Inhibitors of APOL1 and methods of use thereof

Abstract

The present disclosure provides at least one entity selected from a compound of Formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, and a pharmaceutically acceptable salt of any of the foregoing, compositions comprising the entity, and methods of use thereof, including use in the treatment of APOL1-mediated diseases, including pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and / or non-diabetic kidney disease (NDKD).

Description

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

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

[0003] FSGS is a rare kidney disease with an estimated global incidence of 0.2 to 1.1 per 100,000 people per year. FSGS is a disease of podocytes (glomerular epithelial cells) that causes proteinuria and progressive decline in renal function. NDKD is a kidney disease involving damage to the podocytes or glomerular vascular bed that is not caused by diabetes. NDKD is a disease characterized by hypertension and progressive decline in renal function. Human genetics supports a causal role for G1 and G2 APOL1 variants in inducing kidney disease. Individuals with two APOL1 risk alleles have an increased risk of end-stage renal 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 subgroups based on their underlying etiology. A homogeneous subgroup of FSGS is characterized by the presence of 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 pair of related nonsynonymous amino acid changes (S342G and I384M), G2 encodes a two-amino acid deletion near the C-terminus of the protein (N388del:Y389del), and G0 is the ancestral (low-risk) allele. A unique phenotype of NDKD has also been found in patients with genetic risk variants of APOL1. In APOL1-mediated FSGS and NDKD, patients with two risk alleles develop higher levels of proteinuria and more rapid renal function loss compared to patients with no or only one APOL1 genetic risk variant. Alternatively, in AMKD, patients with one risk allele may also develop higher levels of proteinuria and accelerated renal function loss. See G. Vajgel et al., J. Rheumatol., November 2019, jrheum.190684.

[0005] APOL1 is a 44 kDa protein expressed only in humans, gorillas, and baboons. The APOL1 gene is expressed in multiple organs in humans, including the liver and kidneys. APOL1 is primarily produced by the liver and contains a signal peptide that allows its secretion into the bloodstream, where it circulates bound to a subset of high-density lipoproteins. APOL1 is responsible for protection against the invasive parasite Trypanosoma brucei (Tbbrucei). APOL1 is internalized by T. brucei and transported to lysosomes, where it inserts into the lysosomal membrane and forms pores that lead to parasite swelling and death.

[0006] While all three APOL1 variants (G0, G1, and G2) possess the ability to lyse Trypanosoma brucei, the APOL1 G1 and G2 variants provide additional protection against parasite species that have evolved serum resistance-associated proteins (SRAs) that inhibit APOL1 G0. The APOL1 G1 and G2 variants provide additional protection against trypanosomes that cause sleeping sickness. The G1 and G2 variants evade inhibition by SRAs; G1 provides additional protection against Trypanosoma gambiense, while G2 provides additional protection against Trypanosoma rhodesiense.

[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 proteinuria, decreased renal function, podocyte abnormalities, and glomerulosclerosis. Consistent with these data, the G1 and G2 variants of APOL1 play a causal role in inducing FSGS and accelerating its progression in humans. Individuals with the APOL1 risk allele (i.e., homozygotes or compound heterozygotes for the APOL1 G1 or APOL1G2 allele) are at increased risk for developing FSGS, and if they develop FSGS, they are at risk for a rapid decline in renal function. Therefore, inhibition of APOL1 may have a positive impact on individuals carrying the APOL1 risk allele.

[0008] Although normal plasma concentrations of APOL1 are relatively high and can vary at least 20-fold in humans, circulating APOL1 has not been causally associated with kidney disease. However, APOL1 in the kidney is thought to contribute to the development of kidney diseases, including FSGS and NDKD. In certain conditions, proinflammatory cytokines such as interferon or tumor necrosis factor-α can increase APOL1 protein synthesis by approximately 200-fold. In addition, several studies have shown that APOL1 protein forms a pH-gated Na+ molecule in the cell membrane. + / K + pores, leading to intracellular K + The net outflow of inflammatory cells ultimately leads to the activation of local and systemic inflammatory responses, cell swelling and death.

[0009] People of recent sub-Saharan African ancestry have a significantly higher risk of ESKD compared to people of European ancestry. In the United States, ESKD causes almost as many years of life lost as breast cancer in women and more years of life lost in men than colorectal cancer.

[0010] FSGS and NDKD are caused by damage to podocytes, which are part of the glomerular filtration barrier, resulting in proteinuria. Patients with proteinuria are at higher risk of developing end-stage renal disease (ESKD) and proteinuria-related complications such as infection or thromboembolic events. There is no standardized treatment regimen for FSGS or NDKD, and no approved medications. 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 receive high-dose steroids. Current treatment options for NDKD are based on blood pressure control and blockade of the renin-angiotensin system.

[0011] Corticosteroids, alone or in combination with other immunosuppressants, can induce remission in a minority of patients (e.g., remission of proteinuria in a minority of patients) and are associated with a variety of side effects. However, even in patients who initially respond to treatment with corticosteroids and / or immunosuppressants, remission is often irreversible. Consequently, patients, particularly individuals of recent sub-Saharan African descent with two APOL1 risk alleles, experience rapid disease progression leading to end-stage renal disease (ESRD). Consequently, there is an unmet medical need for treatments for FSGS and NDKD. Illustratively, given the evidence that APOL1 plays a causative role in inducing and accelerating the progression of renal disease, inhibition of APOL1 should have a positive impact on patients with APOL1-mediated renal disease, particularly those carrying two APOL1 risk alleles (i.e., homozygous or compound heterozygous for either the G1 or G2 allele).

[0012] Furthermore, APOL1 is a gene that is abnormally expressed in various cancers (Lin et al., Cell Death and Disease (2021), 12:760). Recently, it was found that APOL1 expression is abnormally elevated in human pancreatic cancer tissue compared to adjacent tissues and is associated with poor prognosis in pancreatic cancer patients. In both in vivo and in vitro experiments, APOL1 knockdown significantly inhibited cancer cell proliferation and promoted apoptosis in pancreatic cancer cells.

[0013] One aspect of the present disclosure provides at least one compound selected from the group consisting 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, I′, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I′, IIa0 Compounds of Formula I'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0 (e.g., compounds of Formula I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, Vb'0, 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 the foregoing, can be used to treat diseases mediated by APOL1, such as FSGS and NDKD. For example, at least one compound is a compound represented by Formula I:

[0014]

[0015] where 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.

[0016] In some embodiments, at least one compound of the present disclosure is a compound represented by the following structural formula:

[0017]

[0018] Formula I

[0019] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0020] X 1 Selected from S and -CR 2a And X 2 Selected from S and -CR 2b ,in:

[0021] X 1 and X 2 One is S;

[0022] When X 1 When it is S, then X 2 -CR 2b ;and

[0023] When X 2 When it is S, then X 1 Yes-CR 2a ;

[0024] R 1 is selected from hydrogen, halogen, -OH, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and phenyl, wherein:

[0025] R 1 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, and C1-C4 alkoxy;

[0026] R 1 The C1-C6 alkoxy group is optionally substituted by 1 to 3 groups independently selected from halogen;

[0027] R1 The C3-C6 cycloalkyl is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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; and

[0028] R 1 The phenyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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;

[0029] R 2a is selected from hydrogen, halogen, cyano, -OH, =O and C1-C6 alkyl, wherein:

[0030] R 2a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano, -OH and C1-C4 alkoxy;

[0031] R 2b is selected from hydrogen, halogen, cyano, -OH, =O and C1-C6 alkyl;

[0032] R 3a is selected from halogen, cyano, -OH, C1-C6 alkyl and =O; wherein:

[0033] R 3a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0034] R 3b Selected from C1-C2 alkyl and =O; wherein:

[0035] R 3b The C1-C2 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0036] When R 3a When selected from halogen, cyano, OH, C1-C6 alkyl or when R 3b When selected from C1-C2 alkyl, A single bond at each occurrence; or when R 3a =O or when R 3b =0, Each occurrence is a double bond;

[0037] R 4 selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C2-C6 alkynyl and in:

[0038] R 4 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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- to 10-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl;

[0039] Ring A is selected from C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 aryl and 5- to 10-membered heteroaryl, wherein ring A is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution; wherein:

[0040] R a is independently selected at each occurrence from 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 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl; wherein:

[0041] R a The C1-C6 alkyl, the C1-C6 alkoxy and the C2-C6 alkenyl are each optionally substituted by 1 to 3 groups independently selected from the following groups: C6 to C 10 Aryl (optionally substituted with 1 to 3 R m Group substituted:), 5 to 10 membered heterocyclic group (optionally substituted with 1 to 3 R m substituted with a group), a 5- to 10-membered heteroaryl group (optionally substituted with 1 to 3 R m Group substitution), 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 carbocyclic group (optionally substituted by 1 to 3 R m group substitution);

[0042] R a The C3-C 12 Carbocyclic group, said 3 to 12 membered heterocyclic group, said C6 and C 10 Aryl and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, cyano, C1-C4 alkyl, -NR h R i AND-OR k;in:

[0043] R h 、R i and R j Each occurrence is independently selected from hydrogen, C1-C4 alkyl, C6C 10 Aryl and C3-C6 cycloalkyl; wherein:

[0044] R h 、R i and R j The C1-C4 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen, cyano and -OH;

[0045] R k is independently selected at each occurrence from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl; wherein:

[0046] R k The C1-C4 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen, cyano and -OH;

[0047] R m is independently selected at each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S(=O) p R k AND-OR k ;in:

[0048] R m The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0049] R 5 Selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl; wherein:

[0050] R 5 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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;

[0051] R 5 The C3-C 12 Carbocyclic group, said 3 to 12 membered heterocyclic group, said C6 and C10 Aryl and the 5- to 10-membered heteroaryl are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl) (optionally substituted with -OH), -N(C1-C4 alkyl)2, C1-C5 alkyl (optionally substituted with -OH), C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -NHC(=O)(C1-C4 alkyl), -C(=O)(C1-C4 alkoxy) and -C(=O)N(C1-C4 alkyl)2;

[0052] k is an integer selected from 0, 1 and 2; wherein

[0053] When R 3a When selected from halogen, cyano, -OH and C1-C6 alkyl, k is 1 or 2; and

[0054] When R 3a When =O, k is 1;

[0055] m is an integer selected from 0, 1 and 2, wherein:

[0056] When R 3b When selected from C1-C2 alkyl, m is 1 or 2; and

[0057] When R 3b When =O, m is 1;

[0058] p is an integer selected from 1 and 2; and

[0059] q and r are each an integer selected from 1, 2, 3 and 4.

[0060] In some embodiments, R 4 Selected from C1-C6 alkyl and

[0061] In some embodiments, R 5 Selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl, wherein:

[0062] R 5 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups selected from the group consisting of 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;

[0063] R 5 The C3-C 12 Carbocyclic group, said 3 to 12 membered heterocyclic group, said C6 and C 10 The aryl group and the 5- to 10-membered heteroaryl group are each optionally substituted by 1 to 3 groups selected from the group consisting of 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.

[0064] In some embodiments, at least one compound of the present disclosure (e.g., at least one compound of Formula I) is a compound represented by the following structural formula:

[0065]

[0066] Formula I0

[0067] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0068] X 1 and X 2 Each selected from S and -CR 2 ,in:

[0069] X 1 and X 2 One is S;

[0070] When X 1 When it is S, then X 2 -CR 2b ;and

[0071] When X 2 When it is S, then X 1 Yes-CR 2a ;

[0072] R 1 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and phenyl; wherein:

[0073] R 1 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, and C1-C4 alkoxy;

[0074] R 1 The C1-C6 alkoxy group is optionally substituted by 1 to 3 groups independently selected from halogen;

[0075] R 1 The C3-C6 cycloalkyl is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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; and

[0076] R 1 The phenyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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;

[0077] R 2a is selected from hydrogen, halogen, cyano, -OH, =O and C1-C6 alkyl; wherein:

[0078] R 2a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano, -OH and C1-C4 alkoxy;

[0079] R 2b is selected from hydrogen, halogen, cyano, -OH, =O and C1-C6 alkyl;

[0080] R 3a is selected from halogen, cyano, -OH, C1-C6 alkyl and =O; wherein:

[0081] R 3a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0082] R 3b Selected from C1-C2 alkyl and =O; wherein:

[0083] R 3b The C1-C2 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0084] When R 3a When selected from halogen, cyano, -OH, C1-C6 alkyl or when R 3b When selected from C1-C2 alkyl, A single bond at each occurrence; or when R 3a =O or when R 3b =0, Each occurrence is a double bond;

[0085] R 4 Selected from C1-C6 alkyl and in:

[0086] R 4 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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- to 10-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl;

[0087] Ring A is selected from C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 aryl and 5- to 10-membered heteroaryl, wherein ring A is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution; wherein:

[0088] R a is independently selected at each occurrence from 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 Ri 、C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl; wherein:

[0089] R a The C1-C6 alkyl and the C2-C6 alkenyl are each optionally substituted by 1 to 3 groups independently selected from the following: 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 cycloalkyl;

[0090] R a The C3-C 12 Carbocyclic group, said 3 to 12 membered heterocyclic group, said C6 and C 10 The aryl group and the 5- to 10-membered heteroaryl group are each optionally substituted with 1 to 3 groups selected from the group consisting of halogen, cyano, C1-C4 alkyl, -NR h R i AND-OR k ;in:

[0091] R h 、R i and R j is independently selected at each occurrence from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl; wherein:

[0092] R h 、R i and Rj The C1-C4 alkyl group of any one of the following is optionally substituted with 1 to 3 groups selected from halogen, cyano and -OH;

[0093] R k is independently selected at each occurrence from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl; wherein:

[0094] R k The C1-C4 alkyl group of any one of which is optionally substituted with 1 to 3 groups selected from halogen, cyano and -OH;

[0095] R 5 Selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl; wherein:

[0096] R 5 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups selected from the group consisting of 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;

[0097] R 5 The C3-C 12 Carbocyclic group, said 3 to 12 membered heterocyclic group, said C6 and C 10 Aryl and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups selected from the group consisting of 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;

[0098] When R 3a When selected from halogen, cyano, -OH, C1-C6 alkyl, k is an integer selected from 0, 1 and 2; or when R 3a =0, k is an integer selected from 0 and 1;

[0099] When R 3b When selected from C1-C2 alkyl, m is an integer selected from 0, 1 and 2; and when R 3b =0, m is an integer selected from 0 and 1;

[0100] p is an integer selected from 1 and 2; and

[0101] q and r are each an integer selected from 1, 2, 3 and 4.

