0270] compound 37 (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-4-[4-(trifluoromethyl)-3-pyridyl]piperidin-4-ol (37) [ka] Compound 37 was synthesized from compound S2 using the appropriate aryl halide with modification from compound 33 according to the method described for compound 30. The fractions were concentrated to give the title compound 35 (26.5 mg, 24%) as a white solid. 1H NMR (300MHz, methanol-d4) δ8.93(s, 1H), 8.23(d, J=8.2Hz, 1H), 8.11(s, 1H), 7.89(d, J=8.4Hz, 1H), 5.05(dd, J=12.6, 3.2Hz, 1 H), 4.16(s, 3H), 3.99(s, 1H), 2.61(t, J=13.5Hz, 1H), 2.34(d, J=14.2Hz, 1H), 2.14(d, J=11.0Hz, 2H), 1.47(d, J=6.6Hz, 3H). LCMSm / z342.31[M+H]+.

[0271] compound 38 (2S,4S,6S)-4-(4-(difluoromethyl)phenyl)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-4-ol (38) [ka] Compound 38 was synthesized from compound S2 following the method described for compound 30 using the appropriate aryl halide with modification from compound 33, but the allyl intermediate was not purified. Concentration of fractions afforded the title compound 38 (formic acid) (60 mg, 37%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ8.20(s,1H),7.97(s,1H),7.64(d,J=8.1Hz,2H),7.54(d,J=8.1Hz,2H),7.02(t,J=56.0Hz,1H),5.28(s,1H),4.40(dd ,J=9.3,5.1Hz,1H),4.02(s,3H),2.00-1.90(m,2H),1.69(d,J=13.0Hz,1H),1.61-1.51(m,1H),1.09(d,J=6.3Hz,3H).LCMSm / z323.25[M+H]+.

[0272] compound 39 (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-4-[4-(trifluoromethyl)-3-pyridyl]piperidin-4-ol (39) [ka] To an oven-dried vial containing 1-bromo-4(1,1-difluoroethyl)benzene (566 mg, 2.56 mmol), 2-methyltetrahydrofuran (2.3 mL) was added followed by isopropylmagnesium chloride-lithium chloride complex (2.3 mL of 1.3 M, 2.99 mmol) and stirred at room temperature for 4 h. At this point, the reaction mixture was cooled to -10 °C and solid S2 was added in one portion and stirred for 1 h. The reaction mixture was quenched with water and saturated aqueous ammonium chloride solution, then extracted with ethyl acetate (2x). The organic layer was passed through a phase separator and concentrated. The residual oil was placed in an inert glovebox and a vial was charged with 2-sulfanylbenzoic acid (53 mg, 0.344 mmol) dissolved in THF (300 μL). A separate vial was charged with Pd2dba3 (3 mg, 3.28 μmol), dppb (3 mg, 7.04 μmol), and THF (300 μL) and then stirred for 10 min. This solution was added to the other mixture and the reaction was stirred for 3 h. At this point, the mixture was diluted with TBME, followed by extraction with 1 M HCl (2×). The aqueous layers were removed, combined, and then pH adjusted with 6 M aqueous NaOH, followed by saturated aqueous ammonium chloride to obtain a pH of about 9. The mixture was diluted and extracted with TBME (3×10 mL), and the combined organic layers were filtered through a phase separator and concentrated to a crude residue. Purification by reverse phase HPLC. (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 micron. Gradient: acetonitrile in water with 0.2 formic acid) afforded the title compound 39 (31.7 mg, 31%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ8.29(d,J=1.2Hz,2H),7.94(s,1H),7.62-7.49(m,4H),4.35(dd,J=9.0,5.2Hz,1H),4.01(s,3H),3.28(t ,J=8.6Hz,1H),1.96(t,J=18.8Hz,3H),1.88(d,J=4.0Hz,1H),1.71-1.45(m,2H),1.06(d,J=6.3Hz,3H).LCMSm / z337.30[M+H]+.

[0273] compound 40 (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-4-[4-(trifluoromethyl)-3-pyridyl]piperidin-4-ol (40) [ka] Compound 40 was synthesized from compound S2 following the method described for compound 29 using the appropriate aryl halide to give the title compound 40 (16 mg, 19%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.94(s,1H),7.91-7.84(m,1H),7.54(dd,J=8.1,1.4Hz,1H),7.48(s,1H),5.46(s,1H),4.34(dd,J=8.6,5 .6Hz,1H),4.01(s,3H),1.97-1.87(m,2H),1.66(d,J=12.9Hz,1H),1.53(dd,J=13.1,11.0Hz,1H),1.06(d,J=6.3Hz,3H).LCMSm / z387.3[M+H]+.

