Inhibitors of APOL1 and methods of using the same

Abstract

To provide inhibitors of APOL1 and methods of using the same.SOLUTION: The disclosure provides compositions comprising compounds of the formula I in the figure, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharmaceutically acceptable salts of any of them, and methods of using the substances.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 070,705, filed August 26, 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure provides compounds that can inhibit apolipoprotein L1 (APOL1) and methods of using these compounds to treat APOL1-mediated kidney 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 levels of APOL1 (e.g., elevated levels of APOL1 in pancreatic cancer tissue). [Background technology]

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

[0004] FSGS and NDKD can be divided into distinct subpopulations based on the underlying etiology. One homogeneous subpopulation of FSGS is characterized by independent common sequence variants in the apolipoprotein L1 (APOL1) gene, designated G1 and G2, which are referred to as "APOL1 risk alleles." G1 encodes a correlated pair of nonsynonymous amino acid changes (S342G and I384M), G2 encodes a two-amino acid deletion (N388del:Y389del) near the C-terminus of the protein, and G0 is the ancestral (low-risk) allele. Distinct NDKD phenotypes are also observed in patients with APOL1 genetic risk variants. In both APOL1-mediated FSGS and NDKD, higher levels of proteinuria and more accelerated 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. Alternatively, in AMKD, even patients with one risk allele may develop high levels of proteinuria and accelerated 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. The APOL1 gene is expressed in multiple organs in humans, including the liver and kidney. APOL1 is primarily produced by the liver and contains a signal peptide that allows it to be secreted into the bloodstream, where it circulates bound to a subset of high-density lipoproteins. APOL1 is also expressed in the invasive parasite Trypanosoma brucei brucei. APOL1 is responsible for protection against the Tbbrucei (trypanosoma brucei) bacterium. It is endocytosed by Tbbrucei and transported to lysosomes, where it inserts into the lysosomal membrane, forming pores that lead to swelling and death of the parasite.

[0006] Although the ability to lyse Tb brucei is common to all three APOL1 variants (G0, G1, and G2), the APOL1 G1 and G2 variants confer additional protection against parasite species that have evolved serum resistance-associated proteins (SRA) that inhibit APOL1 G0. Thus, the APOL1 G1 and G2 variants confer additional protection against trypanosome species that cause sleeping sickness. The G1 and G2 variants avoid SRA inhibition. Thus, G1 confer additional protection against Tb gambiense (which causes West African sleeping sickness), and G2 confer additional protection against Tb brucei (which causes East African sleeping sickness).

[0007] In the kidney, APOL1 is expressed in podocytes, endothelial cells (including glomerular endothelial cells), and some tubular cells. Podocyte-specific expression of APOL1 G1 or G2 (but not G0) in transgenic mice induces structural and functional changes, including albuminuria, decreased renal function, podocyte abnormalities, and glomerular sclerosis. Consistent with these data, APOL1 G1 and G2 variants play a causative role in inducing FSGS and accelerating its progression in humans. Individuals with APOL1 risk alleles (i.e., homozygous or compound heterozygous for the APOL1 G1 or APOL1 G2 allele) are at increased risk of developing FSGS and, if they do develop FSGS, are at risk for a rapid decline in renal function. Therefore, 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 can vary by at least 20-fold in humans, circulating APOL1 is not causally associated with kidney disease. However, renal APOL1 is thought to contribute to the pathogenesis of kidney diseases, including FSGS and NDKD. Under certain circumstances, APOL1 protein synthesis can be increased approximately 200-fold by pro-inflammatory cytokines, such as interferon and tumor necrosis factor-α. In addition, APOL1 protein binds to the cell membrane via a pH-dependent Na+ transporter. + / K + pores, resulting in intracellular K + Several studies have shown that a net excretion of inflammatory cytokines occurs, ultimately leading to activation of 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, part of the glomerular filtration barrier, resulting in proteinuria. Patients with proteinuria are at high risk for developing end-stage kidney disease (ESKD) and proteinuria-related complications, such as infection or thromboembolic events. There are no standardized treatment regimens or approved medications for FSGS or NDKD. Currently, FSGS and NDKD are managed with symptomatic treatment (including blood pressure control using renin-angiotensin system blockers), and patients with FSGS and severe proteinuria may be provided with high-dose steroids. Current treatment options for NDKD are fixed on blood pressure control and renin-angiotensin system blockade.

[0011] Corticosteroids, alone or in combination with other immunosuppressants, have produced remissions in a small percentage of patients (e.g., remission of proteinuria in a small percentage of patients) and are associated with many side effects. Even in patients who respond to steroid and / or immunosuppressant treatment, remission often does not last long. As a result, patients, particularly those of Holocene sub-Saharan African descent who carry two APOL1 risk alleles, rapidly progress to end-stage renal disease (ESRD). Therefore, there is an unmet medical need for treatments for FSGS and NDKD. For example, given evidence that APOL1 plays a causal role in inducing and promoting renal disease progression, APOL1 inhibition should have a beneficial effect on patients with APOL1-mediated renal disease, particularly those who carry two APOL1 risk alleles (i.e., homozygous or compound heterozygous for the G1 or G2 allele). Furthermore, APOL1 is a gene that is abnormally expressed in multiple cancers (Lin et al., Cell Death and Disease (2021), 12:760). Recently, APOL1 was found to be abnormally elevated in human pancreatic cancer tissue compared with adjacent tissue and was associated with poor prognosis in pancreatic cancer patients. In in vivo and in vitro experiments, knockdown of APOL1 significantly inhibited cancer cell proliferation and promoted apoptosis of pancreatic cancer cells. [Prior art documents] [Non-patent literature]

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

[0013] One embodiment of the present disclosure is a compound represented by the formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, The present invention provides at least one compound selected from compounds of formulas Va'0 and Vb'0 (e.g., compounds of formula I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0 and Vb'0), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, which can be employed in the treatment of diseases mediated by APOL1, such as FSGS and NDKD. For example, the at least one compound is a compound represented by the following formula I: [ka] In the formula, X 1 , X 2 , R 1 , R 3a , R 3b , R 4 , R 5 , k and m are as defined in the embodiments disclosed herein.

[0014] In some embodiments, at least one compound 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 pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 is S and -CR 2a and X 2 is S and -CR 2b is selected from: X 1 and X 2 One of them is S, X 1 If S, then X 2 -CR 2b and X 2 If S, then X 1 -CR 2a and R 1 is selected from hydrogen, halogen, —OH, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and phenyl, wherein: R 1 wherein the C1-C6 alkyl 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 C1-C4 alkoxy; R 1 wherein the C1-C6 alkoxy is optionally substituted with 1 to 3 groups independently selected from halogen; R 1 C3-C6 cycloalkyl is optionally 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) -C(=O)N(C1-C4 alkyl)2, and -C(=O)N(C1-C4 alkyl)2; R1 wherein the phenyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C alkoxy, —C(═O)NH, —C(═O)NH(C-C alkyl), and —C(═O)N(C-C alkyl); R 2a is selected from hydrogen, halogen, cyano, —OH, ═O, and C1-C6 alkyl, wherein: R 2a wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C4 alkoxy; R 2b is selected from hydrogen, halogen, cyano, —OH, ═O, and C1-C6 alkyl; R 3a is selected from halogen, cyano, —OH, C1-C6 alkyl, and ═O, wherein R 3a wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R 3b is selected from C1-C2 alkyl and =O, wherein R 3b wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; [ka] are R 3a is selected from halogen, cyano, —OH, C1-C6 alkyl, or R 3b is a single bond when selected from C1-C2 alkyl, or [ka] are R 3a If =O, or R 3b is ═O, it is a double bond, R4 is C1-C6 alkyl, —C(═O)O(C1-C4 alkyl), C2-C6 alkynyl, and [ka] is selected from: R 4 wherein the C1-C6 alkyl 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 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Ring A is C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5-10 membered heteroaryl, and ring A optionally contains 1, 2, 3, 4, or 5 R a is substituted with a group, wherein R a are each independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkene, Nyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 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(CH2) q ]r O(C1-C6 alkyl), -S(=O) p R k , -S(=O) p NR h R i , -C(=O)OR k , C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5-10 membered heteroaryl, wherein R a C 1- C6 alkyl, C 1- C6 alkoxy and C2-C6 alkenyl are each C6 to C 10 aryl (optionally, 1 to 3 R m group), 5-10 membered heterocyclyl (optionally 1-3 R m group), 5-10 membered heteroaryl (optionally 1-3 R m substituted with a -C(=O)R 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 and C3-C6 carbocyclyl (optionally 1 to 3 R moptionally substituted with 1 to 3 groups independently selected from R a C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 The aryl and 5- to 10-membered heteroaryl are each selected from halogen, cyano, C1-C4 alkyl, -NR h R i AND-OR k and optionally substituted with 1 to 3 groups independently selected from: R h , R i and R j are hydrogen, C1-C4 alkyl, and C6-C 10 aryl, and C3-C6 cycloalkyl, wherein: R h , R i , and R j wherein any one of the C1-C4 alkyl groups is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R k are each independently selected from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl, R k wherein any one of the C1-C4 alkyl groups is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R m are halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S(=O) p R k , and -OR k are independently selected from R m wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R 5 is C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C10 aryl, and 5-10 membered heteroaryl, wherein R 5 wherein the C1-C6 alkyl 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; R 5 C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 The aryl, and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH, -NH(C-C alkyl (optionally substituted with -OH), -N(C-C alkyl), C-C alkyl (optionally substituted with -OH), C-C alkoxy, -C(=O)NH, -C(=O)NH(C-C alkyl), -NHC(=O)(C-C alkyl), -C(=O)(C-C alkoxy), and -C(=O)N(C-C alkyl); k is an integer selected from 0, 1, and 2, wherein R 3a When is selected from halogen, cyano, —OH, and C1-C6 alkyl, k is 1 or 2, and R 3a If =0, then k is 1, m is an integer selected from 0, 1, and 2, wherein R 3b C 1- When selected from C alkyl, m is 1 or 2; and R 3b When =0, m is 1; p is an integer selected from 1 and 2, and q and r are integers selected from 1, 2, 3, and 4, respectively.

[0015] In some embodiments, R 4 is C1-C6 alkyl and [ka] is selected from.

[0016] In some embodiments, R 5 is C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5- to 10-membered heteroaryl, wherein R 5 wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups 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; R 5 C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 The aryl, and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), C-C alkyl, C-C alkoxy, -C(=O)NH, -C(=O)NH(C-C alkyl), and -C(=O)N(C-C alkyl).

[0017] In some embodiments, at least one compound of the present disclosure (at least one 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 pharmaceutically acceptable salt of any of the foregoing, wherein: X 1and X 2 are S and -CR, respectively. 2 is selected from: X 1 and X 2 One of them is S, X 1 If S, then X 2 -CR 2b and X 2 If S, then X 1 -CR 2a and R 1 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and phenyl, wherein: R 1 wherein the C1-C6 alkyl 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 C1-C4 alkoxy; R 1 wherein the C1-C6 alkoxy is optionally substituted with 1 to 3 groups independently selected from halogen; R 1 wherein the C3-C6 cycloalkyl 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; R 1 wherein the phenyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C alkoxy, —C(═O)NH, —C(═O)NH(C-C alkyl), and —C(═O)N(C-C alkyl); R 2a is selected from hydrogen, halogen, cyano, —OH, ═O, and C1-C6 alkyl, wherein: R 2a wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C4 alkoxy; R 2b is selected from hydrogen, halogen, cyano, —OH, ═O, and C1-C6 alkyl; R 3a is selected from halogen, cyano, —OH, C1-C6 alkyl, and ═O, wherein R 3a wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R 3b is selected from C1-C2 alkyl and =O, wherein R 3b wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; [ka] are R 3a is selected from halogen, cyano, —OH, C1-C6 alkyl, or R 3b is a single bond when selected from C1-C2 alkyl, or [ka] respectively, R 3a If =O, or R 3b is ═O, it is a double bond, R 4 is C1-C6 alkyl and [ka] is selected from: R 4wherein the C1-C6 alkyl 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 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Ring A is C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5-10 membered heteroaryl, and ring A optionally contains 1, 2, 3, 4, or 5 R a is substituted with a group, wherein R a are each independently halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 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(CH2) q ] r O(C1-C6 alkyl), -S(=O) p R k , -S(=O) p NR h R i , C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10aryl, and 5-10 membered heteroaryl, wherein R a wherein C1-C6 alkyl and C2-C6 alkenyl are each optionally substituted with 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 and C-C cycloalkyl, R a C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 The aryl and 5- to 10-membered heteroaryl are each selected from halogen, cyano, C1-C4 alkyl, -NR h R i AND-OR k and optionally substituted with 1 to 3 groups selected from: R h , R i , and R j are each independently selected from hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl, R h , R i , and R jwherein any one of the C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, and —OH; R k are each independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R k wherein any one of the C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, and —OH; R 5 is C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5- to 10-membered heteroaryl, wherein R 5 wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups 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; R 5 C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 The aryl, and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C alkoxy, —C(═O)NH, —C(═O)NH(C-C alkyl), and —C(═O)N(C-C alkyl); k is R 3a is an integer selected from 0, 1, and 2 when R is selected from halogen, cyano, —OH, C1-C6 alkyl, or k is an integer selected from 0, 1, and 2 when R 3a is an integer selected from 0 and 1 when =0; m is R 3bis an integer selected from 0, 1, and 2 when selected from C1-C2 alkyl, and R 3b When =0, m is an integer selected from 0 and 1; p is an integer selected from 1 and 2, and A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein q and r are integers selected from 1, 2, 3, and 4, respectively.

[0018] In one embodiment of the present disclosure, the compound of Formula I is selected from Compounds 1-391 (e.g., Compounds 1-220), such that at least one substance is selected from Compounds 1-391 (e.g., Compounds 1-220), a pharmaceutically acceptable salt of said compound, a solvate of any of them, and a deuterated derivative of any of them.

[0019] In some embodiments, the present disclosure provides compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, Pharmaceutical compositions are provided that include at least one substance selected from compounds of IIIa', IIIb', IVa', IVb', Va', and Vb' (e.g., compounds of Formulas I, IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', and Vb'), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them. In some embodiments, pharmaceutical compositions may include at least one compound selected from compounds 1-391 (e.g., compounds 1-220), pharmaceutically acceptable salts of any of the compounds, solvates of any of them, and deuterated derivatives of any of them. These compositions may further include at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0020] Another aspect of the present disclosure provides a method of treating an APOL1-mediated disease (e.g., an APOL1-mediated renal disease), the method comprising administering to a subject in need thereof a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IIIa''', IIIb''', I Compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa, IIIb', IVa, IVb', Va, and Vb' (e.g., compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa, IIIb', IVa, IVb', Va, and Vb') In some embodiments, the method comprises administering at least one substance selected from Compounds 1-391 (e.g., Compounds 1-220), their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, or a pharmaceutical composition comprising the at least one substance.

[0021] Another aspect of the present disclosure provides a method of treating APOL1-mediated cancer (e.g., pancreatic cancer), comprising administering to a subject in need thereof a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I10, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I11, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I12, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I13, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I14, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I15, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I16, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I17, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I18, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0 In some embodiments, the method comprises administering at least one substance selected from compounds of Formulas I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb (e.g., compounds of Formulas I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb), tautomers thereof, deuterated derivatives of the compounds or tautomers, pharmaceutically acceptable salts of any of them, or a pharmaceutical composition comprising the at least one substance. In some embodiments, the method comprises administering at least one substance selected from compounds 1-391 (e.g., compounds 1-220), tautomers thereof, deuterated derivatives of the compounds or tautomers, pharmaceutically acceptable salts of any of them.

[0022] Another aspect of the present disclosure provides a method of treating FSGS and / or NDKD, the method comprising administering to a subject in need thereof a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, The method includes administering at least one substance selected from compounds of IIa', IIb', IIIa', IIIb', IVa', IVb', Va', and Vb' (e.g., compounds of Formulas I, IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', and Vb'), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, or a pharmaceutical composition comprising the at least one substance. In some embodiments, the method includes administering at least one substance selected from compounds 1-391 (e.g., compounds 1-220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them.

[0023] In some embodiments, the method of treatment includes administering to a subject in need thereof at least one additional active agent to a subject having a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa In some embodiments, the method comprises administering, in the same pharmaceutical composition or in separate compositions, at least one agent selected from compounds of Formulas I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa, IIIb', IVa', IVb', Va', and Vb', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them. In some embodiments, the method comprises administering, in the same pharmaceutical composition or in separate compositions, at least one agent selected from compounds 1-391 (e.g., compounds 1-220), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them.

[0024] Also provided is a method of inhibiting APOL1, comprising administering to a subject in need thereof a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, V, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa'''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, The method comprises administering at least one substance selected from compounds of IIIa', IIIb', IVa', IVb', Va', and Vb' (e.g., compounds of Formulas I, IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', and Vb'), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, or a pharmaceutical composition comprising the at least one substance. In some embodiments, the method for inhibiting APOL1 comprises administering at least one substance selected from compounds 1-391 (e.g., compounds 1-220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, or a pharmaceutical composition comprising the at least one substance. [Brief explanation of the drawings]

[0025] [Figure 1] FIG. 1 shows the XRPD diffractogram of the phosphate salt hydrate of compound 181 at 25±2° C. and 40% RH.

[0026] [Figure 2] FIG. 2 shows the XRPD diffractograms of the phosphate salt hydrate of compound 181 at 25±2° C. and 5% RH (black line) or 90% RH (gray line).

[0027] [Figure 3]FIG. 3 shows the TGA thermogram of the phosphate salt hydrate of compound 181.

[0028] [Figure 4] FIG. 4 shows the DSC curve of the phosphate hydrate of Compound 181.

[0029] [Figure 5] FIG. 5 shows the solid-state 13C NMR spectrum of the phosphate salt hydrate of compound 181.

[0030] [Figure 6] FIG. 6 shows the solid-state 19F NMR spectrum of the phosphate salt hydrate of compound 181 at 43% RH.

[0031] [Figure 7] FIG. 7 shows the effect of relative humidity on the solid-state 19F NMR spectrum of the phosphate salt hydrate of compound 181.

[0032] [Figure 8] FIG. 8 shows the solid state 31P NMR spectrum of the phosphate salt hydrate of compound 181 at 43% RH.

[0033] [Figure 9] FIG. 9 shows the effect of relative humidity on the solid-state 31P NMR spectrum of the phosphate salt hydrate of compound 181.

[0034] [Figure 10] FIG. 10 shows the XRPD diffractogram of the free form monohydrate of Compound 181.

[0035] [Figure 11] FIG. 11 shows the TGA thermogram of the free form monohydrate of Compound 181.

[0036] [Figure 12] FIG. 12 shows the DSC curve of the free form monohydrate of Compound 181.

[0037] [Figure 13] FIG. 13 shows the solid-state 13C NMR spectrum of the free form monohydrate of compound 181.

[0038] [Figure 14] FIG. 14 shows the solid-state 13C NMR spectrum of the dehydrated free form monohydrate of Compound 181.

[0039] [Figure 15] FIG. 15 shows the solid-state 19F NMR spectrum of the free form monohydrate of compound 181.

[0040] [Figure 16] FIG. 16 shows the solid-state 19F NMR spectrum of the dehydrated free form monohydrate of Compound 181.

[0041] [Figure 17] FIG. 17 shows the XRPD diffractogram of the phosphate salt methanol solvate of compound 181.

[0042] [Figure 18] FIG. 18 shows the solid-state 13C NMR spectrum of the phosphate salt methanol solvate of compound 181.

[0043] [Figure 19] FIG. 19 shows the solid-state 19F NMR spectrum of the phosphate salt methanol solvate of compound 181.

[0044] [Figure 20] FIG. 20 shows the solid-state 31P NMR spectrum of the phosphate salt methanol solvate of compound 181.

[0045] [Figure 21] FIG. 21 shows the XRPD diffractogram of the phosphate salt MEK solvate of compound 181.

[0046] [Figure 22] FIG. 22 shows the solid-state 13C NMR spectrum of the phosphate salt MEK solvate of compound 181.

[0047] [Figure 23] FIG. 23 shows the solid-state 19F NMR spectrum of the phosphate salt MEK solvate of compound 181.

[0048] [Figure 24] FIG. 24 shows the XRPD diffractogram of the phosphate salt hemihydrate of compound 174.

[0049] [Figure 25] FIG. 25 shows the TGA thermogram of the phosphate salt hemihydrate of Compound 174.

[0050] [Figure 26] FIG. 26 shows the DSC curve of the phosphate salt hemihydrate of Compound 174.

[0051] [Figure 27] FIG. 27 shows the solid-state 13C NMR spectrum of the phosphate salt hemihydrate of compound 174.

[0052] [Figure 28] FIG. 28 shows the solid-state 13C NMR spectrum of the dehydrated phosphate hemihydrate of Compound 174.

[0053] [Figure 29] FIG. 29A shows the solid-state 31P NMR spectrum of the phosphate salt hemihydrate of compound 174.

[0054] Figure 29B shows the solid state of the dehydrated phosphate hemihydrate of Compound 174. 31 The P NMR spectrum is shown.

[0055] [Figure 30] FIG. 30 shows the XRPD diffractogram of the hemihydrate of compound 174.

[0056] [Figure 31] FIG. 31 shows the TGA thermogram of the hemihydrate of Compound 174.

[0057] [Figure 32] FIG. 32 shows the DSC curve of the hemihydrate of compound 174.

[0058] [Figure 33] FIG. 33 shows the solid-state 13C NMR spectrum of the hemihydrate of compound 174.

[0059] [Figure 34] FIG. 34 shows the solid-state 13C NMR spectrum of the dehydrated hemihydrate of Compound 174. DETAILED DESCRIPTION OF THE INVENTION

[0060] definition The terms "selected" and "chosen" are used interchangeably herein.

[0061] As used herein, the term "APOL1" refers to the apolipoprotein L1 protein and the term "APOL1" refers to the apolipoprotein L1 gene.

[0062] 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, etc.). 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., patients who are homozygous or compound heterozygous for the G1 allele or the G2 allele. In some embodiments, the APOL1-mediated disease is associated with patients with one APOL1 risk allele.

[0063] The term "APOL1-mediated renal disease" refers to a disease or condition in which renal function is impaired and may be caused by APOL1. In some embodiments, APOL1-mediated renal disease is associated with patients who have two APOL1 risk alleles, such as patients who are homozygous or compound heterozygous for the G1 allele or the G2 allele. In some embodiments, the APOL1-mediated renal disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arteriosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1-mediated renal disease is chronic kidney disease or proteinuria.

[0064] As used herein, the term "FSGS" refers to focal segmental glomerulosclerosis, a disease of podocytes (the epithelial cells of the glomerular parenchyma) that causes proteinuria and progressive kidney function decline and is associated with two common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0065] As used herein, the term "NDKD" refers to non-diabetic kidney disease characterized by severe hypertension and progressive renal function decline and is associated with two common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0066] The terms "ESKD" and "ESRD" are used interchangeably herein to refer to end-stage renal disease or end-stage renal disease. ESKD / ESRD refers to the final stage of kidney disease, i.e., kidney failure, in which the kidneys no longer function sufficiently and the patient cannot survive without dialysis or a kidney transplant. In some embodiments, ESKD / ESRD is associated with two APOL1 risk alleles.

[0067] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having identical chemical structures, unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic variations may exist among the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom shown also includes lesser amounts of isotopic substitutions having a hydrogen atom at one or more of the designated deuterium positions in the structure. The relative amounts of such isotopic substitutions in the compounds of the present disclosure will depend on several factors, including the isotopic purity of the reagents used to make the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as noted above, the relative amount of such isotopic substitutions overall will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitution overall will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0068] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally," refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0069] The term "isotopologue" refers to a species whose chemical structure differs from a reference compound only in its isotopic composition. Additionally, unless otherwise specified, structures depicted herein also refer to chemical structures that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of carbon by C, are within the scope of this disclosure.

[0070] Unless otherwise indicated, structures depicted herein are also intended to include all isomeric forms of the structure, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds of the present invention are within the scope of this disclosure. Unless otherwise specified, all tautomeric forms of the compounds of this disclosure are within the scope of this disclosure.

[0071] The term "tautomer" as used herein refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by migration of atoms, e.g., hydrogen atoms, or groups, within the molecule.

[0072] "Stereoisomers" as used herein refers to enantiomers and diastereomers.

[0073] As used herein, a "deuterated derivative" has the same chemical structure as a reference compound, but contains a deuterium atom ("D" or " 2"Deuterated derivatives" refers to compounds having one or more hydrogen atoms replaced by deuterium at a level well above its natural isotopic abundance (typically about 0.015%). It will be recognized that some variation in natural isotopic abundance will occur in synthesized compounds depending on the source of the chemicals used in their synthesis. The concentration of naturally occurring stable hydrogen isotopes, despite this variation, is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Thus, unless otherwise specified, when reference is made to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen is replaced with deuterium at a level well above its natural isotopic abundance (which is typically about 0.015%). In some embodiments, deuterated derivatives of the present disclosure have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).

[0074] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0075] As used herein, the term "alkyl" refers to a fully saturated, straight-chain (i.e., linear or unbranched), substituted or unsubstituted hydrocarbon chain. Unless otherwise specified, alkyl groups contain 1-20 alkyl carbon atoms. In some embodiments, alkyl groups contain 1-10 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1-8 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1-6 alkyl carbon atoms, and in some embodiments, alkyl groups contain 1-4 alkyl carbon atoms. In other embodiments, alkyl groups contain 1-3 alkyl carbon atoms, and in still other embodiments, alkyl groups contain 1-2 alkyl carbon atoms. In some embodiments, alkyl groups are substituted. In some embodiments, alkyl groups are unsubstituted. In some embodiments, alkyl groups are linear or straight-chain or unbranched. In some embodiments, alkyl groups are branched.

[0076] The terms "cycloalkyl" or "cyclic alkyl" as used herein , monocyclic C 3-8 hydrocarbon or fully saturated spirocyclic, fused, or bridged bicyclic or tricyclic C 8-14 "cycloalkyl" refers to a hydrocarbon group, where any individual ring in the bicyclic ring system has 3 to 7 members. In some embodiments, the cycloalkyl group is substituted. In some embodiments, the cycloalkyl group is unsubstituted. In some embodiments, the cycloalkyl group is a C3 to C6 alkyl group. 12 In some embodiments, the cycloalkyl is a C3-C8 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0077] The term "carbocyclyl" or "alicyclic" as used herein encompasses the term "cycloalkyl" or "cyclic alkyl" and refers to a monocyclic C 3-8Hydrocarbons or spirocyclic, fused, or bridged bicyclic or tricyclic C rings that are fully saturated or partially saturated if they contain one or more unsaturated units but are not aromatic 8-14 "Carbocyclyl" refers to a hydrocarbon, where any individual ring in the bicyclic ring system has 3 to 7 members. Bicyclic carbocyclyl includes the combination of a monocyclic carbocyclic ring fused to a phenyl. In some embodiments, the carbocyclyl group is substituted. In some embodiments, the carbocyclyl group is unsubstituted. In some embodiments, the carbocyclyl is a C3-C 12 In some embodiments, the carbocyclyl is a C3-C 10 In some embodiments, the carbocyclyl is a C3-C8 carbocyclyl.

[0078] As used herein, the term "heteroalkyl" or "heteroaliphatic" refers to an alkyl group or an aliphatic group, as defined above, where one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon.

[0079] As used herein, the term "alkenyl" refers to a straight-chain (i.e., linear or unbranched), branched, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, an alkenyl group is substituted. In some embodiments, an alkenyl group is unsubstituted. In some embodiments, an alkenyl group is straight-chain. In some embodiments, an alkenyl group is branched.

[0080] As used herein, the terms "heterocycle," "heterocyclyl," "heteroaliphatic," or "heterocyclic" mean a non-aromatic (i.e., fully saturated or partially saturated if it contains one or more units of unsaturation but is not aromatic), monocyclic, or spirocyclic, or fused or bridged bicyclic or tricyclic ring system in which one or more ring members are independently selected heteroatoms. Bicyclic heterocyclyls include the following combinations of monocyclic rings: 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.

[0081] In some embodiments, the heterocycle includes ring atoms substituted with one or more oxo groups (eg, C=O, S=O, or SO2 groups).