[0102] In one aspect of the present disclosure, the compound of Formula I is selected from compounds 1 to 391 (e.g., compounds 1 to 220), such that at least one entity is selected from compounds 1 to 391 (e.g., compounds 1 to 220), a pharmaceutically acceptable salt of any of these compounds, a solvate of any of the foregoing, and a deuterated derivative of any of the foregoing.

[0103] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one entity selected from the group consisting 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, Compounds of formula I0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa0, IIb0, IIIa0, IIIb0, IVa0, IVb0, Va0, and Vb0, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical composition may comprise at least one compound selected from the group consisting of compounds 1 to 391 (e.g., compounds 1 to 220), pharmaceutically acceptable salts of any of these compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing. These compositions may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0104] Another aspect of the present disclosure provides a method of treating an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease) comprising administering to a subject in need thereof at least one entity selected from the group consisting 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, IIb a0, 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 (e.g., a compound 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 the foregoing. In some embodiments, the method comprises administering at least one entity selected from Compounds 1-391 (eg, Compounds 1-220), tautomers thereof, deuterated derivatives of said compounds or tautomers, or a pharmaceutically acceptable salt of any of the foregoing.

[0105] Another aspect of the present disclosure provides a method of treating an APOL1-mediated cancer, such as, for example, pancreatic cancer, comprising administering to a subject in need thereof at least one entity selected from the group consisting 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′, I1, IIb′, IIIb′, IVa′, IVb′, Va′, Vb′, IIa″, IIb″, IIIa″′, IIIb′, IVa′, IVb′, I0, IIa′, I1 Ib0, 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 compounds (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), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the methods comprise administering at least one entity selected from Compounds 1 to 391 (e.g., Compounds 1 to 220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing.

[0106] Another aspect of the present disclosure provides a method of treating FSGS and / or NDKD comprising administering to a subject in need thereof at least one entity selected from the group consisting 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′, IIIb′, IVa′, IVb′, Va′, Vb′, IIa″, IIb″, IIIa″′, IIIb′, IVa′, IVb′, I0, IIa′, IIb′, IIIb′, IVa′, IVb′, I0, IIa′, IIb′, IIIb′, IVa′, IVb′ , Ia'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, Vb'0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0 compounds (e.g., compounds of Formula I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, Vb'0, 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 the foregoing. In some embodiments, the method comprises administering at least one entity selected from Compounds 1 to 391 (e.g., Compounds 1 to 220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing.

[0107] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one additional active agent in the same pharmaceutical composition, or as a separate composition, as at least one entity selected from the group consisting 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′, IIIb′, IVa′, IVb′, I0, IIa′, IIb′ , 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 (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), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method comprises administering at least one entity selected from Compounds 1 to 391 (e.g., Compounds 1 to 220), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, with at least one additional active agent, either in the same pharmaceutical composition or in separate compositions.

[0108] Also provided are methods of inhibiting APOL1 comprising administering to a subject in need thereof at least one entity selected from the group consisting 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″′, I0, IIa′, IIb′, IIIa′, IIIb′, IVa′, IVb′, I0, IIa′, IIb′, IIIa′, IIIb′, IVa′, IVb′, I0, IIa′, IIb′, IIIb′, IVa′ IIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0 compounds (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), tautomers thereof, deuterated derivatives of said compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method of inhibiting APOL1 comprises administering at least one entity selected from the group consisting of Compounds 1 to 391 (e.g., Compounds 1 to 220), tautomers thereof, deuterated derivatives of said compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. BRIEF DESCRIPTION OF THE DRAWINGS

[0109] Figure 1 Depicted is the XRPD diffraction pattern of Compound 181 phosphate hydrate at 25 ± 2 °C and 40% RH.

[0110] Figure 2 Depicted are XRPD diffractograms of Compound 181 phosphate hydrate at 25 ± 2°C and 5% RH (black trace) or 90% (grey trace).

[0111] Figure 3 Depicted is the TGA thermogram of Compound 181 phosphate hydrate.

[0112] Figure 4 Depicted is the DSC curve of Compound 181 phosphate hydrate.

[0113] Figure 5 Depicts the solid-state state of compound 181 phosphate hydrate 13 C NMR spectroscopy.

[0114] Figure 6Depicts the solid state of compound 181 phosphate hydrate at 43% RH 19 F NMR spectroscopy.

[0115] Figure 7 The effect of relative humidity on the solid-state properties of compound 181 phosphate hydrate is described. 19 Effects of F NMR spectroscopy.

[0116] Figure 8 Depicts the solid state of compound 181 phosphate hydrate at 43% RH 31 P NMR spectroscopy.

[0117] Figure 9 The effect of relative humidity on the solid-state properties of compound 181 phosphate hydrate is described. 31 Effect of P NMR spectroscopy.

[0118] Figure 10 Depicted is the XRPD diffraction pattern of Compound 181 free form monohydrate.

[0119] Figure 11 Depicted is the TGA thermogram of Compound 181 free form monohydrate.

[0120] Figure 12 Depicted is the DSC curve of the free form monohydrate of Compound 181.

[0121] Figure 13 Depicted is the solid-state of the free form monohydrate of compound 181. 13 C NMR spectroscopy.

[0122] Figure 14 Depicts the solid state of the free form monohydrate of anhydrous compound 181 13 C NMR spectroscopy.

[0123] Figure 15 Depicted is the solid-state of the free form monohydrate of compound 181. 19 F NMR spectroscopy.

[0124] Figure 16 Depicts the solid state of the free form monohydrate of anhydrous compound 181 19 F NMR spectroscopy.

[0125] Figure 17 Depicted is the XRPD diffraction pattern of Compound 181 phosphate methanol solvate.

[0126] Figure 18 Depicted is the solid state of compound 181 phosphate methanol solvate 13 C NMR spectroscopy.

[0127] Figure 19 Depicted is the solid state of compound 181 phosphate methanol solvate 19 F NMR spectroscopy.

[0128] Figure 20 Depicted is the solid state of compound 181 phosphate methanol solvate 31 P NMR spectroscopy.

[0129] Figure 21 Depicted is the XRPD diffraction pattern of Compound 181 phosphate MEK solvate.

[0130] Figure 22 Depicted is the solid state of compound 181 phosphate MEK solvate 13 C NMR spectroscopy.

[0131] Figure 23 Depicted is the solid state of compound 181 phosphate MEK solvate 19 F NMR spectroscopy.

[0132] Figure 24 Depicted is the XRPD diffraction pattern of Compound 174 phosphate salt hemihydrate.

[0133] Figure 25 Depicted is the TGA thermogram of Compound 174 phosphate salt hemihydrate.

[0134] Figure 26 Depicted is the DSC curve of Compound 174 phosphate hemihydrate.

[0135] Figure 27 Depicted is the solid state of compound 174 phosphate hemihydrate 13 C NMR spectroscopy.

[0136] Figure 28 Depicts the solid state of the dehydrated compound 174 phosphate hemihydrate 13 C NMR spectroscopy.

[0137] Figure 29A Depicted is the solid state of compound 174 phosphate hemihydrate 31 P NMR spectroscopy.

[0138] Figure 29B Depicts the solid state of the anhydrated compound 174 phosphate hemihydrate 31 P NMR spectroscopy.

[0139] Figure 30 Depicted is the XRPD diffraction pattern of Compound 174 hemihydrate.

[0140] Figure 31 Depicted is the TGA thermogram of Compound 174 hemihydrate.

[0141] Figure 32 Depicted is the DSC curve of Compound 174 hemihydrate.

[0142] Figure 33 Depicted is the solid state of compound 174 hemihydrate 13 C NMR spectroscopy.

[0143] Figure 34 Depicts the solid state of the anhydrated compound 174 hemihydrate 13 C NMR spectroscopy. DETAILED DESCRIPTION

[0144] definition

[0145] The terms "selected from" and "chosen from" are used interchangeably herein.

[0146] As used herein, the term "APOL1" means apolipoprotein L1 protein, and the term "APOL1" means apolipoprotein L1 gene.

[0147] The term "APOL1-mediated disease" refers to a disease or condition associated with abnormal APOL1 (e.g., certain APOL1 genetic variants; elevated APOL1 levels). In some embodiments, the APOL1-mediated disease is an APOL1-mediated kidney disease. In some embodiments, the APOL1-mediated disease is associated with patients who have two APOL1 risk alleles, e.g., patients who are homozygous or compound heterozygous for the G1 or G2 alleles. In some embodiments, the APOL1-mediated disease is associated with patients who have one APOL1 risk allele.

[0148] The term "APOL1-mediated kidney disease" refers to a disease or condition that impairs kidney function and is attributable to APOL1. In some embodiments, the APOL1-mediated kidney disease is associated with patients who have two APOL1 risk alleles, e.g., patients who are homozygous or compound heterozygous for the G1 or G2 alleles. In some embodiments, the APOL1-mediated kidney disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arteriosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1-mediated kidney disease is chronic kidney disease or proteinuria.

[0149] As used herein, the term "FSGS" refers to focal segmental glomerulosclerosis, a disease of podocytes (epithelial cells lining the glomeruli) that causes proteinuria and progressive decline in renal function and is associated with two common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0150] As used herein, the term "NDKD" refers to non-diabetic kidney disease characterized by severe hypertension and progressive decline in renal function and is associated with two common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0151] The terms "ESKD" and "ESRD" are used interchangeably herein and refer to end-stage renal disease or ESRD. ESKD / ESRD is the final stage of kidney disease, i.e., kidney failure, and means that the kidneys have stopped working well enough for the patient to survive without dialysis or a kidney transplant. In some embodiments, ESKD / ESRD is associated with two APOL1 risk alleles.

[0152] When referring to the compounds of the present disclosure, the term "compound" refers to a collection of molecules having the same chemical structure except that there may be isotopic variations between the constituent atoms of the molecules, 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). Thus, it will be clear to those skilled in the art that a compound represented by a particular chemical structure containing an indicated deuterium atom will also contain a smaller amount of isotopologues having hydrogen atoms at one or more designated deuterium positions in the structure. The relative amount of such isotopologues in the compounds of the present disclosure will depend on many factors, including the isotopic purity of the reagents used to prepare the compounds and the efficiency of incorporation of the isotopes in the various synthetic steps used to prepare the compounds. However, as explained above, the relative amount of all such isotopologues will be less than 49.9% of the compound. In other embodiments, the relative amount of all such isotopologues 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.

[0153] As used herein, "optionally substituted" is used interchangeably with the expression "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals 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 can be substituted with more than one substituent selected from a specified group, the substituents at each position may be the same or different. Combinations of substituents contemplated by the present disclosure are those that result in the formation of stable or chemically feasible compounds.

[0154] The term "isotopologue" refers to a species in which a chemical structure differs from a reference compound only in its isotopic composition. Additionally, unless otherwise indicated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium, or replacing 13 C or 14 Compounds having the present structures except for the substitution of C for a carbon are within the scope of this disclosure.

[0155] Unless otherwise indicated, structures depicted herein are also intended to include all isomeric forms of the structures, 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. Therefore, geometric and conformational mixtures of the compounds of the present invention are within the scope of this disclosure. Unless otherwise indicated, all tautomeric forms of the compounds of the present disclosure are within the scope of this disclosure.

[0156] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by migration of atoms, such as hydrogen atoms or radicals, within the molecule.

[0157] As used herein, "stereoisomers" refer to enantiomers and diastereomers.

[0158] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as the reference compound but with one or more hydrogen atoms replaced by a deuterium atom ("D" or " 2H"). It will be appreciated that, depending on the origin of the chemical materials used in the synthesis, some variation in natural isotopic abundance will occur in the synthesized compounds. Despite this variation, the concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the extent of stable isotopic substitution in the deuterated derivatives described herein. Thus, unless otherwise indicated, when referring to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen has been substituted with deuterium at a level well above its natural isotopic abundance (typically about 0.015%). In some embodiments, the deuterated derivatives of the present disclosure have an isotopic enrichment factor per 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).

[0159] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0160] As used herein, the term "alkyl" or "aliphatic" means a fully saturated straight chain (i.e., linear or unbranched) or branched, substituted or unsubstituted hydrocarbon chain. Unless otherwise specified, an alkyl group contains 1 to 20 alkyl carbon atoms. In some embodiments, an alkyl group contains 1 to 10 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1 to 8 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1 to 6 alkyl carbon atoms, and in some embodiments, an alkyl group contains 1 to 4 alkyl carbon atoms. In other embodiments, an alkyl group contains 1 to 3 alkyl carbon atoms, and in other embodiments, an alkyl group contains 1 to 2 alkyl carbon atoms. In some embodiments, an alkyl group is substituted. In some embodiments, an alkyl group is unsubstituted. In some embodiments, an alkyl group is linear or straight chain or unbranched. In some embodiments, an alkyl group is branched.