[0274] compound 41 (2S,4S,6S)-4-(1,1-difluoro-2,3-dihydro-1H-inden-5-yl)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-4-ol (41) [ka] Compound 41 was synthesized from compound S2 following the method described for compound 29 using the appropriate aryl halide to give the title compound 41 (33.2 mg, 31%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.01(s,1H),7.51(s,3H),4.45(dd,J= 11.6,2.9Hz,1H),4.02(s,3H),3.38(ddd,J=9.9,6.3,3.2Hz,1H),3.03(tt,J =6.7,3.1Hz,2H),2.67-2.52(m,2H),2.13-1.99(m,1H),1.93(dt,J=13.4,2 .6Hz,1H),1.75-1.58(m,2H),1.11(d,J=6.3Hz,3H).LCMSm / z349.31[M+H]+.

[0275] compound 42 (2S,4S,6S)-4-[3-methoxy-4-(trifluoromethyl)phenyl]-1,2-dimethyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (42) [ka] To a mixture of Mg (17 mg, 699 μmol), LiCl (430 uL of 0.5M in THF) in THF (500 μL) was added 1,2-dibromomethane followed by 1-bromo-3-methoxy-4(trifluoromethyl)benzene (165 mg, 647 μmol). The mixture was stirred at room temperature for 1 hour and then heated to 40° C. After 1 hour, compound S2 (50 mg, 209 μmol) was added as a solution in THF (500 μL) at room temperature. At this point, MeI (60 μL, 964 μmol) was added and the reaction was stirred. After 25 minutes, the reaction was heated to 40° C. The reaction was stirred for 18 hours. At this point, the reaction mixture was diluted with saturated aqueous ammonium chloride (1 mL) and DCM (3 mL). The layers were phase separated and the aqueous layer was washed with additional DCM (3 mL). The combined organic layers were concentrated and minimally diluted in DCM for column chromatography (silica gel, 0-10% MeOH:DCM). Fractions containing product were pooled and concentrated. The crude oil and 2-sulfanylbenzoic acid (10 mg, 65 μmol) in an inert glovebox were charged with THF (125 μL), followed by a solution of Pd2dba3 (0.25 mg, 0.261 μmol) / DPPB (approximately 0.25 mg, 0.523 μmol) in THF (125 μL). The mixture was sealed, removed from the glovebox, and stirred for 1 h. At this point, the mixture was diluted with TBME (500 μL) and 1 M HCl (500 μL). The organic layer was extracted two more times with 1 M HCl (2 × 500 mL). The combined aqueous layers were adjusted to a pH of approximately 9 using saturated NaOH and saturated aqueous ammonium chloride. The aqueous layer was extracted with TBME (3×500 μL) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound 42 (12.2 mg, 15%).1H NMR (300 MHz, chloroform-d) δ 7.48 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.23 (s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 4.01 (d, J = 8.3 Hz, 1H), 3.98 (s, 3H), 3.86 (s, 3H), 3.14 (s, 1 H), 2.80(s, 1H), 2.28(t, J=12.9Hz, 1H), 2.13(s, 3H), 2.03~1.91(m, 1H), 1.88 (dt, J=13.8, 3.2Hz, 1H), 1.76(dt, J=13.8, 2.9Hz, 1H), 1.16(d, J=6.3Hz, 3H). LCMSm / z385.16[M+H]+.