[0082] In some embodiments, a "heterocycle," "heterocyclyl," "heteroaromatic," or "heterocyclic" group has 3 to 14 ring members, wherein one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has one heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocycle has one heteroatom that is a sulfur atom. In some embodiments, the heterocycle has one heteroatom that is an oxygen atom. In some embodiments, the heterocycle has two heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle has three heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle is substituted. In some embodiments, the heterocycle is unsubstituted. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl, tetrahydrothiophenyl 1,1-dioxide, and the like.

[0083] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (e.g., any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (Including N-substituted pyrrolidinyl).

[0084] As used herein, the term "unsaturated" 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.

[0085] As used herein, the term "alkoxy" or "thioalkyl" refers to an alkyl group, as defined above, where one carbon of the alkyl group is replaced with an oxygen atom ("alkoxy") or a sulfur atom ("thioalkyl"), respectively, provided that the oxygen atom and sulfur atom are linked between two carbon atoms. Non-limiting examples of alkoxy groups include methoxy, ethoxy, methylmethoxy, and the like. "Cyclic alkoxy" refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group and is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl. In some embodiments, the "alkoxy" and / or "thioalkyl" groups are substituted. In some embodiments, the "alkoxy" and / or "thioalkyl" groups are unsubstituted.

[0086] As used herein, the terms "haloalkyl," "haloalkenyl," and "haloalkoxy" refer to straight- or branched-chain alkyl, alkenyl, or alkoxy, respectively, substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF, -CHF, -CF, -CF-, and perhaloalkyl groups such as -CFCF. Non-limiting examples of haloalkoxy groups include -OCHF, -OCHF, -OCF, and -OCF.

[0087] The term "halogen" refers to F, Cl, Br, and I, i.e., fluoro, respectively. Includes bi-, chloro-, bromo-, and iodo-.

[0088] The term "aminoalkyl" refers to an alkyl group that is substituted with or contains an amino group.

[0089] As used herein, "amino" refers to a group that is a primary, secondary, or tertiary amine.

[0090] As used herein, a "carbonyl" group refers to C=O.

[0091] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0092] As used herein, a "hydroxy" group refers to an --OH group.

[0093] As used herein, a "thiol" group refers to -SH.

[0094] As used herein, "tert" and "t-" each refer to tertiary.

[0095] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system having delocalized pi orbitals consisting of [4n+2]p electrons, where n is an integer ranging from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0096] The term "aryl" used alone or as part of a larger moiety as in "arylalkyl," "arylalkoxy," or "aryloxyalkyl" refers to a monocyclic or spirocyclic, fused, or bridged, bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, wherein each ring in the system is an aromatic ring containing only carbon atoms, and each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl rings (C6) and naphthyl rings (C 10 In some embodiments, the aryl group is substituted. In some embodiments, the aryl group is unsubstituted.

[0097] The term "heteroaryl" used alone or as part of a larger moiety, such as in "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, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the bicyclic or tricyclic ring system 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 phenyl. In some embodiments, heteroaryl groups are substituted. In some embodiments, heteroaryl groups have one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl groups have one heteroatom. In some embodiments, heteroaryl groups have two heteroatoms. In some embodiments, the heteroaryl group is a monocyclic ring system having five ring members. In some embodiments, the heteroaryl group is a monocyclic ring system having six ring members. In some embodiments, the heteroaryl group is unsubstituted. 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 , 5-10 membered heteroaryl. In some embodiments, heteroaryl is 5-8 membered heteroaryl. In some embodiments, heteroaryl is 5- or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls include pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, and the like.

[0098] In some embodiments, the heteroaryl includes a ring atom substituted with one or more oxo groups (e.g., a C=O group, an S=O group, or an SO group). Illustrative, non-limiting example of a heteroaryl group is a benzo[d]oxazol-2(3H)-one group.

[0099] 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-fluorenylmethylcarbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods for adding (a process commonly referred to as "protecting") and removing (a process commonly referred to as "deprotecting") such amine protecting groups are well known in the art, and are described, for example, in P.J. Kocienski, Protecting Groups, Thieme, 1994, and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999), which are incorporated herein by reference in their entireties. th Edition (John Wiley & Sons,New Jersey, 2014).

[0100] Non-limiting examples of suitable solvents that can be used in the methods of the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0101] Non-limiting examples of suitable bases that can be used in the methods of the present disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (KCO), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropyl-ethylamine (i-PrEtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH).

[0102] The present disclosure includes pharmaceutically acceptable salts of the disclosed compounds, which are formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0103] The term "pharmaceutically acceptable" as used herein refers to those components which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salts" are those which, upon administration to a recipient, will undergo the effects of the present disclosure. " refers to any non-toxic salt that is capable of providing, either directly or indirectly, the compound of formula (I). Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0104] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include, 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-diol ... Included are oate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0105] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4(Alkyl) 4 salts are also included. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable, non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0106] The terms "patient" and "subject" are used interchangeably herein and refer to animals, including humans.

[0107] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of compound to which it is administered that produces the desired effect (e.g., amelioration of FSGS and / or NDKD symptoms, reduction in the severity of FSGS and / or NDKD or symptoms of FSGS and / or NDKD, and / or reduction in the progression of FSGS and / or NDKD or symptoms of FSGS and / or NDKD). The exact amount of the effective dose will depend on the purpose of treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0108] As used herein, the term "treatment" and its cognate terms refer to the slowing or stopping of disease progression. As used herein, "treatment" and its cognate terms include, but are not limited to, complete or partial remission, lower risk of renal failure (e.g., ESRD), and disease-related complications (e.g., edema, susceptibility to infection, or thromboembolic events). The improvement or reduction in severity of any of these symptoms can be easily assessed according to methods and techniques known in the art or subsequently developed.

[0109] The terms "about" and "approximately," when used in reference to a dose, amount, or weight percent of a component of a composition or dosage form, include a particular dose, amount, or weight percent value, or a range of doses, amounts, or weight percent, that would be recognized by one of skill in the art as providing an equivalent pharmacological effect to that obtained from the particular dose, amount, or weight percent.

[0110] Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''' , IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, At least one substance selected from compounds of Va'0 and Vb'0 (e.g., compounds of formulae I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, may be administered once a day, twice a day, or three times a day, for example, for the purpose of treating FSGS. In some embodiments, the nucleotides of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa', IIIb', IIIa'', IIb', IIIa'', IIIb', IVa'', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa', IIIb', IIIa'', IIb', IIIa'', IIIb', IVa'', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb', IIIa'', IIIb', IVa'', IVb', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa', IIIb', IIIa'', IIb', IIIa'', IIIb', IVa'', IVb', I0, IIa0, IIb0, IIIa0, IIIb0, IVa The compounds of a'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0 (e.g., compounds of Formula I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0) are selected from compounds 1-391 (e.g., compounds 1-220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them.In some embodiments, the nucleotides of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, II At least one substance selected from compounds of formula Ia', IIIb', IVa', IVb', Va', and Vb' (e.g., compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa, IIIb', IVa', IVb', Va', and Vb'), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, is administered once daily. In some embodiments, compounds 1-391 (e.g., compounds 1-220), tautomers thereof, deuterated derivatives of the compounds or tautomers. In some embodiments, at least one agent selected from the group consisting of a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, II At least one substance selected from compounds of formula Ia', IIIb', IVa', IVb', Va', and Vb' (e.g., compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa, IIIb', IVa', IVb', Va', and Vb'), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, is administered twice daily. In some embodiments, at least one substance selected from compounds 1-391 (e.g., compounds 1-220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, is administered twice daily.In some embodiments, the nucleotides of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, II At least one substance selected from compounds of formula Ia', IIIb', IVa', IVb', Va', and Vb' (e.g., compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa, IIIb', IVa', IVb', Va', and Vb'), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, is administered three times daily. In some embodiments, at least one substance selected from compounds 1-391 (e.g., compounds 1-220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, is administered three times daily.

[0111] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb, II ... At least one substance selected from compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb (e.g., compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, is administered once daily, twice daily, or three times daily. In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one agent selected from Compounds 1-391 (e.g., Compounds 1-220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them is administered once daily, twice daily, or three times daily.

[0112] One of ordinary skill in the art will appreciate that when an amount of a compound is disclosed, the relative amount of a pharmaceutically acceptable salt form of the compound. It will be recognized that the amount of a compound, pharmaceutically acceptable salt, solvate, and deuterated derivative disclosed herein is based on the free base form of the reference compound. For example, "1000 mg of at least one compound selected from the compound of formula (I) and a pharmaceutically acceptable salt thereof" includes 1000 mg of the compound of formula I and the concentration of a pharmaceutically acceptable salt of the compound of formula I equivalent to 1000 mg of the compound of formula I.

[0113] As used herein, the term "ambient conditions" means room temperature, outside air conditions, and uncontrolled humidity conditions.

[0114] As used herein, the terms "crystalline form" and "form" refer interchangeably to a crystalline structure (or polymorph) having a particular molecular packing arrangement within a crystal lattice. Crystalline 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, the term "Form A of compound [X]" or "Form A of compound [X]" refers to a unique crystalline form that can be identified and distinguished from other crystalline forms of Compound I 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).

[0115] As used herein, the term "SSNMR" refers to the analytical characterization method of solid-state nuclear magnetic resonance. SSNMR spectra can be recorded at ambient conditions, or at other conditions (e.g., 275 K), for any magnetically active isotopes present in the sample. Typical examples of active isotopes for small molecule active pharmaceutical ingredients include: 1 H, 2 H, 13 C. 19 F, 31 P, 15 N, 14 N, 35 Cl, 11 B. 7 Li, 17 O. 23 Na, 79 Br, and 195 Contains Pt.

[0116] 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 transmission or reflection geometry using a diffractometer.

[0117] 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; 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), shown on the abscissa of the X-ray powder diffractogram, which may be expressed as "a signal at ... degrees 2-theta," "a signal at ... 2-theta values," and / or "a signal at least ... 2-theta values ​​selected from ...."

[0118] As used herein, a "signal" or "peak" refers to a point in an XRPD pattern where the intensity, as 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, for example, may not be apparent 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 Rietveld refinement.

[0119] As used herein, "signals at ... degrees 2-theta," "signals at [ ] 2-theta values ​​of ...," and / or "signals at at least ... 2-theta values ​​selected from ..." refer to X-ray reflection positions measured and observed in an X-ray powder diffraction experiment (° 2θ).

[0120] The reproducibility of the angle values ​​is within ±0.2 degrees 2-theta, i.e., the angle value can be at the recited angle value +0.2 degrees 2-theta, angle value -0.2 degrees 2-theta, or any value between those two endpoints (angle value +0.2 degrees 2-theta and angle value -0.2 degrees 2-theta).

[0121] 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).

[0122] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

[0123] As used herein, the term "TGA" refers to the analytical method of Thermo Gravimetric (or thermogravimetric) analysis.

[0124] As used herein, "crystalline hydrate" refers to a crystalline form that contains water stoichiometrically or non-stoichiometrically in the crystal lattice. In the case of non-stoichiometric hydrates, the amount of water present in the crystalline hydrate may vary at least as a function of relative humidity (RH). The presence (or absence) of water or different amounts of water may cause a shift in the peak position of the X-ray diffractogram, or the appearance or disappearance of peaks. The presence (or absence) of water or different amounts of water may cause a shift in the peaks, or even the appearance of new peaks, in the solid-state NMR spectrum of proton, carbon, fluorine, phosphorus, nitrogen, chlorine (or other NMR-active nuclei). Compounds and Compositions

[0125] In some embodiments, at least one substance 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 pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 is S and -CR 2a and X 2 is S and -CR 2b is selected from: X 1 and X 2 One of them is S, X 1 If S, then X 2 -CR 2b and X 2 If S, then X 1 -CR 2a and R 1 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and phenyl, wherein: R 1 wherein the C1-C6 alkyl 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 C1-C4 alkoxy; R 1 wherein the C1-C6 alkoxy is optionally substituted with 1 to 3 groups independently selected from halogen; R 1 wherein the C3-C6 cycloalkyl 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; R 1wherein the phenyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C alkoxy, —C(═O)NH, —C(═O)NH(C-C alkyl), and —C(═O)N(C-C alkyl); R 2a is selected from hydrogen, halogen, cyano, —OH, ═O, and C1-C6 alkyl, wherein: R 2a wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C4 alkoxy; R 2b is selected from hydrogen, halogen, cyano, —OH, ═O, and C1-C6 alkyl; R 3a is selected from halogen, cyano, —OH, C1-C6 alkyl, and ═O, wherein R 3a wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R 3b is selected from C1-C2 alkyl and =O, wherein R 3b wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; [ka] are R 3a is selected from halogen, cyano, —OH, C1-C6 alkyl, or R 3b is a single bond when selected from C1-C2 alkyl, or [ka] are R 3a If =O, or R 3b is ═O, it is a double bond, R 4is C1-C6 alkyl, —C(═O)O(C1-C4 alkyl), C2-C6 alkynyl, and [ka] is selected from: R 4 wherein the C1-C6 alkyl 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 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Ring A is C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5-10 membered heteroaryl, and ring A optionally contains 1, 2, 3, 4, or 5 R a is substituted with a group, wherein R a are each independently halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 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(CH2) q ] rO(C1-C6 alkyl), -S(=O) p R k , -S(=O) p NR h R i , -C(=O)OR k , C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5-10 membered heteroaryl, wherein R a C 1- C6 alkyl, C 1- C6 alkoxy and C2-C6 alkenyl are each C6 to C 10 aryl (optionally, 1 to 3 R m group), 5-10 membered heterocyclyl (optionally 1-3 R m group), 5-10 membered heteroaryl (optionally 1-3 R m substituted with a -C(=O)R 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 and C3-C6 carbocyclyl (optionally 1 to 3 R m optionally substituted with 1 to 3 groups independently selected from Ra C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 The aryl and 5- to 10-membered heteroaryl are each selected from halogen, cyano, C1-C4 alkyl, -NR h R i AND-OR k and optionally substituted with 1 to 3 groups independently selected from: R h , R i and R j are hydrogen, C1-C4 alkyl, and C6-C 10 aryl, and C3-C6 cycloalkyl, wherein: R h , R i , and R j wherein any one of the C1-C4 alkyl groups is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R k are each independently selected from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl, R k wherein any one of the C1-C4 alkyl groups is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R m are halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S(=O) p R k , and -OR k are independently selected from R m wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R 5 is C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5-10 membered heteroaryl, wherein R 5 wherein the C1-C6 alkyl 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; R 5 C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 The aryl, and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH, -NH(C-C alkyl (optionally substituted with -OH), -N(C-C alkyl), C-C alkyl (optionally substituted with -OH), C-C alkoxy, -C(=O)NH, -C(=O)NH(C-C alkyl), -NHC(=O)(C-C alkyl), -C(=O)(C-C alkoxy), and -C(=O)N(C-C alkyl); k is an integer selected from 0, 1, and 2, wherein R 3a is selected from halogen, cyano, —OH, and C1-C6 alkyl, k is 1 or 2; and R 3a If =0, then k is 1, m is an integer selected from 0, 1, and 2, wherein R 3b C 1- When selected from C alkyl, m is 1 or 2; and R 3b When =0, m is 1; p is an integer selected from 1 and 2, and q and r are integers selected from 1, 2, 3, and 4, respectively.

[0126] In certain embodiments, compounds of the present disclosure are represented by one of the following structural formulas: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R 2a is selected from hydrogen, halogen, cyano, and C1-C4 alkyl, wherein: R 2a wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, —OH, and C1-C2 alkoxy; R 2b is selected from hydrogen, halogen, cyano, and C1-C4 alkyl, and k is an integer selected from 0, 1, and 2; All other variables not specifically defined herein are as defined in the preceding embodiments.

[0127] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 is C1-C4 alkyl and [ka] is selected from: R 4 wherein the C1-C4 alkyl 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; All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0128] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 is C1-C2 alkyl and [ka] is selected from: R 4 wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and 5- to 6-membered heterocyclyl; All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0129] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 is selected from —CH 3 , —CH 2 OH, and (tetrahydro-2H-pyran-4-yl)methyl, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0130] In certain embodiments, compounds of the present disclosure are represented by one of the following structural formulas: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Each ring A is selected from C3-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl, each of which optionally has 1, 2, 3, 4, or 5 R a is substituted with a group, All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0131] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, ring A is selected from cyclopropyl, 5-10 membered heterocyclyl, phenyl, and 5-9 membered heteroaryl, each of which optionally has 1, 2, 3, 4, or 5 R a All other variables substituted with groups and not specifically defined herein are as defined in any one of the preceding embodiments.

[0132] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, ring A 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 optionally is selected from 1, 2, 3, 4, or 5 R a All other variables substituted with groups and not specifically defined herein are as defined in any one of the preceding embodiments.

[0133] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, ring A 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, phenyl, 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, and a 9-membered heteroaryl containing 1-3 heteroatoms selected from N and O, each of which optionally contains 1, 2, 3, 4, or 5 R a All other variables substituted with groups and not specifically defined herein are as defined in any one of the preceding embodiments.

[0134] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is: [ka] each of which optionally has 1, 2, 3, 4 or 5 R a All other variables substituted with groups and not specifically defined herein are as defined in any one of the preceding embodiments.

[0135] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, ring A is: [ka] [ka] each of which optionally has 1, 2, 3, 4 or 5 R a All other variables substituted with groups and not specifically defined herein are as defined in any one of the preceding embodiments.

[0136] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 is selected from -CH3 and ring A, wherein ring A is [ka] each of which optionally has 1, 2, 3, 4 or 5 R a All other variables substituted with groups and not specifically defined herein are as defined in any one of the preceding embodiments.

[0137] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R5 is selected from C1-C4 alkyl, —C(═O)O(C1-C2 alkyl), C3-C6 cycloalkyl, and 5-10 membered heterocyclyl, wherein: R 5 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C2 alkoxy, and R 5 wherein the C3-C6 cycloalkyl and the 5- to 10-membered heterocyclyl are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, C1-C2 alkyl, and C1-C2 alkoxy; All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0138] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 5 is selected from C1-C2 alkyl, —C(═O)O(C1-C2 alkyl), cyclopropyl, cyclobutyl, and 5-6 membered heterocyclyl, wherein R 5 wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups independently selected from F, Cl, Br, cyano, —OH, and C1-C2 alkoxy; and R 5 wherein the cyclopropyl, cyclobutyl, and 5- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups independently selected from F, Cl, Br, cyano, —OH, C1-C2 alkyl, and C1-C2 alkoxy; All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0139] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 5is selected from —CH, —CHCH, —CHOH, —C(═O)OCH, —CHOCH, —CH(CH), cyclopropyl, difluorocyclopropyl, and tetrahydro-2H-pyranyl, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0140] In certain embodiments, compounds of the present disclosure are represented by one of the following structural formulas: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0141] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is selected from hydrogen, halogen, cyano, —OH, C1-C4 alkyl, C1-C4 alkoxy, and C3-C6 cycloalkyl, wherein: R 1 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C2 alkoxy; R 1 The C1-C4 alkoxy optionally contains 1 to 3 independently selected halogens. substituted with a group, and R 1 wherein the C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C2 alkoxy; All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0142] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is selected from F, Cl, Br, C1-C4 alkyl and C3-C6 cycloalkyl, wherein: R 1 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH, and R 1 wherein the C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0143] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is selected from F, Cl, Br, C1-C4 alkyl and C3-C6 cycloalkyl, wherein: R 1 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH, and R 1 wherein the C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0144] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is selected from Cl, Br, —CH, —CF, —CHCH, —CH(CH), —CHCHF, —CHCH(CH), difluorocyclobutyl, and cyclohexyl, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0145] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 is Cl, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0146] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3a is selected from —OH and C1-C4 alkyl, wherein: R 3a wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0147] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3a is selected from F, Cl, Br, —OH and C1-C2 alkyl, wherein: R 3a wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups independently selected from F, Cl, and —OH; All other variables not specifically defined herein are defined in any one of the preceding embodiments. As defined in

[0148] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3a is selected from F, —OH, —CH 3 , —CHF 2 , and —CH 2 OH, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0149] In certain embodiments, compounds of the present disclosure are represented by one of the following structural formulas: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0150] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R a are each independently halogen, cyano, C1-C6 alkyl, C1-C4 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -OR k , -[O(CH2) q ] r O(C1-C6 alkyl), -S(=O)2R k , -S(=O)2NR h R i , C3-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl, wherein R a The C1-C6 alkyl is optionally selected from cyano, -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 , -S(=O)2R k , -S(=O) p NR h R iand C3-C6 cycloalkyl, R a C3-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl are each optionally selected from halogen, C1-C2 alkyl, and -OR k and wherein the alkyl group is substituted with 1 to 3 groups independently selected from R h , R i , and R j are each independently selected from hydrogen, C1-C2 alkyl, cyclopropyl, and cyclobutyl, R h , R i , and R j wherein any one of the C1-C2 alkyl groups is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; R k are each independently selected from hydrogen and C1-C4 alkyl, R k wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH, and p and r are each an integer selected from 1, 2, and 3; All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0151] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R a are each independently halogen, cyano, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -OR k , -[O(CH2) q ] rO(C1-C4 alkyl), -S(=O)2R k , -S(=O)2NR h R i , cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein R a The C1-C6 alkyl is optionally selected from cyano, -C(=O)NR h R i , -NR h R i , -OR k , cyclopropyl, and cyclobutyl; R a wherein the cyclopropyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, —CH3, —OH, and —OCH3, R h and R i are each independently selected from hydrogen, —CH3, cyclopropyl, and cyclobutyl, R h and R i any one —CH3 is optionally substituted with 1 to 3 groups independently selected from F, Cl, and —OH; R k are each independently selected from hydrogen and —CH3, R k -CH3 is optionally substituted with 1 to 3 groups independently selected from halogen and -OH; All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0152] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R a each independently represents F, Cl, Br, cyano, C1-C6 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, or -C(=O)NR h Ri , -NR h R i , -NR h C(=O)R k , -OR k , -[O(CH2) q ] r O(C1-C2 alkyl), -S(=O)2R k , -S(=O)2NR h R i , cyclopropyl, cyclobutyl, 5-membered heterocyclyl, phenyl, and 6-membered heteroaryl, wherein R a The C1-C6 alkyl is optionally selected from cyano, -C(=O)NR h R i , -OR k and cyclopropyl; R a wherein the cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, —CH3, —OH, and —OCH3, R h and R i are each independently selected from hydrogen, —CH3, and cyclopropyl, R h and R i any one —CH3 is optionally substituted with 1 to 3 groups independently selected from F, Cl, and —OH; R k are each independently selected from hydrogen and —CH3, and q and r are integers selected from 1 and 2, All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0153] In certain embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R aare 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)2SO, respectively. 2CH3, -CH2C(=O)N(CH3)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-methoxypiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl, and tetrahydrothiophenyl 1,1-dioxide, and all other variables independently selected from 2CH3, -CH2C(=O)N(CH3)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-methoxypiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl, and tetrahydrothiophenyl 1,1-dioxide, and not specifically defined herein, are as defined in any one of the preceding embodiments.

[0154] In certain embodiments, compounds of the present disclosure are represented by one of the following structural formulas: [ka] [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0155] In certain embodiments, compounds of the present disclosure are represented by one of the following structural formulas: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0156] In certain embodiments, compounds of the present disclosure are represented by one of the following structural formulas: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0157] In some embodiments, at least one compound of the present disclosure is selected from compounds 1-220 shown in Table I, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them. A wavy line in the compounds of Table I, i.e., [ka] depicts a bond between two atoms and indicates the location of mixed stereochemistry for a collection of molecules such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. An asterisk adjacent to an atom in a compound of Table I, e.g., [ka] indicates a chiral position in the molecule.

[0158] In certain embodiments, at least one compound of the present disclosure is selected from compounds 221-391 shown in Table II, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them. [ka] depicts a bond between two atoms and indicates the location of mixed stereochemistry for a collection of molecules such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. An asterisk adjacent to an atom in the compounds of Table II, e.g., [ka] indicates a chiral position in the molecule.

[0159] In certain embodiments, at least one compound of the present disclosure is selected from compounds 1-391 shown in Table I or II, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them.

[0160] In certain embodiments, at least one compound of the present disclosure is selected from the compounds shown in Table III, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharmaceutically acceptable salts of any of them. The wavy line in the compounds of Table III, i.e., [ka] depicts a bond between two atoms and indicates the location of mixed stereochemistry for a collection of molecules such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. An asterisk adjacent to an atom in the compounds of Table III, e.g., [ka] indicates a chiral position in the molecule. [ka] [ka] [ka] [ka] [ka]

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[0161] Some embodiments of the present disclosure relate to derivatives of compounds 1-391 (e.g., compounds 1-220), or compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, I0, IIa0, IIb0, IIIa0, IIIb0, I ... In some embodiments, the compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb (e.g., compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them. In the formula (I), the derivative is a silicon derivative, and the derivative is a compound selected from compounds 1 to 391 (e.g., compounds 1 to 220), or a compound represented by formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va In the compounds of Formulas I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb (e.g., compounds of Formulas I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb), their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, at least one carbon atom is replaced by silicon.In some embodiments, the derivative is a boron derivative, wherein the derivative is a compound selected from Compounds 1-391 (e.g., Compounds 1-220), or a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa, IIb, IIIa, IIIb, IVa, IVb, I10, IIa, IIb, IIIa, IIIb, IVa, IVb, I20, IIb, IIIa, IIIb, IVa, IVb, I30, IIb, IIIa, IIIb, IVa, IVb, I40, IIb, I50, IIb, I60, IIb, I70, IIb, I80, IIIb, I90, IIIb, I10, IIIb, I11, IIIb, I120, IIIb, I130, IIIb, I210, IIIb, I30, IIIb, I40, I50, IIb, I60, IIb, I70, IIIb, I80, IIIb, I90, IIIb, I90, IIIb, I110, IIIb, I120, IIIb, I130, IIIb, I140, I140, I150, IIb, I150, IIIb, I160, IIIb, I170, IIIb, I180, IIIb, I190, IIIb, I20, IIIb, I210, IIIb, I220, I230, I240, I250, I260, IIb In the compounds of Formulas I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb (e.g., compounds of Formulas I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb), their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, at least one carbon atom is replaced by boron.In other embodiments, the derivative is a phosphorus derivative, and the derivative is a compound selected from Compounds 1-391 (e.g., Compounds 1-220), or a compound represented by Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, ... , VaO, VbO, I'O, IIa'O, IIb'O, IIIa'O, IIIb'O, IVa'O, IVb'O, Va'O, and Vb'O (e.g., compounds of Formula IO, IIaO, IIbO, IIIaO, IIIbO, IVaO, IVbO, VaO, VbO, I'O, IIa'O, IIb'O, IIIa'O, IIIb'O, IVa'O, IVb'O, Va'O, and Vb'O), their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, at least one carbon atom is replaced by phosphorus.

[0162] In some embodiments, the derivative is a silicon derivative, and the derivative is a compound selected from Compounds 1-391 (e.g., Compounds 1-220), or a compound represented by Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa' Compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, V, I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, V, I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and V, In the compounds of Ib0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0, their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, at least one carbon atom 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, fluorine is replaced by a silicon derivative (e.g., -Si(CH3)3). In some embodiments, the silicon derivatives of the present disclosure may contain one or more hydrogen atoms replaced by deuterium. In some embodiments, a compound selected from compounds 1-391 (e.g., compounds 1-220), or a compound of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I10, II11, II12, III13, III14, III15, III16, III17, III18, III19, III20, III219, III220, III23, III24, III25, III26, III27, III28, III29, III30, III310, III321, III33, III34, III35, III36, III37, III38, III39, III39, III40, III410, III420, III421, III43, III44, III45, III46, III47, III48, III49, III50, III510, III520, III530, III540, III550, III560, III570, III580, III590, III591, III592, III593, III594, III595, III596, III597, III598, III599, III599, III599, III599, III599, III599, III599, III599, III599 The silicon derivatives of the compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb (e.g., compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb), their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, may incorporate silicon within a heterocycle.

[0163] In some embodiments, the derivative is a boron derivative, wherein the derivative is a compound selected from Compounds 1-391 (e.g., Compounds 1-220), or a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa, IIb, IIIa, IIIb, IVa, IVb, In the compounds of Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0 (e.g., compounds of formula I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0), their tautomers, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, one carbon atom is replaced by boron or a boron derivative.