[0161] As used herein, the term "cycloalkyl" or "cyclic alkyl" refers to a fully saturated monocyclic C 3-8 Hydrocarbon or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14 In some embodiments, the cycloalkyl group is C3 to C 12Cycloalkyl. In some embodiments, the cycloalkyl is a C3 to C8 cycloalkyl. In some embodiments, the cycloalkyl is a C3 to C6 cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0162] As used herein, the term "carbocyclyl" or "alicyclic" includes the term "cycloalkyl" or "cycloalkyl" and refers to a monocyclic C 3-8 Hydrocarbon or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14 A hydrocarbon that is fully saturated or partially saturated because it contains one or more unsaturated units, but is not aromatic, wherein any single ring in the bicyclic system has 3 to 7 members. Bicyclic carbocyclyls include combinations of monocyclic carbocycles fused to phenyl. In some embodiments, the carbocyclyl group is substituted. In some embodiments, the carbocyclyl group is unsubstituted. In some embodiments, the carbocyclyl group is C3 to C 12 In some embodiments, the carbocyclyl group is C3 to C 10 In some embodiments, the carbocyclyl group is a C3 to C8 carbocyclyl group.

[0163] As used herein, the term "heteroalkyl" or "heteroaliphatic" refers to an alkyl or aliphatic group as defined above in which one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon.

[0164] As used herein, the term "alkenyl" means a straight (i.e., straight or unbranched), branched, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, the alkenyl group is substituted. In some embodiments, the alkenyl group is unsubstituted. In some embodiments, the alkenyl group is straight. In some embodiments, the alkenyl group is branched.

[0165] As used herein, the terms "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocycle" refer to a non-aromatic (i.e., fully saturated or partially saturated, because it contains one or more unsaturated units, but is not aromatic) monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system in which one or more ring members are independently selected heteroatoms. Bicyclic heterocyclyls include the following monocyclic combinations: a monocyclic heteroaryl fused to a monocyclic heterocyclyl; a monocyclic heterocyclyl fused to another monocyclic heterocyclyl; a monocyclic heterocyclyl fused to a phenyl; a monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and a monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl.

[0166] In some embodiments, the heterocycle contains ring atoms substituted with one or more oxo groups (eg, for example, a C=O group, an S=O group, or an SO2 group).

[0167] In some embodiments, a "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" group has 3 to 14 ring members, one or more of which is a heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring constituent atoms. 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 nitrogen 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 group is a 3- to 12-membered heterocyclyl group. In some embodiments, the heterocyclyl group is a 3- to 10-membered heterocyclyl group. In some embodiments, the heterocyclyl group is a 3- to 8-membered heterocyclyl group. In some embodiments, the heterocyclyl group is a 5- to 10-membered heterocyclyl group. In some embodiments, the heterocyclyl group is a 5- to 8-membered heterocyclyl group. In some embodiments, the heterocyclyl group is a 5- or 6-membered heterocyclyl group. Non-limiting examples of monocyclic heterocyclyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl, tetrahydrothiophenyl 1,1-dioxide, and the like.

[0168] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; a quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0169] As used herein, the term "unsaturated" means that a moiety has one or more units or degrees of unsaturation. Unsaturation is the state in which not all available valences in a compound are occupied by substituents and thus the compound contains double or triple bonds.

[0170] As used herein, the term "alkoxy" or "thioalkyl" refers to an alkyl group as defined above, wherein one of the carbons of the alkyl group is replaced by oxygen ("alkoxy") or sulfur ("thioalkyl") atoms, with the prerequisite that oxygen and sulfur atoms are connected between two carbon atoms. The limiting examples of alkoxy groups include methoxy, ethoxy, methylmethoxy, etc. "Cyclic alkoxy" refers to a monocycle, spirocycle, bicyclic, bridged bicyclic, tricyclic or bridged tricyclic hydrocarbon containing at least one alkoxy group but not aromatic. The limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanes, 8-oxabicyclo[3.2.1]octanyl and oxepane. In some embodiments, "alkoxy" and / or "thioalkyl" groups are substituted. In some embodiments, "alkoxy" and / or "thioalkyl" groups are unsubstituted.

[0171] As used herein, the terms "haloalkyl," "haloalkenyl," and "haloalkoxy" refer to straight or branched chain alkyl, alkenyl, or alkoxy groups, respectively, substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CF2-, and perhaloalkyl groups, such as -CF2CF3. Non-limiting examples of haloalkoxy groups include -OCHF2, -OCH2F, -OCF3, and -OCF2-.

[0172] The term "halogen" includes F, Cl, Br and I, ie, fluorine, chlorine, bromine and iodine, respectively.

[0173] The term "aminoalkyl" refers to an alkyl group substituted with or containing an amino group.

[0174] As used herein, "amino" refers to a group that is a primary, secondary, or tertiary amine.

[0175] As used herein, a "carbonyl" group refers to C=O.

[0176] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0177] As used herein, a "hydroxy" group refers to -OH.

[0178] As used herein, a "thiol" group refers to -SH.

[0179] As used herein, "tert" and "t-" each refer to tertiary.

[0180] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system having a delocalized π electron orbital consisting of [4n+2] p orbital electrons, where n is an integer ranging from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0181] 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 five to fourteen ring members, wherein each ring in the system is aromatic containing only carbon atoms, and wherein each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include benzene (C6) and naphthalene (C8). 10 In some embodiments, the aryl group is substituted. In some embodiments, the aryl group is unsubstituted.

[0182] 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 and tricyclic ring system having a total of five to fourteen 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 wherein each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Bicyclic heteroaryl includes a combination of the following monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl. In some embodiments, the heteroaryl group is substituted. In some embodiments, the heteroaryl group has one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group has one heteroatom. In some embodiments, the heteroaryl group has two heteroatoms. In some embodiments, the heteroaryl group is a monocyclic ring system with five ring constituent atoms. In some embodiments, the heteroaryl group is a monocyclic ring system with six ring constituent atoms. In some embodiments, the heteroaryl group is unsubstituted. In some embodiments, the heteroaryl group is a 3- to 12-membered heteroaryl group. In some embodiments, the heteroaryl group is a 3- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 3- to 8-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 8-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- or 6-membered heteroaryl group. Non-limiting examples of monocyclic heteroaryl groups are pyridyl, pyrimidinyl, thienyl, thiazolyl, isoxazolyl, and the like.

[0183] In some embodiments, the heteroaryl group comprises a ring atom substituted with one or more oxo groups (e.g., C=O group, S=O group, or SO2 group). Illustrative, non-limiting examples of heteroaryl groups are benzo[d]oxazol-2(3H)-one groups.

[0184] The limiting examples of useful protecting groups of nitrogenous groups such as amine groups include, for example, tert-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylamine and p-toluenesulfonamide. The method of adding (commonly referred to as the process of "protection") and removing (commonly referred to as the process of "deprotection") such amine protecting groups is well known in the art, and can be obtained in, for example, PJ Kocienski, Protecting Groups, Thieme, 1994, which are incorporated herein by reference in their entirety, and in Greene and Wuts, Protective Groups in Organic Synthesis, the 3rd edition (John Wiley & Sons, New York, 1999) and the 4th edition (John Wiley & Sons, New Jersey, 2014), obtaining.

[0185] 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" (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropanol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0186] 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 (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropylethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

[0187] The present disclosure includes pharmaceutically acceptable salts of the disclosed compounds.Salts of a compound 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.

[0188] As used herein, the term "pharmaceutically acceptable" refers to components that are suitable for contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt that, when administered to a recipient, is capable of providing, directly or indirectly, a compound of the present disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0189] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, 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, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4- Pharmaceutically acceptable acid addition salts include, but are not limited to, 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 salts formed with mineral acids such as hydrochloric acid and hydrobromic acid and salts formed with organic acids such as maleic acid.

[0190] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4alkyl) 4 salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Other 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, low-carbon alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0191] The terms "patient" and "subject" are used interchangeably herein and refer to animals, including humans.

[0192] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that produces the desired effect of its administration (e.g., improving the symptoms of FSGS and / or NDKD, reducing the severity of FSGS and / or NDKD or symptoms of FSGS and / or NDKD, and / or reducing the progression of FSGS and / or NDKD or symptoms of FSGS and / or NDKD). The exact amount of an effective dose will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0193] As used herein, the term "treat" and its cognate words refer to slowing down or stopping the progression of a disease. As used herein, "treat" and its cognate words include, but are not limited to, complete or partial relief, reduction in the risk of renal failure (e.g., ESRD) and disease-related complications (e.g., edema, susceptibility to infection or thromboembolic events). The improvement of any one of these symptoms or the alleviation of its severity can be easily assessed according to methods and techniques known in the art or subsequently developed.

[0194] When used in connection with a dose, amount, or weight percentage of an ingredient of a composition or dosage form, the terms "about" and "approximately" include values ​​of the specified dose, amount, or weight percentage, or ranges of the specified dose, amount, or weight percentage, that one of ordinary skill in the art would recognize as providing a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percentage.

[0195] At least one entity selected from the group consisting 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'', I0, IIa, IIb, IIIa, IIIb, IVa'', IVb'', I0, IIa, IIb, IIIa, IIIb, IVa'', IVb'', I0 a0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0 and Vb'0 (e.g., a compound 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 the foregoing. In some embodiments, 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′, IIb0, IIIb0, IVa′, IVb0 b'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0 and Vb'0 compounds (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 to 391 (e.g., selected from compounds 1 to 220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing.In some embodiments, at least one entity selected from the group consisting 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, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0 (e.g., compounds selected from 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), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, at least one entity selected from Compounds 1 to 391 (e.g., Compounds 1 to 220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing is administered once daily. In some embodiments, at least one entity selected from the group consisting 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, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0 and Vb'0 (e.g., a compound selected from 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 the foregoing.In some embodiments, at least one entity selected from Compounds 1 to 391 (e.g., selected from Compounds 1 to 220), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing is administered twice daily. In some embodiments, at least one entity selected from 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, Va'0 and Vb'0 compounds (e.g., compounds selected from 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), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, at least one entity selected from Compounds 1 to 391 (e.g., selected from Compounds 1 to 220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing is administered three times daily.

[0196] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one entity selected from 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′, IIa″, IIb″, IIIa″′, IIIb′, IVa″, IVb″, IIa″′, IIb″′, IIIa″′, IIIb′, IVa″′, IVb′, I0, IIa, IIb, IIIa′, IIIb′ , IIIb0, IVa0, IVb0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0 and Vb'0 (e.g., a compound selected from 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 the foregoing. In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one entity selected from Compounds 1 to 391 (e.g., selected from Compounds 1 to 220), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing is administered once a day, twice a day, or three times a day.

[0197] Those skilled in the art will recognize that when disclosing the amount of a compound, the amount of the pharmaceutically acceptable salt form of the relevant compound is the amount equivalent to the concentration of the free base of the compound. The amounts of the compounds, pharmaceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based on the free base form of the reference compound. For example, "1000 mg of at least one compound selected from the group consisting of a compound of Formula I and a pharmaceutically acceptable salt thereof" includes 1000 mg of the compound of Formula I and a concentration of a pharmaceutically acceptable salt of the compound of Formula I equivalent to 1000 mg of the compound of Formula I.

[0198] As used herein, the term "ambient conditions" means room temperature, open air conditions, and uncontrolled humidity conditions.

[0199] As used herein, the terms "crystalline form" and "form" refer interchangeably to a crystal structure (or polymorph) having a specific molecular packing arrangement in the 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 terms "Form A of Compound [X]" or "Compound [X] Form A" refer to a unique crystalline form that can be identified and distinguished from other crystalline forms of Compound 1 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).

[0200] As used herein, the term "SSNMR" refers to the analytical characterization method of solid-state nuclear magnetic resonance. SSNMR spectra can be recorded under ambient conditions or alternative conditions (e.g., at 275K) for any magnetically active isotopes present in the sample. Typical examples of active isotopes of 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 Pt.

[0201] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded using a diffractometer in transmission or reflection geometry under ambient conditions.

[0202] As used herein, the terms "X-ray powder diffraction pattern," "X-ray powder diffraction pattern," and "XRPD pattern" refer interchangeably to an experimentally obtained pattern that plots signal position (on the abscissa) versus signal intensity (on the ordinate). For an amorphous material, an X-ray powder diffraction pattern may include one or more broad signals; and for a crystalline material, an X-ray powder diffraction pattern may include one or more signals, each identified by its angular value measured in degrees 2θ (°2θ), plotted on the abscissa of the X-ray powder diffraction pattern, which may be denoted as "signal at °2θ," "signal at a 2θ value of," and / or "signal at at least ... selected from 2θ values ​​of."

[0203] As used herein, a "signal" or "peak" refers to a point in an XRPD pattern where the intensity, measured in counts, is at a local maximum. One of ordinary skill in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may not be apparent, for example, to the naked eye. Indeed, one of ordinary skill in the art will recognize that several industry-recognized methods are capable of and are suitable for determining whether a signal is present in a pattern, such as Rietveld refinement.

[0204] As used herein, “a signal at °2θ”, “a signal at a 2θ value [ ] of” and / or “a signal at at least 2θ values ​​selected from” refers to the positions (°2θ) of X-ray reflections as measured and observed in an X-ray powder diffraction experiment.