[0276] compound 43 (2S,4S,6S)-4-[3-hydroxy-4-(trifluoromethyl)phenyl]-2-methyl-6- (1-Methyltriazol-4-yl)piperidin-4-ol (43) [ka] To a mixture of LiCl (28 mg, 661 μmol) and Mg turnings (15 mg, 617 μmol) was added 1,2-dibromoethane (1 μL, 11.6 μmol) followed by THF (1000 μL). The reaction mixture was heated to 50 °C and stirred for 1 h. At this point, all the solid magnesium was consumed. The solution was cooled to -20 °C and to the solution was added a solution of piperidone S2 (50 mg, 209 μmol) in THF (500 μL). After 5 min, the mixture was diluted with saturated aqueous ammonium chloride (10 mL) and TBME (10 mL). The layers were phase separated and the organic layer was washed with brine (10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude oil was dissolved in DCM (1 mL) and loaded onto a silica gel column for purification (0-10% MeOH:DCM). Fractions containing the product were pooled and concentrated. To the purified oil was added Pd / C (50 mg of 2.5% w / w, 11.8 μmol) followed by MeOH (1 mL) and the mixture was stirred under 40 psig hydrogen for 21 h. At this point, the mixture was passed through a 0.45 micron membrane filter, rinsed with methanol (0.5 mL) and concentrated. The crude concentrate was dissolved in DMSO (1 mL) and purified by reverse phase HPLC (Method: C18 Waters Sunfire column (30×150 mm, 5 micron). Gradient: MeCN in H2O with 0.2% formic acid). The title compound 43 (5.5 mg, 7%) was isolated as a white solid. 1H NMR(300MHz,Methanol-d4)δ8.08(s,1H),7.53(d,J=8.2Hz,1H),7.23(s,1H),7.07(d,J=8.2Hz,1H),4.99(dd,J=12.4,3.1Hz,1H),4.15(s ,3H),4.05-3.80(m,1H),2.58-2.48(m,1H),2.24(d,J=13.9Hz,1H),2.06(d,J=8.5Hz,2H),1.44(d,J=6.6Hz,3H).LCMSm / z357.31[M+H]+.

[0277] The process to produce compound 33 also produces compound 33a. [ka] In some embodiments, compound 33a is specifically excluded from the formulas of the present disclosure by a proviso.

[0278] compound 44 (2S,4S,6S)-4-[2-hydroxy-4-(trifluoromethyl)phenyl]-2-methyl-6- (1-Methyltriazol-4-yl)piperidin-4-ol (44) [ka] To a mixture of LiCl (28 mg, 661 μmol) and Mg turnings (15 mg, 617 μmol) was added 1,2-dibromoethane (1 μL, 11.6 μmol) followed by THF (1000 μL). The reaction mixture was heated to 50° C. and stirred for 1 h. At this point, all the solid magnesium was consumed. The solution was cooled to −20° C. and to the solution was added a solution of S2 (50 mg, 209 μmol) in THF (500 μL). After 5 min, the reaction mixture was diluted with saturated aqueous ammonium chloride (10 mL) and TBME (10 mL). The layers were phase separated and the organic layer was washed with brine (10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. At this point, the crude oil was taken up in aqueous HCl (1000 μL of 37% w / w, 12.18 mmol) / MeOH (1 mL), which was then heated to 50° C. (3:15). After 45 min, the mixture was diluted with water (10 mL) and with TBME (10 mL). The organic layer was extracted with 1 M HCl (3×5 mL). The combined aqueous layers were pH adjusted to pH ∼8 with 6 M aqueous NaOH and extracted with DCM (3×15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. To the residual oil was added 2-sulfanylbenzoic acid (16 mg, 104 μmol) and charged in an inert glovebox with THF (250 μL) followed by a solution of Pd2dba3 (0.5 mg, 0.546 μmol) / DPPB (0.5 mg, 1.17 μmol) in THF (250 μL). The mixture was stirred for 1 h, at which point it was diluted with TBME (500 μL) and extracted with 1M HCl (3×500 μL). The aqueous layer was then purified directly by reverse-phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 0.2% formic acid. The formate salt of title compound 44 (15.7 mg, 18%) was isolated as a white solid.1H NMR(300MHz,Methanol-d4)δ8.05(s,1H),7.72(d,J=8.2Hz,1H),7.19(d,J=8.1Hz,1H),7.11(d,J=1.8Hz,1H),5.03-4.95(m,1H),4.14(s,3H),3.90(dd,J =7.5,4.1Hz,1H),3.17-3.03(m,1H),2.68(dd,J=14.5,12.2Hz,1H),2.24-2. 09(m,1H),2.02-1.93(m,1H),1.42(d,J=6.6Hz,3H).LCMSm / z357.31[M+H]+.