[0164] In some embodiments, the derivative is a phosphorus derivative, and the derivative is a compound selected from Compounds 1-391 (e.g., Compounds 1-220), or a compound represented by Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', ... , IVbO, VaO, VbO, I'O, IIa'O, IIb'O, IIIa'O, IIIb'O, IVa'O, IVb'O, Va'O, and Vb'O (e.g., compounds of Formulas IO, IIaO, IIbO, IIIaO, IIIbO, IVaO, IVbO, VaO, VbO, I'O, IIa'O, IIb'O, IIIa'O, IIIb'O, IVa'O, IVb'O, Va'O, and Vb'O), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them, wherein one carbon atom is selected from the group consisting of phosphorus and phosphorus derivatives. is replaced by

[0165] Another aspect of the present disclosure is directed to compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, Provided are pharmaceutical compositions comprising at least one compound according to any one of formulas selected from IVb'O, Va'O, and Vb'O (e.g., compounds of formula I0, IIaO, IIbO, IIIaO, IIIbO, IVaO, IVbO, VaO, VbO, I'O, IIa'O, IIb'O, IIIa'O, IIIb'O, IVa'O, IVb'O, Va'O, and Vb'O), and compounds 1-391 (e.g., compounds 1-220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them. In some embodiments, the nucleotides of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, I A pharmaceutical composition comprising at least one compound selected from Vb'0, Va'0, and Vb'0 (e.g., compounds of formula I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0), and compounds 1-391 (e.g., compounds 1-220), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, is administered to a subject in need thereof.

[0166] The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the at least one pharmaceutically acceptable is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0167] 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, the pharmaceutical compositions of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and V A pharmaceutical composition comprising at least one compound selected from compounds of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', and Vb', a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any thereof, may be administered as a separate composition simultaneously with, prior to, or subsequent to a composition comprising at least one other active therapeutic agent. In some embodiments, compounds 1-391 (e.g., compounds 1-220), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any thereof, may be administered as a separate composition simultaneously with, prior to, or subsequent to a composition comprising at least one other active therapeutic agent. A pharmaceutical composition comprising at least one compound selected from the deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of either thereof, may be administered as a separate composition simultaneously with, prior to, or subsequent to a composition comprising at least one other active therapeutic agent.

[0168] As described above, the pharmaceutical compositions disclosed herein may further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, the at least one pharmaceutically acceptable carrier includes any solvent, diluent, other liquid vehicle, dispersion aid, suspension aid, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder, and lubricant suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), saturated vegetable fatty acids, partial glyceride mixtures of water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxymethylcellulose sodium), and the like. Examples of suitable carriers include, but are not limited to, cellulose acetate, sodium, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0169] 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.

[0170] In some embodiments, the disclosed methods include administering to a patient in need thereof an oral administration of a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb and Vb'O, a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa, IIIb, IVa, IVb', Va, Vb'O, and Vb'O (e.g., a compound of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa, IIIb', IVa, IVb', Va, Vb'O, and Vb'O), a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the compounds. In some embodiments, the compound of Formula I is selected from compounds 1-391 (e.g., compounds 1-220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them. In some embodiments, the patient in need thereof carries APOL1 genetic variants, i.e., G1:S342G:I384M and G2:N388del:Y389del.

[0171] Another aspect of the present disclosure provides a method for inhibiting APOL1 activity, the method comprising combining the APOL1 with a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb''', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb In some embodiments, the method comprises contacting at least one substance selected from a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb (e.g., a compound of Formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them. In some embodiments, the method comprises contacting the APOL1 with at least one substance selected from compounds 1-391 (e.g., compounds 1-220), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them. Non-limiting exemplary embodiment 1

[0172] Some embodiments of the present disclosure include, but are not limited to, the following. 1. A compound represented by the following structural formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer thereof, or any of the foregoing Any pharmaceutically acceptable salt thereof, wherein: X 1 is S and -CR 2a and X 2 is S and -CR2b is selected from: X 1 and X 2 One of them is S, X 1 If S, then X 2 -CR 2b and X 2 If S, then X 1 -CR 2a and R 1 is selected from hydrogen, halogen, cyano, —OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and phenyl, wherein: R 1 wherein the C1-C6 alkyl 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 C1-C4 alkoxy; R 1 wherein the C1-C6 alkoxy is optionally substituted with 1 to 3 groups independently selected from halogen; R 1 wherein the C3-C6 cycloalkyl 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; R 1 wherein the phenyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C alkoxy, —C(═O)NH, —C(═O)NH(C-C alkyl), and —C(═O)N(C-C alkyl); R 2a is selected from hydrogen, halogen, cyano, —OH, ═O, and C1-C6 alkyl, wherein: R 2awherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C4 alkoxy; R 2b is selected from hydrogen, halogen, cyano, —OH, ═O, and C1-C6 alkyl; R 3a is selected from halogen, cyano, —OH, C1-C6 alkyl, and ═O, wherein R 3a wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R 3b is selected from C1-C2 alkyl and =O, wherein R 3b wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; [ka] are R 3a is selected from halogen, cyano, —OH, C1-C6 alkyl, or R 3b is a single bond when selected from C1-C2 alkyl, or [ka] are R 3a If =O, or R 3b is ═O, it is a double bond, R 4 is C1-C6 alkyl, —C(═O)O(C1-C4 alkyl), C2-C6 alkynyl, and [ka] is selected from: R 4wherein the C1-C6 alkyl 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 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Ring A is C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5-10 membered heteroaryl, where ring A optionally contains 1, 2, 3, 4, or 5 R a is substituted with a group, wherein R a are each independently halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 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(CH2) q ] r O(C1-C6 alkyl), -S(=O) p R k , -S(=O) p NR h R i , -C(=O)OR k , C3-C 12Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5-10 membered heteroaryl, wherein R a C 1- C6 alkyl, C 1- C6 alkoxy and C2-C6 alkenyl are each C6 to C 10 aryl (optionally, 1 to 3 R m group), 5-10 membered heterocyclyl (optionally 1-3 R m group), 5-10 membered heteroaryl (optionally 1-3 R m substituted with a -C(=O)R 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 and C3-C6 carbocyclyl (optionally 1 to 3 R m optionally substituted with 1 to 3 groups independently selected from R a C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 The aryl and 5- to 10-membered heteroaryl are each selected from halogen, cyano, C1-C4 alkyl, -NRh R i AND-OR k and optionally substituted with 1 to 3 groups independently selected from: R h , R i and R j are hydrogen, C1-C4 alkyl, and C6-C 10 aryl, and C3-C6 cycloalkyl, wherein: R h , R i , and R j wherein any one of the C1-C4 alkyl groups is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R k are each independently selected from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl, R k wherein any one of the C1-C4 alkyl groups is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R m are halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S(=O) p R k , and -OR k are independently selected from R m C1-C6 alkyl is optionally, independently of halogen, cyano, and -OH. and is substituted with 1 to 3 groups selected from R 5 is C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5-10 membered heteroaryl, wherein R 5wherein the C1-C6 alkyl 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; R 5 C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 The aryl, and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH, -NH(C-C alkyl (optionally substituted with -OH), -N(C-C alkyl), C-C alkyl (optionally substituted with -OH), C-C alkoxy, -C(=O)NH, -C(=O)NH(C-C alkyl), -NHC(=O)(C-C alkyl), -C(=O)(C-C alkoxy), and -C(=O)N(C-C alkyl); k is an integer selected from 0, 1, and 2, wherein R 3a is selected from halogen, cyano, —OH, and C1-C6 alkyl, k is 1 or 2; and R 3a If =0, then k is 1, m is an integer selected from 0, 1, and 2, wherein R 3b C 1- When selected from C alkyl, m is 1 or 2; and R 3b When =0, m is 1; p is an integer selected from 1 and 2, and A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, wherein q and r are integers selected from 1, 2, 3, and 4, respectively. 2. The compound is represented by one of the following structural formulas: [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R 2a is selected from hydrogen, halogen, cyano, and C1-C4 alkyl, wherein: R 2a wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, —OH, and C1-C2 alkoxy; R 2b is selected from hydrogen, halogen, cyano, and C1-C4 alkyl, and k is an integer selected from 0, 1, and 2; All other variables not specifically defined herein are as defined in embodiment 1. 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein: 3.R 4 is C1-C4 alkyl and [ka] is selected from: R 4 wherein the C1-C4 alkyl 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; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 1 or Embodiment 2, wherein all other variables not specifically defined herein are as defined in Embodiment 1 or Embodiment 2. 4. R 4 is C1-C2 alkyl and [ka] is selected from: R4 wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and 5- to 6-membered heterocyclyl; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Embodiments 1-3, wherein all other variables not specifically defined herein are as defined in any one of Embodiments 1-3. 5.R 4 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4, wherein R is selected from -CH, -CHOH, and (tetrahydro-2H-pyran-4-yl)methyl, and all other variables not specifically defined herein are as defined in any one of embodiments 1-4. 6. The compound is represented by one of the following structural formulas: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Each ring A is selected from C3-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl, each of which optionally has 1, 2, 3, 4, or 5 R a is substituted with a group, The compound of any one of embodiments 1-4, wherein all other variables not specifically defined herein are as defined in any one of embodiments 1-5. 7. Ring A is selected from cyclopropyl, 5-10 membered heterocyclyl, phenyl, and 5-9 membered heteroaryl, each of which optionally contains 1, 2, 3, 4, or 5 R a7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4 and 6, wherein R is substituted with a group and all other variables not specifically defined herein are as defined in any one of embodiments 1-6. 8. Ring A 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 optionally contains 1, 2, 3, 4, or 5 R a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4, 6, and 7, wherein the compound is substituted with a group and all other variables not specifically defined herein are as defined in any one of embodiments 1-7. 9. Ring A is selected from cyclopropyl, 5-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, 6-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, 9-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, 10-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, phenyl, 5-membered heteroaryl containing 1-3 heteroatoms selected from N and O, 6-membered heteroaryl containing 1-3 heteroatoms selected from N and O, and 9-membered heteroaryl containing 1-3 heteroatoms selected from N and O, each of which optionally contains 1, 2, 3, 4, or 5 R a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4 and 6-8, wherein the compound is substituted with a group and all other variables not specifically defined herein are as defined in any one of embodiments 1-8. 10. Ring A is [ka] each of which optionally has 1, 2, 3, 4 or 5 R aA compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4 and 6-9, wherein the compound is substituted with a group and all other variables not specifically defined herein are as defined in any one of embodiments 1-9. 11. Ring A is [ka] [ka] each of which optionally has 1, 2, 3, 4 or 5 R a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4 and 6-10, wherein the compound is substituted with a group and all other variables not specifically defined herein are as defined in any one of embodiments 1-4 and 6-10. 12.R 4 is selected from -CH3 and ring A, wherein ring A is [ka] each of which optionally has 1, 2, 3, 4 or 5 R a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4 and 6-11, wherein the compound is substituted with a group and all other variables not specifically defined herein are as defined in any one of embodiments 1-4 and 6-11. 13.R 5 is selected from C1-C4 alkyl, —C(═O)O(C1-C2 alkyl), C3-C6 cycloalkyl, and 5-10 membered heterocyclyl, wherein: R 5 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C2 alkoxy; and R 5wherein the C3-C6 cycloalkyl and the 5- to 10-membered heterocyclyl are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, C1-C2 alkyl, and C1-C2 alkoxy; The compound of any one of embodiments 1 to 12, wherein all other variables not specifically defined herein are as defined in any one of embodiments 1 to 12. a derivative, a deuterated derivative, or a pharmaceutically acceptable salt. 14.R 5 is selected from C1-C2 alkyl, —C(═O)O(C1-C2 alkyl), cyclopropyl, cyclobutyl, and 5-6 membered heterocyclyl, wherein R 5 wherein the C1-C2 alkyl is optionally selected from F, Cl, Br, cyano, -OH, and substituted with 1 to 3 groups independently selected from C1-C2 alkoxy, and R 5 wherein the cyclopropyl, cyclobutyl, and 5- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups independently selected from F, Cl, Br, cyano, —OH, C1-C2 alkyl, and C1-C2 alkoxy; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Embodiments 1-13, wherein all other variables not specifically defined herein are as defined in any one of Embodiments 1-13. 15.R 5 is selected from —CH, —CHCH, —CHOH, —C(═O)OCH, —CHOCH, —CH(CH), cyclopropyl, difluorocyclopropyl, and tetrahydro-2H-pyranyl, and all other variables not specifically defined herein are as defined in any one of embodiments 1-14. 16. The compound is represented by one of the following structural formulas: [ka] The compound of any one of embodiments 1-4 and 6-15, which is a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, and all other variables not specifically defined herein are as defined in any one of embodiments 1-4 and 6-15. 17.R 1 is selected from hydrogen, halogen, cyano, —OH, C1-C4 alkyl, C1-C4 alkoxy, and C3-C6 cycloalkyl, wherein: R 1 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C2 alkoxy; R 1 wherein the C1-C4 alkoxy is optionally substituted with 1 to 3 independently selected halogen groups, and R 1 The C3-C6 cycloalkyl is optionally selected from halogen, cyano, -OH, and substituted with 1 to 3 groups independently selected from C1-C2 alkoxy; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-16, wherein all other variables not specifically defined herein are as defined in any one of embodiments 1-16. 18.R 1 is selected from F, Cl, Br, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein: R 1 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH, and R 1 wherein the C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-17, wherein all other variables not specifically defined herein are as defined in any one of embodiments 1-17. 19.R 1 is selected from F, Cl, Br, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein: R 1 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-18, wherein all other variables not specifically defined herein are as defined in any one of embodiments 1-18. 20.R 1 is selected from Cl, Br, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH2CHF2, -CH2CH(CH3)2, difluorocyclobutyl, and cyclohexyl. 21. R 1 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-20, wherein R is Cl, and all other variables not specifically defined herein are as defined in any one of embodiments 1-20. 22.R 3a is selected from —OH and C1-C4 alkyl, wherein: R 3a wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Embodiments 1-21, wherein all other variables not specifically defined herein are as defined in any one of Embodiments 1-21. 23.R 3ais selected from F, Cl, Br, —OH and C1-C2 alkyl, wherein: R 3a wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups independently selected from F, Cl, and —OH; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-22, wherein all other variables not specifically defined herein are as defined in any one of embodiments 1-22. 24.R 3a is selected from F, —OH, —CH, —CHF, and CHOH, and all other variables not specifically defined herein are as defined in any one of embodiments 1-23. 25. The compound is represented by one of the following structural formulas: [ka] The compound of any one of embodiments 1-4 and 6-24, wherein the compound is a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, and all other variables not specifically defined herein are as defined in any one of embodiments 1-4 and 6-24. 26.R a are each independently halogen, cyano, C1-C6 alkyl, C1-C4 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -OR k , -[O(CH2) q ] r O(C1-C6 alkyl), -S(=O)2R k , -S(=O)2NR h R i, C3-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl, wherein: R a The C1-C6 alkyl is optionally selected from cyano, -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 , -S(=O)2R k , -S(=O) p NR h R i and C-C cycloalkyl, R a C3-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl are each optionally selected from halogen, C1-C2 alkyl, and -OR k and wherein the alkyl group is substituted with 1 to 3 groups independently selected from R h , R i , and R j are each independently selected from hydrogen, C1-C2 alkyl, cyclopropyl, and cyclobutyl, R h , R i , and R j wherein any one of the C1-C2 alkyl groups is optionally substituted with 1 to 3 groups independently selected from halogen and —OH; R k are each independently selected from hydrogen and C1-C4 alkyl, R k wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH, and p and r are each an integer selected from 1, 2, and 3; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4 and 6-25, wherein all other variables not specifically defined herein are as defined in any one of embodiments 1-4 and 6-25. 27.R a are each independently halogen, cyano, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -OR k , -[O(CH2) q ] r O(C1-C4 alkyl), -S(=O)2R k , -S(=O)2NR h R i , cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein R a The C1-C6 alkyl is optionally selected from cyano, -C(=O)NR h R i , -NR h R i , -OR k , cyclopropyl, and cyclobutyl; is substituted with groups, R a wherein the cyclopropyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, —CH3, —OH, and —OCH3, R h and R i are each independently selected from hydrogen, —CH3, cyclopropyl, and cyclobutyl, R h and Ri any one —CH3 is optionally substituted with 1 to 3 groups independently selected from F, Cl, and —OH; R k are each independently selected from hydrogen and —CH3, R k -CH3 is optionally substituted with 1 to 3 groups independently selected from halogen and -OH; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4 and 6-26, wherein all other variables not specifically defined herein are as defined in any one of embodiments 1-4 and 6-26. 28.R a each independently represents F, Cl, Br, cyano, C1-C6 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, or -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -OR k , -[O(CH2) q ] r O(C1-C2 alkyl), -S(=O)2R k , -S(=O)2NR h R i , cyclopropyl, cyclobutyl, 5-membered heterocyclyl, phenyl, and 6-membered heteroaryl, wherein R a The C1-C6 alkyl is optionally selected from cyano, -C(=O)NR h R i , -OR k and cyclopropyl; R a wherein the cyclopropyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, —CH3, —OH, and —OCH3, R h and R iare each independently selected from hydrogen, —CH3, and cyclopropyl, R h and R i any one —CH3 is optionally substituted with 1 to 3 groups independently selected from F, Cl, and —OH; R k are each independently selected from hydrogen and —CH3, and q and r are integers selected from 1 and 2, The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4 and 6-27, wherein all other variables not specifically defined herein are as defined in any one of embodiments 1-4 and 6-27. 29.R a are each independently 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, A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-4 and 6-28 selected from -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 herein are as defined in embodiments 1-4 and 6-28. 30. The compound is represented by one of the following structural formulas: [ka] [ka] The compound of embodiment 1, wherein the compound is a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments. 31. A compound selected from the compounds of Table I, its tautomers, deuterated derivatives of said compounds or tautomers, and pharmaceutically acceptable salts of any of them. 32. A compound selected from the compounds of Table II, its tautomers, deuterated derivatives of said compounds or tautomers, and pharmaceutically acceptable salts of any of them. 33. A compound selected from the compounds of Table III, its tautomers, deuterated derivatives of said compounds or tautomers, and pharmaceutically acceptable salts of any of them. 34. A pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-33, and a pharmaceutically acceptable carrier. 35. 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 33, or a pharmaceutical composition according to embodiment 34. 36. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33, or the pharmaceutical composition according to embodiment 34, for the manufacture of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 37. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33, or a medicament according to embodiment 34, for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. composition. 38. A method for inhibiting the activity of APOL1, comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34. 39. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34, for the manufacture of a medicament for inhibiting the activity of APOL1. 40. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34, for use in inhibiting the activity of APOL1. 41. A method for treating an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease), comprising administering to a patient in need thereof at least one compound according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34. 42. The method of embodiment 41, wherein the APOL1-mediated disease is cancer. 43. The method of embodiment 41 or embodiment 42, wherein the APOL1-mediated disease is pancreatic cancer. 44. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34, for the manufacture of a medicament for the treatment of an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease). 45. The use according to embodiment 44, wherein the APOL1-mediated disease is cancer. 46. ​​The use according to embodiment 44 or embodiment 45, wherein the APOL1-mediated disease is pancreatic cancer. 47. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34, for use in treating an APOL1-mediated disease (e.g., an APOL1-mediated renal disease). 48. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, or pharmaceutical composition for use according to embodiment 47, wherein the APOL1-mediated disease is cancer. 49. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, or pharmaceutical composition for use according to embodiment 47 or embodiment 48, wherein the APOL1-mediated disease is pancreatic cancer. 50. A method for inhibiting the activity of APOL1, comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34. 51. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34, for the manufacture of a medicament for inhibiting the activity of APOL1. 52. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33, or a pharmaceutical composition according to embodiment 34, for use in inhibiting the activity of APOL1. 53. A silicon derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-33. 54. A pharmaceutical composition comprising the silicon derivative according to embodiment 53. 55. A method for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising administering to a patient in need thereof the silicon derivative of embodiment 53 or the pharmaceutical composition of embodiment 54. 56. Use of the silicon derivative according to embodiment 53 or the pharmaceutical composition according to embodiment 54 for the manufacture of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 57. The silicon derivative according to embodiment 53 or the pharmaceutical composition according to embodiment 54 for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 58. A method for treating an APOL1-mediated disease (e.g., an APOL1-mediated renal disease), comprising administering to a patient in need thereof a silicon derivative according to embodiment 53 or a pharmaceutical composition according to embodiment 54. 59. The method of embodiment 58, wherein the APOL1-mediated disease is cancer. 60. The method of embodiment 58 or embodiment 59, wherein the APOL1-mediated disease is pancreatic cancer. 61. Use of the silicon derivative according to embodiment 53 or the pharmaceutical composition according to embodiment 54 for the manufacture of a medicament for the treatment of an APOL1-mediated disease (for example, an APOL1-mediated kidney disease). 62. The use according to embodiment 61, wherein the APOL1-mediated disease is cancer. 63. The use according to embodiment 61 or embodiment 62, wherein the APOL1-mediated disease is pancreatic cancer. 64. The silicon derivative according to embodiment 53 or the pharmaceutical composition according to embodiment 54, for use in the treatment of an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease). 65. The silicon derivative or pharmaceutical composition for use according to embodiment 64, wherein the APOL1 mediated disease is cancer. 66. The silicon derivative or pharmaceutical composition for use according to embodiment 64 or embodiment 65, wherein the APOL1 mediated disease is pancreatic cancer. 67. A boron derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-33. 68. A pharmaceutical composition comprising the boron derivative according to embodiment 67. 69. A method for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising administering to a patient in need thereof the boron derivative of embodiment 67, or the pharmaceutical composition of embodiment 68. 70. Use of the boron derivative according to embodiment 67 or the pharmaceutical composition according to embodiment 68 for the manufacture of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 71. The boron derivative according to embodiment 67 or the pharmaceutical composition according to embodiment 68 for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 72. A method for treating an APOL1-mediated disease (e.g., an APOL1-mediated renal disease), comprising administering to a patient in need thereof a boron derivative according to embodiment 67, or a pharmaceutical composition according to embodiment 68. 73. The method of embodiment 72, wherein the APOL1-mediated disease is cancer. 74. The method of embodiment 72 or embodiment 73, wherein the APOL1-mediated disease is pancreatic cancer. 75. Use of a boron derivative according to embodiment 67 or a pharmaceutical composition according to embodiment 68 for the manufacture of a medicament for the treatment of an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease). 76. The use according to embodiment 75, wherein the APOL1-mediated disease is cancer. 77. The use according to embodiment 75 or embodiment 76, wherein the APOL1-mediated disease is pancreatic cancer. 78. Use in the treatment of APOL1-mediated diseases (e.g., APOL1-mediated kidney diseases) 69. A boron derivative according to embodiment 67 or a pharmaceutical composition according to embodiment 68. 79. The boron derivative or pharmaceutical composition for use according to embodiment 78, wherein the APOL1 mediated disease is cancer. 80. The boron derivative or pharmaceutical composition for use according to embodiment 78 or embodiment 79, wherein the APOL1-mediated disease is pancreatic cancer. 81. A phosphorus derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1-33. 82. A pharmaceutical composition comprising a phosphorus derivative according to embodiment 81. 83. 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 81 or a pharmaceutical composition according to embodiment 82. 84. Use of a phosphorus derivative according to embodiment 81 or a pharmaceutical composition according to embodiment 82 for the manufacture of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 85. The phosphorus derivative according to embodiment 81 or the pharmaceutical composition according to embodiment 82, for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 86. A method for treating an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease), comprising administering to a patient in need thereof the phosphorus derivative according to embodiment 81 or the pharmaceutical composition according to embodiment 82. 87. The method of embodiment 86, wherein the APOL1-mediated disease is cancer. 88. The method of embodiment 86 or embodiment 87, wherein the APOL1-mediated disease is pancreatic cancer. 89. Use of a phosphorus derivative according to embodiment 81 or a pharmaceutical composition according to embodiment 82 for the manufacture of a medicament for the treatment of an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease). 90. The use according to embodiment 89, wherein the APOL1-mediated disease is cancer. 91. The use according to embodiment 89 or embodiment 90, wherein the APOL1-mediated disease is pancreatic cancer. 92. A phosphorus derivative according to embodiment 81 or a pharmaceutical composition according to embodiment 82, for use in the treatment of an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease). 93. The phosphorus derivative or pharmaceutical composition for use according to embodiment 92, wherein the APOL1 mediated disease is cancer. 94. The phosphorus derivative or pharmaceutical composition for use according to embodiment 92 or embodiment 93, wherein the APOL1-mediated disease is pancreatic cancer. 95. A method of treating a patient, a substance (e.g., a compound, tautomer, deuterated derivative, pharmaceutically acceptable salt, silicon derivative, boron derivative, phosphorus derivative) or pharmaceutical composition for use in treating a patient, or use of a substance or pharmaceutical composition in treating a patient, as described in any embodiment herein, wherein the patient has two APOL1 risk alleles. 96. A method of treating a patient, a substance (e.g., a compound, tautomer, deuterated derivative, pharmaceutically acceptable salt, silicon derivative, boron derivative, phosphorus derivative) or pharmaceutical composition for use in treating a patient, or use of a substance or pharmaceutical composition in treating a patient, as described in any embodiment herein, wherein the patient has one APOL1 risk allele. 97. The compound is represented by one of the following structural formulas: [ka] The compound of embodiment 1, wherein the compound is a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments. 98. The compound is represented by one of the following structural formulas: [ka] The compound of embodiment 1, wherein the compound is a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of them, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments. 99. A pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 97 or embodiment 98, and a pharmaceutically acceptable carrier. 100. A method for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 97 or embodiment 98, or a pharmaceutical composition of embodiment 99. 101. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 97 or embodiment 98, or a pharmaceutical composition according to embodiment 99, for the manufacture of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 102. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 97 or embodiment 98, or a pharmaceutical composition according to embodiment 99, for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 103. A method for inhibiting the activity of APOL1, comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 97 or embodiment 98, or a pharmaceutical composition according to embodiment 99. 104. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 97 or embodiment 98, or a pharmaceutical composition according to embodiment 99, for the manufacture of a medicament for inhibiting the activity of APOL1. 105. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 97 or embodiment 98, or a pharmaceutical composition according to embodiment 99, for use in inhibiting the activity of APOL1. 106. A method for treating an APOL1-mediated disease (e.g., an APOL1-mediated renal disease), comprising administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in embodiment 97 or embodiment 98, or a pharmaceutical composition described in embodiment 99. 107. The method of embodiment 106, wherein the APOL1-mediated disease is cancer. 108. The method of embodiment 106 or embodiment 107, wherein the APOL1-mediated disease is pancreatic cancer. 109. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 97 or embodiment 98, or a pharmaceutical composition according to embodiment 99, for the manufacture of a medicament for the treatment of an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease). 110. The use according to embodiment 109, wherein the APOL1-mediated disease is cancer. 111. The use according to embodiment 109 or embodiment 110, wherein the APOL1-mediated disease is pancreatic cancer. 112. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 97 or embodiment 98, or a pharmaceutical composition according to embodiment 99, for use in the treatment of an APOL1-mediated disease (e.g., an APOL1-mediated renal disease). 113. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, or pharmaceutical composition for use according to embodiment 112, wherein the APOL1 mediated disease is cancer. 114. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt, or pharmaceutical composition for use according to embodiment 112 or embodiment 113, wherein the APOL1-mediated disease is pancreatic cancer. 115. A method for inhibiting the activity of APOL1, comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 97 or embodiment 98, or a pharmaceutical composition according to embodiment 99. 116. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 97 or embodiment 98, or a pharmaceutical composition according to embodiment 99, for the manufacture of a medicament for inhibiting the activity of APOL1. 117. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 97 or embodiment 98, or a pharmaceutical composition according to embodiment 99, for use in inhibiting the activity of APOL1. Non-limiting exemplary embodiment 2