[0205] The repeatability of the angle values ​​is within the range of ±0.2°2θ, that is, the angle value can be at the stated angle value +0.2°2θ, at the angle value -0.2°2θ, or at any value between these two endpoints.

[0206] As used herein, the terms "signal intensity" and "peak intensity" refer interchangeably to the relative signal intensity within a given X-ray powder diffraction pattern. Factors that may affect the relative signal or peak intensity include sample thickness and preferred orientation (e.g., crystalline particles are not randomly distributed).

[0207] As used herein, the term "DSC" refers to the analytical method of Differential Scanning Calorimetry.

[0208] As used herein, the term "TGA" refers to the analytical method of thermogravimetric (or thermogravimetric) analysis.

[0209] As used herein, "crystalline hydrate" is a crystalline form that contains stoichiometric or non-stoichiometric amounts of water in the crystal lattice. In the case of non-stoichiometric hydrates, the amount of water present in the crystalline hydrate can vary at least as a function of relative humidity ("RH"). The presence (or absence) or varying amounts of water can cause X-ray diffraction pattern peak positions to shift, or cause the appearance or disappearance of peaks. The presence (or absence) or varying amounts of water can cause peak shifts or even the appearance of new peaks in the solid-state NMR spectrum of protons, carbon, fluorine, phosphorus, nitrogen, chlorine (or other NMR-active nuclei).

[0210] Compounds and compositions

[0211] In some embodiments, at least one entity of the present disclosure is a compound represented by the following structural formula:

[0212]

[0213] Formula I

[0214] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0215] X 1 Selected from S and -CR 2a And X 2 Selected from S and -CR 2b ,in:

[0216] X 1 and X 2 One is S;

[0217] When X 1 When it is S, then X 2 -CR 2b ;and

[0218] When X 2 When it is S, then X 1 Yes-CR 2a ;

[0219] R 1 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and phenyl, wherein:

[0220] R 1 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, and C1-C4 alkoxy;

[0221] R 1 The C1-C6 alkoxy group is optionally substituted by 1 to 3 groups independently selected from halogen;

[0222] R 1 The C3-C6 cycloalkyl is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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; and

[0223] R 1The phenyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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;

[0224] R 2a is selected from hydrogen, halogen, cyano, -OH, =O and C1-C6 alkyl, wherein:

[0225] R 2a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano, -OH and C1-C4 alkoxy;

[0226] R 2b is selected from hydrogen, halogen, cyano, -OH, =O and C1-C6 alkyl;

[0227] R 3a is selected from halogen, cyano, -OH, C1-C6 alkyl and =O; wherein:

[0228] R 3a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0229] R 3b Selected from C1-C2 alkyl and =O; wherein:

[0230] R 3b The C1-C2 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0231] When R 3a When selected from halogen, cyano, OH, C1-C6 alkyl or when R 3b When selected from C1-C2 alkyl, A single bond at each occurrence; or when R 3a =O or when R 3b =0, Each occurrence is a double bond;

[0232] R 4 selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C2-C6 alkynyl and in:

[0233] R 4The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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- to 10-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl;

[0234] Ring A is selected from C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 aryl and 5- to 10-membered heteroaryl, wherein ring A is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution; wherein:

[0235] R a is independently selected at each occurrence from 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 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl; wherein:

[0236] R aThe C1-C6 alkyl, the C1-C6 alkoxy and the C2-C6 alkenyl are each optionally substituted by 1 to 3 groups independently selected from the following groups: C6 to C 10 Aryl (optionally substituted with 1 to 3 R m Group substituted:), 5 to 10 membered heterocyclic group (optionally substituted with 1 to 3 R m substituted with a group), a 5- to 10-membered heteroaryl group (optionally substituted with 1 to 3 R m Group substitution), 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 carbocyclic group (optionally substituted by 1 to 3 R m group substitution);

[0237] R a The C3-C 12 Carbocyclic group, said 3 to 12 membered heterocyclic group, said C6 and C 10 Aryl and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, cyano, C1-C4 alkyl, -NR h R i AND-OR k ;in:

[0238] R h 、R i and R j Each occurrence is independently selected from hydrogen, C1-C4 alkyl, C6C 10 Aryl and C3-C6 cycloalkyl; wherein:

[0239] R h 、R i and R j The C1-C4 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen, cyano and -OH;

[0240] R k is independently selected at each occurrence from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl; wherein:

[0241] R k The C1-C4 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen, cyano and -OH;

[0242] R m is independently selected at each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S(=O) p R k AND-OR k ;in:

[0243] R m The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0244] R 5 Selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl; wherein:

[0245] R 5 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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;

[0246] R 5 The C3-C 12 Carbocyclic group, said 3 to 12 membered heterocyclic group, said C6 and C 10Aryl and the 5- to 10-membered heteroaryl are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl) (optionally substituted with -OH), -N(C1-C4 alkyl)2, C1-C5 alkyl (optionally substituted with -OH), C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -NHC(=O)(C1-C4 alkyl), -C(=O)(C1-C4 alkoxy) and -C(=O)N(C1-C4 alkyl)2;

[0247] k is an integer selected from 0, 1 and 2; wherein

[0248] When R 3a When selected from halogen, cyano, -OH and C1-C6 alkyl, k is 1 or 2; and

[0249] When R 3a When =O, k is 1;

[0250] m is an integer selected from 0, 1 and 2, wherein:

[0251] When R 3b When selected from C1-C2 alkyl, m is 1 or 2; and

[0252] When R 3b When =O, m is 1;

[0253] p is an integer selected from 1 and 2; and

[0254] q and r are each an integer selected from 1, 2, 3 and 4.

[0255] In certain embodiments, the compounds of the present disclosure are represented by one of the following structural formulas:

[0256]

[0257] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0258] R 2a is selected from hydrogen, halogen, cyano and C1-C4 alkyl; wherein:

[0259] R 2a The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, -OH and C1-C2 alkoxy;

[0260] R 2b is selected from hydrogen, halogen, cyano and C1-C4 alkyl; and

[0261] k is an integer selected from 0, 1 and 2;

[0262] And all other variables not specifically defined herein are as defined in the preceding embodiments.

[0263] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 4 Selected from C1-C4 alkyl and in:

[0264] R 4 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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;

[0265] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0266] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 4 Selected from C1-C2 alkyl and in:

[0267] R 4 The C1-C2 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano, -OH and 5 to 6-membered heterocyclyl;

[0268] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0269] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 4 is selected from the group consisting of -CH3, -CH2OH, and (tetrahydro-2H-pyran-4-yl)methyl; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0270] In certain embodiments, the compounds of the present disclosure are represented by one of the following structural formulas:

[0271]

[0272] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0273] Ring A is selected at each occurrence from C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl; each of which is optionally substituted by 1, 2, 3, 4, or 5 Ra group substitution;

[0274] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0275] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, Ring A is selected from cyclopropyl, 5- to 10-membered heterocyclyl, phenyl, and 5- to 9-membered heteroaryl; each of which is optionally substituted by 1, 2, 3, 4, or 5 R a and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0276] In certain embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of the present disclosure, Ring A is selected from cyclopropyl, 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, phenyl and 5- to 9-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O; each of which is optionally substituted by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0277] 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 to 3 heteroatoms selected from N and O, a 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a 9-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a phenyl, a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, a 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, and a 9-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O; each of which is optionally substituted by 1, 2, 3, 4, or 5 R a and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0278] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, Ring A is selected from

[0279] Each of which is optionally replaced by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0280] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, Ring A is selected from Each of which is optionally replaced by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0281] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 4 Selected from -CH3 and Ring A; wherein Ring A is selected from Each of which is optionally replaced by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0282] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 5 Selected from C1-C4 alkyl, -C(=O)-O(C1-C2 alkyl), C3-C6 cycloalkyl and 5- to 10-membered cycloalkyl, wherein:

[0283] R 5 The C1-C4 alkyl group is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH and C1-C2 alkoxy; and

[0284] R 5 The C3-C6 cycloalkyl and 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;

[0285] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0286] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 5 is selected from C1-C2 alkyl, C(=O)O(C1-C2 alkyl), cyclopropyl, cyclobutyl and 5- to 6-membered heterocyclyl; wherein:

[0287] R 5 The C1-C2 alkyl group is optionally substituted by 1 to 3 groups independently selected from F, Cl, Br, cyano, -OH and C1-C2 alkoxy; and

[0288] R 5The cyclopropyl, the cyclobutyl and the 5- to 6-membered heterocyclic group are each optionally substituted with 1 to 3 groups independently selected from F, Cl, Br, cyano, -OH, C1-C2 alkyl and C1-C2 alkoxy;

[0289] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0290] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 5 is selected from -CH3, -CH2CH3, -CH2OH, -C(=O)OCH3, -CH2OCH3, -CH(CH3)2, cyclopropyl, difluorocyclopropyl, and tetrahydro-2H-pyranyl; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0291] In certain embodiments, the compounds of the present disclosure are represented by one of the following structural formulas:

[0292]

[0293] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0294] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 1 is selected from hydrogen, halogen, cyano, -OH, C1-C4 alkyl, C1-C4 alkoxy and C3-C6 cycloalkyl; wherein:

[0295] R 1 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano, -OH and C1-C2 alkoxy;

[0296] R 1 The C1-C4 alkoxy group is optionally substituted with 1 to 3 independently selected halogen groups; and

[0297] R 1 The C3-C6 cycloalkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano, -OH and C1-C2 alkoxy;

[0298] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0299] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R1 is selected from F, Cl, Br, C1-C4 alkyl and C3-C6 cycloalkyl; wherein:

[0300] R 1 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH; and

[0301] R 1 The C3-C6 cycloalkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH;

[0302] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0303] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 1 is selected from F, Cl, Br, C1-C4 alkyl and C3-C6 cycloalkyl; wherein:

[0304] R 1 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH; and

[0305] R 1 The C3-C6 cycloalkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH;

[0306] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0307] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 1 is selected from Cl, Br, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH2CHF2, -CH2CH(CH3)2, difluorocyclobutyl, and cyclohexyl; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0308] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 1 is Cl; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0309] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 3a is selected from halogen, -OH and C1-C4 alkyl; wherein:

[0310] R3a The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH;

[0311] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0312] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 3a is selected from F, Cl, Br, -OH and C1-C2 alkyl; wherein:

[0313] R 3a The C1-C2 alkyl group is optionally substituted by 1 to 3 groups independently selected from F, Cl and -OH;

[0314] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0315] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R 3a is selected from the group consisting of F, -OH, -CH3, -CHF2, and -CH2OH; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0316] In certain embodiments, the compounds of the present disclosure are represented by one of the following structural formulas:

[0317]

[0318] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0319] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R a Each occurrence is independently selected from 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)2NRh R i , C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl; wherein:

[0320] R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the following groups: 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 C3-C6 cycloalkyl;

[0321] R a The C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, phenyl and 5- to 8-membered heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C2 alkyl and -OR k wherein:

[0322] R h 、R i and R j is independently selected at each occurrence from hydrogen, C1-C2 alkyl, cyclopropyl and cyclobutyl; wherein:

[0323] R h 、R i and R j The C1-C2 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen and -OH;

[0324] R k is independently selected at each occurrence from hydrogen and C1-C4 alkyl; wherein:

[0325] R k The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH; and

[0326] q and r are each an integer selected from 1, 2, and 3;

[0327] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0328] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R a is independently selected at each occurrence from 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:

[0329] R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from cyano, -C(=O)NR h R I 、-NR h R i 、-OR k , cyclopropyl and cyclobutyl group substitution;

[0330] R a The cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl groups are each optionally substituted with 1 to 3 groups independently selected from halogen, -CH3, -OH and -OCH3; wherein:

[0331] R h and R i is independently selected at each occurrence from hydrogen, -CH3, cyclopropyl, and cyclobutyl; wherein:

[0332] R h and R i The -CH3 of any one of is optionally substituted with 1 to 3 groups independently selected from F, Cl and -OH;

[0333] R k is independently selected at each occurrence from hydrogen and -CH3; wherein:

[0334] R kThe -CH3 is optionally substituted by 1 to 3 groups independently selected from halogen and -OH;

[0335] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0336] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R a independently selected at each occurrence from F, Cl, Br, cyano, C1-C6 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -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 heterocyclic group, phenyl and 6-membered heteroaryl; wherein:

[0337] R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from cyano, -C(=O)NR h R I 、-OR k and cyclopropyl group substitution;

[0338] R a The cyclopropyl, the cyclobutyl, the 5- to 6-membered heterocyclyl, the phenyl and the 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, -CH3, -OH and -OCH3; wherein:

[0339] R h and R i is independently selected at each occurrence from hydrogen, -CH3 and cyclopropyl; wherein:

[0340] R h and R i The -CH3 of any one of is optionally substituted with 1 to 3 groups independently selected from F, Cl and -OH;

[0341] R k is independently selected at each occurrence from hydrogen and -CH3; and

[0342] q and r are each an integer selected from 1 and 2;

[0343] And all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0344] In certain embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, R a is independently selected at each occurrence from 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)2CH2OH, -NHC(=O)CH3, -SO2CH3, -SO2NH2, cyclopropyl, 2-methoxyphenyl, N-methylpiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl, and tetrahydrothiophene 1,1-dioxide; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0345] In certain embodiments, the compounds of the present disclosure are represented by one of the following structural formulas:

[0346]

[0347]

[0348] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0349] In certain embodiments, the compounds of the present disclosure are represented by one of the following structural formulas:

[0350]

[0351]

[0352] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0353] In certain embodiments, the compounds of the present disclosure are represented by one of the following structural formulas:

[0354]

[0355]

[0356] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0357] In certain embodiments, at least one compound of the present invention is selected from compounds 1 to 220 shown in Table 1, tautomers thereof, deuterated derivatives of said compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. The wavy lines (i.e., ) depicts a bond between two atoms and indicates the position of the stereochemistry of a molecular assembly such as a racemic mixture, cis / trans isomers, or a mixture of (E) / (Z) isomers. In the compounds of Table 1, an asterisk adjacent to an atom (e.g., ) represents the chiral position in the molecule.