[0279] compound 45 (2S,4S,6S)-4-(((4-bromophenyl)sulfonyl)methyl)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-4-ol (45) [ka] To a mixture of 1-bromo-4-methylsulfonyl-benzene (150 mg, 638 μmol) in THF (1 mL) cooled to -78°C was added a solution of hexyllithium in hexanes (280 μL of 2.3 M, 644 μmol). After 5 min, a solution of piperidone S2 (50 mg, 213 μmol) in THF (500 μL) was added and the mixture was allowed to warm to room temperature. At this point, the mixture was quenched with saturated aqueous ammonium chloride (1 mL). The crude mixture was allowed to warm to room temperature and diluted with TBME (5 mL) and water (2 mL). The organic layer was removed, washed with brine (5 mL), dried over magnesium sulfate, filtered, and concentrated. To this crude mixture was added 2-sulfanylbenzoic acid (33 mg, 214 μmol) at which point the reaction was transferred to an inert glove box when THF (0.5 mL) and a solution of Pd2dba3 (1 mg, 1.09 μmol) / dppb (1 mg, 2.35 μmol) in THF (0.5 mL) were added. The reaction was stirred for 1 h at which point the mixture was diluted with TBME (500 μL) and extracted with 1N HCl (3×500 μL). The aqueous layers were combined and purified by reverse phase HPLC (Method: C18 Waters Sunfire column (30×150 mm, 5 micron). Gradient: MeCN in H2O with 0.2% formic acid). The title compound 45 (4.9 mg, 5%) was isolated as a clear oil. 1H NMR(300MHz,Methanol-d4)δ8.05(s,1H),7.96-7.80(m,4H),4.16(s,3H),3.77(s,1H),3.59(s,2H),3.29(d,J=1.6Hz,1H), 2.43(d,J=11.3Hz,2H),2.27(d,J=14.2Hz,1H),1.96(dd,J=14.5,12.2Hz,1H),1.40(d,J=6.6Hz,3H).LCMSm / z428.95[M+H]+

[0280] compound 46 (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-4-[4-(trifluoromethyl)phenyl] Piperidine-4-carbonitrile (46) [ka] Step 1. Synthesis of (2S,6S)-1-allyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)piperidine-4-carbonitrile (C12) To a solution of piperidone S2 (150 mg, 0.608 mmol) in DME (5 mL) / tBuOH (0.1 mL) was added t-BuOK in THF (1.25 mL of 1 M, 1.2500 mmol) dropwise. The reaction was stirred at room temperature for 3 h. Water (10 mL) was added, the phases were separated, and the aqueous phase was extracted with EtOAc (3×15 mL). The organic phases were combined, washed with brine (40 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. Purification by silica gel chromatography (0-15% MeOH in DCM) afforded the title compound C12 (111 mg, 59%) as a pale orange solid. 1H NMR (400MHz, CDCl3) δ7.48(s, 1H), 7.44(s, 1H), 6.02~5.77(m, 2H), 5.19~4.98(m, 3H), 4.19~4.02(m, 5H), 3.85(dd, J=11.6, 2.7Hz, 1H), 3.39~3.25(m, 2H), 3.10~2.94(m, 2H), 2.67~2.54(m, 2H), 2.20(br dd. LCMSm / z246.2[M+H]+

[0281] Step 2. Synthesis of (2S,4S,6S)-1-allyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-4-(4-(trifluoromethyl)phenyl)piperidine-4-carbonitrile (C13) To a solution of piperidine C12 (85 mg, 0.3461 mmol) and 1-fluoro-4-(trifluoromethyl)benzene (78 mg, 0.06 mL, 0.473 mmol) in freshly distilled THF (2 mL) at room temperature was added dropwise KHMDS in THF (0.5 mL of 1 M, 0.500 mmol). The reaction was stirred for 3 h, after which water (5 mL) and a few drops of saturated NH4Cl solution were added until a pH of 8-9 was reached. The aqueous phase was extracted with EtOAc (3 × 10 mL) and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Purification by silica gel chromatography (column 40 g Combiflash® Isco, gradient: 0-15% MeOH in DCM) afforded (2S,4S,6S)-1-allyl-2-methyl-6-(1-methyltriazol-4-yl)-4-[4-(trifluoromethyl)phenyl]piperidine-4-carbonitrile (94 mg, 70%) as a sticky yellow solid. LCMS m / z 390.2 [M+H]+

[0282] Step 3. Synthesis of (2S,4S,6S)-2-methyl-6-(1-methyltriazol-4-yl)-4-[4-(trifluoromethyl)phenyl]piperidine-4-carbonitrile (46) To a solution of (2S,4S,6S)-1-allyl-2-methyl-6-(1-methyltriazol-4-yl)-4-[4-(trifluoromethyl)phenyl]piperidine-4-carbonitrile (73 mg, 0.1873 mmol) and N,N-dimethylbarbituric acid (40 mg, 0.2408 mmol) in DCM (2 mL) was added Pd(PPh3)4 (20 mg, 0.0171 mmol). The reaction was stirred for 2 h. The solvent was removed under vacuum and then the residue...