[0173] Some embodiments / provisions of the present disclosure include, but are not limited to: 1. A compound represented by the following structural formula: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 and X 2 are S and -CR, respectively. 2 is selected from: X 1 and X 2 One of them is S, X 1 If S, then X 2 -CR 2b and X 2 If S, then X 1 -CR 2a and R 1 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and phenyl, wherein: R 1 wherein the C1-C6 alkyl 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 C1-C4 alkoxy; R 1 wherein the C1-C6 alkoxy is optionally substituted with 1 to 3 groups independently selected from halogen; R 1wherein the C3-C6 cycloalkyl 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; R 1 wherein the phenyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C alkoxy, —C(═O)NH, —C(═O)NH(C-C alkyl), and —C(═O)N(C-C alkyl); R 2a is selected from hydrogen, halogen, cyano, —OH, ═O, and C1-C6 alkyl, wherein: R 2a wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C4 alkoxy; R 2b is selected from hydrogen, halogen, cyano, —OH, ═O, and C1-C6 alkyl; R 3a is selected from halogen, cyano, —OH, C1-C6 alkyl, and ═O, wherein R 3a wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R 3b is selected from C1-C2 alkyl and =O, wherein R 3b wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; [ka] are R 3a is selected from halogen, cyano, —OH, C1-C6 alkyl, or R3b is a single bond when selected from C1-C2 alkyl, or [ka] respectively, R 3a If =O, or R 3b is ═O, it is a double bond, R 4 is C1-C6 alkyl and [ka] is selected from: R 4 wherein the C1-C6 alkyl 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 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl; Ring A is C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5-10 membered heteroaryl, and ring A optionally contains 1, 2, 3, 4, or 5 R a is substituted with a group, wherein R a are each independently halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkenyl, C1-C6 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(CH2) q ] r O(C1-C6 alkyl), -S(=O) p R k , -S(=O) p NR h R i , C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5-10 membered heteroaryl, wherein R a The C1-C6 alkyl, and C2-C6 alkenyl are optionally substituted with 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 , and C3-C6 substituted with 1 to 3 groups independently selected from cycloalkyl; R a C3-C 12Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 The aryl and 5- to 10-membered heteroaryl are each selected from halogen, cyano, C1-C4 alkyl, -NR h R i AND-OR k and optionally substituted with 1 to 3 groups selected from: R h , R i , and R j are each independently selected from hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl, R h , R i , and R j wherein any one of the C1-C4 alkyl groups is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R k are each independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R k wherein any one of the C1-C4 alkyl groups is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH; R 5 is C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10 aryl, and 5- to 10-membered heteroaryl, wherein R 5 wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups 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; R 5 C3-C 12 Carbocyclyl, 3-12 membered heterocyclyl, C6 and C 10The aryl, and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C alkoxy, —C(═O)NH, —C(═O)NH(C-C alkyl), and —C(═O)N(C-C alkyl); k is R 3a is an integer selected from 0, 1, and 2 when R is selected from halogen, cyano, —OH, C1-C6 alkyl, or k is an integer selected from 0, 1, and 2 when R 3a is an integer selected from 0 and 1 when =0; m is R 3b is an integer selected from 0, 1, and 2 when selected from C1-C2 alkyl, and R 3b When =0, m is an integer selected from 0 and 1; p is an integer selected from 1 and 2, and q and r are integers selected from 1, 2, 3, and 4, respectively. 2. The compound is represented by one of the following structural formulas: [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R 2a is selected from hydrogen, halogen, cyano, and C1-C4 alkyl, wherein: R 2a wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, —OH, and C1-C2 alkoxy; R 2b is selected from hydrogen, halogen, cyano, and C1-C4 alkyl, and k is an integer selected from 0, 1, and 2; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in Clause 1, wherein all other variables not specifically defined herein are as defined in Clause 1. 3.R 4 is C1-C4 alkyl and [ka] is selected from: R 4 wherein the C1-C4 alkyl 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; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in Clause 1 or Clause 2, wherein all other variables not specifically defined herein are as defined in Clause 1 or Clause 2. 4.R 4 is C1-C2 alkyl and [ka] is selected from: R 4 wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, and 5- to 6-membered heterocyclyl; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1-3, wherein all other variables not specifically defined herein are as defined in any one of clauses 1-3. 5.R 4 is selected from -CH, -CHOH, and (tetrahydro-2H-pyran-4-yl)methyl, and all other variables not specifically defined herein are as defined in any one of clauses 1-4. 6. The compound is represented by one of the following structural formulas: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt thereof, wherein: Each ring A is selected from C3-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl, each of which optionally has 1, 2, 3, 4, or 5 R a is substituted with a group, A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1-4, wherein all other variables not specifically defined herein are as defined in any one of clauses 1-5. 7. Ring A is selected from cyclopropyl, 5-10 membered heterocyclyl, phenyl, and 5-9 membered heteroaryl, each of which optionally contains 1, 2, 3, 4, or 5 R a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1-4 and 6, wherein all other variables substituted with groups and not specifically defined herein are as defined in any one of clauses 1-6. 8. Ring A 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 followed by 1, 2, 3, 4, or 5 R a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1-4, 6 and 7, wherein all other variables substituted with groups and not specifically defined herein are as defined in any one of clauses 1-7. 9. Ring A is selected from cyclopropyl, 5-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, 6-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, 9-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, 10-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, phenyl, 5-membered heteroaryl containing 1-3 heteroatoms selected from N and O, 6-membered heteroaryl containing 1-3 heteroatoms selected from N and O, and 9-membered heteroaryl containing 1-3 heteroatoms selected from N and O, each of which optionally contains 1, 2, 3, 4, or 5 R a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1-4 and 6-8, wherein all other variables substituted with groups and not specifically defined herein are as defined in any one of clauses 1-8. 10. Ring A is [ka] each of which optionally has 1, 2, 3, 4 or 5 R a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1-4 and 6-9, wherein all other variables substituted with groups and not specifically defined herein are as defined in any one of clauses 1-9. 11. Ring A is [ka] [ka] each of which optionally has 1, 2, 3, 4 or 5 R aA compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1-4 and 6-10, wherein all other variables substituted with groups and not specifically defined herein are as defined in any one of clauses 1-4 and 6-10. 12.R 4 is selected from -CH3 and ring A, wherein ring A is [ka] each of which optionally has 1, 2, 3, 4 or 5 R a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1-4 and 6-11, wherein all other variables substituted with groups and not specifically defined herein are as defined in any one of clauses 1-4 and 6-11. 13.R 5 is selected from C1-C4 alkyl, —C(═O)O(C1-C2 alkyl), C3-C6 cycloalkyl, and 5-10 membered heterocyclyl, wherein: R 5 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, and C1-C2 alkoxy; and R 5 wherein the C3-C6 cycloalkyl and 5-10 membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, C1-C2 alkyl, and C1-C2 alkoxy; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 12, wherein all other variables not specifically defined herein are as defined in any one of clauses 1 to 12. 14.R 5 is selected from C1-C2 alkyl, C(=O)O(C1-C2 alkyl), cyclopropyl, cyclobutyl, and 5- to 6-membered heterocyclyl, wherein , R 5wherein the C1-C2 alkyl is optionally selected from F, Cl, Br, cyano, -OH, and substituted with 1 to 3 groups selected from C1-C2 alkoxy, and R 5 wherein the cyclopropyl, cyclobutyl, and 5- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from F, Cl, Br, cyano, —OH, C1-C2 alkyl, and C1-C2 alkoxy; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 13, wherein all other variables not specifically defined herein are as defined in any one of clauses 1 to 13. 15.R 5 is selected from -CH3, -CH2CH3, -CH2OH, -C(=O)OCH3, -CHOCH3, -CH(CH3)2, cyclopropyl, difluorocyclopropyl, and tetrahydro-2H-pyranyl, and all other variables not specifically defined herein are as defined in any one of clauses 1-14. 16. The compound is represented by one of the following structural formulas: [ka] A compound according to any one of clauses 1-4 and 6-15, which is a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt thereof, and all other variables not specifically defined herein are as defined in any one of clauses 1-4 and 6-15. 17.R 1 is selected from hydrogen, halogen, cyano, —OH, C1-C4 alkyl, C1-C4 alkoxy, and C3-C6 cycloalkyl, wherein: R 1 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, and C1-C2 alkoxy; R 1 wherein the C1-C4 alkoxy is optionally substituted with 1 to 3 halogen groups, and R 1 wherein the C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, —OH, and C1-C2 alkoxy; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 16, wherein all other variables not specifically defined herein are as defined in any one of clauses 1 to 16. 18.R 1 is selected from F, Cl, Br, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein: R 1 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen and —OH, and R 1 wherein the C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halogen and —OH; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein all other variables not specifically defined herein are as defined in any one of clauses 1 to 17. 19.R 1 is selected from F, Cl, Br, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein: R 1 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen and —OH; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 18, wherein all other variables not specifically defined herein are as defined in any one of clauses 1 to 18. 20.R 119. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of clauses 1 to 18, wherein is selected from Cl, Br, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH2CHF2, -CH2CH(CH3)2, difluorocyclobutyl, and cyclohexyl. 21.R 1 22.R is Cl, and all other variables not specifically defined herein are as defined in any one of clauses 1-20. 3a is selected from —OH and C1-C4 alkyl, wherein: R 3a wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen and —OH; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 21, wherein all other variables not specifically defined herein are as defined in any one of clauses 1 to 21. 23.R 3a is selected from F, Cl, Br, —OH and C1-C2 alkyl, wherein: R 3a wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups selected from F, Cl, and —OH; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 22, wherein all other variables not specifically defined herein are as defined in any one of clauses 1 to 22. 24.R 3a is selected from F, —OH, —CH3, —CHF2, and CH2OH, and all other variables not specifically defined herein are as defined in any one of clauses 1-23. 25. The compound is represented by one of the following structural formulas: [ka] A compound according to any one of clauses 1-4 and 6-24, which is a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt thereof, and all other variables not specifically defined herein are as defined in any one of clauses 1-4 and 6-24. 26.R a are each independently halogen, cyano, C1-C6 alkyl, C1-C4 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -OR k , -[O(CH2) q ] r O(C1-C6 alkyl), -S(=O)2R k , -S(=O)2NR h R i , C3-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl, wherein: R a The C1-C6 alkyl is optionally selected from cyano, -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 , -S(=O)2R k , -S(=O) p NR h R iand C3-C6 cycloalkyl, R a C3-C6 cycloalkyl, 5-10 membered heterocyclyl, phenyl, and 5-8 membered heteroaryl are each optionally selected from halogen, C1-C2 alkyl, and -OR k and wherein the formula is: R h , R i , and R j are each independently selected from hydrogen, C1-C2 alkyl, cyclopropyl, and cyclobutyl, R h , R i , and R j wherein any one of the C1-C2 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen and —OH; R k are each independently selected from hydrogen and C1-C4 alkyl, R k wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen and —OH, and p and r are each an integer selected from 1, 2, and 3; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1-4 and 6-25, wherein all other variables not specifically defined herein are as defined in any one of clauses 1-4 and 6-25. 27.R a are each independently halogen, cyano, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -OR k , -[O(CH2) q ] r O(C1-C4 alkyl), -S(=O)2R k, -S(=O)2NR h R i , cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein R a The C1-C6 alkyl is optionally selected from cyano, -C(=O)NR h R i , -NR h R i , -OR k , cyclopropyl, and cyclobutyl; R a wherein the cyclopropyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 groups selected from halogen, —CH3, —OH, and —OCH3, R h and R i are each independently selected from hydrogen, —CH3, cyclopropyl, and cyclobutyl, R h and R i any one —CH3 is optionally substituted with 1 to 3 groups selected from F, Cl, and —OH; R k are each independently selected from hydrogen and —CH3, R k -CH3 is optionally substituted with 1 to 3 groups selected from halogen and -OH; A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1-4 and 6-26, wherein all other variables not specifically defined herein are as defined in any one of clauses 1-4 and 6-26. 28.R a each independently represents F, Cl, Br, cyano, C1-C6 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, or -C(=O)NR h R i , -NR h R i , -NR h C(=O)Rk , -OR k , -[O(CH2) q ] r O(C1-C2 alkyl), -S(=O)2R k , -S(=O)2NR h R i , cyclopropyl, cyclobutyl, 5-membered heterocyclyl, phenyl, and 6-membered heteroaryl, wherein R a The C1-C6 alkyl is optionally selected from cyano, -C(=O)NR h R i , -OR k and cyclopropyl, R a wherein the cyclopropyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 groups selected from halogen, —CH3, —OH, and —OCH3, R h and R i are each independently selected from hydrogen, —CH3, and cyclopropyl, R h and R i any one —CH3 is optionally substituted with 1 to 3 groups selected from F, Cl, and —OH; R k are each independently selected from hydrogen and —CH3, and q and r are integers selected from 1 and 2, A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1-4 and 6-27, wherein all other variables not specifically defined herein are as defined in any one of clauses 1-4 and 6-27. 29.R aare F, cyano, -OH, -CH3, -CF3, -CH(CH3)2, -(CH2)2OH, -(CH2)2OCH3, -CH2CH(OH)C2H5, -CH2C(CH3)(CH2OH)2, -OCH3, -OCH2CH3, -[O(CH2)2]2OCH3, -CH2C(=O)NHCH3, -(CH2)2SO2CH3, -CH2C(=O)N(CH3)2, -CH2(cyclopropyl), -C(=O)NH2, -C(=O)NH(cyclopropyl), -NH2, -NHCH3, -N(CH3)2, -NHC(CH3)2CH 2OH, -NHC(=O)CH3, -SO2CH3, -SO2NH2, cyclopropyl, 2-methoxyphenyl, N-methoxypiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl and tetrahydrothiophenyl 1,1-dioxide, and all other variables not specifically defined herein are as defined in any one of clauses 1-4 and 6-28. 30. The compound is represented by one of the following structural formulas: [ka] [ka] 29. The compound of clause 1, wherein the compound is a tautomer, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt thereof, and wherein all other variables not specifically defined herein are as defined in any one of clauses 1-29. 31. A compound selected from the compounds of Table I, its tautomers, deuterated derivatives of said compounds or tautomers, and pharmaceutically acceptable salts of any of them. 32. A pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 31, and a pharmaceutically acceptable carrier. 33. 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 clauses 1 to 31, or a pharmaceutical composition according to clause 32. 34. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 31, or a pharmaceutical composition according to clause 32, for the manufacture of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 35. At least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 31 or the pharmaceutical composition according to clause 32 for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 36. A method for inhibiting the activity of APOL1, comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 31 or the pharmaceutical composition according to clause 32. 37. Any of the compounds of clauses 1 to 31 for the manufacture of a pharmaceutical product for inhibiting the activity of APOL1. 33. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 31 to 32, or a pharmaceutical composition according to clause 32. 38. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 31, or a pharmaceutical composition according to clause 32, for use in inhibiting the activity of APOL1. 39. A silicon derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 31. 40. A pharmaceutical composition comprising a silicon derivative according to clause 39. 41. A method for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising administering to a patient in need thereof a silicon derivative as defined in clause 39 or a pharmaceutical composition as defined in clause 40. 42. Use of a silicon derivative according to clause 39 or a pharmaceutical composition according to clause 40 for the manufacture of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 43. A silicon derivative according to clause 39 or a pharmaceutical composition according to clause 40 for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 44. A boron derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 31. 45. A pharmaceutical composition comprising a boron derivative according to clause 44. 46. ​​A method for treating focal segmental glomerulosclerosis and / or non-diabetic kidney disease, comprising administering to a patient in need thereof a boron derivative as defined in clause 44 or a pharmaceutical composition as defined in clause 45. 47. Use of a boron derivative according to clause 44 or a pharmaceutical composition according to clause 45 for the manufacture of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 48. A boron derivative according to clause 44 or a pharmaceutical composition according to clause 45 for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 49. A phosphorus derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 31. 50. A pharmaceutical composition comprising a phosphorus derivative according to clause 48. 51. 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 clause 48 or a pharmaceutical composition according to clause 49. 52. Use of a phosphorus derivative according to clause 48 or a pharmaceutical composition according to clause 49 for the manufacture of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. 53. A phosphorus derivative according to clause 48 or a pharmaceutical composition according to clause 49 for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic kidney disease. [Example]

[0174] In order that the disclosure set forth herein may be more fully understood, the following examples are set forth, it being understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any manner.

[0175] The compounds of the present disclosure can be made according to standard chemical practices or as described herein through the following synthetic schemes and by the use of compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I', IIa', IIb', IIIa', IIIb', IVa', IVb', Va', Vb', IIa'', IIb'', IIIa'', IIIb'', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa'', IVb'', IIa''', IIb''', IIIa''', IIIb''', IVa''', IVb''', I0, IIa0, IIb0, III The following abbreviations are used in describing the preparation of compounds a0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0, compounds 1-391, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of them: Abbreviation AIBN = azobisisobutyronitrile ARP = Assay Ready Plate BBBPY = 4,4'-di-tert-butyl-2,2'-dipyridyl BF3 = boron trifluoride BF3.OEt2 = boron trifluoride diethyl etherate BocO = di-tert-butyl bicarbonate CBzCl = benzyl chloroformate CDMT = 2-chloro-4,6-dimethoxy-1,3,5-triazine DAST = diethylaminosulfur trifluoride DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DCM = dichloromethane DIBAL-H = diisobutylaluminum hydride DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMAP = dimethylaminopyridine DMA = dimethylacetamide DME = dimethoxyethane DMEM = Dulbecco's Modified Eagle's Medium DMF = dimethylformamide DMPU = N,N'-dimethylpropylene urea DMSO = dimethyl sulfoxide DPPA = diphenylphosphoryl azide EtOAc = ethyl acetate EtOH = ethanol Et2O = diethyl ether FBS = fetal bovine serum FLU = Fluorescence Unit HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphorus hexafluoride ion) HDMC = N-[(5-chloro-3-oxido-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-hexafluorophosphate methylmethanaminium HEPES = 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HBSS = Hank's Balanced Salt Solution IPA = Isopropyl alcohol Ir[df(CF3)ppy]2(dtbbpy)PF6 = phosphorus hexafluoride LDA = lithium diisopropylamide LED = Light Emitting Diode MeCN = acetonitrile MeI = methyl iodide MeOH = methanol MsOH = methanesulfonic acid MTBE or TBME = methyl tert-butyl ether n-BuLi = n-butyllithium NBS = n-bromosuccinimide NMM = N-methylmorpholine NMP = N-methylpyrrolidine PBS = phosphate-buffered saline Pd(dppf)2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(PPh3)2 = bis(triphenylphosphine) palladium(II) dichloride PP = Polypropylene PTSA = p-toluenesulfonic acid monohydrate T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TBAF = tetra-n-butylammonium fluoride TBSCl = tert-butyldimethylsilyl chloride TEA = triethylamine Tet = tetracycline TFA or TFAA = trifluoroacetic acid TfOH = triflic acid THF = tetrahydrofuran 2-Me-THF = 2-methyltetrahydrofuran THP = tetrahydropyran TMSCl = trimethylsilyl chloride TMSS = Tris(trimethylsilyl)silane Example 1. Synthesis of Compounds

[0176] All specific generic compounds and intermediates disclosed for making those compounds are considered to be part of the disclosure disclosed herein. Synthesis of starting materials

[0177] The preparation describes synthetic routes to intermediates used in the synthesis of compounds 1–391. General scheme:

[0178] In some embodiments, processes for preparing compounds of Formula I include the reactions depicted in Schemes 1-6.

[0179] Scheme 1 shows a process for preparing compounds of formula I. 1 , R 3 , R 4 R 5 , X 1 , X 2 , m, and k are defined above. A piperidone of Formula 1-3 may be produced via reaction of an aminoketone of Formula 1-1 with an aldehyde of Formula 1-2. In some embodiments, the reaction may occur in the presence of an amine catalyst, such as L-proline, a base, such as triethylamine, and a magnesium sulfate reagent. Compounds of Formula 1-3 may be prepared using any method suitable for preparing piperidones. Compounds of Formula 1-3 may be prepared from a piperidone of Formula 1-3 and an alcohol of Formula 1-4 using any conditions suitable for carrying out a Pictet-Spengler reaction. The reaction may be carried out in the presence of an acid, such as trifluoromethylsulfonic acid, and a solvent, such as 1,4-dioxane. In an alternative embodiment, an acid, such as methanesulfonic acid, may be used. The reaction may be carried out in a solvent, such as dichloromethane, in the presence of heat (e.g., 40° C.). Scheme 1 [ka]

[0180] Scheme 2 shows the process for preparing compounds of formula 2-3. 1 is any suitable nitrogen protecting group. For example, in some embodiments, PG 1is a trifluoroacetate group. Compounds of formula 2-2 can be prepared from 2-1 using any method suitable for benzylic oxidation. For example, in some embodiments, the reaction is carried out in the presence of oxygen gas under balloon pressure, N-hydroxyphthalamide, and a cobalt diacetate catalyst. In some embodiments, the reaction is carried out in the presence of acetonitrile. The reaction can be carried out in the presence of heat (e.g., 60 °C). Compounds of formula 2-3 can be prepared from compounds of formula 2-2 using any method suitable for the reduction of ketones to alcohols. For example, Corey-Bakshi-Shibata catalyst (CBS catalyst) in the presence of a reducing agent such as borane can be used. In another embodiment, a transition metal catalyzed transfer hydrogenation system can be used. Asymmetric reduction of ketones can occur by performing a transition metal transfer hydrogenation reaction in the presence of a chiral ligand. Scheme 2 [ka]

[0181] Scheme 3 shows the process for preparing compounds of formula 3-4. 2 is any suitable alcohol protecting group, such as, for example, THP. The heterocyclic bromide of formula 3-1 may be coupled with the trifluoroborate salt of formula 3-2 using any method suitable for coupling a halide with an alkyl boronate. For example, in some embodiments, the reaction may be carried out in the presence of a catalyst system such as palladium(II) dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane methanesulfonate N-methyl-2-phenyl-aniline and a base such as, for example, Cs2CO3. The reaction may be carried out in the presence of heat (e.g., 100°C). In some embodiments, the reaction is carried out in a solvent such as, for example, toluene. Compounds of formula 3-4 may be prepared using any method suitable for removing an alcohol protecting group. For example, PG 2 When is THP, an acid such as p-toluenesulfonic acid in a solvent such as methanol may be used. The reaction may be carried out at room temperature. Scheme 3 [ka]

[0182] Scheme 4 illustrates a process for preparing alcohols of formula 4-5 from aryl halides of formula 3-1. Any reagent suitable for performing lithium-halogen exchange on heteroaryl bromides, such as treatment with n-butyllithium, may be used to generate the heteroaryl organometallic reagent in situ. The reaction may be carried out at low temperatures (e.g., 0 to −78° C.) in solvents such as THF or diethyl ether. Addition of the organometallic reagent to an epoxide, such as ethylene oxide, in the presence of a Lewis acid, such as trifluoroboron diethyl etherate, provides alcohols of formula 4-2. In some embodiments, the lithium halogen exchange reaction may be carried out under continuous flow conditions.

[0183] In another process for preparing a compound of formula 4-2, an aldehyde of formula 4-3 may undergo a Wittig reaction with a reagent such as an ylide of formula 4-4 to provide an enol ether of formula 4-5. In some embodiments, the reaction is carried out in a solvent such as diethyl ether in the presence of a base such as potassium tert-butoxide. In some embodiments, the enol ether of formula 4-5 may be converted to a compound of formula 4-6 by treatment with an acid such as HCl. In some embodiments, a compound of formula 4-2 may be prepared from a compound of formula 4-6 using any reagent suitable for reducing an aldehyde to an alcohol, such as sodium borohydride in methanol. Scheme 4 [ka]

[0184] Scheme 5 shows the process for preparing compounds of formula 1-1. 3 is any suitable nitrogen protecting group. The compound of formula 5-1 may be protected with any suitable nitrogen protecting group. For example, PG 3When is a Boc group, any reagent suitable for adding a Boc group to an amine may be used. Compounds of formula 5-3 (Weinreb amides) may be prepared from compounds of formula 5-2 and N-methyl N-methoxyamine using any suitable amide coupling reagent. For example, the reaction may be carried out in a solvent such as dichloromethane in the presence of T3P and DIPEA. Compounds of formula 5-5 may be prepared from compounds of formula 5-3 by adding an organometallic reagent such as methylmagnesium iodide. The reaction may be carried out at low temperature (e.g., 0°C) in a solvent such as THF. Compounds of formula 1-1 may be prepared from compounds of formula 5-5 using any method suitable for removing nitrogen protecting groups. For example, PG 3 When is Boc, a solution of HCl in 1,4-dioxane may be used. Scheme 5 [ka]

[0185] Scheme 6 shows an alternative process for preparing compounds of formula 1-3 from N-protected beta amino acids of formula 6-1. 4 may be Boc or any suitable nitrogen protecting group. The dimagnesium salt of compound 6-2 may be coupled to a compound of formula 6-1 using a reagent such as CDI in a solvent such as THF. Condensation of a compound of formula 6-3 with an aldehyde of formula 6-4 produces a compound of formula 6-5. In some embodiments, the reaction may be carried out by treating a compound of formula 6-3 with an acid such as TFA in a solvent such as dichloromethane, followed by addition of an aldehyde of formula 6-4. A compound of formula 1-3 may be prepared from a compound of formula 6-5 by treating with an acid such as methanesulfonic acid in a solvent such as dichloromethane. The reaction may be carried out in the presence of heat (e.g., reflux conditions). Scheme 6 [ka] Preparation of S1 2-(3-thienyl)ethanol (S1) [ka]

[0186] 2-(3-Thienyl)ethanol (S1) was obtained commercially. Preparation of S2 2-(5-chloro-3-thienyl)ethanol (S2) [ka] Step 1. Synthesis of tert-butyl-dimethyl-[2-(3-thienyl)ethoxy]silane (C1)

[0187] To a solution of 2-(3-thienyl)ethanol S1 (18 g, 140.4 mmol) in DMF (100 mL) were added imidazole (12 g, 176.3 mmol) and tert-butyl-chloro-dimethyl-silane (24 g, 159.2 mmol) sequentially. No exotherm was observed. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with MTBE (500 mL) and washed with water (200 mL), 0.5 N HCl (200 mL), water (200 mL), and brine (200 mL). The organic layer was dried, filtered, and concentrated in vacuo. The organic layer was dissolved in heptane and passed through a silica gel plug, which was washed with 1–5% MTBE / heptane. The solvent was removed to give tert-butyl-dimethyl-[2-(3-thienyl)ethoxy]silane C1 (34 g, 99%). 1 H NMR (400 MHz, chloroform-d) δ 7.28–7.13 (m, 1H), 7.04–6.91 (m, 2H), 3.80 (t, J = 6.9 Hz, 2H), 2.90–2.75 (m, 2H), 0.88 (s, 9H), −0.00 (s, 6H). Step 2. Synthesis of tert-butyl-[2-(5-chloro-3-thienyl)ethoxy]-dimethyl-silane (C2)

[0188] To a solution of 2,2,6,6-tetramethylpiperidine (36 mL, 213.3 mmol) in tetrahydrofuran (200 mL) cooled to 0° C. was added a solution of hexyllithium (92 mL of 2.3 M, 211.6 mmol). The reaction was stirred at −78° C. for 30 minutes. A solution of tert-butyl-dimethyl-[2-(3-thienyl)ethoxy]silane C1 (34 g, 138.8 mmol) in THF (150 mL) was added to the reaction over 20 minutes. The reaction was stirred at −30° C. for 45 minutes. The reaction was cooled to −78° C., and 1,1,1,2,2,2-hexachloroethane (54 g, 228.1 mmol) was added in several portions. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride (125 mL), diluted with water (100 mL), extracted with EtOAc (500 mL), and back-extracted with EtOAc (100 mL). The combined organic layers were washed with 0.5 N HCl (200 mL), water (300 mL), and brine (200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude tert-butyl-[2-(5-chloro-3-thienyl)ethoxy]-dimethyl-silane C2. Step 3. Synthesis of 2-(5-chloro-3-thienyl)ethanol (S2)

[0189] To a solution of tert-butyl-[2-(5-chloro-3-thienyl)ethoxy]-dimethyl-silane C2 (12.5 g, 42.89 mmol) in 2-Me-THF (120 mL) was added TBAF (63 mL of a 1 M THF solution, 63.00 mmol). The reaction was stirred at room temperature overnight. The reaction was partitioned between EtOAc (400 mL) and water (400 mL). The layers were separated, and the organic layer was extracted with EtOAc (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0 to 50% EtOAc in heptane) gave the product, 2-(5-chloro-3-thienyl)ethanol S2 (4.5 g, 58%). 1H NMR (300 MHz, chloroform-d) δ 6.82 (d, J = 0.9 Hz, 2H), 3.89 - 3.71 (m, 2H), 2.79 (t, J = 6.4 Hz, 2H), 2.05 (s, 1H). LCMS m / z 162.91 [M+H] + . Preparation of S3 2-[5-(trifluoromethyl)-3-thienyl]ethanol (S3) [ka] Step 1. Synthesis of 2-[2-[5-(trifluoromethyl)-3-thienyl]ethoxy]tetrahydropyran (C5)