[0358] In certain embodiments, at least one compound of the present invention is selected from compounds 221 to 391 depicted in Table II, tautomers thereof, deuterated derivatives of said compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. The wavy lines (i.e., ) depicts a bond between two atoms and indicates the position of the stereochemistry of a molecular assembly such as a racemic mixture, cis / trans isomers, or a mixture of (E) / (Z) isomers. In the compounds of Table II, an asterisk adjacent to an atom (e.g., ) represents the chiral position in the molecule.

[0359] In certain embodiments, at least one compound of the present invention is selected from compounds 1 to 391 depicted in Tables I or II, tautomers thereof, deuterated derivatives of said compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing.

[0360] In certain embodiments, at least one compound of the present invention is selected from the compounds depicted in Table III, tautomers thereof, deuterated derivatives of said compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. The wavy lines (i.e., ) depicts a bond between two atoms and indicates the position of the stereochemistry of a molecular assembly such as a racemic mixture, cis / trans isomers, or a mixture of (E) / (Z) isomers. In the compounds of Table III, an asterisk adjacent to an atom (e.g., ) represents the chiral position in the molecule.

[0361] Table I. Compounds 1 to 220

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374] Table II. Compounds 221 to 391

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386] Table III. Deduced Stereochemistry of Certain Compounds in Tables I and II

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400] *Using racemic starting material, the stereochemistry depicted is relative, a mixture of 2 enantiomers

[0401] 1 3:2 mixture

[0402] 2 4.5:1 mixture

[0403] 3 2:1 mixture

[0404] 4 3:1 mixture

[0405] 5 5:1 mixture

[0406] 6 3.5:1 mixture

[0407] 7 2:1 mixture

[0408] Some embodiments of the present disclosure include compounds 1 to 391 (e.g., compounds 1 to 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″′, I0, IIa, IIb, IIIa′, IIIb′, IVa′, IVb′, I0, IIb′, IIb′, IIIa′, IIIb′, IVa′, IVb′, I0, IIb′, IIb′, IIIb′, IVa′, IVb′ 0, Va0, Vb0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0 and Vb'0 (e.g., a compound 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 the foregoing. In some embodiments, the derivative is a silicon derivative, wherein at least one carbon atom in a compound selected from compounds 1 to 391 (e.g., for example, selected from compounds 1 to 220) or 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′, , 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 (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), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing.In some embodiments, the derivative is a boron derivative, wherein at least one carbon atom in a compound selected from compounds 1 to 391 (e.g., for example, selected from compounds 1 to 220) or 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', , 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 (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), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In other embodiments, the derivative is a phosphorus derivative, wherein at least one carbon atom in a compound selected from Compounds 1 to 391 (e.g., Compounds 1 to 220) or 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, A compound 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 (e.g., a compound 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 the foregoing.

[0409] In some embodiments, the derivative is a silicon derivative, wherein at least one carbon atom in a compound selected from Compounds 1 to 391 (e.g., Compounds 1 to 220) or Formulas 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, Va'0, and Vb'0 compounds (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), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. The carbon replaced by silicon can 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 include one or more hydrogen atoms replaced with deuterium.In some embodiments, a silicon derivative of a compound selected from Compounds 1 to 391 (e.g., for example, Compounds 1 to 220) or Formulas 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′, IIa″, IIb″, IIIa″′, IIIb″, IVa″, IVb″, IIa″′, IIb″′, IIIa″′, IIIb″, IVa′, IVb′, I0, IIa, IIb, IIIa′, IIIb′ , IIIb0, IVa0, IVb0, 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), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing.

[0410] In some embodiments, the derivative is a boron derivative, wherein one carbon atom in a compound selected from Compounds 1 to 391 (e.g., Compounds 1 to 220) or 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', IIb', IIIa'', IIIb', IVa', IVb', I0, IIa, IIb', IIb', IIIa'', IIIb', IVa', IVb', I0, IIa, IIb', IIb', IIIa'', IIIb', IVa', IVb', I0, IIa, IIb', IIb' 0, 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 (e.g., a compound 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 the foregoing.

[0411] In some embodiments, the derivative is a phosphorus derivative, wherein one carbon atom in a compound selected from Compounds 1 to 391 (e.g., Compounds 1 to 220) or 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', I0, IIb', I0 0, 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 (e.g., a compound 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 the foregoing.

[0412] Another aspect of the present disclosure provides pharmaceutical compositions comprising at least one compound selected from the group consisting 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, I′0, A compound of any of the formulae IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0 (e.g., a compound of formula I0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, Vb'0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, and Vb'0) and compounds 1 to 391 (e.g., compounds 1 to 220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the pharmaceutical composition comprises at least one compound selected from the group consisting 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 0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0 and Vb'0 (e.g., compounds of Formula I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0, Vb'0, I'0, IIa'0, IIb'0, IIIa'0, IIIb'0, IVa'0, IVb'0, Va'0 and Vb'0) and compounds 1 to 391 (e.g., from compounds 1 to 220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing.

[0413] 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, a disintegrant, a surfactant, a binder, and a lubricant.

[0414] It will also be understood that the pharmaceutical compositions of the present disclosure can be employed in combination therapy; that is, the pharmaceutical compositions described herein can further comprise at least one additional active therapeutic agent. Alternatively, the pharmaceutical compositions comprising at least one compound selected from the group consisting 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, IIIb0, can be administered as separate compositions simultaneously with, prior to, or after administration of a composition comprising at least one other active therapeutic agent. 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, a compound 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 the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound selected from compounds 1 to 391 (e.g., selected from compounds 1 to 220), a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing can be administered as a separate composition simultaneously with, before, or after a composition comprising at least one other active therapeutic agent.

[0415] As mentioned above, the pharmaceutical composition disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. At least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersing aids, suspending aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders and lubricants suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J.Swarbrick and J.C. Boylan, 1988 to 1999, Marcel Dekker, New York discloses various carriers for the preparation of pharmaceutical compositions and known techniques for preparing them. Unless any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, its use is contemplated to be within the scope of the present disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., Such as, for example, sodium carboxymethylcellulose, ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (such as, for example, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer solution, nontoxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweeteners, flavoring agents, aromas, preservatives and antioxidants.

[0416] 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.

[0417] In some embodiments, the methods of the present disclosure comprise administering to a patient in need thereof at least one entity selected from the group consisting 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′, Va′, Vb′, IIa″, IIb′, IIIa′, IIIb′, IVa′, IVb′ In some embodiments, the compound of Formula I is selected from compounds 1 to 391 (e.g., selected from compounds 1 to 220), tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any one of the foregoing. In some embodiments, the patient in need thereof has the APOL1 genetic variants G1:S342G:I384M and G2:N388del:Y389del.

[0418] Another aspect of the present disclosure provides a method of inhibiting APOL1 activity, comprising contacting the APOL1 with at least one entity selected from the group consisting 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′, I0, IIa′, IIb′, IIIa′, IIIb′, IVa′, IVb′ In some embodiments, the method of inhibiting APOL1 activity comprises contacting APOL1 with at least one entity selected from compounds 1 to 391 (e.g., selected from compounds 1 to 220), tautomers thereof, deuterated derivatives of said compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing.

[0419] Non-limiting exemplary embodiment 1

[0420] Without limitation, some embodiments of the present disclosure include:

[0421] 1. A compound represented by the following structural formula:

[0422]

[0423] Formula I

[0424] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0425] X 1 Selected from S and -CR 2a And X 2 Selected from S and -CR 2b ,in:

[0426] X 1 and X 2 One is S;

[0427] When X 1 When it is S, then X 2 -CR 2b ;and

[0428] When X 2 When it is S, then X 1 Yes-CR 2a ;

[0429] R 1 is selected from hydrogen, halogen, cyano, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and phenyl, wherein:

[0430] R 1 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, and C1-C4 alkoxy;

[0431] R 1 The C1-C6 alkoxy group is optionally substituted by 1 to 3 groups independently selected from halogen;

[0432] R 1 The C3-C6 cycloalkyl is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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; and

[0433] R 1 The phenyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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;

[0434] R 2a is selected from hydrogen, halogen, cyano, -OH, =O and C1-C6 alkyl, wherein:

[0435] R 2a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano, -OH and C1-C4 alkoxy;

[0436] R 2b is selected from hydrogen, halogen, cyano, -OH, =O and C1-C6 alkyl;

[0437] R 3a is selected from halogen, cyano, -OH, C1-C6 alkyl and =O; wherein:

[0438] R 3a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0439] R 3b Selected from C1-C2 alkyl and =O; wherein:

[0440] R 3b The C1-C2 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0441] When R 3a When selected from halogen, cyano, OH, C1-C6 alkyl or when R 3b When selected from C1-C2 alkyl, A single bond at each occurrence; or when R 3a =O or when R 3b =0, Each occurrence is a double bond;

[0442] R 4 selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C2-C6 alkynyl and in:

[0443] R 4 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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- to 10-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl;

[0444] Ring A is selected from C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 aryl and 5- to 10-membered heteroaryl, wherein ring A is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution; wherein:

[0445] R a is independently selected at each occurrence from 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 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl; wherein:

[0446] R a The C1-C6 alkyl, the C1-C6 alkoxy and the C2-C6 alkenyl are each optionally substituted by 1 to 3 groups independently selected from the following groups: C6 to C 10 Aryl (optionally substituted with 1 to 3 R m Group substituted:), 5 to 10 membered heterocyclic group (optionally substituted with 1 to 3 R m substituted with a group), a 5- to 10-membered heteroaryl group (optionally substituted with 1 to 3 R m Group substitution), 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 hS(=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 carbocyclic group (optionally substituted by 1 to 3 R m group substitution);

[0447] R a The C3-C 12 Carbocyclic group, said 3 to 12 membered heterocyclic group, said C6 and C 10 Aryl and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, cyano, C1-C4 alkyl, -NR h R i AND-OR k ;in:

[0448] R h 、R i and R j Each occurrence is independently selected from hydrogen, C1-C4 alkyl, C6C 10 Aryl and C3-C6 cycloalkyl; wherein:

[0449] R h 、R i and R j The C1-C4 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen, cyano and -OH;

[0450] R k is independently selected at each occurrence from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl; wherein:

[0451] R k The C1-C4 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen, cyano and -OH;

[0452] R m is independently selected at each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S(=O) p R k AND-OR k ;in:

[0453] R m The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0454] R 5 Selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl; wherein:

[0455] R 5 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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;

[0456] R 5 The C3-C 12 Carbocyclic group, said 3 to 12 membered heterocyclic group, said C6 and C 10 Aryl and the 5- to 10-membered heteroaryl are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl) (optionally substituted with -OH), -N(C1-C4 alkyl)2, C1-C5 alkyl (optionally substituted with -OH), C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -NHC(=O)(C1-C4 alkyl), -C(=O)(C1-C4 alkoxy) and -C(=O)N(C1-C4 alkyl)2;

[0457] k is an integer selected from 0, 1 and 2; wherein

[0458] When R 3a When selected from halogen, cyano, -OH and C1-C6 alkyl, k is 1 or 2; and

[0459] When R 3a When =O, k is 1;

[0460] m is an integer selected from 0, 1 and 2, wherein:

[0461] When R 3b When selected from C1-C2 alkyl, m is 1 or 2; and

[0462] When R 3b When =O, m is 1;

[0463] p is an integer selected from 1 and 2; and

[0464] q and r are each an integer selected from 1, 2, 3 and 4.

[0465] 2. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to embodiment 1, wherein the compound is represented by one of the following structural formulas:

[0466]

[0467] or a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0468] R 2a is selected from hydrogen, halogen, cyano and C1-C4 alkyl; wherein:

[0469] R 2a The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, -OH and C1-C2 alkoxy;

[0470] R 2b is selected from hydrogen, halogen, cyano and C1-C4 alkyl; and

[0471] k is an integer selected from 0, 1 and 2;

[0472] And all other variables not specifically defined herein are as defined in Embodiment 1.

[0473] 3. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to embodiment 1 or embodiment 2, wherein R 4 Selected from C1-C4 alkyl and in:

[0474] R 4 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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;

[0475] And all other variables not specifically defined herein are as defined in Embodiment 1 or Embodiment 2.

[0476] 4. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 3, wherein R 4 Selected from C1-C2 alkyl and in:

[0477] R4 The C1-C2 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano, -OH and 5- to 6-membered heterocyclyl;

[0478] And all other variables not specifically defined herein are as defined in any of Embodiments 1 to 3.

[0479] 5. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 4, wherein R 4 is selected from -CH3, -CH2OH, and (tetrahydro-2H-pyran-4-yl)methyl; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 4.

[0480] 6. The compound according to any one of embodiments 1 to 4, wherein the compound is represented by one of the following structural formulas:

[0481]

[0482] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0483] Ring A is selected at each occurrence from C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl; each of which is optionally substituted by 1, 2, 3, 4, or 5 R a group substitution;

[0484] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5.