Claims

1. A compound represented by the formula: 【Chemistry 142】 a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring A is C ６ aryl, and 5- and 6-membered heteroaryl groups; R １ is, for each occurrence, halogen, —OH, ═O, cyano, phenyl, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C ６ Carbocyclyl, 4- to 6-membered heterocyclyl, —C(═O)N(R ｃ ) ２ , and -SO ２ (R ｃ ) groups, R ｃ For each occurrence, hydrogen and C １ -C ４ independently selected from alkyl 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 Two R's １ groups, together with the ring A atoms to which they are connected, form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring; The 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl are each selected from halogen, —OH, and C １ -C ４ optionally substituted with 1 to 4 groups selected from alkyl; R ２ But C １ -C ６ Alkyl, —C(═O)O(C １ -C ４ alkyl), C ２ -C ６ alkynyl, and 【Chemistry 128】 is selected from R ２ 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), -C(=O)N(C １ -C ４ alkyl) ２ , C ３ -C ６ Carbocyclyl, 5- to 10-membered heterocyclyl, C ６ substituted with 1 to 3 groups independently selected from aryl, and 5- to 10-membered heteroaryl groups; Ring B is C ３ -C １２ Carbocyclyl, 3- to 12-membered heterocyclyl, C ６ and C １０ aryl, and 5- to 10-membered heteroaryl groups, and Ring B is selected from 1, 2, 3, 4, or 5 R ａ optionally substituted with a group, R ａ For each occurrence, halogen, cyano, 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 ３ -C １２ selected from carbocyclyl, 3- to 12-membered heterocyclyl, 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 R ４ is a halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -(CH ２ ) ｎ C(=O)NR ｎ R ｏ , -NR ｎ R ｏ , -NR ｏ C(=O)R ｐ , -NR ｎ S (= O) ｐ R ｐ 、 - (CH ２ ) ｎ OR ｐ , -S(=O) ｐ R ｐ , and -(CH ２ ) ｎ C(=O)OR ｐ is selected from the group R ｎ and R ｏ are hydrogen and C for each occurrence, respectively. １ -C ４ independently selected from alkyl groups, R ｐ For each occurrence, hydrogen, C １ -C ４ Alkyl, and C １ -C ４ haloalkyl groups, m is an integer selected from 0, 1, 2, 3, 4, and 5; n is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; A compound, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein q and r are, for each occurrence, integers independently selected from 1, 2, 3, and 4.

2. The compound is represented by the following structural formula: 【Chemistry 131】 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, which is a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

3. R ４ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein: is -OH.

4. R ３ But C １ -C ４ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein: R is an integer from 1 to 10; ... and R is an integer from 1 to 10.

5. R ２ But C １ -C ４ Alkyl and 【Chemistry 132】 is selected from the group R ２ The above C １ -C ４ Alkyl is halogen, cyano, —OH, —NH ２ , —NH(C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , C １ -C ２ Alkoxy, C ３ -C ６ 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, substituted with 1 to 3 groups independently selected from cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl groups.

6. Ring B is 【Chemistry 135】 each of which is selected from 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.

7. Ring B is one R ａ optionally substituted with a group 【Chemistry 137】 2. The compound of claim 1, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein:

8. R １ For each occurrence, halogen, cyano, —OH, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, —C(═O)N(R ｃ ) ２ , and C ３ -C ６ cycloalkyl groups, wherein R ｃ For each occurrence, hydrogen and C １ -C ２ independently selected from alkyl groups, R １ The above C １ -C ４ The alkyl is selected from halogen, cyano, —OH, and C １ -C ２ optionally substituted with 1 to 3 groups independently selected from alkoxy groups; R １ The above C １ -C ４ the alkoxy is optionally substituted with 1 to 3 independently selected halogen groups; R １ The above C ３ -C ６ Cycloalkyl is selected from halogen, cyano, —OH, and C １ -C ２ 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, optionally substituted with 1 to 3 groups independently selected from alkoxy groups.