[0190] To a mixture of 4-bromo-2-(trifluoromethyl)thiophene C3 (9 g, 38.96 mmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane; methanesulfonate; N-methyl-2-phenyl-aniline palladium(2+) (1.8 g, 2.117 mmol), and potassium trifluoro(2-tetrahydropyran-2-yloxyethyl)boranide C4 (10 g, 42.36 mmol) was added toluene (75 mL) and water (25 mL). Nitrogen was passed over the reaction, followed by CsCO. 3( To the reaction mixture was added 40 g (122.8 mmol). A reflux condenser was added and the reaction was heated at 100 °C for 48 h. The reaction mixture was diluted with EtOAc (150 mL) and water (100 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0 to 20% EtOAc in heptane) gave the product, 2-[2-[5-(trifluoromethyl)-3-thienyl]ethoxy]tetrahydropyran C5 (9 g, 82%). 1H NMR (300 MHz, chloroform-d) δ 7.37 (t, J = 1.3 Hz, 1H), 7.22 (d, J = 1.5 Hz, 1H), 4.62 (dd, J = 4.2, 2.8 Hz, 1H), 3.96 (dt, J = 9.6, 6.7 Hz, 1H), 3.75 (ddd, J = 11.3,8.0,3.4 Hz,1H),3.62 (dt,J = 9.6,6.5 Hz,1H),3.55 - 3.41 (m,1H),2.93 (t,J = 6.6 Hz,2H),1.83 (ddd,J = 14.2,6.6,3.4 Hz,1H),1.73 (td,J = 9.0,4.2 Hz,1H),1.66 - 1.50 (m,4H). Step 2. Synthesis of 2-[5-(trifluoromethyl)-3-thienyl]ethanol (S3)

[0191] To a stirred solution of 2-[2-[5-(trifluoromethyl)-3-thienyl]ethoxy]tetrahydropyran C5 (1.8 g, 6.100 mmol) in MeOH (25 mL) was added 4-methylbenzenesulfonic acid monohydrate (1.2 g, 6.309 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with MTBE (2 x 100 mL). The combined organic layers were washed with dilute NaHCO3 (10 mL). The residue was washed with NaHCO3 and 10 mL of water and brine (10 mL), dried over sodium sulfate, filtered, and evaporated in vacuo to give the crude compound. Purification by silica gel chromatography (gradient: heptane, 0-30% EtOAc) gave the product 2-[5-(trifluoromethyl)-3-thienyl]ethanol S3 (820 mg, 69%). 1 H NMR (400 MHz, chloroform-d) δ 7.35 (p, J = 1.3 Hz, 1H), 7.23 (dt,J = 1.7,0.9 Hz,1H),3.85 (td,J = 7.1,6.5,2.7 Hz,2H),2.87 (td,J = 6.4,0.8 Hz,2H),2.06 (d,J = 4.3 Hz,1H). Alternative preparation of S3 2-[5-(trifluoromethyl)-3-thienyl]ethanol (S3) [ka]

[0192] A solution of 4-bromo-2-(trifluoromethyl)thiophene C3 (50.13 g, 217.0 mmol) in Et2O (500 mL) was cooled to -78 °C, and nBuLi (91 mL of 2.48 M, 225.7 mmol) was added at a rate adapted to maintain a temperature below -68 °C. The reaction was stirred for 20 minutes, and ethylene oxide (14 g, 317.8 mmol) was added at a rate adapted to maintain a temperature below -70 °C. BF3.OEt2 (28 mL, 226.9 mmol) was added at a rate adapted to maintain a temperature below -68 °C. The addition of BF3.OEt2 was highly exothermic. The reaction was stirred at -78 °C for 1 hour, then poured into 500 mL of 1 N HCl and extracted with 500 mL of Et2O. The extract was dried over MgSO, filtered, and evaporated in vacuo. Purification by column chromatography (1600 g: isocratic gradient: 10% CHCN-DCM) afforded 2-[5-(trifluoromethyl)-3-thienyl]ethanol S3 (22.48 g, 53%). 1 H NMR (300 MHz, chloroform-d) δ 7.36 (t, J = 1.3 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H), 3.88 (q, J = 6.0 Hz, 2H), 2.90 (t, J = 6.3 Hz, 2H), 1.55 (t,J = 5.4 Hz,1H) ppm.19F NMR (282 MHz, chloroform-d) δ -55.36 ppm. Preparation of S4 2-(5-ethyl-3-thienyl)ethanol (S4) [ka] Step 1. Synthesis of 5-bromothiophene-3-carbaldehyde (C7)

[0193] To a stirred solution of thiophene-3-carbaldehyde C6 (50 g, 40.717 mL, 0.4458 mol) in DMF (500 mL) was added NBS (119.02 g, 0.6687 mol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice-water (600 mL) and extracted with EtOAc (2 × 600 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. Purification by silica gel chromatography (gradient: 0–2% EtOAc in petroleum ether) gave the product, 5-bromothiophene-3-carbaldehyde C7 (39.2 g, 44%). 1 H NMR (400 MHz, chloroform-d) δ 9.77 (s,1H), 7.99 (d,J =1.2 Hz,1H), 7.505 (d,J =1.6 Hz,1H). Step 2. Synthesis of 2-bromo-4-[(E)-2-methoxyvinyl]thiophene (C8)

[0194] To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (115.1 g, 0.3358 mol) in diethyl ether (450.00 mL) at 0 °C, potassium tert-butoxide (1 M in THF) (381 mL of 1 M, 0.3810 mol) was added dropwise. The reaction was stirred at 0 °C for 1 h. A solution of 5-bromothiophene-3-carbaldehyde C7 (45 g, 0.2215 mol) in diethyl ether (90 mL) was added, and the reaction mixture was then stirred at room temperature for 30 min. The reaction mixture was quenched with NH4Cl solution (900 mL) at 0 °C and extracted with EtOAc (2 × 700 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (eluent: petroleum ether) gave the product 2-bromo-4-[(E)-2-methoxyvinyl]thiophene C8 (44.1 g, 82%). 1 H NMR (400 MHz, chloroform-d) δ 7.25 (d, J = 2 Hz, 1H), 7.18 (d, J = 0.8 Hz, 1H), 7.00 (d,J = 1.8 Hz,1H),6.91 (d,J = 12.8 Hz,1H),6.97 (d,J =1.2 Hz,1H),6.05 (d,J = 6.8 Hz, 1H), 5.72 (d,J = 12.8 Hz, 1H), 5.22 (d,J = 6.4 Hz, 1H), 3.77 (d,J = 2.8 Hz, 3H), 3.64 (d,J = 5.2 Hz, 3H). NMR showed the E and Z isomers. This shows a 1:1 mixture of Step 3. Synthesis of 2-(5-bromo-3-thienyl)acetaldehyde (C9)

[0195] To a stirred solution of 2-bromo-4-[(E)-2-methoxyvinyl]thiophene C8 (14.1 g, 0.0602 mol) in 1,4-dioxane (141.00 mL) was added HCl (60.200 mL of a 4 M solution in dioxane, 0.2408 mol) at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated NaHCO3 at 0 °C and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give 2-(5-bromo-3-thienyl)acetaldehyde C9 (13.1 g, 89%). 1 H NMR (400 MHz, chloroform-d) δ 9.72 (t, J = 2.4 Hz, 1H), 7.04 (s, 1H), 6.94 (d, J = 1.2 Hz, 1H), 3.66 (d, J = 1.6 Hz, 2H). Step 4: Synthesis of 2-(5-bromo-3-thienyl)ethanol (C10)

[0196] To a stirred solution of 2-(5-bromo-3-thienyl)acetaldehyde C9 (38.5 g, 0.1524 mol) in MeOH (390 mL) was added NaBH4 (13.3 g, 0.3515 mol) at 0 °C. The reaction was stirred for 1 h. The reaction mixture was quenched with ice water (400 mL) and concentrated in vacuo to remove MeOH. The crude residue was diluted with water (500 mL) and extracted with EtOAc (3 × 300 mL). The separated organic layer was dried over Na2SO4, filtered, and concentrated. Purification by column chromatography on neutral alumina (eluent: 35% EtOAc in petroleum ether) afforded the product, 2-(5-bromo-3-thienyl)ethanol C10 (30.2 g, 84%), as a pale yellow liquid. . 1 H NMR (300 MHz,DMSO-d6) δ 7.20 (t,J = 0.9 Hz,1H),7.10 (d,J =1.2 Hz,1H),4.64 (q,J =5.2 Hz,1H),3.59-3.55 (m,2H),2.67 (t,J = 6.8 Hz,2H). Step 5. Synthesis of 2-[2-(5-bromo-3-thienyl)ethoxy]tetrahydropyran (C11)

[0197] To a stirred solution of 2-(5-bromo-3-thienyl)ethanol C10 (8 g, 0.0328 mol) in THF (80 mL) was added 3,4-dihydro-2H-pyran (3.7696 g, 3.8 mL, 0.0448 mol) and PTSA (259 mg, 0.0015 mol) at room temperature, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous K2CO3 (300 mL) and extracted with EtOAc (2 x 600 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (gradient: 0-5% EtOAc in petroleum ether) gave the product, 2-[2-(5-bromo-3-thienyl)ethoxy]tetrahydropyran C11 (10.1 g, 90%). 1 H NMR (400 MHz, chloroform-d) δ 6.95 (d,J = 1.6 Hz,1H),6.92 (d,J = 0.8,1H),4.59 (t,J = 2.8 Hz,1H),3.94-3.74 (m,2H),3.60-3.46 (m,2H),2.85 (q,J = 6.4 Hz, 2H), 1.80-1.61 (m, 6H). LCMS m / z 291.03 [M+H] + . Step 6. Synthesis of 2-[2-(5-ethyl-3-thienyl)ethoxy]tetrahydropyran (C12)

[0198] To a stirred solution of 2-[2-(5-bromotetrahydrothiophen-3-yl)ethoxy]tetrahydropyran C11 (25 g, 0.0719 mol) in THF (250.00 mL) was added n-BuLi (2.5 M in hexanes) (46.1 mL of 2.5 M, 0.1153 mol) at −76 °C. The reaction was stirred for 1 h. Ethyl iodide (24.832 g, 12.8 mL, 0.1592 mol) was added at −76 °C, and the reaction temperature was then gradually raised to room temperature and stirred for 16 h. The reaction mixture was quenched with NH4Cl solution (500 mL) and extracted with EtOAc (2 × 300 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (gradient: 0-3% EtOAc in petroleum ether) gave the product 2-[2-(5-ethyl-3-thienyl)ethoxy]tetrahydropyran C12 (13.2 g, 59%). LCMS m / z 241.21 [M+H] + . Step 7. Synthesis of 2-(5-ethyl-3-thienyl)ethanol (S4)

[0199] To a stirred solution of 2-[2-(5-ethyl-3-thienyl)ethoxy]tetrahydropyran C12 (4.4 g, 0.0142 mol) in MeOH (44 mL) was added PTSA (3.0 g, 0.0174 mol) at room temperature, and the reaction was stirred for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution (150 mL), extracted with EtOAc (2 × 150 mL), dried over Na2SO4, filtered, and concentrated. Purification by column chromatography on neutral alumina (eluent: 10% EtOAc in petroleum ether) gave the product, 2-(5-ethyl-3-thienyl)ethanol S4 (1.1 g, 45%). 1 H NMR (400 MHz,DMSO-d6) δ 6.90 (d,J = 1.2 Hz,1H),6.71 (d,J = 1.2 Hz,1H),4.62-4.58 (m,1H),3.59-3.55 (m,2H),2.77-2.71 (m,2H),2.64 (t,J = 7.2,2H),1.22-1.85 (m,3H). Preparation of S5 2-(5-ethyl-2-thienyl)ethanol (S5) [ka] Step 1. Synthesis of 2-(5-ethyl-2-thienyl)ethanol (S5)

[0200] To a solution of 2-ethylthiophene C13 (54 g, 466.9 mmol) in anhydrous THF (1 L) at 0 °C, a solution of n-BuLi in hexanes (255 mL of 2.2 M, 561.0 mmol) was added over 45 min. A light yellow / orange solution was obtained. The temperature range during the addition was 0–10 °C. The mixture was stirred at room temperature for 30 min. After cooling to 0 °C, ethylene oxide solution (200 mL of 2.9 M, 580.0 mmol) was added over 30 min. The reaction was stirred at 0 °C for 2 h and then warmed to room temperature. The reaction mixture was quenched with water (700 mL) and saturated NH4Cl (200 mL), and the THF was evaporated. The product was extracted with EtOAc (1 × 400 mL, 2 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The organic layer was passed through a silica gel plug, washing with DCM (1000 mL), 80% EtOAc / heptane (2×200 mL), and DCM (2×250 mL) to give 2-(5-ethyl-2-thienyl)ethanol S5 (71.25 g, 93%). 1 H NMR (300 MHz, chloroform-d) δ 6.69 (dt,J = 3.4,0.9 Hz,1H),6.64 (dt,J = 3.3,1.0 Hz,1H),3.84 (t,J = 6.3 Hz,2H),3.08 - 2.97 (m,2H),2.82 (qd,J = 7.5,1.0 Hz,2H),1.31 (t,J = 7.5 Hz,4H). Preparation of S6 2-[5-(trifluoromethyl)-2-thienyl]ethanol (S6) [ka] Step 1. Synthesis of 2-(5-iodo-2-thienyl)ethanol (C15)

[0201] To a stirred solution of NIS (104.83 g, 0.4680 mol) in DCM (1000 mL) was added 2-(2-thienyl)ethanol C14 (50 g, 0.3900 mol) at 0 °C. The reaction was warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with DCM (500 mL), washed with saturated sodium thiosulfate, brine, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography (eluent: 20% EtOAc in petroleum ether) gave the product, 2-(5-iodo-2-thienyl)ethanol C15 (62 g, 56%). 1 H NMR (400 MHz, chloroform-d) δ 7.08 (d,J = 3. 6 Hz,1H),6.57-6.56 (m,1H),3.82 (q,J = 6 Hz,2H),3.05 (q,J = 6.4 Hz,2H) LCMS m / z 254.89 [M+H] + . Step 2. Synthesis of 2-[2-(5-iodo-2-thienyl)ethoxy]tetrahydropyran (C16)

[0202] To a stirred solution of 2-(5-iodo-2-thienyl)ethanol C15 (15 g, 0.0525 mol) and 3,4-dihydro-2H-pyran (6.6284 g, 0.0788 mol) in THF (60 mL) was added PTSA (1.3604 g, 1.2714 mL, 0.0079 mol) at room temperature. The reaction was stirred under argon balloon pressure for 16 hours. The reaction mixture was concentrated under reduced pressure. Purification by silica gel chromatography (eluent: 5% EtOAc in petroleum ether) afforded the product, 2-[2-(5-iodo-2-thienyl)ethoxy]tetrahydropyran C16 (12.8 g, 68%). 1 H NMR (400 MHz,DMSO-d6) δ 7.14 (d,J = 3.6 Hz,1H),6.64 (d,J = 3.6 Hz,1H),4.59 (t,J =3.6 Hz,1H),3.80-3.76 (m,1H),3.74-3.67 (m,1H),3.54-3.50 (m,1H),3.48-3.41 (m,1H),3.03 (t,J = 6 Hz,2H),1.75-1.69 (m,1H),1.61-1.59 (m,1H),1.51-1.42 (m,4H). Step 3. Synthesis of 2-[2-[5-(trifluoromethyl)-2-thienyl]ethoxy]tetrahydropyran (C17)

[0203] To a stirred solution of 2-[2-(5-iodo-2-thienyl)ethoxy]tetrahydropyran C16 (10 g, 0.0219 mol) and methyl 2,2-difluoro-2-fluorosulfonylacetate (12.63 g, 0.0657 mol) in DMF (40 mL) was added copper(I) iodide dimethyl sulfide complex 99% (2.241 g, 0.0109 mol). The reaction was stirred at 100 °C for 16 h. The reaction was warmed to room temperature, diluted with EtOAc (100 mL), filtered, and washed with EtOAc (50 mL). The filtrate was washed with chilled brine solution, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography using neutral alumina (eluent: 5% EtOAc in petroleum ether) gave the product 2-[2-[5-(trifluoromethyl)-2-thienyl]ethoxy]tetrahydropyran C17 (2.9 g, 41%). 1 H NMR (400 MHz, chloroform-d) δ 7.25 (s,1H),6.82-6.81(m,1H),4.63 (t,J =3.6 Hz,1H),4.00-3.95 (m,1H),3.78-3.75 (m,1H),3.64-3.58 (m,1H),3.51-3.48 (m,1H),3.12 (d,J = 6.4 Hz,2H),1.90-1.80 (m,1H),1.73-1.64 (m,1H),1.65-1.51 (m,4H). GCMS:87.26%, m / z:280 [M] + . Step 4: Synthesis of 2-[5-(trifluoromethyl)-2-thienyl]ethanol (S6)

[0204] To a stirred solution of 2-[2-[5-(trifluoromethyl)-2-thienyl]ethoxy]tetrahydropyran C17 (5.8 g, 0.0170 mol) in MeOH (100 mL) was added PTSA (2.93 g, 0.0170 mol) at room temperature. The reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography on neutral alumina (eluent: 10% EtOAc in petroleum ether) gave the product, 2-[5-(trifluoromethyl)-2-thienyl]ethanol S6 (2.3 g, 61%). 1 H NMR (400 MHz,DMSO-d6) δ 7.52-7.51 (m,1H),6.99-6.98 (m,1H),4.92 (t,J = 4.8 Hz,1H),3.65-3.61 (m,2H),2.98 (t,J = 6 Hz,2H). 19 F NMR (376.22 MHz,DMSO-d6) δ -53.53 (s,3F). GCMS:88.56% m / z:196.0 [M] + . Preparation of S7 2-[5-(trifluoromethyl)-2-thienyl]propan-1-ol (S7) [ka] Step 1. Synthesis of 2-(2-thienyl)ethyl acetate (C19)

[0205] To a stirred solution of 2-(2-thienyl)acetic acid C18 (100 g, 703.35 mmol) in ethanol (2000 mL) was added HCl (aq) (50 mL of 36% (w / v), 493.68 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 12 h. The mixture was concentrated, and the resulting crude material was diluted with EtOAc (1000 mL) and washed with 5% aqueous NaCO solution (3 × 200 mL), and brine (200 mL). The organic layer was dried and concentrated to give the desired product, ethyl 2-(2-thienyl)acetate C19 (100 g, 82%). 1H NMR (chloroform-d,400 MHz) δ 7.22-7.21 (dd,J = 1.2 Hz,J = 3.6 Hz,1H),6.97-6.95 (m,2H),4.21-4.16 (q,J = 7.2 Hz,2H),3.83 (s,2H),1.30-1.26 (t,J = 7.2Hz,3H). LCMS m / z 171.26 [M+H] + . Step 2. Synthesis of ethyl 2-(2-thienyl)propanoate (C20)

[0206] To a solution of ethyl 2-(2-thienyl)acetate C19 (1.36 g, 7.99 mmol) in 20 mL of THF at -78 °C was added (diisopropylamino)lithium (8 mL of 1 M, 8.000 mmol). After 15 min, Mel (500 μL, 8.032 mmol) was added and the reaction was stirred at -78 °C for 2 h. The reaction was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc. The organic layer was dried and concentrated to an oil. Purification by silica chromatography (gradient: 0 to 25% EtOAc in heptane) gave the product, ethyl 2-(2-thienyl)propanoate C20 (1.04 g, 71%). 1 H NMR (300 MHz, chloroform-d) δ 7.25 - 7.17 (m, 1H), 7.02 - 6.93 (m,2H),4.18 (d,J = 7.2 Hz,2H),4.02 (q,J = 7.1 Hz,1H),1.60 (d,J = 7.2 Hz,3H),1.28 (t,J = 7.1 Hz,3H). Step 3. Synthesis of ethyl 2-(5-iodo-2-thienyl)propanoate (C21)

[0207] To a stirred solution of ethyl 2-(2-thienyl)propanoate C20 (35 g, 143.99 mmol) in acetic acid (350 mL) was added N-iodosuccinimide (38.875 g, 172.79 mmol). The reaction mixture was stirred at 100 °C for 1 h. The mixture was concentrated, and the resulting crude material was diluted with EtOAc (700 mL) and washed sequentially with water (300 mL), saturated sodium bicarbonate solution (300 mL), saturated sodium thiosulfate solution (300 mL), and brine solution (250 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product. Silica gel chromatography (eluent: 3% in petroleum ether) was performed. Purification with HCl (Et0Ac) gave the product ethyl 2-(5-iodo-2-thienyl)propanoate C21 (30 g, 42%). 1 H NMR (chloroform-d, 400 MHz) δ 7.08 (d,J = 4 Hz,1H),6.62 (d,J = 4 Hz,1H),4.19-4.13 (m,2H),3.98-3.92 (m,1H),1.55-1.51 (m,3H),1.28-1.24 (m,3H). LCMS m / z 309.9 [M+H] + . Step 4: Synthesis of ethyl 2-[5-(trifluoromethyl)-2-thienyl]propanoate (C22)

[0208] To a stirred solution of ethyl 2-(5-iodo-2-thienyl)propanoate C21 (5 g, 9.9629 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (9.57 g, 49.814 mmol) in DMF (50 mL) was added CuI (2.2768 g, 11.955 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 12 h. The mixture was filtered through Celite® and the Celite® bed was washed with diethyl ether (2 × 100 mL). The filtrate was quenched with cold water (100 mL). The two layers were separated, and the aqueous layer was extracted with diethyl ether (2 × 50 mL). The combined organic layer was washed with brine (30 mL), dried, and concentrated. Purification by silica gel chromatography (eluent: 3% EtOAc in petroleum ether) gave the product ethyl 2-[5-(trifluoromethyl)-2-thienyl]propanoate C22 (2 g, 58%). 1 H NMR (chloroform-d, 400 MHz) δ 7.29-7.26 (m, 1H), 6.92-6.90 (m, 1H), 4.21-4.15 (m, 2H), 3.99-3.96 (m, 1H), 1.57-1.53 ​​(m, 3H), 1.23-1.27 (m, 3H). GCMS: m / z: 252.1 [M] + . Step 5. Synthesis of 2-[5-(trifluoromethyl)-2-thienyl]propan-1-ol (S7)

[0209] To a stirred solution of ethyl 2-[5-(trifluoromethyl)-2-thienyl]propanoate C22 (12 g, 41.701 mmol) in THF (250 mL) was added DIBAL-H (35.584 mL of 25% w / v, 62.5 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The mixture was slowly quenched with saturated NH4Cl solution (300 mL) at 0 °C, and the suspension was filtered through Celite®, and the Celite® bed was washed with EtOAc (2 × 200 mL). The filtrate was separated into layers. The aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated. Purification by silica gel chromatography (eluent: 3% EtOAc in petroleum ether) gave the crude product. Racemic 2-[5-(trifluoromethyl)-2-thienyl]propan-1-ol (1.6 g, 7.3067 mmol) was separated from the over-alkylation by-product dimethyl using chiral SFC separation. Column: Daicel Chilalpak® AD-H, 30 x 250 mm; Mobile phase: 10% methanol / hexane mixture (7:3), 90% Carbon dioxide. Flow rate: 90 g / min. 2-[5-(trifluoromethyl)-2-thienyl]propan-1-ol S7 (3.64 g). 1 H NMR (400 MHz, chloroform-d) δ 7.52 (m,1H),7.00 (m,1H),4.97 (t,J =5.6 Hz,1H),3.51 (t,J =6.0 Hz,2H) 3.17 (m,1H),1.27 (d,J = 6.8 Hz,3H). GCMS:m / z:210.0 [M] + . Preparation of S8 2-Methyl-2-[5-(trifluoromethyl)-2-thienyl]propan-1-ol (S8) [ka]

[0210] S8 was obtained during SFC purification of S7 as a by-product of the over-alkylation in step 2 above. Preparation of S9, S10 and S11 2-Methyl-2-[5-(chloro)-2-thienyl]propan-1-ol (S9) 2-[5-(chloro)-2-thienyl]propan-1-ol (S10 [ENANT-1], S11 [ENANT-2]) [ka] Step 1. Synthesis of ethyl 2-(5-chloro-2-thienyl)propanoate (C24)

[0211] To a stirred solution of ethyl 2-(2-thienyl)propanoate C20 (1 g, 4.1139 mmol) in acetic acid (10 mL) was added N-chlorosuccinimide C23 (549.34 mg, 4.1139 mmol). The reaction mixture was stirred at 100 °C for 1 h. The mixture was concentrated, and the resulting crude material was diluted with EtOAc (25 mL) and washed with water (10 mL), saturated sodium bicarbonate solution (10 mL), saturated sodium thiosulfate solution (10 mL), and brine solution (10 mL). The organic layer was dried over NaSO, filtered, and concentrated to give the crude product. Purification by silica gel chromatography (eluent: 3% EtOAc in petroleum ether) gave the product, ethyl 2-(5-chloro-2-thienyl)propanoate C24 (700 mg, 60%). 1 H NMR (chloroform-d, 400 MHz): δ = 6.75-6.73 (m, 1H), 6.71-6.69 (m, 1H), 4.20-4.14 (m, 2H), 3.88-3.73 (q, J = 6.4 Hz, 1H), 1.55-1.53 ​​(t, J = 2.8 Hz, 3H), 1.30-1.221 (m, 3H). GCMS: m / z: 218.0 [M] + . Step 2. Synthesis of 2-(5-chloro-2-thienyl)-2-methyl-propan-1-ol and 2-(5-chloro-2-thienyl)propan-1-ol (S9) and (C25)

[0212] To a stirred solution of ethyl 2-(5-chloro-2-thienyl)propanoate C24 (25 g, 86.877 mmol) in THF (500 mL) was added DIBAL-H (74.135 mL of 25% w / v, 130.32 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The mixture was slowly quenched with saturated NH4Cl solution (300 mL) at 0 °C, and the suspension was filtered through Celite®, and the Celite® bed was washed with EtOAc (2 × 200 mL). The filtrate was separated into two layers. The aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and concentrated. Purification by silica gel chromatography (eluent: 3% EtOAc in petroleum ether) gave S9, 2-(5-chloro-2-thienyl)-2-methyl-propan-1-ol (410 mg, 2%). 1 H NMR (chloroform-d, 400 MHz) δ 6.76-6.75 (d, J = 4 Hz, 1H), 6.67-6.65 (t, J = 4 Hz, 1H), 3.54-3.52 (d, J = 6.8 Hz, 2H), 1.47-1.43 (t, J = 6.8 Hz, 1H), 1.34 (s, 6H). GCMS: m / z: 190.0 [M] + ; and 2-(5-chloro-2-thienyl)propan-1-ol C25 (12 g, 72%). 1 H NMR (chloroform-d, 400 MHz) δ 6.76-6.75 (d, J = 3.6 Hz, 1H), 6.66-6.65 (dd, J = 4.4 Hz, 1H), 3.71-3.61 (m, 2H), 3.15-3.10 (m,1H),1.57-1.52 (m,1H),1.34-1.31 (t,J = 6 Hz,3H). GCMS:m / z:176.0 [M] + NOTE: The dimethyl compound (S9) was formed as a by-product from over-alkylation during the synthesis of C20. Step 3. Synthesis of 2-(5-chloro-2-thienyl)propan-1-ol (S10) and (S11)

[0213] Racemic 2-(5-chloro-2-thienyl)propan-1-ol C25 (12 g, 62.492 mmol) was separated into its constituent enantiomers by chiral SFC separation. Column: Daicel Chilalpak® AD-H, 30 x 250 mm; Mobile phase: 10% methanol / hexane (7:3), 90% carbon dioxide. Flow rate: 90 g / min. 2-(5-chloro-2-thienyl)propan-1-ol S10 (4 g, 35%). 1 H NMR (chloroform-d, 400 MHz) δ 6.76-6.75 (d, J = 3.6 Hz,1H),6.66-6.65 (dd,J = 3.6 Hz,1H),3.73-3.61 (m,2H),3.17-3.10 (m,1H),1.52-1.49 (t,J = 5.2 Hz,1H),1.32-1.30 (d,J = 6.8 Hz,3H). GCMS:m / z:176.0 [M] + and 2-(5-chloro-2-thienyl)propan-1-ol S11 (3.75 g, 34%). 1 H NMR (chloroform-d, 400 MHz) δ 6.76-6.75 (d, J = 4 Hz, 1H), 6.66-6.65 (dd, J = 3.6 Hz, 1H), 3.73-3.61 (m, 2H), 3.15-3.10 (q, J = 6.8 Hz,1H),1.51-1.48 (t,J = 5.6 Hz,1H),1.33-1.30 (d,J = 7.2Hz,3H). GCMS:m / z:176.0 [M] + . Preparation of S12 and S13 2-(5-ethyl-2-thienyl)propan-1-ol (S12 ENANT-1) and (S13 ENANT-2) [ka] Step 1. Synthesis of ethyl 2-(5-acetyl-2-thienyl)propanoate (C26)