[0485] 7. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 4 and 6, wherein ring A is selected from cyclopropyl, 5 to 10 membered heterocyclyl, phenyl and 5 to 9 membered heteroaryl; each of which is optionally substituted by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 6.

[0486] 8. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 4, 6 and 7, wherein ring A is selected from cyclopropyl, 5 to 10 membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, phenyl and 5 to 9 membered heteroaryl containing 1 to 3 heteroatoms selected from N and O; each of which is optionally substituted by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 7.

[0487] 9. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 4 and 6 to 8, wherein Ring A is selected from cyclopropyl, a 5-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a 9-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, phenyl, a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, a 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, and a 9-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O; each of which is optionally substituted by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 8.

[0488] 10. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 4 and 6 to 9, wherein ring A is selected from Each of which is optionally replaced by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 9.

[0489] 11. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 4 and 6 to 10, wherein ring A is selected from Each of which is optionally replaced by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 4 and 6 to 10.

[0490] 12. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 4 and 6 to 11, wherein R 4 Selected from -CH3 and Ring A; wherein Ring A is selected from Each of which is optionally replaced by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 4 and 6 to 11.

[0491] 13. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 12, wherein R 5Selected from C1-C4 alkyl, C(=O)O(C1-C2 alkyl), C3-C6 cycloalkyl and 5- to 10-membered cycloalkyl; wherein:

[0492] R 5 The C1-C4 alkyl group is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH and C1-C2 alkoxy; and

[0493] R 5 The C3-C6 cycloalkyl and 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;

[0494] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 12.

[0495] 14. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 13, wherein R 5 is selected from C1-C2 alkyl, C(=O)O(C1-C2 alkyl), cyclopropyl, cyclobutyl and 5- to 6-membered heterocyclyl; wherein:

[0496] R 5 The C1-C2 alkyl group is optionally substituted by 1 to 3 groups independently selected from F, Cl, Br, cyano, -OH and C1-C2 alkoxy; and

[0497] R 5 The cyclopropyl, the cyclobutyl and the 5- to 6-membered heterocyclic group are each optionally substituted by 1 to 3 groups independently selected from F, Cl, Br, cyano, -OH, C1-C2 alkyl and C1-C2 alkoxy;

[0498] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 13.

[0499] 15. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 14, wherein R 5 is selected from -CH3, -CH2CH3, -CH2OH, -C(=O)OCH3, -CH2OCH3, -CH(CH3)2, cyclopropyl, difluorocyclopropyl and tetrahydro-2H-pyranyl; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 14.

[0500] 16. The compound according to any one of embodiments 1 to 4 and 6 to 15, wherein the compound is represented by one of the following structural formulas:

[0501]

[0502] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 4 and 6 to 15.

[0503] 17. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 16, wherein R 1 is selected from hydrogen, halogen, cyano, -OH, C1-C4 alkyl, C1-C4 alkoxy and C3-C6 cycloalkyl; wherein:

[0504] R 1 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano, -OH and C1-C2 alkoxy;

[0505] R 1 The C1-C4 alkoxy group is optionally substituted with 1 to 3 independently selected halogen groups; and

[0506] R 1 The C3-C6 cycloalkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano, -OH and C1-C2 alkoxy;

[0507] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 16.

[0508] 18. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 17, wherein R 1 is selected from F, Cl, Br, C1-C4 alkyl and C3-C6 cycloalkyl; wherein:

[0509] R 1 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH; and

[0510] R 1 The C3-C6 cycloalkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH;

[0511] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 17.

[0512] 19. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 18, wherein R 1 is selected from F, Cl, Br, C1-C4 alkyl and C3-C6 cycloalkyl; wherein:

[0513] R 1 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH;

[0514] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 18.

[0515] 20. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 18, wherein R 1 Selected from Cl, Br, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH2CHF2, -CH2CH(CH3)2, difluorocyclobutyl and cyclohexyl.

[0516] 21. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 20, wherein R 1 is Cl; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 20.

[0517] 22. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 21, wherein R 3a is selected from halogen, -OH and C1-C4 alkyl; wherein:

[0518] R 3a The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH;

[0519] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 21.

[0520] 23. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 22, wherein R 3a is selected from F, Cl, Br, -OH and C1-C2 alkyl; wherein:

[0521] R 3a The C1-C2 alkyl group is optionally substituted by 1 to 3 groups independently selected from F, Cl and -OH;

[0522] And all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 22.

[0523] 24. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 23, wherein R 3ais selected from F, -OH, -CH3, -CHF2, and CH2OH; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 23.

[0524] 25. The compound of any one of embodiments 1 to 4 and 6 to 24, wherein the compound is represented by one of the following structural formulas:

[0525]

[0526] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 4 and 6 to 24.

[0527] 26. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 4 and 6 to 25, wherein R a independently selected at each occurrence from 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- to 10-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl; wherein:

[0528] R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the following groups: 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 、-ORk 、-S(=O)2R k 、-S(=O) p NR h R i and C3-C6 cycloalkyl;

[0529] R a The C3-C6 cycloalkyl, the 5- to 10-membered heterocyclyl, the phenyl and the 5- to 8-membered heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C2 alkyl and -OR k wherein:

[0530] R h 、R i and R j is independently selected at each occurrence from hydrogen, C1-C2 alkyl, cyclopropyl and cyclobutyl; wherein:

[0531] R h 、R i and R j The C1-C2 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen and -OH;

[0532] R k is independently selected at each occurrence from hydrogen and C1-C4 alkyl; wherein:

[0533] R k The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH; and

[0534] q and r are each an integer selected from 1, 2, and 3;

[0535] And all other variables not specifically defined herein are as defined in any of Embodiments 1 to 4 and 6 to 25.

[0536] 27. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 4 and 6 to 26, wherein R a is independently selected at each occurrence from 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:

[0537] R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from cyano, -C(=O)NR h R I 、-NR h R i 、-OR k , cyclopropyl and cyclobutyl group substitution;

[0538] R a The cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl groups are each optionally substituted with 1 to 3 groups independently selected from halogen, -CH3, -OH and -OCH3; wherein:

[0539] R h and R i is independently selected at each occurrence from hydrogen, -CH3, cyclopropyl, and cyclobutyl; wherein:

[0540] R h and R i The -CH3 of any one of is optionally substituted with 1 to 3 groups independently selected from F, Cl and -OH;

[0541] R k is independently selected at each occurrence from hydrogen and -CH3; wherein:

[0542] R k The -CH3 is optionally substituted by 1 to 3 groups independently selected from halogen and -OH;

[0543] And all other variables not specifically defined herein are as defined in any of Embodiments 1 to 4 and 6 to 26.

[0544] 28. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 4 and 6 to 27, wherein R a independently selected at each occurrence from F, Cl, Br, cyano, C1-C6 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -C(=O)NR h R i 、-NR h R i 、-NR h C(=O)R k 、-ORk 、-[O(CH2) q ] r O(C1-C2 alkyl), -S(=O)2R k 、-S(=O)2NR h R i , cyclopropyl, cyclobutyl, 5-membered heterocyclic group, phenyl and 6-membered heteroaryl; wherein:

[0545] R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from cyano, -C(=O)NR h R I 、-OR k and cyclopropyl group substitution;

[0546] R a The cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl groups are each optionally substituted with 1 to 3 groups independently selected from halogen, -CH3, -OH and -OCH3; wherein:

[0547] R h and R i is independently selected at each occurrence from hydrogen, -CH3 and cyclopropyl; wherein:

[0548] R h and R i The -CH3 of any one of is optionally substituted with 1 to 3 groups independently selected from F, Cl and -OH;

[0549] R k is independently selected at each occurrence from hydrogen and -CH3; and

[0550] q and r are each an integer selected from 1 and 2;

[0551] And all other variables not specifically defined herein are as defined in any of Embodiments 1 to 4 and 6 to 27.

[0552] 29. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 4 and 6 to 28, wherein R ais independently selected at each occurrence from 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,

[0553] -NHC(CH3)2CH2OH, -NHC(=O)CH3, -SO2CH3, -SO2NH2, cyclopropyl, 2-methoxyphenyl, N-methylpiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl and tetrahydrothiophene 1,1-dioxide; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 4 and 6 to 28.

[0554] 30. The compound according to embodiment 1, wherein the compound is represented by one of the following structural formulas:

[0555]

[0556]

[0557] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0558] 31. A compound selected from the group consisting of compounds of Table I, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0559] 32. A compound selected from the group consisting of compounds of Table II, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0560] 33. A compound selected from the group consisting of compounds of Table III, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0561] 34. A pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 33 and a pharmaceutically acceptable carrier.

[0562] 35. A method for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy, 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.

[0563] 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 preparation of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0564] 37. 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 use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0565] 38. A method of inhibiting APOL1 activity, the method comprising contacting the APOL1 with 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.

[0566] 39. 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 preparation of a medicament for inhibiting APOL1 activity.

[0567] 40. 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 use in inhibiting APOL1 activity.

[0568] 41. A method of 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.

[0569] 42. The method of embodiment 41, wherein the APOL1-mediated disease is cancer.

[0570] 43. The method of embodiment 41 or embodiment 42, wherein the APOL1-mediated disease is pancreatic cancer.

[0571] 44. Use of at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 33, or a pharmaceutical composition according to Embodiment 34, in the preparation of a medicament for treating an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease).

[0572] 45. The use according to embodiment 44, wherein the APOL1-mediated disease is cancer.

[0573] 46. ​​The use according to embodiment 44 or embodiment 45, wherein the APOL1-mediated disease is pancreatic cancer.

[0574] 47. At least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of Embodiments 1 to 33, or the pharmaceutical composition of Embodiment 34, for use in treating an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease).

[0575] 48. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt for use, or pharmaceutical composition for use, of Embodiment 47, wherein the APOL1 -mediated disease is cancer.

[0576] 49. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt for use, or pharmaceutical composition for use, of Embodiment 47 or Embodiment 48, wherein the APOL1 -mediated disease is pancreatic cancer.

[0577] 50. A method of inhibiting APOL1 activity, the method comprising contacting the APOL1 with 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.

[0578] 51. 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 preparation of a medicament for inhibiting APOL1 activity.

[0579] 52. 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 use in inhibiting APOL1 activity.

[0580] 53. A silicon derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33.

[0581] 54. A pharmaceutical composition comprising the silicon derivative according to embodiment 53.

[0582] 55. A method for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy, comprising administering the silicon derivative according to embodiment 53 or the pharmaceutical composition according to embodiment 54 to a patient in need thereof.

[0583] 56. Use of the silicon derivative according to embodiment 53 or the pharmaceutical composition according to embodiment 54 for the preparation of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0584] 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 nephropathy.

[0585] 58. A method of treating an APOL1-mediated disease (eg, an APOL1-mediated kidney disease), comprising administering the silicon derivative according to embodiment 53 or the pharmaceutical composition according to embodiment 54 to a patient in need thereof.

[0586] 59. The method of embodiment 58, wherein the APOL1-mediated disease is cancer.

[0587] 60. The method of embodiment 58 or embodiment 59, wherein the APOL1 -mediated disease is pancreatic cancer.

[0588] 61. Use of the silicon derivative according to embodiment 53 or the pharmaceutical composition according to embodiment 54 for the preparation of a medicament for treating an APOL1-mediated disease (eg, an APOL1-mediated kidney disease).

[0589] 62. The use according to embodiment 61, wherein the APOL1-mediated disease is cancer.

[0590] 63. The use according to embodiment 61 or embodiment 62, wherein the APOL1-mediated disease is pancreatic cancer.

[0591] 64. The silicon derivative according to embodiment 53 or the pharmaceutical composition according to embodiment 54, for use in treating an APOL1-mediated disease (eg, an APOL1-mediated kidney disease).

[0592] 65. The silicon derivative or pharmaceutical composition for use according to embodiment 64, wherein the APOL1 mediated disease is cancer.

[0593] 66. The silicon derivative or pharmaceutical composition for use according to embodiment 64 or embodiment 65, wherein the APOL1 mediated disease is pancreatic cancer.

[0594] 67. A boron derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33.

[0595] 68. A pharmaceutical composition comprising the boron derivative according to embodiment 67.

[0596] 69. A method for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy, comprising administering the boron derivative according to embodiment 67 or the pharmaceutical composition according to embodiment 68 to a patient in need thereof.

[0597] 70. Use of the boron derivative according to embodiment 67 or the pharmaceutical composition according to embodiment 68 for the preparation of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0598] 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 nephropathy.

[0599] 72. A method of treating an APOL1-mediated disease (eg, an APOL1-mediated kidney disease), comprising administering the boron derivative according to embodiment 67 or the pharmaceutical composition according to embodiment 68 to a patient in need thereof.

[0600] 73. The method of embodiment 72, wherein the APOL1-mediated disease is cancer.

[0601] 74. The method of embodiment 72 or embodiment 73, wherein the APOL1-mediated disease is pancreatic cancer.

[0602] 75. Use of the boron derivative according to embodiment 67 or the pharmaceutical composition according to embodiment 68 for the preparation of a medicament for treating an APOL1-mediated disease (eg, an APOL1-mediated kidney disease).

[0603] 76. The use according to embodiment 75, wherein the APOL1-mediated disease is cancer.

[0604] 77. The use according to embodiment 75 or embodiment 76, wherein the APOL1-mediated disease is pancreatic cancer.