9. 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:

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

11. R ａ For each occurrence, F, cyano, —OH, —CH ３ , -CF ３ , -CH(CH ３ ) ２ , -(CH ２ ) ２ OH, -(CH ２ ) ２ OCH ３ , -CH ２ CH(OH)C ２ H ５ , -CH ２ C(CH ３ ) (CH ２ OH) ２ , -OCH ３ , -OCH ２ CH ３ , -[O(CH ２ ) ２ ] ２ OCH ３ , -CH ２ C(=O)NHCH ３ , -(CH ２ ) ２ SO ２ CH ３ , -CH ２ C(=O)N(CH ３ ) ２ , -CH ２ (cyclopropyl), —C(═O)NH ２ , —C(═O)NH(cyclopropyl), —NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -NHC(CH ３ ) ２ CH ２ OH, -NHC(=O)CH ３ , -SO ２ CH ３ , -SO ２ NH ２ , cyclopropyl, 2-methoxyphenyl, N-methylpiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl, and tetrahydrothiophenyl 1,1-dioxide.

12. R ａ For each occurrence, -CH ３ , and -(CH ２ ) ２ SO ２ CH ３ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, independently selected from:

13. 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein Ring A is phenyl. 【Request Item 14】 【Chemistry 141】 【change】 【change】 【change】 【change】 and tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

15. Compound 16 【Chemistry 143】 a compound selected from: a tautomer thereof, a deuterated derivative of compound 16 or a tautomer thereof, and a pharmaceutically acceptable salt of any of the foregoing.

16. Compound 16 【Chemistry 144】 or a pharmaceutically acceptable salt thereof.

17. Compound 16 【Chemistry 145】 A compound which is

18. A compound represented by the formula: 【Chemistry 146】 a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R １ａ and R １ｂ is a halogen, hydrogen, C １ -C ４ Alkyl, and C １ -C ４ haloalkyl groups, R １ｃ is selected from halogen, hydrogen, CH3, —OH, and —CH2OH, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

19. 19. A silicon, boron, or phosphorus derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 18.

20. Form A of compound 16, (a) an X-ray powder diffractogram comprising signals at two or more °2θ values ​​selected from 10.9±0.2, 14.1±0.2, 15.4±0.2, 16.1±0.2, 17.5±0.2, 18.2±0.2, 19.3±0.2, 19.9±0.2, 20.0±0.2, 20.5±0.2, 20.6±0.2, 21.4±0.2, 21.7±0.2, 22.8±0.2, 23.3±0.2, 23.8±0.2, 26.1±0.2, and 26.2±0.2; and / or (b) a 13 C SSNMR spectrum comprising one or more signals selected from 153.5±0.2 ppm, 151.5±0.2 ppm, 126.9±0.2 ppm, 125.1±0.2 ppm, 123.9±0.2 ppm, 122.1±0.2 ppm, 73.6±0.2 ppm, 49.9±0.2 ppm, 47.2±0.2 ppm, 37.2±0.2 ppm, and 23.0±0.2 ppm; and / or (c) a 19 F SSNMR spectrum containing a signal at −58.0±0.2 ppm; and / or (d) Unit cell with orthorhombic crystal system, P2 1 2 1 2 1 space group, and dimensions measured at 100 K on a Bruker diffractometer with Cu Kα radiation (λ=1.54178 Å): Table 16 and / or (e) Unit cell with orthorhombic crystal system, P2 1 2 1 2 1 space group, and dimensions measured at 298 K on a Bruker diffractometer with Cu Kα radiation (λ = 1.54178 Å). Table 17 Form A of compound 16, characterized by:

21. A pharmaceutical composition comprising: (i) a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 18 or Form A of compound 16 of claim 20; and (ii) a pharmaceutically acceptable carrier.

22. Use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 18, or Form A of compound 16 of claim 20, in the manufacture of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease.

23. Use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 18, or Form A of compound 16 of claim 20, in the manufacture of a medicament for treating an APOL1-mediated disease.

24. The use according to claim 23, wherein the APOL1-mediated disease is cancer.

25. 21. A composition for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 18, or Form A of compound 16 of claim 20.

26. 21. A composition for use in the treatment of an APOL1 mediated disease, comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 18, or Form A of compound 16 of claim 20.

27. 21. A composition for use in the treatment of APOL1-mediated cancer, comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 18, or Form A of compound 16 of claim 20.

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