[0214] To a stirred solution of ethyl 2-(2-thienyl)propanoate C20 (80 g, 336.92 mmol) in DCM (1500 mL) was added acetyl chloride (39.671 g, 35.934 mL, 505.38 mmol) dropwise at 0 °C, followed by the addition of AlCl3 (67.388 g, 505.38 mmol) at 0 °C. The reaction mixture was stirred for 2 h at 0 °C. The mixture was slowly quenched with ice water (1000 mL), the two layers were separated, and the aqueous layer was extracted with DCM (2 × 500 mL). The combined organic layers were washed with brine (500 mL) and dried over sodium sulfate. Purification by silica gel chromatography (gradient: 0–5% EtOAc in petroleum ether) gave the product, ethyl 2-(5-acetyl-2-thienyl)propanoate C26 (60 g, 73%). 1 H NMR (chloroform-d, 400 MHz) δ 7.56-7.54 (t, J = 4.0 Hz, 1H), 6.99-6.98 (m, 1H), 4.20-4.14 (m, 2H), 4.01-3.9 6 (q,J = 7.2 Hz,1H),2.52 (s,3H),1.60-1.56 (d,J = 7.2 Hz,3H),1.28-1.23 (m,3H). LCMS m / z 227.1 [M+H] + . Step 2. Synthesis of ethyl 2-(5-ethyl-2-thienyl)propanoate (C27)

[0215] To a stirred solution of ethyl 2-(5-acetyl-2-thienyl)propanoate C26 (60 g, 245.79 mmol) in TFA (400 mL) was added triethylsilane (42.870 g, 58.9 mL, 368.69 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction was concentrated, quenched with ice-water (500 mL), and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (250 mL), dried over sodium sulfate, and concentrated to give the crude product. Purification by silica gel chromatography (gradient: 0–3% EtOAc in petroleum ether) gave the product, ethyl 2-(5-ethyl-2-thienyl)propanoate C27 (50 g, 82%). 1H NMR (chloroform-d, 400 MHz) δ 6.73-6.72 (dd, J = 3.6 Hz, 1H), 6.62-6.60 (m, 1H), 4.18-4.13 (m, 2H), 3.93-3.88 (q, J = 7.2 Hz, 1H), 2.82-2.78 (m, 2H), 1.55-1.53 ​​(d, J = 7.2 Hz, 3H) 1.30-1.23 (m, 6H). LCMS m / z 213.2 [M+H] + . Step 3. Synthesis of 2-(5-ethyl-2-thienyl)propan-1-ol (C28)

[0216] To a stirred solution of ethyl 2-(5-ethyl-2-thienyl)propanoate C27 (50 g, 200.18 mmol) in THF (1000 mL) was added DIBAL-H (25% in toluene, 25%) (227.75 mL of 25% (w / v), 400.36 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The mixture was slowly quenched with saturated NH4Cl solution (500 mL) at 0 °C and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine (250 mL), dried over sodium sulfate, and concentrated. Purification by silica gel chromatography (gradient: 0–5% EtOAc in petroleum ether) gave the product, 2-(5-ethyl-2-thienyl)propan-1-ol C28 (31 g, 89%). 1 H NMR (chloroform-d, 400 MHz): δ 6.69-6.68 (d, J = 3.6 Hz,1H),6.64-6.62 (m,1H),3.72-3.60 (m,2H),3.18-3.13 (q,J = 6.8 Hz,1H),2.83-2.77 (m,2H),1.61-1.5 (m,1H),1.35-1.28 (m,6H). LCMS m / z 171.02 [M+H] + . Step 4: Synthesis of 2-(5-ethyl-2-thienyl)propan-1-ol (S12) and (S13)

[0217] Racemic 2-(5-ethyl-2-thienyl)propan-1-ol C28 (31 g, 178.06 mmol) was separated into its constituent enantiomers by chiral SFC separation. Column: Daicel Chilalpak® AD-H, 30 × 250 mm; Mobile phase: 10% methanol / hexane mixture (7:3), 85% carbon dioxide. 2-(5-ethyl-2-thienyl)propan-1-ol S12 (13.45 g, 43%). 1 H NMR (chloroform-d, 400 MHz): δ = 6.69-6.68 (d, J = 3.2 Hz, 1H), 6.63-6.62 (d, J = 3.2 Hz, 1H), 3.73-3.61 (m, 2H), 3.19-3.14 (q, J = 6.8 Hz, 1H), 2.83-2.78 (m, 2H), 1.54-1.47 (m, 1H), 1.35-1.27 (m, 6H). LCMS m / z 171.1 [M+H] + and 2-(5-ethyl-2-thienyl)propan-1-ol S13 (11.35 g, 37%). 1 H NMR (chloroform-d, 400 MHz): δ 6.68-6.67 (d, J = 3.6 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H), 3.73-3.61 (m, 2H), 3.20-3.12 (m, 1H), 2.83-2.77 (q, J = 7.6 Hz,2H),1.54-1.45 (m,1H),1.33-1.27 (m,6H). LCMS m / z 171.1 [M+H] + . Preparation of S14 Synthesis of 2-(5-methyl-3-thienyl)ethanol (S14) [ka]

[0218] To a stirred solution of 2-(5-bromo-3-thienyl)ethanol C10 (2.5 g, 0.0098 mol) in 1,4-dioxane (16.000 mL) was added K2CO3 (4.9 g, 0.036 mol) in a sealed tube at room temperature. The reaction mixture was degassed with argon gas for 10 minutes. Xphos Pd G2 (457 mg, 580.83 μmol) was added and degassed again for 5 minutes. Trimethylboroxine (50% solution in THF) (24.605 mL of 50% w / v solution, 0.0980 mol) was added and heated to 80 °C for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (eluent: 20% EtOAc in petroleum ether) gave the product S14 2-(5-methyl-3-thienyl)ethanol (950 mg, 66%) as a yellow liquid. 1 H NMR (400 MHz,DMSO-d6) δ 6.87 (d,J = 0.8 Hz,1H),6.68 (s,1H),4.59 (t,J = 5.2 Hz,1H),3.58-3.53 (m,2H),2.63 (t,J = 7.2 Hz,2H),2.38 (d,J = 0.8 Hz,3H). Preparation of S15 Preparation of 2-(5-methyl-2-thienyl)ethanol (S15) [ka] Step 1. Synthesis of 2-(5-bromo-2-thienyl)ethanol (C30)

[0219] A solution of 2-(2-thienyl)ethanol C29 (15 g, 0.1170 mol) in DMF (150.00 mL) was added dropwise to a solution of NBS (20.824 g, 0.1170 mol) in DMF at −10° C. The reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with 6% KOH solution, ice water (2×150 mL), and brine (150 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (eluent: 10% EtOAc in petroleum ether) gave the product, 2-(5-bromo-2-thienyl)ethanol C30 (20.5 g, 79%). 1 H NMR (400 MHz, chloroform-d) δ 6.89 (d,J = 3.6 Hz, 1H), 6.64 - 6.28 (m, 1H), 3.82 (t,J = 6.0 Hz, 2H), 2.99 (t,J = 6.0 Hz, 2H). Step 2. 2-[2-(5-bromo-2-thienyl)ethoxy]tetrahydropyran (C3 Synthesis of 1)

[0220] To a stirred solution of 2-(5-bromo-2-thienyl)ethanol C30 (20 g, 0.0869 mol) and 3,4-dihydro-2H-pyran (10.969 g, 0.1304 mol) in THF (80 mL) was added PTSA (603 mg, 0.5636 mL, 0.0035 mol), and the reaction was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate solution (50 mL), water, and brine. The organic layer was separated, dried over sodium sulfate, and concentrated. Purification by silica gel chromatography (gradient: 0–5% EtOAc in petroleum ether) afforded 2-[2-(5-bromo-2-thienyl)ethoxy]tetrahydropyran C31 (18.5 g, 64%). 1 H NMR (400 MHz, chloroform-d) δ 6.86 (d, J = 3.6 Hz, 1H), 6.61-6.60 (m, 1H), 4.62 (t, J = 3.6 Hz, 1H), 3.99-3.50 (m, 4H), 3.05-3.01 (m, 2H), 1.73-1.50 (m, 6H). Step 3. Synthesis of 2-[2-(5-methyl-2-thienyl)ethoxy]tetrahydropyran (C32)

[0221] To a solution of 2-[2-(5-bromo-2-thienyl)ethoxy]tetrahydropyran C31 (19 g, 0.0555 mol) in THF (380.00 mL) was added n-BuLi (33.320 mL of 2.5 M, 0.0833 mol) dropwise at −78 °C. The reaction was stirred at −78 °C for 1 h. Iodomethane (15.755 g, 6.9101 mL, 0.1110 mol) was added dropwise at −78 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NH4Cl solution and diluted with water. The aqueous layer was extracted with EtOAc (2 × 250 mL). Purification by silica gel chromatography (eluent: 100% petroleum ether) gave 2-[2-(5-methyl-2-thienyl)ethoxy]tetrahydropyran C32 (19 g, 130%). 1 H NMR (400 MHz, chloroform-d) δ 6.61 (d,J = 3.2 Hz,1H),6.55-6.54 (m,1H),4.63 (m,1H),3.96-3.50 (m,4H),3.03 (t,J = 2.8 Hz, 2H), 2.42 (s, 3H), 1.72-1.42 (m, 6H). Step 4: Synthesis of 2-(5-methyl-2-thienyl)ethanol (S15)

[0222] To a solution of 2-[2-(5-methyl-2-thienyl)ethoxy]tetrahydropyran C32 (14 g, 0.0532 mol) in MeOH (280.00 mL) was added PTSA (10.9 g, 10.187 mL, 0.0633 mol) at room temperature. The reaction was stirred for 24 h. The reaction mixture was diluted with EtOAc (500 mL) and then washed with water (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (2 × 100 mL). The aqueous layer was extracted again with EtOAc (2 × 100 mL). The combined organic layers were dried over Na2SO4. Purification by silica gel chromatography (gradient: 0–15% EtOAc in petroleum ether) gave 2-(5-methyl-2-thienyl)ethanol S15 (6.56 g, 82%). 1 H NMR (400 MHz,DMSO-d6) δ 6.61 (d,J = 3.6 Hz,1H),6.58-6.57 (d,J = 4.0 Hz,1H),4.73 (t,J = 5.2 Hz,1H),3.58-3.53 (m,2H),2.82 (t,J = 6.8 Hz,2H),2.36 (s,3H). Preparation of S16 Methyl [4-(2-hydroxyethyl)-2-(trifluoromethyl)-3-thienyl]acetate (S16) [ka] Step 1. Synthesis of tert-butyl-dimethyl-[2-[5-(trifluoromethyl)-3-thienyl]ethoxy]silane (C33)

[0223] To a mixture of 2-[5-(trifluoromethyl)-3-thienyl]ethanol S3 (500 mg, 2.498 mmol) in DCM (10 mL) was added imidazole (190 mg, 2.791 mmol), followed by TBSCl (420 mg, 2.787 mmol). A white solid precipitated immediately. The solid was filtered, and the organic layer was washed with 1 N HCl (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (gradient: heptane, 0–30% EtOAc) afforded the product, tert-butyl-dimethyl-[2-[5-(trifluoromethyl)-3-thienyl]ethoxy]silane C33, which was assumed to be quantitative and was carried forward without further purification. Step 2. Synthesis of tert-butyl-dimethyl-[2-[5-(trifluoromethyl)-2-trimethylsilyl-3-thienyl]ethoxy]silane (C34)

[0224] A mixture of tert-butyl-dimethyl-[2-[5-(trifluoromethyl)-3-thienyl]ethoxy]silane C33 in THF (10 mL) was cooled to -78 °C and sec-butyllithium (2.3 mL of 1.4 M, 3.220 mmol) was added, followed by TMSCl (3 mL of 1 M, 3.000 mmol). After 5 min, the yellow mixture was quenched with saturated aqueous ammonium chloride. The mixture was diluted with water (10 mL) and MTBE (10 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Purification was carried out by silica gel chromatography (gradient: 0–10% EtOAc in heptane) to give tert-butyl-dimethyl-[2-[5-(trifluoromethyl)-2-trimethylsilyl-3-thienyl]ethoxy]silane C34 (400 mg, 42%). 1 H NMR (300 MHz, chloroform-d) δ 7.41 (d, J = 1.2 Hz, 1H), 3.80 - 3.75 (m, 2H), 2.87 (t, J = 6.8 Hz, 2H), 0.87 (s, 9H), 0.36 (s, 9H), -0.00 (d, J = 2.2 Hz, 6H). Step 3. Synthesis of 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(trifluoromethyl)-5-trimethylsilyl-thiophene-3-carbaldehyde (C35)

[0225] tert-Butyl-dimethyl-[2-[5-(trifluoromethyl)-2-trimethylsilyl-3-thienyl]ethoxy]silane C34 (400 mg, 1.024 mmol) To a mixture of THF (10 mL) cooled to −78° C. was added sec-butyllithium (1.2 mL of 1.4 M, 1.680 mmol), followed by DMF (3 mL of 1 M, 3.000 mmol). After 5 min, the yellow mixture was quenched with saturated aqueous ammonium chloride. The mixture was diluted with EtOAc (20 mL) and water (20 mL) and separated. The organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (eluent: 100% heptane) afforded the product, 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(trifluoromethyl)-5-trimethylsilyl-thiophene-3-carbaldehyde C35. The mixture was concentrated, diluted with heptane (5 mL), and washed with water (5 mL). The organic layer was passed through a phase separator, concentrated, and carried directly to the next step. Step 4: Synthesis of [4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(trifluoromethyl)-5-trimethylsilyl-3-thienyl]methanol (C36)

[0226] 4-[2-[tert-Butyl(dimethyl)silyl]oxyethyl]-2-(trifluoromethyl)-5-trimethylsilyl-thiophene-3-carbaldehyde C35 was diluted in MeOH (1 mL) and NaBH4 (7 mg, 0.1850 mmol) was added to the mixture. After 10 min, the mixture was concentrated and rediluted in heptane (2 mL) and water (2 mL). The organic layer was separated and the aqueous layer was extracted with additional heptane. The organic layer was passed through a phase separator and concentrated. Purification by silica gel chromatography (gradient: 0-10% EtOAc in heptane) gave the product C36.1 H NMR (300 MHz, chloroform-d) δ 4.65 (d, J = 6.3 Hz, 2H), 4.00 - 3.72 (m, 2H), 3.34 (t, J = 6.3 Hz, 1H), 2.97 (t, J = 6.1 Hz, 2H), 0.82 (s, 10H), 0.36 (s, 9H). Step 5. Synthesis of methyl [4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(trifluoromethyl)-5-trimethylsilyl-3-thienyl]acetate (C37)

[0227] To a solution of [4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(trifluoromethyl)-5-trimethylsilyl-3-thienyl]methanol C36 in DCM (4 mL) was added DMAP (2 mg, 0.016 mmol) and DIPEA (50 μL, 0.2871 mmol), followed by AcO (30 μL, 0.3180 mmol). The mixture was concentrated, diluted with heptane (5 mL), and washed with water (5 mL). The organic layer was passed through a phase separator and concentrated to give the product, which was carried on directly to the next step. Step 6. Synthesis of methyl [4-(2-hydroxyethyl)-2-(trifluoromethyl)-3-thienyl]acetate (S16)

[0228] From step 5, [4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(trifluoromethyl)-5-trimethylsilyl-3-thienyl]methyl acetate C37 was diluted with EtOAc (2 mL). To the mixture was added a solution of TBAF in THF (1 mL of 1 M, 1.000 mmol), and the mixture was stirred. The reaction was stirred for 48 h. The mixture was diluted with additional EtOAc (3 mL), washed with water, passed through a phase separator, and concentrated. Purification by silica gel chromatography (gradient: 0 to 60% EtOAc in heptane) gave the product, [4-(2-hydroxyethyl)-2-(trifluoromethyl)-3-thienyl]methyl acetate S16 (35 mg, 12%). 1H NMR (300 MHz, chloroform-d) δ 7.26 (s, 1H), 5.14 (d, J = 1.1 Hz, 2H), 3.86 (t, J = 6.4 Hz, 2H), 2.97 - 2.74 (m, 2H), 2.07 (s, 3H), 1.80 (s, 1H). LCMS m / z 269.21 [M+H] + . Preparation of S17 1-Methyltriazole-4-carbaldehyde (S17) [ka]

[0229] 1-Methyltriazole-4-carbaldehyde S17 was obtained from a commercial source. Preparation of S18 1-(2-Methylsulfonylethyl)triazole-4-carbaldehyde (S18) [ka] Step 1. Synthesis of 1-azido-2-methylsulfonyl-ethane (C40)

[0230] A solution of 2-methylsulfonylethanol C38 (5 g, 0.04 mol) and diphenylphosphoryl azide C39 (8.8614 g, 0.0322 mol) in toluene (50 mL) was stirred at 0 °C for 10 min. DBU (5.5 g, 5.42 mL, 0.04 mol) was added dropwise at 0 °C for 10 min, and the reaction was stirred at room temperature for 16 h. The reaction was quenched with water (25 mL) and EtOAc (100 mL) and stirred for 20 min. The organic layer was separated, and the aqueous layer was re-extracted with EtOAc (2 × 100 mL). The organic layer was dried over NaSO and concentrated. Purification by silica gel chromatography (gradient: 0–100% ethyl acetate in petroleum ether) afforded 1-azido-2-methylsulfonyl-ethane C40 (5.2 g, 86%). 1H NMR (400 MHz,DMSO-d6) δ 3.77-3.73 (t,J = 8.8 Hz,2H),3.44-3.42 (t,J = 8.8 Hz,2H),3.03 (s,3H). Step 2. Synthesis of 1-(2-methylsulfonylethyl)triazole-4-carbaldehyde (S18)

[0231] A mixture of 3,3-diethoxyprop-1-yne (555 μL, 3.897 mmol), 1-azido-2-methylsulfonyl-ethane C40 (600 mg, 4.022 mmol), CuSO4 (15 mg, 0.09398 mmol), 1-(1-benzyltriazol-4-yl)-N,N-bis[(1-benzyltriazol-4-yl)methyl]methanamine (100 mg, 0.1885 mmol), and sodium ascorbate (700 mg, 3.974 mmol) in MeOH (12 mL) / water (3 mL) was heated to 60 °C for 2 h. The reaction was cooled to room temperature, concentrated, and diluted with EtOAc (100 mL) and water (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined layers were dried, diluted with 1N HCl (20 mL), and stirred overnight, at which point the solution was concentrated to give 1-(2-methylsulfonylethyl)triazole-4-carbaldehyde (hydrochloride salt) S18 (553 mg, 59%). 1 H NMR (400 MHz, methanol-d4) δ 8.07 (s, 1H), 5.58 - 5.45 (m, 1H), 4.89 - 4.82 (m, 2H), 3.76 - 3.67 (m, 2H), 3.24 (s, 3H). LCMS m / z 204.47 [M+H] + . Preparation of S19 1-(2-Methylsulfonylethyl)pyrazole-4-carbaldehyde (S19) [ka]

[0232] A solution of 1H-pyrazole-4-carbaldehyde C42 (10 g, 104.1 mmol), 11-methylsulfonylethylene C41 (10 mL, 114.2 mmol), and K2CO3 (25 g, 180.9 mmol) in THF (200 mL) was stirred at 60 °C. After stirring overnight, the mixture was cooled to room temperature and concentrated to dryness. The product was triturated by suspending it in diethyl ether (100 mL) and stirring for 2 h. The product was filtered and dried overnight to give 11-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde S19 (20.28 g, 83%). 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s,1H),8.54 (d,J = 0.7 Hz,1H),8.05 (d,J = 0.7 Hz,1H),4.64 (t,J = 6.8 Hz,2H),3.80 - 3.67 (m,2H),2.96 (d,J = 0.7 Hz,3H). LCMS m / z 203.01 [M+H] + . Preparation of S20 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazole-4-carbaldehyde (S20) [ka] Step 1. Synthesis of tert-butyl-(2-iodoethoxy)-dimethyl-silane (C44)

[0233] To a stirred solution of 2-iodoethanol C43 (2 g, 0.0116 mol) and imidazole (1.58 g, 0.0232 mol) in DCM (40 mL) was added tert-butyl-chloro-dimethyl-silane (1.9 g, 0.0126 mol) at 0 °C. The reaction was warmed to room temperature and stirred for 4 h. The reaction mixture was diluted with DCM (100 mL), washed with saturated NaHCO and brine, dried over NaSO, and concentrated under reduced pressure to give tert-butyl-(2-iodoethoxy)-dimethyl-silane C44 (2.5 g, 68%). 1H NMR (400 MHz, chloroform-d) δ 3.83 (t, J = 6.8 Hz, 2H), 3.20 (t, J = 6.8 Hz, 2H), 0.90 (s, 9H), 0.08 (s, 6H). Step 2. Synthesis of 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazole-4-carbaldehyde (S20)

[0234] To a solution of 1H-pyrazole-4-carbaldehyde C42 (20 g, 208.1 mmol) and K2CO3 (115 g, 832.1 mmol) in MeCN (200 mL) was added tert-butyl-(2-iodoethoxy)-dimethyl-silane C44 (65 g, 227.1 mmol). The reaction was heated to 80 °C. The reaction was stirred for 5 h. The reaction was cooled to 50 °C and stirred for 16 h. The reaction mixture was allowed to equilibrate to ambient temperature, filtered, and the solid was washed with MeCN (200 mL). The solid was discarded, and the filtrate was concentrated. The residue was partitioned between EtOAc (400 mL) and water (400 mL). The organic layer was separated and the water (400 mL) and brine (400 mL), dried over MgSO, filtered, and concentrated. Purification by silica gel chromatography (800 g column, hexanes, 0–80% EtOAc) afforded the product, 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazole-4-carbaldehyde S20 (46 g, 87%) as a pale yellow oil. 1 H NMR (300 MHz, chloroform-d) δ 9.86 (s, 1H), 7.98 (s, 2H), 4.25 (dd, J = 5.5, 4.5 Hz, 2H), 3.96 (dd, J = 5.5, 4.5 Hz, 2H), 0.83 (s, 9H), -0.06 (s, 6H). LCMS m / z 255.14 [M+H] + . Preparation of S21 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (S21) [ka] Step 1. Synthesis of 2-(bromomethyl)-2-methyl-propane-1,3-diol (C46)

[0235] To a mixture of (3-methyloxetan-3-yl)methanol C45 (10 mL, 100.3 mmol) in THF (70 mL) at 0 °C was added hydrogen bromide (14 mL of 48% w / w, 123.7 mmol). After stirring for 24 h, the mixture was concentrated to a minimum volume, diluted in DCM / MeOH, and excess HBr was quenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was dried over Na2SO4, filtered, rinsed with methanol, and concentrated to give 2-(bromomethyl)-2-methyl-propane-1,3-diol C46 (13.6682 g, 74%). 1 H NMR (400 MHz, methanol-d4) δ 3.47 (d,J = 1.1 Hz,6H),0.96 (s,3H). Step 2. Synthesis of [2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propoxy]-tert-butyl-dimethyl-silane (C47)

[0236] To a mixture of 2-(bromomethyl)-2-methyl-propane-1,3-diol C46 (10 g, 54.09 mmol) in DCM (200 mL) was added imidazole (7.7 g, 113.1 mmol), followed by TBSCl (17 g, 112.8 mmol). After 5 minutes, the mixture precipitated a white crystalline solid. The mixture was filtered, rinsed with DCM, and concentrated. The mixture was diluted with heptane (25 mL) to precipitate more imidazole / imidazole HCl, filtered, and the solid was washed with additional heptane (10 mL). The mixture was concentrated to precipitate more solid. The mixture was diluted with heptane (50 mL) and concentrated twice more to give [2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propoxy]-tert-butyl-dimethyl-silane C47 (22.246 g, 100%).1 H NMR (400 MHz, chloroform-d) δ 3.44 (s,4H),3.40 (s,2H),0.94 (s,3H),0.89 (s,18H),0.04 (d,J = 1.2 Hz, 12H). Step 3. Synthesis of 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (S21)

[0237] To a vial was added a solution of 1H-pyrazole-4-carbaldehyde C42 (2 g, 20.81 mmol), K2CO3 (4 g, 28.94 mmol), and [2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propoxy]-tert-butyl-dimethyl-silane C47 (9.5 g, 23.08 mmol) in DMF (20 mL). The mixture was heated to 130 °C. After 3 h, the mixture was cooled to room temperature and diluted with water (100 mL) and heptane (100 mL). The layers were mixed, and the aqueous layer was washed with heptane (2 × 100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), and the organic layer was dried over Na2SO4 and concentrated. Purification by silica gel chromatography (gradient: 0–60% EtOAc:heptane) afforded the product 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde S21 (2.39 mg, 23%). 1 H NMR (400 MHz, chloroform-d) δ 9.85 (s, 1H), 7.98 - 7.91 (m, 2H), 4.12 (s, 2H), 3.43 - 3.29 (m, 4H), 0.91 (s, 18H), 0.84 (s, 3H), 0.05 (d, J = 0.6 Hz, 12H). LCMS m / z 427.31 [M+H] + . Preparation of S22 2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]pyrimidine-5-carbaldehyde (S22) [ka] Step 1. Synthesis of ethyl 2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]pyrimidine-5-carboxylate (C49)

[0238] To a stirred solution of ethyl 2-chloropyrimidine-5-carboxylate C48 (25 g, 0.1340 mol) in ethanol (750 mL) was added 2-amino-2-methyl-propan-1-ol (14.333 g, 15.412 mL, 0.1608 mol), followed by DIPEA (34.637 g, 46.681 mL, 0.2680 mol) at room temperature. The reaction was stirred at 80 °C for 8 hours. The reaction was warmed to room temperature and concentrated under reduced pressure. Purification was carried out by silica gel chromatography (eluent: petroleum ether, 70% EtOAc). Ethyl 2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]pyrimidine-5-carboxylate C49 (18 g, 55%) was obtained. 1 H NMR (400 MHz,DMSO-d6) δ 8.70 (s,2H),7.39 (s,1H),4.86 (t,J = 6 Hz,1H),4.25 (q,J = 6.8 Hz,2H),3.52 (d,J = 6 Hz,2H),1.32 (s,6H),1.28 (t,J = 6.8 Hz,3H). LCMS m / z 240.27 [M+H] + . Step 2. Synthesis of ethyl 2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidine-5-carboxylate (C50)

[0239] To a stirred solution of ethyl 2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]pyrimidine-5-carboxylate C49 (10 g, 0.0410 mol) and tert-butyl-chloro-dimethyl-silane (9.2694 g, 0.0615 mol) in DCM (500 mL) was added imidazole (8.3735 g, 0.1230 mol), followed by DMAP (1.0018 g, 0.0082 mol) at room temperature and stirred for 16 hours. The reaction was concentrated under reduced pressure. The crude material was diluted with water (500 mL) and pentane (500 mL). The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under reduced pressure to give ethyl 2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidine-5-carboxylate C50 (14.9 g, 100%). 1 H NMR (400 MHz,DMSO-d6) δ 8.70 (s,2H),7.46 (s,1H),4.25 (q,J = 7.2 Hz,2H),3.77 (s,2H),1.30 (s,6H),1.28 (t,J = 7.6 Hz,3H),0.82 (s,9H),-0.06 (s,6H). LCMS m / z 354.3 [M+H] + . Step 3. Synthesis of [2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidin-5-yl]methanol (C51)