[0605] 78. The boron derivative according to embodiment 67 or the pharmaceutical composition according to embodiment 68, for use in treating an APOL1-mediated disease (eg, an APOL1-mediated kidney disease).

[0606] 79. The boron derivative or pharmaceutical composition for use according to embodiment 78, wherein the APOL1-mediated disease is cancer.

[0607] 80. The boron derivative or pharmaceutical composition for use according to embodiment 78 or embodiment 79, wherein the APOL1 -mediated disease is pancreatic cancer.

[0608] 81. A phosphorus derivative of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33.

[0609] 82. A pharmaceutical composition comprising the phosphorus derivative according to embodiment 81.

[0610] 83. A method for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy, comprising administering the phosphorus derivative according to embodiment 81 or the pharmaceutical composition according to embodiment 82 to a patient in need thereof.

[0611] 84. Use of the phosphorus derivative according to embodiment 81 or the pharmaceutical composition according to embodiment 82 for the preparation of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0612] 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 nephropathy.

[0613] 86. A method of treating an APOL1-mediated disease (eg, an APOL1-mediated kidney disease), comprising administering the phosphorus derivative according to embodiment 81 or the pharmaceutical composition according to embodiment 82 to a patient in need thereof.

[0614] 87. The method of embodiment 86, wherein the APOL1-mediated disease is cancer.

[0615] 88. The method of embodiment 86 or embodiment 87, wherein the APOL1-mediated disease is pancreatic cancer.

[0616] 89. Use of the phosphorus derivative according to embodiment 81 or the pharmaceutical composition according to embodiment 82 for the preparation of a medicament for treating an APOL1-mediated disease (eg, an APOL1-mediated kidney disease).

[0617] 90. The use according to embodiment 89, wherein the APOL1-mediated disease is cancer.

[0618] 91. The use according to embodiment 89 or embodiment 90, wherein the APOL1-mediated disease is pancreatic cancer.

[0619] 92. The phosphorus derivative according to embodiment 81 or the pharmaceutical composition according to embodiment 82, for use in treating an APOL1-mediated disease (eg, an APOL1-mediated kidney disease).

[0620] 93. The phosphorus derivative or pharmaceutical composition for use according to embodiment 92, wherein the APOL1 -mediated disease is cancer.

[0621] 94. The phosphorus derivative or pharmaceutical composition according to embodiment 92 or embodiment 93, wherein the APOL1-mediated disease is pancreatic cancer.

[0622] 95. A method of treating a patient; an entity (e.g., a compound, a tautomer, a deuterated derivative, a pharmaceutically acceptable salt, a silicon derivative, a boron derivative, a phosphorus derivative) or a pharmaceutical composition for treating a patient; or use of an entity or a pharmaceutical composition for treating a patient according to any embodiment herein, wherein the patient has two APOL1 risk alleles.

[0623] 96. A method of treating a patient; an entity (e.g., a compound, a tautomer, a deuterated derivative, a pharmaceutically acceptable salt, a silicon derivative, a boron derivative, a phosphorus derivative) or a pharmaceutical composition for treating a patient; or use of an entity or a pharmaceutical composition for treating a patient according to any embodiment herein, wherein the patient has one APOL1 risk allele.

[0624] 97. The compound of embodiment 1, wherein the compound is represented by one of the following structural formulas:

[0625]

[0626] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0627] 98. The compound of embodiment 1, wherein the compound is represented by one of the following structural formulas:

[0628]

[0629]

[0630] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; and all other variables not specifically defined herein are as defined in any of the preceding embodiments.

[0631] 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.

[0632] 100. A method of treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy, 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.

[0633] 101. Use of at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of Embodiment 97 or Embodiment 98, or a pharmaceutical composition of Embodiment 99, for the preparation of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0634] 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 treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0635] 103. A method of inhibiting APOL1 activity comprising contacting the 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.

[0636] 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 preparation of a medicament for inhibiting APOL1 activity.

[0637] 105. At least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to Embodiment 97 or Embodiment 98, or the pharmaceutical composition according to Embodiment 99, for use in inhibiting APOL1 activity.

[0638] 106. A method of treating an APOL1-mediated disease (e.g., an APOL1-mediated 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.

[0639] 107. The method of embodiment 106, wherein the APOL1-mediated disease is cancer.

[0640] 108. The method of embodiment 106 or embodiment 107, wherein the APOL1-mediated disease is pancreatic cancer.

[0641] 109. Use of at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of Embodiment 97 or Embodiment 98, or a pharmaceutical composition of Embodiment 99, in the preparation of a medicament for treating an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease).

[0642] 110. The use according to embodiment 109, wherein the APOL1-mediated disease is cancer.

[0643] 111. The use according to embodiment 109 or embodiment 110, wherein the APOL1-mediated disease is pancreatic cancer.

[0644] 112. At least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of Embodiment 97 or Embodiment 98, or the pharmaceutical composition of Embodiment 99, for use in treating an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease).

[0645] 113. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt for use, or pharmaceutical composition for use, of Embodiment 112, wherein the APOL1 -mediated disease is cancer.

[0646] 114. At least one compound for use, tautomer, deuterated derivative, or pharmaceutically acceptable salt, or pharmaceutical composition for use, of Embodiment 112 or Embodiment 113, wherein the APOL1 -mediated disease is pancreatic cancer.

[0647] 115. A method of inhibiting APOL1 activity comprising contacting the 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.

[0648] 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 preparation of a medicament for inhibiting APOL1 activity.

[0649] 117. At least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to Embodiment 97 or Embodiment 98, or the pharmaceutical composition according to Embodiment 99, for use in inhibiting APOL1 activity.

[0650] Non-limiting exemplary embodiment 2

[0651] Without limitation, some embodiments / clauses of the present disclosure include:

[0652] 1. A compound represented by the following structural formula:

[0653]

[0654] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0655] X 1 and X 2 Each selected from S and -CR 2 ,in:

[0656] X 1 and X 2 One is S;

[0657] When X 1 When it is S, then X 2 -CR 2b ;and

[0658] When X 2 When it is S, then X 1 Yes-CR 2a ;

[0659] R 1 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and phenyl; wherein:

[0660] R 1 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, and C1-C4 alkoxy;

[0661] R 1The C1-C6 alkoxy group is optionally substituted by 1 to 3 groups independently selected from halogen;

[0662] R 1 The C3-C6 cycloalkyl is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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; and

[0663] R 1 The phenyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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;

[0664] R 2a is selected from hydrogen, halogen, cyano, -OH, =O and C1-C6 alkyl; wherein:

[0665] R 2a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano, -OH and C1-C4 alkoxy;

[0666] R 2b is selected from hydrogen, halogen, cyano, -OH, =O and C1-C6 alkyl;

[0667] R 3a is selected from halogen, cyano, -OH, C1-C6 alkyl and =O; wherein:

[0668] R 3a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0669] R 3b Selected from C1-C2 alkyl and =O; wherein:

[0670] R 3b The C1-C2 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH;

[0671] When R 3a When selected from halogen, cyano, -OH, C1-C6 alkyl or when R 3b When selected from C1-C2 alkyl, A single bond at each occurrence; or when R3a =O or when R 3b =0, Each occurrence is a double bond;

[0672] R 4 Selected from C1-C6 alkyl and in:

[0673] R 4 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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- to 10-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl;

[0674] Ring A is selected from C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 aryl and 5- to 10-membered heteroaryl, wherein ring A is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution; wherein:

[0675] R a is independently selected at each occurrence from 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) pNR h R i 、C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl; wherein:

[0676] R a The C1-C6 alkyl and the C2-C6 alkenyl are optionally substituted by 1 to 3 groups independently selected from the following groups: 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 cycloalkyl;

[0677] R a The C3-C 12 Carbocyclic group, said 3 to 12 membered heterocyclic group, said C6 and C 10 The aryl group and the 5- to 10-membered heteroaryl group are each optionally substituted with 1 to 3 groups selected from the group consisting of halogen, cyano, C1-C4 alkyl, -NR h R i AND-OR k ;in:

[0678] R h 、R i and R j is independently selected at each occurrence from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl; wherein:

[0679] R h 、R iand R j The C1-C4 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen, cyano and -OH;

[0680] R k is independently selected at each occurrence from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl; wherein:

[0681] R k The C1-C4 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen, cyano and -OH;

[0682] R 5 Selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl; wherein:

[0683] R 5 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups selected from the group consisting of 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;

[0684] R 5 The C3-C 12 Carbocyclic group, said 3 to 12 membered heterocyclic group, said C6 and C 10 Aryl and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups selected from the group consisting of 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;

[0685] When R 3a When selected from halogen, cyano, -OH, C1-C6 alkyl, k is an integer selected from 0, 1 and 2; or when R 3a =0, k is an integer selected from 0 and 1;

[0686] When R 3b When selected from C1-C2 alkyl, m is an integer selected from 0, 1 and 2; and when R 3b =0, m is an integer selected from 0 and 1;

[0687] p is an integer selected from 1 and 2; and

[0688] q and r are each an integer selected from 1, 2, 3 and 4.

[0689] 2. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to clause 1, wherein the compound is represented by one of the following structural formulas:

[0690]

[0691] or a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0692] R 2a is selected from hydrogen, halogen, cyano and C1-C4 alkyl; wherein:

[0693] R 2a The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, -OH and C1-C2 alkoxy;

[0694] R 2b is selected from hydrogen, halogen, cyano and C1-C4 alkyl; and

[0695] k is an integer selected from 0, 1 and 2;

[0696] And all other variables not specifically defined herein are as defined in Embodiment 1.

[0697] 3. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to clause 1 or clause 2, wherein R 4 Selected from C1-C4 alkyl and in:

[0698] R 4 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups selected from the group consisting of 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;

[0699] And all other variables not specifically defined herein are as defined in Clause 1 or Clause 2.

[0700] 4. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 3, wherein R 4 Selected from C1-C2 alkyl and in:

[0701] R 4The C1-C2 alkyl group is optionally substituted by 1 to 3 groups selected from halogen, cyano, -OH and 5 to 6-membered heterocyclic groups;

[0702] And all other variables not specifically defined herein are as defined in any of clauses 1 to 3.

[0703] 5. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 4, wherein R 4 is selected from -CH3, -CH2OH, and (tetrahydro-2H-pyran-4-yl)methyl; and all other variables not specifically defined herein are as defined in any one of clauses 1 to 4.

[0704] 6. The compound according to any one of clauses 1 to 4, wherein the compound is represented by one of the following structural formulas:

[0705]

[0706] Its tautomers, deuterated derivatives of the compound or tautomers, or pharmaceutically acceptable salts thereof, wherein:

[0707] Ring A is selected at each occurrence from C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl; each of which is optionally substituted by 1, 2, 3, 4, or 5 R a group substitution;

[0708] And all other variables not specifically defined herein are as defined in any of clauses 1 to 5.

[0709] 7. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 4 and 6, wherein ring A is selected from cyclopropyl, 5- to 10-membered heterocyclyl, phenyl and 5- to 9-membered heteroaryl; each of which is optionally substituted by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any one of clauses 1 to 6.

[0710] 8. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 4, 6 and 7, wherein ring A is selected from cyclopropyl, a 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a phenyl group and a 5- to 9-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O; each of which is optionally substituted by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any one of clauses 1 to 7.

[0711] 9. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 4 and 6 to 8, wherein Ring A is selected from cyclopropyl, a 5-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a 9-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, phenyl, a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, a 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O and a 9-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O; each of which is optionally substituted by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any one of clauses 1 to 8.

[0712] 10. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 4 and 6 to 9, wherein ring A is selected from

[0713] Each of which is optionally replaced by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any one of clauses 1 to 9.

[0714] 11. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 4 and 6 to 10, wherein ring A is selected from Each of which is optionally replaced by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any of clauses 1 to 4 and 6 to 10.

[0715] 12. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 4 and 6 to 11, wherein R 4 Selected from -CH3 and Ring A; wherein Ring A is selected from Each of which is optionally replaced by 1, 2, 3, 4 or 5 R a and all other variables not specifically defined herein are as defined in any of clauses 1 to 4 and 6 to 11.

[0716] 13. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 12, wherein R 5 Selected from C1-C4 alkyl, -C(=O)O(C1-C2 alkyl), C3-C6 cycloalkyl and 5- to 10-membered cycloalkyl; wherein:

[0717] R 5 The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH and C1-C2 alkoxy; and

[0718] R 5 The C3-C6 cycloalkyl and 5- to 10-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C2 alkyl and C1-C2 alkoxy;

[0719] And all other variables not specifically defined herein are as defined in any of clauses 1 to 12.

[0720] 14. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 13, wherein R 5 is selected from C1-C2 alkyl, C(=O)O(C1-C2 alkyl), cyclopropyl, cyclobutyl and 5- to 6-membered heterocyclyl; wherein:

[0721] R 5 The C1-C2 alkyl group is optionally substituted by 1 to 3 groups selected from F, Cl, Br, cyano, -OH and C1-C2 alkoxy; and

[0722] R 5 The cyclopropyl, the cyclobutyl and the 5- to 6-membered heterocyclic group are each optionally substituted by 1 to 3 groups selected from F, Cl, Br, cyano, -OH, C1-C2 alkyl and C1-C2 alkoxy;

[0723] And all other variables not specifically defined herein are as defined in any of clauses 1 to 13.

[0724] 15. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 14, wherein R 5 is selected from -CH3, -CH2CH3, -CH2OH, -C(=O)OCH3, -CH2OCH3, -CH(CH3)2, cyclopropyl, difluorocyclopropyl and tetrahydro-2H-pyranyl; and all other variables not specifically defined herein are as defined in any one of clauses 1 to 14.