[0240] To a stirred solution of ethyl 2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidine-5-carboxylate C50 (15 g, 0.0411 mol) in THF (600 mL) at −78° C. under a nitrogen atmosphere, DIBAL-H (1 M in toluene) (205.50 mL of 1 M, 0.2055 mol) was slowly added. The reaction was stirred at −78° C. for 30 minutes, then warmed to room temperature and stirred for 4 hours. The reaction mixture was quenched with saturated NH4Cl (500 mL) at 0° C., and the compound was extracted with EtOAc (2×500 mL). The organic layer was washed with 1 N HCl (100 mL), brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by silica gel chromatography (eluent: 50% EtOAc in petroleum ether) gave [2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidin-5-yl]methanol C51 (6 g, 46%). 1 H NMR (400 MHz,DMSO-d6) δ 8.19 (s,2H),6.25 (s,1H),4.99 (t,J = 5.6 Hz,1H),4.27 (d,J = 5.6 Hz,2H),3.71 (s,2H),1.30 (s,6H),0.84 (s,9H),-0.03 (s,6H). LCMS m / z 312.23 [M+H] + . Step 4: Synthesis of 2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidine-5-carbaldehyde (C52)

[0241] To a stirred solution of [2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidin-5-yl]methanol C51 (120 mg, 271.55 μmol) in DCM (10 mL) was added MnO (851.98 mg, 0.0098 mol) at room temperature and stirred for 6 h. The reaction was filtered through Celite® and washed with DCM (10 mL). The filtrate was concentrated under reduced pressure to give 2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidine-5-carbaldehyde C52 (90 mg, 99%). 1 H NMR (400 MHz,DMSO-d6) δ 9.71 (s,1H),8.71 (d,J = 11.6 Hz,2H),7.72 (s,1H),3.78 (s,2H),1.34 (s,6H),0.84 (s,9H),-0.05 (s,6H). LCMS m / z 310.22 [M+H] + . Step 5. 2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]pyrimidine-5 Synthesis of -carbaldehyde (S22)

[0242] To a stirred solution of 2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidine-5-carbaldehyde C52 (2.9 g, 0.0087 mol) in THF (20 mL), TBAF (1 M in THF) (21.700 mL of 1 M, 0.0217 mol) was added at room temperature and stirred for 2 h. The reaction was diluted with EtOAc (100 mL), washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was washed with pentane and dried to give 2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]pyrimidine-5-carbaldehyde S22 (1.47 g, 86%). 1H NMR (400 MHz,DMSO-d6) δ 9.72 (s,1H),8.71 (d,J = 13.2 Hz,2H),7.64 (s,1H),4.87 (t,J = 6 Hz,1H),3.54 (d,J = 6 Hz,2H),1.33 (s,6H). LCMS m / z 196.35 [M+H] + . Preparation of S23 (3S)-3-aminobutanoic acid (S23) [ka]

[0243] (3S)-3-aminobutanoic acid (S23) was obtained from a commercial source. Preparation of S24 4-Aminopentan-2-one hydrochloride (S24) [ka]

[0244] 4-Aminopentan-2-one hydrochloride (S24) was obtained from a commercial source. Preparation of S25 (4S)-4-Aminopentan-2-one hydrochloride (S25) [ka] Step 1. Synthesis of (3S)-3-(tert-butoxycarbonylamino)butanoic acid (C53)

[0245] To a solution of (3S)-3-aminobutanoic acid S23 (100 g, 969.7 mmol) in dioxane (600 mL), aqueous NaOH (950 mL of 1 M, 950.0 mmol) was added over 15 min, followed by BocO (300 g, 1.375 mol). The reaction mixture was stirred at room temperature for 12 h. The reaction was diluted with 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 to pH 2 with 1 N HCl and extracted with DCM (3 x 600 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated in vacuo to give (3S)-3-(tert-butoxycarbonylamino)butanoic acid C53 (176 g, 89%) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 4.92 (s, 1H), 4.04 (s, 1H), 2.56 (dd, J = 5.5, 2.9 Hz, 2H), 1.44 (s, 9H), 1.25 (d, J = 6.8 Hz,3H). Step 2. Synthesis of tert-butyl N-[(1S)-3-[methoxy(methyl)amino]-1-methyl-3-oxo-propyl]carbamate (C54)

[0246] To a solution of (3S)-3-(tert-butoxycarbonylamino)butanoic acid C53 (160 g, 787.3 mmol) in DCM (1.5 L) was added N-methoxymethanamine (hydrochloride) (81 g, 830.4 mmol), followed by DIPEA (560 mL, 3.215 mol) over 10 min. The reaction mixture was cooled to 0 °C, and T3P (600 g, 942.9 mmol of a 50% (w / w) solution in EtOAc) was added over 45 min. After the addition, the cooling bath was removed, and the reaction was stirred at room temperature for 1 h. The reaction mixture was cooled to 10 °C, 1 N aqueous NaOH (700 mL) was added, and the solution was stirred for 15 min. The organic layer was separated, washed with saturated aqueous ammonium chloride (200 mL) and brine (200 mL), dried, filtered through a silica plug, and concentrated in vacuo to afford tert-butyl N-[(1S)-3-[methoxy(methyl)amino]-1-methyl-3-oxo-propyl]carbamate C54 (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). Step 3. Synthesis of tert-butyl N-[(1S)-1-methyl-3-oxo-butyl]carbamate (C55)

[0247] To a solution of tert-butyl N-[(1S)-3-[methoxy(methyl)amino]-1-methyl-3-oxo-propyl]carbamate C54 (220 g, 893.2 mmol) in THF (4 L) at 0 °C, iodine(methyl)magnesium (900 mL of 3 M, 2.700 mol) was added 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 layers were washed with saturated ammonium chloride solution (1 L), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-70% EtOAc in heptane) afforded the product tert-butyl N-[(1S)-1-methyl-3-oxo-butyl]carbamate C55 (115 g, 64%) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 4.83 (s,1H),4.12 - 3.87 (m,1H),2.69 (dd,J = 16.5,5.2 Hz,1H),2.63 - 2.47 (m,1H),2.15 (d,J = 2.3 Hz,3H),1.43 (d,J = 2.4 Hz,9H),1.20 (dd,J = 6.8,2.4 Hz,3H). Step 4: Synthesis of (4S)-4-aminopentan-2-one (hydrochloride) (S25)

[0248] To a solution of tert-butyl N-[(1S)-1-methyl-3-oxo-butyl]carbamate C55 (16.3 g, 80.18 mmol) in MeOH (30 mL) was added hydrogen chloride (50 mL of a 4 M solution 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 dissolved in EtOH (2 × 30 mL). ) and dried under vacuum to give (4S)-4-aminopentan-2-one (hydrochloride salt) S25 (12 g, 98%) as a pink viscous oil. 1 H NMR (300 MHz, chloroform-d) δ 8.06 (s,3H), 3.48 (d,J = 6.8 Hz,1H), 2.88 (dd,J = 18.0,5.8 Hz,1H),2.75 (dd,J = 18.0,7.2 Hz,1H),2.13 (s,3H),1.17 (d,J = 6.6 Hz,3H). Preparation of S26 (Method A) (2S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S26) [ka] Step 1. Synthesis of (2S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (C56)

[0249] To a mixture of (4S)-4-aminopentan-2-one (hydrochloride) S25 (12 g, 78.48 mmol) in EtOH (300 mL) was added 1-methyltriazole-4-carbaldehyde S17 (9 g, 81.01 mmol), L-proline (2 g, 17.37 mmol), magnesium sulfate (12 g, 99.69 mmol), and TEA (13 mL, 93.27 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered and concentrated under reduced pressure. The crude residue was quenched with saturated sodium bicarbonate solution (150 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0 to 60% 20% MeOH / DCM in DCM) afforded the product (2S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one C56 (6.7 g, 44%) in a cis / trans ratio of 5:1. Furthermore, the chromatographic fraction of the S25 stereoisomer was reduced to approximately 85%.

[0250] NMR of the major (CIS) stereoisomer in C56: 1 H NMR (300 MHz, chloroform-d) δ 7.47 (s,1H),4.26 (dd,J = 10.3,4.9 Hz,1H),4.11 (s,3H),3.17 (dqd,J = 12.2,6.2,3.0 Hz,1H),2.73 - 2.56 (m,2H),2.47 (ddd,J = 14.2,3.0,1.6 Hz,1H),2.21 (dd,J = 14.2,11.7 Hz,2H),1.28 (d,J = 6.2 Hz,3H).

[0251] NMR justification for the assignment of stereoisomers in C56: Note that the major component in C56 was assigned as the cis stereoisomer using NMR coupling constant data for the peak at 4.26 ppm (C5-methylene proton). The triazole at C6 is assumed to occupy an equatorial position in its lowest energy conformation. The coupling between the C4 CH axis and one of the C5 CH protons (J = 10.3 Hz) exhibits a 180° relationship as defined by the Karplus equation. The minor trans product was removed in a subsequent recrystallization step to give S26. Step 2. Synthesis of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S26)

[0252] A solution of (2S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one C56 (6.7 g) in MTBE (100 mL) in a cis / trans ratio of 5:1 The mixture was heated to reflux for 30 minutes. Ethanol (20 mL) was added slowly until all solids were dissolved. The solution was refluxed for 30 minutes and allowed to cool slowly overnight. The crystallized solid was diluted with MTBE (30 mL), filtered, and dried under vacuum to give (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one S26 (3.2 g, 48%) as a white solid. The enantiomeric ratio was greater than 85% and was used in all further syntheses utilizing S26 as a starting material unless otherwise noted (except for examples where SFC purification was performed). 1 H NMR (300 MHz, chloroform-d) δ 7.45 (s,1H),4.23 (dd,J = 10.3,4.9 Hz,1H),4.09 (s,3H),3.14 (ddp,J = 12.2,6.1,3.1 Hz,1H),2.71 - 2.52 (m,2H),2.44 (ddd,J = 14.1,3.0,1.5 Hz,1H),2.27 - 2.00 (m,2H),1.26 (d,J = 6.2 Hz,3H). Alternative Preparation of S26 (Method B) ((2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S26) [ka] Step 1. Synthesis of bis[(3-tert-butoxy-3-oxo-propanoyl)oxy]magnesium (C109)

[0253] A solution of 3-tert-butoxy-3-oxo-propanoic acid C108 (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 minutes, removed from the ice bath, and stirred at room temperature overnight. The reaction was filtered through a plug of Celite®, and the plug was washed with additional THF. The clear, colorless filtrate was evaporated in vacuo to give a sticky solid. The solid was triturated with 1 L of diethyl ether and filtered. The filter cake was washed with Et2O and dried in vacuo. The filtrate was evaporated again in vacuo, then triturated with a small amount of Et2O and filtered to give a second crop of product. The mass was combined and dried in vacuo to give bis[(3-tert-butoxy-3-oxo-propanoyl)oxy]magnesium C109 (294.49 g, 90%) as a white solid. 1 H NMR (300 MHz, methanol-d4) δ 4.92 (s,4H), 1.48 (s,18H) ppm. Step 2. Synthesis of tert-butyl (5S)-5-(tert-butoxycarbonylamino)-3-oxo-hexanoate (C111)

[0254] To a solution of (3S)-3-(tert-butoxycarbonylamino)butanoic acid C110 (170.15 g, 837.2 mmol) in THF (1.5 L) was added CDI (149.8 g, 923.8 mmol). Over the next few minutes, the milky suspension became clear. Gas evolution was observed. The reaction was stirred at room temperature for 3 hours. Bis[(3-tert-butoxy-3-oxopropanoyl)oxy]magnesium C109 (172.19 g, 502.6 mmol) was added. Another milky suspension formed, which clarified after stirring for 30 minutes. The reaction was stirred for 48 hours. The reaction was poured into 1.5 L of 1 N HCl and extracted with MTBE (1 L). The pH was confirmed to be approximately 3. The extract was washed with saturated aqueous NaHCO3, separated, dried over MgSO4, filtered and evaporated in vacuo to give tert-butyl (5S)-5-(tert-butoxycarbonylamino)-3-oxo-hexanoate C111 (248.5 g, 98.5%). 1 H NMR (300 MHz, chloroform-d) δ 4.90 (d,J = 18.1 Hz,1H),4.04 (dt,J = 13.8,6.6 Hz,1H),3.47 - 3.22 (m,2H),2.76 (qd,J = 17.0,5.7 Hz,2H),1.48 (s,9H),1.44 (s,9H),1.23 (d,J = 6.8 Hz,3H) ppm. Step 3. Synthesis of tert-butyl (2S,3R,6S)-6-methyl-2-(1-methyltriazol-4-yl)-4-oxo-piperidine-3-carboxylate (C112)

[0255] To a solution of tert-butyl (5S)-5-(tert-butoxycarbonylamino)-3-oxo-hexanoate C111 (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 in vacuo at 25 °C. The remaining solid was triturated with 500 mL of pentane and filtered. The filter cake was washed with pentane, and most of the solvent was drawn off from the filter cake. The cake was returned to the reaction flask and dissolved in 1 L of DCM.

[0256] 1-Methyltriazole-4-carbaldehyde S17 (120.7 g, 1.086 mol) was added. The reaction was stirred overnight at room temperature. Brine (100 mL) was added, followed by 6N NaOH until the aqueous layer remained alkaline upon shaking the funnel. The organic layer was isolated and the aqueous layer was extracted with DCM (1 L). The combined organic layers were dried over MgSO4 and filtered through a plug of silica gel. The plug was eluted with 10% MeOH in EtOAc. The filtrate was evaporated in vacuo to give a solid, which was triturated with MTBE (500 mL) and filtered. The filter cake was washed with MTBE and dried in vacuo to give one crop of product. The triturated mother liquor was concentrated. The precipitated solid was filtered to give a second crop of product. The chunks were combined to give (2S,3R,6S)-6-methyl-2-(1-methyltriazol-4-yl)-4-oxo-piperidine-3-carboxylate C112 (105.45 g, 43%). 1 H NMR (300 MHz, chloroform-d) δ 7.48 (s,1H),4.52 (d,J = 11.0 Hz,1H),4.09 (s,3H),3.61 (dd,J = 11.0,1.0 Hz,1H),3.21 (ddd,J = 11.7,6.1,2.9 Hz,1H),2.55 (dd,J = 13.7,2.9 Hz,1H),2.37 - 2.13 (m,1H),1.98 (s,1H),1.39 (s,9H),1.29 (d,J = 6.3 Hz,3H) ppm. Step 4: Synthesis of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S26)

[0257] To a solution of tert-butyl (2S,3R,6S)-6-methyl-2-(1-methyltriazol-4-yl)-4-oxo-piperidine-3-carboxylate C112 (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 and poured into a separatory funnel. Brine (approximately 100 mL) was added. 6N NaOH was added until the aqueous layer remained alkaline after shaking. The organic layer was separated and the aqueous layer was extracted with DCM (2 x 500 mL). The organic layers were combined, dried over MgSO, filtered, and evaporated in vacuo to give (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one S26 (43.74 g, 94%). 1 H NMR (300 MHz, chloroform-d) δ 7.46 (s,1H),4.20 (dd,J = 10.1,5.1 Hz,1H),4.06 (s,3H),3.11 (dqd,J = 12.3,6.2,3.0 Hz,1H),2.73 - 2.48 (m,2H),2.40 (ddd,J = 14.1,3.0,1.5 Hz,1H),2.25 - 2.00 (m,2H),1.23 (d,J = 6.2 Hz,3H) ppm. Preparation of S27 to S29

[0258] Intermediates S27–S29 (see Table 1) were prepared in one step from intermediate S25 using the appropriate aldehyde and the method described for intermediate S26 (Method A). The aldehydes were prepared by the method described above or obtained commercially. For intermediate S26 (prepared by Method A), partial stereochemical reduction of the enantiomerically pure starting material, (4S)-4-aminopentan-2-one (hydrochloride) S25, was observed in Step 1. This resulted in the production of an unresolved mixture of stereoisomers in Step 1. In all cases, the cis product was the major isomer. This mixture is represented by the use of undulating bonds. Modifications to the method are described in Table 1 and the accompanying footnotes. [Table 1] compound 1 (2'S,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine](1) [ka]

[0259] To a solution of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one S26 (1380 mg, 7.11 mmol, S26 prepared by Method A) in DCM (30 mL) was added 2-(5-chloro-3-thienyl)ethanol S2 (1100 μL, 8.894 mmol), followed by MsOH (3 mL, 46.23 mmol). The reaction was heated to reflux for 90 min, then cooled to room temperature and quenched with 2 N NaOH until a pH of 14 was reached. The mixture was diluted with DCM (20 mL), and the organic layer was separated, washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-25% 20% MeOH / DCM in DCM) afforded the product (2'S,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] 1 (1162 mg, 48%) as a pale yellow oil in a >8:1 ratio. Since S26 prepared by Method A also contains a small amount of the other cis enantiomer, the observed minor isomer is presumed to be the enantiomer of compound 1. Note that the relative stereochemistry of compound 1 was assigned through NOE NMR studies. 1 H NMR (400 MHz, chloroform-d) δ 7.42 (s, 1H), 6.58 (s, 1H), 4.41 (dd, J = 11.8, 2.6 Hz, 1H), 4.06 (s, 3H), 4.02 - 3.86 (m, 2H), 3.30 (ddt, J = 12.7, 6.3, 3.2 Hz, 1H), 2.70 - 2.49 (m, 2H), 2.35 (dt, J = 13.6, 2.6 Hz, 1H), 2.06 (dt, J = 13.7, 2.5 Hz, 1H), 1.79 (dd, J = 13.6, 11.8 Hz, 1H), 1.42 (dd, J = 13.7, 11.3 Hz, 1H), 1.31 - 1.19 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H). LCMS m / z 339.0 [M+H] + . Alternative Preparation of Compound 1 (HCl Salt) (2'S,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] hydrochloride (1)

[0260] To a solution of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one S26 (205 mg, 1.055 mmol) in DCM (5 mL) was added 2-(5-chloro-3-thienyl)ethanol S2 (150 μL, 1.213 mmol), followed by MsOH (300 μL, 4.623 mmol). The mixture was heated to reflux for 10 min, then cooled to room temperature and quenched with 2N NaOH until the pH reached 14. The mixture was diluted with DCM (5 mL), and the organic layer was separated and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-25% 20% MeOH / DCM in DCM) afforded the product, which was immediately dissolved in a minimal amount of DCM and treated with HCl (100 μL of 4 M in dioxane, 0.4000 mmol). The mixture was concentrated in vacuo, and the residue was azeotroped with DCM (5 mL) and dried to give (2'S,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (hydrochloride) 1 (171.6 mg, 43%) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.24 (d, J = 8.3 Hz, 1H), 8.29 (s, 1H) , 6.95 (s, 1H), 4.67 (t, J = 11.1 Hz, 1H), 4.09 (s, 3H), 3.95 (t, J = 5.4 Hz, 2H), 3.72 (s, 1H), 2.61 (t, J = 5.3 Hz, 2H), 2.46 - 2.32 (m, 2H), 2.25 (d, J = 15.1 Hz, 1H), 2.01 - 1.86 (m, 1H), 1.29 (d, J = 6.5 Hz, 3H). LCMS m / z 339.0 [M+H] + . compound 2 (2'S,6'S,7S)-2'-methyl-6'-(1-methyltriazol-4-yl)-2-(trifluoromethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine](2) [ka]

[0261] To a solution of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one S26 (250 mg, 1.287 mmol) and 2-[5-(trifluoromethyl)-3-thienyl]ethanol S3 (350 mg, 1.748 mmol) in DCM (5 mL) was added MsOH (500 μL, 7.705 mmol) and the reaction was heated to 40 °C. After 16 h, additional MsOH (200 μL, 3.082 mmol) was added and the reaction was continued to heat overnight. The mixture was diluted with water (4 mL) and DCM (5 mL) and quenched with aqueous NaOH (2 mL of 6 M, 12.00 mmol). The mixture was separated, extracted with DCM (2 × 5 mL), passed through a phase separator, and the organic layer was concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-10% MeOH in DCM) afforded (2'S,6'S,7S)-2'-methyl-6'-(1-methyltriazol-4-yl)-2-(trifluoromethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]2 (445 mg, 93%) as a white solid. Note that the relative stereochemistry of compound 2 was assigned through NOE NMR studies. 1 H NMR (300 MHz, chloroform-d) δ 7.46 (s, 1H), 7.14 (s, 1H), 4.47 (d, J = 11.6 Hz, 1H), 4.08 (d, J = 3.3 Hz, 3H), 4.00 (s, 2H), 3.36 (s, 1H), 2.72 (d, J = 5.6 Hz, 2H), 2.41 (d, J = 14.2 Hz, 1H), 2.12 (d, J = 13.7 Hz, 1H), 1.86 (t, J = 12.7 Hz, 1H), 1.49 (d, J = 12.8 Hz, 1H), 1.15 (d, J = 6.3 Hz, 3H). LCMS m / z 373.07 [M+H] + . Compounds 3~16

[0262] Compounds 3-16 (see Table 2) were prepared from a single Oxa-Pictet Spengler process using isolated piperidones (S26, S29, or C56) and the related thiopheneethanols as described for compounds 1 and 2. The thiopheneethanols and piperidones were prepared by the methods described above or obtained commercially. In the examples where S26 is used, S26 was prepared by Method A; therefore, the piperidone used may contain small amounts of other cis isomers. Modifications made to the method are described in Table 2 and the accompanying footnotes. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] compound 17 [(2'S,6'S,7S)-2'-methyl-6'-(1-methyltriazol-4-yl)-2-(trifluoromethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]methanol (17) [ka] Step 1. Synthesis of methyl [(2S,6S)-2'-methyl-6'-(1-methyltriazol-4-yl)-2-(trifluoromethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]acetate (C57)

[0263] To a mixture of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one S26 (10 mg, 0.05148 mmol) and methyl [4-(2-hydroxyethyl)-2-(trifluoromethyl)-3-thienyl]acetate S16 (18 mg, 0.06710 mmol) in DCM (500 μL) was added MsOH (30 μL, 0.4623 mmol) and the mixture was heated to 40° C. After stirring for 4 h, the reaction was quenched with saturated NaHCO solution, the layers were separated, and the mixture was concentrated to dryness to give crude C57. Step 2. Synthesis of [(2S,6S)-2'-methyl-6'-(1-methyltriazol-4-yl)-2-(trifluoromethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]methanol (17)

[0264] Crude C57 was diluted with MeOH (2 mL) and NaOH (20 μL of 6 M, 0.1200 mmol) was added to the mixture. The reaction was stirred for 5 min. The mixture was concentrated, rediluted in DCM, and washed with brine. The organic layer was passed through a phase separator and concentrated. Silica gel chromatography (gradient: 0-20% MeOH-DCM) gave parent 17.

[0265] The parent 17 from the deprotection was diluted with diethyl ether (1 mL) and HCl (13 μL of a 4 M solution in dioxane, 0.05200 mmol) was added, immediately forming a white solid. The mixture was concentrated and azeotroped three times with diethyl ether to give [(2S,6S)-2'-methyl-6'-(1-methyltriazol-4-yl)-2-(trifluoromethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]methanol 17 (hydrochloride salt) (10.9 mg, 45%). 1 H NMR (300 MHz, DMSO-d6) δ 9.35 (d, J = 9.8 Hz, 1H), 9.04 (s, 1H), 8.26 (s, 1H), 5.32 (s, 1H), 4.73 (s, 1H), 4.48 (s, 2H), 4.09 (s, 3H), 4.01 (s, 2H), 3.62 (s, 1H), 2.73 (s, 2H), 2.34 (s, 2H), 1.91 (d, J = 13.5 Hz, 1H), 1.29 (d, J = 6.5 Hz, 3H). LCMS m / z 403.13 [M+H] + . compound 18 2-[4-[(2S,6S)-2-chloro-6'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-2'-yl]pyrazol-1-yl]-N,N-dimethyl-acetamide (18) [ka]

[0266] To a solution of (2S,6S)-2-chloro-2'-methyl-6'-(1H-pyrazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] S31 (20 mg, 0.05865 mmol) in DMF (280 μL) was added Cs2CO3 (57 mg, 0.1749 mmol). 2-Bromo-N,N-dimethyl-acetamide (7.6 μL, 0.07050 mmol) was added at room temperature. The reaction was stirred for 1 h. The reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (4x). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification by reverse-phase HPLC (method: C18 Waters Sunfire column (30 × 150 mm, 5 microns), gradient: MeCN in water) gave 2-[4-[(2S,6S)-2-chloro-6′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-2′-yl]pyrazol-1-yl]-N,N-dimethyl-acetamide 18 (6.2 mg, 23%). 1H NMR (300 MHz, chloroform-d) δ 7.50 (s, 2H), 6.57 (s, 1H), 4.92 (s, 2H), 4.17 (dd, J = 11.6, 2.5 Hz, 1H), 3.93 (t, J = 5.5 Hz, 2H), 3.25 (d, J = 9.1 Hz, 1H), 3.06 (s, 3H), 2.97 (s, 3H), 2.60 (td, J = 5.4, 1.8 Hz, 2H), 2.25 (d, J = 13.6 Hz, 1H), 2.01 (s, 1H), 1.70 (d, J = 12.5 Hz, 1H), 1.47 - 1.32 (m, 1H), 1.11 (d, J = 6.4 Hz, 3H). LCMS m / z 409.19 [M+H] + . compound 19 (2S)-2-Chloro-2'-methyl-6'-(1-methylpyrazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (19) [ka]

[0267] A solution of (4S)-4-aminopentan-2-one hydrochloride S25 (25 mg, 0.1817 mmol) and TEA (30 μL, 0.2152 mmol) in MeCN (1.000 mL) was added to 1-methylpyrazole-4-carbaldehyde (22.01 mg, 0.20 mmol), MgSO (25 mg, 0.2077 mmol), and L-proline (5 mg, 0.043 mmol). The resulting mixture was allowed to stir at room temperature overnight. The reaction mixture was evaporated to dryness in a Genevac at 40 °C to give crude C58. To this was added a solution of 2-(5-chloro-3-thienyl)ethanol S2 (25 μL, 0.2080 mmol) in dioxane (750 μL), followed by a solution of TfOH (80 μL, 0.90 mmol) in dioxane (750 μL). The mixture was stirred at room temperature for 30 min. Additional triflic acid (50 μL, 0.5650 mmol) was added and stirring continued for 10 min. The reaction was placed under a stream of nitrogen until the volume was reduced by half. The remaining solution was quenched with NaOH (1.5 mL of 2 M, 3.000 mmol) and diluted with DCM (1.500 mL). The resulting biphasic mixture was stirred for several minutes and then passed through a phase separator. The organic layer was blown down with nitrogen. Purification by reverse-phase HPLC (method: C18 Waters Sunfire column (30 × 150 mm, 5 microns), gradient: MeCN in water containing 0.1% trifluoroacetic acid) gave (2S)-2-chloro-2'-methyl-6'-(1-methylpyrazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] 19 as the trifluoroacetate salt (6.6 mg, 11%). Compound 19 was determined to be 88% pure by chiral SFC analysis (method: AD-H column (4.6 × 100 mm), gradient: 10% MeOH containing 5 mM ammonia in 90% CO). 1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 10.8 Hz, 1H), 8.49 (d, J = 11.3 Hz, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 6.94 (s, 1H), 4.49 (t, J = 11.2 Hz, 1H), 3.93 (t, J = 5.5 Hz, 2H), 3.84 (s, 3H), 2.93 (td, J = 13.9, 6.9 Hz, 1H), 2.60 (t, J = 5.5 Hz, 2H), 2.35 (d, J = 17.2 Hz, 1H), 2.21 (q, J = 13.9 Hz, 2H), 1.84 - 1.73 (m, 1H), 1.24 (d, J = 6.6 Hz, 3H). LCMS m / z 338.17 [M+H] + compound 20 2-Chloro-2'-methyl-6'-(3-pyridyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (20) [ka]

[0268] A solution of 4-aminopentan-2-one hydrochloride S24 (25 mg, 0.1817 mmol) in EtOH (1 mL) was added to pyridine-3-carbaldehyde (19.5 mg, 17.06 μL, 0.1817 mmol), MgSO4 (25 mg, 0.2077 mmol), and and L-proline (5 mg, 0.04343 mmol). TEA (30 μL, 0.2152 mmol) was added, and the reaction was stirred at room temperature for 3 days. The reaction mixture was evaporated under a stream of nitrogen to give crude C59. To this was added a solution of 2-(5-chloro-3-thienyl)ethanol S2 (25 μL, 0.2075 mmol) in dioxane (750 μL), followed by a solution of freshly prepared TfOH (100 μL, 1.130 mmol) in dioxane (750 μL). The mixture was stirred at room temperature for 30 min. The reaction was placed under a stream of nitrogen until the volume was reduced by half. The remaining solution was quenched with NaOH (1.5 mL of 2 M, 3.000 mmol) and diluted with DCM (1.500 mL). The resulting biphasic mixture was stirred for several minutes and then passed through a phase separator. The organic layer was blown down with nitrogen. Purification by reverse-phase HPLC (method: C18 Waters Sunfire column (30 × 150 mm, 5 microns), gradient: MeCN in water containing 0.1% trifluoroacetic acid) gave 2-chloro-2'-methyl-6'-(3-pyridyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] 20 as the trifluoroacetate salt (34.4 mg, 56%). Compound 20 was determined to be 94% cis enantiomer and 6% trans enantiomer by chiral SFC analysis (method: AD-H column (4.6 × 100 mm), gradient: 10% MeOH containing 5 mM ammonia in 90% CO). 1 H NMR (300 MHz, methanol-d4) δ 8.87 (d, J = 2.3 Hz, 1H), 8.74 (dd, J = 5.2, 1.5 Hz, 1H), 8.36 - 8.27 (m, 1H), 7.77 (dd, J = 8.1, 5.2 Hz, 1H), 6.75 (s, 1H), 4.93 - 4.88 (m, 1H), 4.03 (t, J = 5.5 Hz, 2H), 3.90 (dqd, J = 13.4, 6.7, 3.1 Hz, 1H), 2.67 (t, J = 5.6 Hz, 2H), 2.51 (dt, J = 14.5, 2.9 Hz, 1H), 2.46 - 2.30 (m, 2H), 1.93 (dd, J = 14.8, 12.2 Hz, 1H), 1.41 (d, J = 6.6 Hz, 3H). LCMS m / z 335.14 [M+H] + . compound 21 (2S)-2-chloro-2'-methyl-6'-(2-methyl-4-pyridyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (21) [ka]

[0269] A solution of (4S)-4-aminopentan-2-one hydrochloride S25 (34.40 mg, 0.2500 mmol) in EtOH (1 mL) was added to 2-methylpyridine-4-carbaldehyde (30.28 mg, 0.2500 mmol), MgSO4 (45 mg, 0.3739 mmol), and L-proline (7 mg, 0.06080 mmol). TEA (40 μL, 0.2870 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was evaporated in a Genevac at 35-40 °C to give crude C60. To C60 was added a solution of 2-(5-chloro-3-thienyl)ethanol S2 (35 μL, 0.2905 mmol) in dioxane (1 mL), followed by a solution of freshly prepared TfOH (130 μL, 1.469 mmol) in dioxane (1 mL). The mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated in a Genevac at 40 °C. The residue was quenched with NaOH (1.7 mL of 2 M, 3.400 mmol) and diluted with DCM (1.7 mL). The resulting biphasic mixture was stirred for several minutes and then passed through a phase separator. The organic layer was blown down with nitrogen. Purification by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 micron), Gradient: MeCN in water containing 0.1% trifluoroacetic acid) gave (2S)-2-chloro-2'-methyl-6'-(2-methyl ... (4-methyl-4-pyridyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] 21 was obtained as the trifluoroacetate salt (19.3 mg, 21%). Compound 21 was determined to be 77% pure by chiral SFC analysis (method: AD-H column (4.6 × 100 mm), gradient: 10% MeOH containing 5 mM ammonia in 90% CO). 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.87 (s, 1H), 8.55 (d, J = 5.3 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 5.3 Hz, 1H), 6.94 (s, 1H), 4.57 (t, J = 11.5, 9.8 Hz, 1H), 3.97 (t, J = 5.4 Hz, 2H), 3.6 (1H hidden under water peak) ), 3.17 - 2.84 (m, 1H), 2.61 (q, J = 5.3 Hz, 2H), 2.52 (s, 3H), 2.43 - 2.13 (m, 3H), 1.90 (t, J = 13.3 Hz, 1H), 1.29 (d, J = 6.4 Hz, 3H). LCMS m / z 349.14 [M+H]+ Compound 22~172

[0270] Compounds 22–172 (see Table 3) were prepared as trifluoroacetate salts in a two-step, one-pot procedure following the method described for compounds 19, 20, or 21. Intermediate S24 or S25, the appropriate aldehyde, and thiopheneethanol S2 were used. The aldehyde was prepared by the method described above or obtained commercially. Under the reaction conditions of Step 1, partial stereochemical reduction of the enantiomerically pure starting material (4S)-4-aminopentan-2-one (hydrochloride salt) S25 was observed, resulting in an unseparated mixture of 2,6-trans piperidine enantiomers. This resulted from a mixture of cis-piperidine intermediates (described above in the Method A preparation of S26), and the subsequent 2,6-trans piperidine final product had cis substituents at the 2- and 6-positions and trans substituents at the 2- and 4-positions. Modifications to the method are described in Table 3 and the accompanying footnotes. [Table 3-1] [Table 3-2] [Table 3-3] Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21 Table 3-22 Table 3-23 Table 3-24 Table 3-25 Table 3-26 Table 3-27 Table 3-28 Table 3-29 Table 3-30 Table 3-31 Table 3-32 Table 3-33 Table 3-34 Table 3-35 Table 3-36 Table 3-37 [Table 3-38] [Table 3-39] [Table 3-40] [Table 3-41] compound 173 (2S)-2-Chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (173) [ka] Step 1. Synthesis of 1-[(2S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone (C61)

[0271] To a solution of 2-(5-chloro-2-thienyl)ethanol S2 (410 mg, 2.521 mmol) and (2S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one C56 (420 mg, 2.141 mmol) in DCM (8 mL) was added methanesulfonic acid (800 μL, 12.33 mmol). The resulting mixture was heated at 40° C. for 40 minutes. Additional methanesulfonic acid (800 μL, 12.33 mmol) was added and the reaction continued to heat for an additional 30 minutes. The reaction was cooled to room temperature, diluted with water, and basified with 2N NaOH. The mixture was passed through a phase separator and extracted with DCM (3 × 20 mL), and the organic layer was concentrated in vacuo to give crude (2S)-2-chloro-2′-methyl-6′-(1-methyltriazol-4-yl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine].

[0272] Crude (2S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[6,7-dihydrothiazolinone] (600 μL, 3.445 mmol) was added. A solution of eno[3,2-c]pyran-4,4'-piperidine] in DCM (9 mL) was cooled to 0 °C. TFAA (390 μL, 2.806 mmol) was added slowly over 2 min, and the reaction was stirred at 0 °C. After 15 min, the reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM (3×). The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0 to 50% EtOAc in heptane) afforded the single major product, 1-[(2S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone C61 (450 mg, 43%). 1 H NMR (300 MHz, chloroform-d) δ 7.58 (s, 1H), 6.91 (s, 1H), 5.57 (s, 1H), 4.40 (d, J = 7.4 Hz, 1H), 4.10 (s, 3H), 3.89 (t, J = 5.4 Hz, 2H), 3.20 (dd, J = 14.9, 6.4 Hz, 1H), 2.80 - 2.61 (m, 2H), 2.45 (dd, J = 14.8, 8.4 Hz, 1H), 2.38 - 2.13 (m, 1H), 2.04 (s, 1H), 1.41 - 1.12 (m, 3H). Step 2. Synthesis of (2S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (173)

[0273] A solution of 1-[(2S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone C61 (20 mg, 0.04415 mmol) in MeOH (1 mL) was treated with NaOH (400 μL of 2 M, 0.8000 mmol). The solution was heated to 50 °C for 3 h, then cooled to room temperature and stirred overnight. The mixture was passed through a phase separator and extracted with DCM (3x), and the organic layer was concentrated in vacuo to give (2S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 173 (14.0 mg, 91%) as an off-white film with an elution of approximately 85%. 1 H NMR (300 MHz, chloroform-d) δ 7.41 (s, 1H), 6.61 (s, 1H), 4.40 (dd, J = 11.8, 2.7 Hz, 1H), 4.05 (s, 3H), 3.96 (td, J = 5.7, 2.0 Hz, 2H), 3.28 (dtd, J = 12.6, 6.3, 2.5 Hz, 1H). 2.85 - 2.60 (m, 2H), 2.18 (dt, J = 13.5, 2.6 Hz, 1H), 1.89 (dt, J = 13.7, 2.5 Hz, 1H), 1.80 (dd, J = 13.6, 11.9 Hz, 1H), 1.44 (dd, J = 13.7, 11.4 Hz, 1H), 1.11 (d, J = 6.3 Hz, 3H). LCMS m / z 339.1 [M+H] + Preparation of S32 (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)-2'-(trifluoromethyl)spiro[piperidine-4,7'-thieno[2,3-c]pyran]-4'-one (S32) [ka] Step 1. Synthesis of 2,2,2-trifluoro-1-[(2'S,6'S,7S)-2'-methyl-6'-(1-methyltriazol-4-yl)-2-(trifluoromethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]ethanone (C62)

[0274] To a solution of (2'S,6'S,7S)-2'-methyl-6'-(1-methyltriazol-4-yl)-2-(trifluoromethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]2 (1260 mg, 3.352 mmol) in DCM (25 mL) cooled to -15 °C, DIPEA (800 μL, 4.593 mmol) was added, followed by TFAA (550 μL, 3.957 mmol). After 5 min, the mixture was quenched with 1 N HCl (25 mL) and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (gradient: 0 to 50% EtOAc in heptane) afforded 2,2,2-trifluoro-1-[(2'S,6'S,7S)-2'-methyl-6'-(1-methyltriazol-4-yl)-2-(trifluoromethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]ethanone C62 (1444 mg, 90%). 1 H NMR (400 MHz, methanol-d4) δ 7.93 (s, 1H), 7.27 (d, J = 1.3 Hz, 1H), 5.63 (s, 1H), 4.46 (h, J = 7.1 Hz, 1H), 4.11 (d, J = 1.4 Hz, 3H). 3.96 (td, J = 5.6, 1.7 Hz, 2H), 3.04 (s, 1H), 2.79 - 2.70 (m, 3H), 2.51 (s, 1H), 2.09 (dd, J = 14.7, 7.3 Hz, 1H), 1.23 (q, J = 9.6, 8.4Hz, 3H). LCMS m / z 469.14 [M+H] + . Step 2. Synthesis of (2S,4S,6S)-2-methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)-2'-(trifluoromethyl)spiro[piperidine-4,7'-thieno[2,3-c]pyran]-4'-one (S32)

[0275] A mixture of 2,2,2-trifluoro-1-[(2'S,6'S,7S)-2'-methyl-6'-(1-methyltriazol-4-yl)-2-(trifluoromethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]ethanone C62 (708 mg, 1.511 mmol) in acetonitrile (10 mL) was treated with N-hydroxyphthalimide (165 mg, 1.011 mmol) and cobalt diacetate. The tetrahydrate (35 mg, 0.1405 mmol) was added, followed by purging the mixture under vacuum three times with an oxygen balloon. The mixture was heated to 60 °C and stirred. After 1.5 hours, the reaction was cooled to room temperature. The mixture was purged under vacuum three times with nitrogen and then diluted with MTBE (25 mL) and saturated aqueous bicarbonate (25 mL). The layers were separated, and the organic layer was washed with NaHCO (2 x 50 mL) and brine (50 mL). The organic layer was dried over NaSO, filtered, and concentrated. Purification by silica gel chromatography (gradient: 0 to 50% EtOAc in heptane) afforded (2S,4S,6S)-2-methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)-2'-(trifluoromethyl)spiro[piperidine-4,7'-thieno[2,3-c]pyran]-4'-one S32 (207 mg, 26%). 1 H NMR (300 MHz, methanol-d4) δ 7.98 (s, 1H), 7.80 (d, J = 1.4 Hz, 1H), 5.70 (s, 1H), 4.48 (s, 1H), 4.45 (s, 2H), 4.12 (s, 3H), 2.95 (dd, J = 14.8, 9.8 Hz, 1H), 2.73 (s, 1H), 2.22 (dd, J = 14.8, 8.4 Hz, 1H), 1.29 (s, 1H), 1.19 (d, J = 14.9 Hz, 3H). LCMS m / z 483.45 [M+H] + . Preparation of intermediates S33 to S36

[0276] Intermediate ketones S33-S36 (see Table 4) were prepared in two steps from the related compounds using TFAA protection and benzylic oxidation as described for intermediate S32. Modifications made to the method are described in Table 4 and the accompanying footnotes. [Table 4-1] [Table 4-2] Preparation of S33 [ka] Step 1. Synthesis of 1-[(2'S,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone (C154)

[0277] To a mixture of (2'S,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] 1 (15.0 g, 43.82 mmol) and DIPEA (10 mL, 57.41 mmol) in DCM (150 mL) cooled to 3 °C, TFAA (6.4 mL, 46.04 mmol) was added. After 5 min, the mixture was quenched with 1 N HCl (100 mL) and the layers were separated. The organic layer was washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. The solid was suspended in TBME (100 mL) and added. Heat to reflux. After 30 minutes, the mixture was cooled to 0° C. After 10 minutes, the material was filtered and rinsed with additional cold TBME. The product was dried to give 1-[(2'S,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone C154 (15.532 g, 81%). LCMS m / z Calculated value 435.18 [M+H] + . Step 2. Synthesis of 2S,4S,6S-2'-chloro-2-methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,7'-thieno[2,3-c]pyran]-4'-one (S33)

[0278] To a mixture of 1-[(2'S,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone (C154) (4.5 g, 10.24 mmol) in acetonitrile (70 mL) was added N-hydroxyphthalimide (1.2 g, 7.36 mmol) and cobalt diacetate tetrahydrate (550 mg, 0.216 mmol), followed by vacuum purging the mixture three times using an oxygen balloon. The reaction was heated to 45 °C and stirred for 18 hours, then cooled to room temperature. The reaction was diluted with DCM, water, and saturated sodium bicarbonate, then extracted with DCM (3 x 150 mL) and collected through a phase separator. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (gradient: 0 to 50% EtOAc in heptane) afforded (2S,4S,6S)-2'-chloro-2-methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,7'-thieno[2,3-c]pyran]-4'-one S33 (3.50 g, 68%). 1H NMR (300 MHz, chloroform-d) δ 7.61 (s, 1H), 7.19 (s, 1H), 5.61 (s, 1H), 4.44 (q, J = 7.1 Hz, 1H), 4.31 (s, 2H), 4.12 (s, 3H), 3.34 (dd, J = 15.1, 6.2 Hz, 1H), 2.78 (dd, J = 15.1, 8.3 Hz, 1H), 2.70 - 2.43 (m, 1H), 2.16 (s, 1H), 1.27 (d, J = 7.3 Hz, 3H). LCMS m / z 449.12 [M+H] + . compound 174 (2'S,4S,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-4-ol (174) [ka] Step 1. Synthesis of 1-[(2'S,4S,6'S,7S)-2-chloro-4-hydroxy-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone (C63)

[0279] To a solution of (2S,4S,6S)-2'-chloro-2-methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,7'-thieno[2,3-c]pyran]-4'-one S33 (3.5 g, 7.025 mmol) in DCM (60 mL) was added a solution of 1,2,3,4,5 pentamethylcyclopentanerhodium(2+) tetrachloride (24 mg, 0.03821 mmol) and N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-4-methyl-benzenesulfonamide (27 mg, 0.074 mmol) in DCM (7 mL), followed by a solution of formic acid (1.4 mL, 37.11 mmol) and triethylamine (2.1 mL, 15.07 mmol). The flask was fitted with an empty balloon to capture the CO2 off-gassing by-product. After two hours, the mixture was washed with saturated aqueous bicarbonate (150 mL). The organic layer was separated and concentrated by passing through a phase separator. Silica gel purification (column: 120 g silica gel, gradient: 0 to 45% EtOAc in heptane) afforded 1-[(2'S,4S,6'S,7S)-2-chloro-4-hydroxy-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone C63 (3.3 g, 86%) as a pale off-white foam. 1 H NMR (300 MHz, chloroform-d) δ 7.59 (s, 1H), 6.83 (s, 1H), 5.53 (s, 1H), 4.46 (dt, J = 9.1, 3.1 Hz, 2H), 4.10 (s, 3H), 4.03 - 3.80 (m, 2H), 3.10 (dd, J = 15.1, 7.3 Hz, 1H), 2.65 (ddd, J = 15.1, 8.1, 2.2 Hz, 1H), 2.47 (s, 1H), 2.21 - 2.08 (m, 1H), 2.08 (d, J = 9.2 Hz, 1H), 1.40 - 1.19 (m, 3H). LCMS m / z 451.05 [M+H] + .

[0280] The stereochemistry of alcohol C63 was determined using NMR NOE studies, as well as the catalyst and Please note that the assignment was based on an understanding of the literature on reductions using chiral rhodium and iridium complexes with chiral diamine ligands. (Reference: New Chiral Rhodium and Iridium Complexes with Chiral Diamine Ligands for Asymmetric Transfer Hydrogenation of Aromatic Ketones. Kunihiko Murata, Takao Ikariya, and Ryoji Noyori. The Journal of Organic Chemistry 1999 64 (7), 2186-2187). Step 2. Synthesis of (2'S,4S,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-4-ol (174)

[0281] To a solution of 1-[(2'S,4S,6'S,7S)-2-chloro-4-hydroxy-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone C63 (3.33 g, 100%) in MeOH (50 mL) was added NaOH (40 mL of 2 M, 80.00 mmol), and the mixture was stirred at 60 °C. After 40 min, the mixture was diluted with saturated aqueous ammonium chloride to pH 10 (approximately 50 mL) and extracted with MTBE (5 × 100 mL) and ethyl acetate (1 × 75 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over NaSO, and concentrated. The residue was taken up in EtOH and spun down (3 ×) to give a white solid. The solid was transferred to a vial and dried under vacuum at 55 °C overnight to give amorphous (2'S,4S,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-4-ol 174 (2.1817 g, 87%). 1H NMR (400 MHz, methanol-d4) δ 7.82 (s, 1H), 6.88 (s, 1H), 4.46 (t, J = 3.8 Hz, 1H), 4.34 - 4.28 (m, 1H), 4.08 (s, 3H), 4.04 (dd, J = 12.2, 3.6 Hz, 1H), 3.81 (dd, J = 12.2, 4.1 Hz, 1H), 3.36 - 3.25 (m, 1H), 2.39 (dt, J = 13.8, 2.6 Hz, 1H), 2.17 (dt, J = 13.7, 2.6 Hz, 1H), 1.71 (dd, J = 13.9, 11.9 Hz, 1H), 1.45 (dd, J = 13.7, 11.4 Hz, 1H), 1.16 (d, J = 6.4 Hz, 3H). LCMS m / z 355.03 [M+H] + . Compounds 175 and 176 (2S)-2-Chloro-2'-methyl-6'-(1-methylimidazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-4-ol (175) [Diastereomer-1] and (176) [Diastereomer-2] [ka] Step 1. Synthesis of 1-[(2S)-2-chloro-4-hydroxy-2'-methyl-6'-(1-methylpyrazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone (C64) [DIAST-1] and (C65) [DIAST-2]

[0282] A solution of (R)-(+)-2-methyl-CBS-oxazaborolidine (40 μL of 1 M, 0.04000 mmol) in THF (1 mL) (1 M solution in THF) was cooled to 0 °C and treated with borane; tetrahydrofuran (220 μL of 1 M, 0.2200 mmol). After 4 min, a solution of (2S,4S,6S)-2'-chloro-2-methyl-6-(1-methylpyrazol-4-yl)-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,7'-thieno[2,3-c]pyran]-4'-one S35 (50 mg, 0.1023 mmol) in THF (300 μL) was slowly added and the reaction was stirred at 0 °C. After 15 min, another solution of (R)-(+)-2-methyl-CBS-oxazaborolidine solution (40 μL of 1 M, 0.04000 mmol) and borane in tetrahydrofuran (220 μL of 1 M, 0.2200 mmol) was prepared and added to the reaction. After 30 min, the reaction was quenched with 2 N HCl, removed from the ice bath, and the mixture was stirred vigorously for 24 h. The reaction was passed through a phase separator and extracted with DCM (3×). The organics were concentrated by rotovap. Purification by silica gel chromatography (0–60% EtOAc in heptane) afforded the racemic intermediate.

[0283] SFC separation (AD-H column, 10% MeOH w / 5 mM ammonia) gave: 1-[(2S) 2-chloro-4-hydroxy-2'-methyl-6'-(1-methylpyrazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone (C64) [DIAST-1] (50 mg, 101%). 1 H NMR (300 MHz, chloroform-d) δ 7.40 (d, J = 5.6 Hz, 2H), 6.88 (s, 1H), 5.52 (s, 1H), 4.52 - 4.37 (m, 2H), 4.00 - 3.76 (m, 5H), 2.74 - 2.48 (m, 2H), 2.27 (s, 1H), 1.81 (dd, J = 14.9, 6.8 Hz, 1H), 1.28 (s, 3H). LCMS m / z 450.07 [M+H] + 1-[(2S)-2-chloro-4-hydroxy-2'-methyl-6'-(1-methylpyrazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2,2 ,2-Trifluoro-ethanone (C65) [DIAST-2] (34 mg, 62%). 1 H NMR (300 MHz, chloro Roform-d) δ 7.43 (s, 1H), 7.35 (s, 1H), 6.85 (s, 1H), 5.43 (s, 1H), 4.56 - 4.40 (m, 2H), 4.02 - 3.79 (m, 5H), 2.71 (ddd, J = 15.1, 8.1, 2.3 Hz, 1H), 2.37 (dd, J = 15.1, 6.4 Hz, 1H), 2.08 (d, J = 9.2 Hz, 1H), 1.95 (dd, J = 14.6, 6.9 Hz, 1H), 1.27 (d, J = 6.6 Hz, 3H). LCMS m / z 450.03[M+H] + . Step 2. Synthesis of (2S)-2-chloro-2'-methyl-6'-(1-methylimidazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-4-ol (175) [DIAST-1] and (176) [DIAST-1]

[0284] A solution of 1-[(2'S,4S,6'S,7S)-2-chloro-4-hydroxy-2'-methyl-6'-(1-methylpyrazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone (C64) (50 mg, 0.094 mmol) in MeOH (2 mL) was treated with NaOH (1 mL of 1 M, 1,000 mmol) and heated to 40 °C for 30 min. Additional NaOH (1 mL of 1 M, 1,000 mmol) was added and the reaction was heated to 50 °C. After an additional two hours, the reaction was diluted with DCM. The organic layer was separated and concentrated by passing through a phase separator. The material was suspended in MTBE (3 mL) and treated dropwise with hydrogen chloride in dioxane (28 μL of 4 M, 0.1120 mmol). A white precipitate formed. The solution was concentrated, and the residue was suspended in water, frozen at −78 °C, and lyophilized over the weekend to give (2S)-2-chloro-2′-methyl-6′-(1-methylpyrazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-4-ol (hydrochloride salt) (175) [DIAST-1] (37.9 mg, 98%). 1 H NMR (400 MHz, methanol-d4) δ 7.72 (s, 1H), 7.58 (s, 1H), 6.92 (s, 1H), 4.52–4.45 (m, 2H), 4.03 (dd, J = 12.2, 3.5 Hz, 1H). 3.88 (s, 3H), 3.83 (dd, J = 12.2, 4.0 Hz, 1H), 3.69 - 3.58 (m, 1H), 2.47 (dt, J = 14.5, 2.8 Hz, 1H), 2.33 (dt, J = 14.4, 2.8 Hz, 1H), 1.98 (t, J = 13.7 Hz, 1H), 1.71 (t, J = 13.1 Hz, 1H), 1.30 (d, J = 6.6 Hz, 3H). LCMS m / z 353.99 [M+H] + .

[0285] A solution of 1-[(2'S,4R,6'S,7S)-2-chloro-4-hydroxy-2'-methyl-6'-(1-methylpyrazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone (C65) (34 mg, 0.07 mmol) in MeOH (1.5 mL) was treated with NaOH (800 μL of 1 M, 0.8 mmol) and heated to 40 °C for 30 min. Additional NaOH (800 μL of 1 M, 0.8 mmol) was added, and the reaction was heated to 50 °C. After an additional two hours, the reaction was cooled to room temperature and diluted with DCM. The organic layer was separated and concentrated by passing through a phase separator. The material was suspended in MTBE (1.5 mL) and treated dropwise with HCl (22 μL of 4 M, 0.08800 mmol). A white precipitate formed. The solution was concentrated by rotovap, and the residue was suspended in water, frozen at −78 °C, and lyophilized overnight to give (2S)-2-chloro-2′-methyl-6′-(1-methylpyrazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-4-ol (hydrochloride salt) (176) [DIAST-2] (26.7 mg, 96%) as a white powder. 1 H NMR (400 MHz, methanol-d4) δ 7.81 (s, 1H), 7.63 (s, 1H), 6.94 (s, 1H), 4.71 (dd, J = 12.6, 2.9 Hz, 1H), 4.50 (t, J = 3.6 Hz, 1H), 4.05 (dd, J = 12.3, 3.4 Hz, 1H), 3.90 (s, 3H), 3.85 (dd, J = 12.2, 3.9 Hz, 1H), 3.71 (dtq, J = 13.4, 6.8, 2.9 Hz, 1H), 2.53 (dt, J = 14.4, 2.8 Hz, 1H), 2.42 (dt, J = 14.8, 2.8 Hz, 1H), 2.21 (dd, J = 14.4, 12.6 Hz, 1H), 1 .72 (dd, J = 14.8, 12.2 Hz, 1H), 1.35 (d, J = 6.6 Hz, 3H). LCMS m / z 354.04 [M+H] + . compound 177 (2'S,4R,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-4-ol] (177) [ka] Step 1. Synthesis of (2'S,4R,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-4-ol] (177)

[0286] To tetrahydrofuran (500 μL) cooled to 0 °C was added (3aR)-1-methyl-3,3-diphenyl-3a,4,5,6-tetrahydropyrrolo[1,2-c][1,3,2]oxazaborole ((R)-CBS catalyst) (25 μL of 1 M, 0.025 mmol), followed by borane tetrahydrofuran (250 μL of 1 M, 0.25 mmol). After stirring for 5 min, a solution of (2S,4S,6S)-2'-chloro-2-methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,7'-thieno[2,3-c]pyran]-4'-one S33 (25 mg, 0.05570 mmol) in THF (1000 μL) was added dropwise. The mixture was stirred at 0 °C for 1 h. The mixture was concentrated, diluted with MeOH (1.5 mL), and quenched with NaOH (100 μL of 6 M, 0.6000 mmol). The mixture was warmed to 50 °C and stirred overnight. Purification by reverse-phase HPLC (method: C18 Waters Sunfire column (30 × 150 mm, 5 microns), gradient: 5 mM HCl in MeCN) gave (2'S,4R,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-4-ol (hydrochloride salt) 177 (3.0 mg, 13%). 1 H NMR (300 MHz, methanol-d4) δ 8.11 (d, J = 2.4 Hz, 1H), 6.94 (s, 1H), 4.90 (d, J = 3.1 Hz, 1H), 4.51 (t, J = 3.6 Hz, 1H), 4.13 (d, J = 2.2 Hz, 3H), 4.07 (dd, J = 12.2, 3.5 Hz, 1H), 3.87 (dd, J = 12.3, 3.9 Hz, 1H), 3.74 (ddt, J = 13.0, 9.4, 6.4 Hz, 1H), 2.78 - 2.51 (m, 1H), 2.51 - 2.19 (m, 2H), 1.87 (ddd, J = 30.8, 14.7, 12.2 Hz, 1H), 1.39 (dd, J = 6.6, 3.1 Hz, 3H). LCMS m / z 355.03 [M+H] + . Compounds 178~182

[0287] Compounds 178-182 (see Table 5) were prepared in two or three steps from the ketone intermediates in Table 5 using reduction and deprotection methods as described for compounds 174-177. The final compounds were made by hydrolysis with NaOH. The modifications made are described in Table 5 and the accompanying footnotes. [Table 5-1] [Table 5-2] [Table 5-3] compound 181 (2S,4S,4'S,6S)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-2'-(trifluoromethyl)-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-4'-ol (181), amorphous form [ka] Step 1. Synthesis of 2,2,2-trifluoro-1-[(2'S,4S,6'S,7S)-4-hydroxy-2'-methyl-6'-(1-methyltriazol-4-yl)-2-(trifluoromethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]ethenon (C153) 【...

Claims

[Claim 1] The invention described in the specification.

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