[0725] 16. The compound according to any one of clauses 1 to 4 and 6 to 15, wherein the compound is represented by one of the following structural formulas:

[0726]

[0727] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing compound; and all other variables not specifically defined herein are as defined in any one of clauses 1 to 4 and 6 to 15.

[0728] 17. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 16, wherein R 1 is selected from hydrogen, halogen, cyano, -OH, C1-C4 alkyl, C1-C4 alkoxy and C3-C6 cycloalkyl; wherein:

[0729] R 1 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups selected from halogen, cyano, -OH and C1-C2 alkoxy;

[0730] R 1 The C1-C4 alkoxy group is optionally substituted by 1 to 3 halogen groups; and

[0731] R 1 The C3-C6 cycloalkyl group is optionally substituted by 1 to 3 groups selected from halogen, cyano, -OH and C1-C2 alkoxy;

[0732] And all other variables not specifically defined herein are as defined in any of clauses 1 to 16.

[0733] 18. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein R 1 is selected from F, Cl, Br, C1-C4 alkyl and C3-C6 cycloalkyl; wherein:

[0734] R 1 The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen and -OH; and

[0735] R 1 The C3-C6 cycloalkyl group is optionally substituted by 1 to 3 groups selected from halogen and -OH;

[0736] And all other variables not specifically defined herein are as defined in any of clauses 1 to 17.

[0737] 19. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 18, wherein R 1 is selected from F, Cl, Br, C1-C4 alkyl and C3-C6 cycloalkyl; wherein:

[0738] R 1The C1-C4 alkyl group is optionally substituted by 1 to 3 groups selected from halogen and -OH;

[0739] And all other variables not specifically defined herein are as defined in any of clauses 1 to 18.

[0740] 20. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 18, wherein R 1 Selected from Cl, Br, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH2CHF2, -CH2CH(CH3)2, difluorocyclobutyl and cyclohexyl.

[0741] 21. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 20, wherein R 1 is Cl; and all other variables not specifically defined herein are as defined in any of clauses 1 to 20.

[0742] 22. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 21, wherein R 3a is selected from halogen, -OH and C1-C4 alkyl; wherein:

[0743] R 3a The C1-C4 alkyl group is optionally substituted by 1 to 3 groups selected from halogen and -OH;

[0744] And all other variables not specifically defined herein are as defined in any of clauses 1 to 21.

[0745] 23. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 22, wherein R 3a is selected from F, Cl, Br, -OH and C1-C2 alkyl; wherein:

[0746] R 3a The C1-C2 alkyl group is optionally substituted by 1 to 3 groups selected from F, Cl and -OH;

[0747] And all other variables not specifically defined herein are as defined in any of clauses 1 to 22.

[0748] 24. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 23, wherein 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 to 23.

[0749] 25. The compound according to any one of clauses 1 to 4 and 6 to 24, wherein the compound is represented by one of the following structural formulas:

[0750]

[0751] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing compound; and all other variables not specifically defined herein are as defined in any one of clauses 1 to 4 and 6 to 24.

[0752] 26. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 4 and 6 to 25, wherein R a independently selected at each occurrence from 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- to 10-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl; wherein:

[0753] R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups selected from the following groups: 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;

[0754] R a The C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, phenyl and 5- to 8-membered heteroaryl are each optionally substituted by 1 to 3 groups selected from halogen, C1-C2 alkyl and -OR k wherein:

[0755] R h 、R i and R j is independently selected at each occurrence from hydrogen, C1-C2 alkyl, cyclopropyl and cyclobutyl; wherein:

[0756] R h 、R i and R j The C1-C2 alkyl group of any one of the following is optionally substituted with 1 to 3 groups selected from halogen and -OH;

[0757] R k is independently selected at each occurrence from hydrogen and C1-C4 alkyl; wherein:

[0758] R k The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen and -OH; and

[0759] q and r are each an integer selected from 1, 2, and 3;

[0760] And all other variables not specifically defined herein are as defined in any of clauses 1 to 4 and 6 to 25.

[0761] 27. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 4 and 6 to 26, wherein R a is independently selected at each occurrence from 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:

[0762] R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups selected from cyano, -C(=O)NR h R I 、-NR h R i 、-OR k , cyclopropyl and cyclobutyl group substitution;

[0763] R a The cyclopropyl, the cyclobutyl, the 5- to 6-membered heterocyclyl, the phenyl and the 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 groups selected from halogen, -CH3, -OH and -OCH3; wherein:

[0764] R h and R i is independently selected at each occurrence from hydrogen, -CH3, cyclopropyl, and cyclobutyl; wherein:

[0765] R h and R i The -CH3 of any one of is optionally substituted by 1 to 3 groups selected from F, Cl and -OH;

[0766] R k is independently selected at each occurrence from hydrogen and -CH3; wherein:

[0767] R k -CH3 is optionally substituted by 1 to 3 groups selected from halogen and -OH;

[0768] And all other variables not specifically defined herein are as defined in any of clauses 1 to 4 and 6 to 26.

[0769] 28. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 4 and 6 to 27, wherein R a independently selected at each occurrence from F, Cl, Br, cyano, C1-C6 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -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 heterocyclic group, phenyl and 6-membered heteroaryl; wherein:

[0770] R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups selected from cyano, -C(=O)NR h R I 、-OR k and cyclopropyl group substitution;

[0771] R a The cyclopropyl, the cyclobutyl, the 5- to 6-membered heterocyclyl, the phenyl and the 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 groups selected from halogen, -CH3, -OH and -OCH3; wherein:

[0772] R h and R i is independently selected at each occurrence from hydrogen, -CH3 and cyclopropyl; wherein:

[0773] R h and R i The -CH3 of any one of is optionally substituted by 1 to 3 groups selected from F, Cl and -OH;

[0774] R k is independently selected at each occurrence from hydrogen and -CH3; and

[0775] q and r are each an integer selected from 1 and 2;

[0776] And all other variables not specifically defined herein are as defined in any of clauses 1 to 4 and 6 to 27.

[0777] 29. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 4 and 6 to 28, wherein R aindependently selected at each occurrence from 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) yl), -C(=O)NH2, -C(=O)NH(cyclopropyl), -NH2, -NHCH3, -N(CH3)2, -NHC(CH3)2CH2OH, -NHC(=O)CH3, -SO2CH3, -SO2NH2, cyclopropyl, 2-methoxyphenyl, N-methylpiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl, and tetrahydrothiophene 1,1-dioxide; and all other variables not specifically defined herein are as defined in any of clauses 1 to 4 and 6 to 28.

[0778] 30. The compound according to clause 1, wherein the compound is represented by one of the following structural formulas:

[0779]

[0780]

[0781] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing compound; and all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0782] 31. A compound selected from the group consisting of compounds of Table I, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0783] 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.

[0784] 33. A method for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy, 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.

[0785] 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 preparation of a medicament for the treatment of focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0786] 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 nephropathy.

[0787] 36. A method of inhibiting APOL1 activity comprising contacting the APOL1 with 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.

[0788] 37. 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 preparation of a medicament for inhibiting APOL1 activity.

[0789] 38. 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 inhibiting APOL1 activity.

[0790] 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.

[0791] 40. A pharmaceutical composition comprising the silicon derivative according to clause 39.

[0792] 41. A method for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy, comprising administering the silicon derivative according to Item 39 or the pharmaceutical composition according to Item 40 to a patient in need thereof.

[0793] 42. Use of the silicon derivative according to Item 39 or the pharmaceutical composition according to Item 40 for the preparation of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0794] 43. The silicon derivative according to item 39 or the pharmaceutical composition according to item 40, for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0795] 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.

[0796] 45. A pharmaceutical composition comprising the boron derivative according to clause 44.

[0797] 46. ​​A method for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy, comprising administering the boron derivative according to Item 44 or the pharmaceutical composition according to Item 45 to a patient in need thereof.

[0798] 47. Use of the boron derivative according to Item 44 or the pharmaceutical composition according to Item 45 for the preparation of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0799] 48. The boron derivative according to item 44 or the pharmaceutical composition according to item 45, for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0800] 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.

[0801] 50. A pharmaceutical composition comprising the phosphorus derivative according to clause 48.

[0802] 51. A method for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy, comprising administering the phosphorus derivative according to Item 48 or the pharmaceutical composition according to Item 49 to a patient in need thereof.

[0803] 52. Use of the phosphorus derivative according to Item 48 or the pharmaceutical composition according to Item 49 for the preparation of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0804] 53. The phosphorus derivative according to item 48 or the pharmaceutical composition according to item 49, for use in the treatment of focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

[0805] Example

[0806] In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the disclosure in any way.

[0807] The compounds of the present disclosure can be prepared according to standard chemical practices or as described herein. In the following synthetic schemes and in the methods for preparing 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' In the description of compounds of the invention, compounds 1 to 391, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, the following abbreviations are used:

[0808] abbreviation

[0809] AIBN = Azobisisobutyronitrile

[0810] ARP = assay ready plate

[0811] BBBPY = 4,4′-di-tert-butyl-2,2′-bipyridine

[0812] BF3 = Boron trifluoride

[0813] BF3.OEt2=boron trifluoride etherate

[0814] Boc2O=di-tert-butyl dicarbonate

[0815] CBzCl = benzyl chloroformate

[0816] CDMT=2-chloro-4,6-dimethoxy-1,3,5-triazine

[0817] DAST = diethylaminosulfur trifluoride

[0818] DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

[0819] DCM = dichloromethane

[0820] DIBAL-H = Diisobutylaluminum hydride

[0821] DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propane-2-amine

[0822] DMAP = dimethylaminopyridine

[0823] DMA = dimethylacetamide

[0824] DME = dimethoxyethane

[0825] DMEM = Dulbecco's modified Eagle's medium

[0826] DMF = dimethylformamide

[0827] DMPU=N,N'-dimethylpropyleneurea

[0828] DMSO = dimethyl sulfoxide

[0829] DPPA = diphenylphosphoryl azide

[0830] EtOAc = ethyl acetate

[0831] EtOH = ethanol

[0832] Et2O = ether

[0833] FBS = fetal bovine serum

[0834] FLU = Fluorescence value

[0835] HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphorus hexafluoride ion)

[0836] HDMC = N-[(5-chloro-3-oxo-1H-benzotriazol-1-yl)-4-morpholinylidene]-N-methylmethanamine hexafluorophosphate

[0837] HEPES = 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

[0838] HBSS = Hank's balanced salt solution

[0839] IPA = Isopropyl alcohol

[0840] Ir[df(CF3)ppy]2(dtbbpy)PF6=phosphorus hexafluoride

[0841] LDA = lithium diisopropylamide

[0842] LED = Light Emitting Diode

[0843] MeCN = acetonitrile

[0844] MeI = methyl iodide

[0845] MeOH = methanol

[0846] MsOH = methanesulfonic acid

[0847] MTBE or TBME = methyl tert-butyl ether

[0848] n-BuLi = n-butyllithium

[0849] NBS = n-bromosuccinimide

[0850] NMM = N-methylmorpholine

[0851] NMP = N-methylpyrrolidine

[0852] PBS = Phosphate-buffered saline

[0853] Pd(dppf)2Cl2=[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0854] PdCl2(PPh3)2=Bis(triphenylphosphine)palladium(II) dichloride

[0855] PP = Polypropylene

[0856] PTSA = p-toluenesulfonic acid monohydrate

[0857] T3P=2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphaninane-2,4,6-trioxide

[0858] TBAF = Tetra-n-butylammonium fluoride

[0859] TBSCl = tert-butyldimethylsilyl chloride

[0860] TEA = triethylamine

[0861] Tet = Tetracycline

[0862] TFA or TFAA = trifluoroacetic acid

[0863] TfOH = trifluoromethanesulfonic acid

[0864] THF = Tetrahydrofuran

[0865] 2-Me-THF = 2 = methyltetrahydrofuran

[0866] THP = Tetrahydropyran

[0867] TMSCl = trimethylsilyl chloride

[0868] TMSS = tris(trimethylsilyl)silane

[0869] Example 1: Synthesis of compounds

[0870] All specific and generic compounds and intermediates disclosed for the preparation of those compounds are considered to be part of the disclosure disclosed herein.

[0871] Synthesis starting materials

[0872] Preparations Synthetic routes for the intermediates used to synthesize compounds 1 to 391 are described.

[0873] General approach

[0874] In some embodiments, the methods for preparing compounds of Formula I comprise the reactions depicted in Schemes 1-6.

[0875] Scheme 1 shows a method for preparing compounds of formula I. 1 、R 3 、R 4 R 5 、X 1 、X 2 , m and k are as defined above. The aminoketone of formula 1-1 can react with the aldehyde of formula 1-2 to obtain the piperidone of formula 1-3. In some embodiments, the reaction can occur in the presence of an amine catalyst such as L-proline, in the presence of a base such as triethylamine and a magnesium sulfate reagent. The compound of formula 1-3 can be prepared using any suitable method for preparing piperidone. The compound of formula 1-3 can be prepared from the piperidone of formula 1-3 and the alcohol of formula 1-4 using any suitable conditions for the Pictet-Spengler reaction. For example, the reaction can 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 can be used. The reaction can be carried out in a solvent such as dichloromethane in the presence of additional heat (e.g., 40°C).

[0876] Solution 1

[0877]

[0878] Scheme 2 shows a method 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 suitable benzylic oxidation method. For example, in some embodiments, the reaction is carried out in the presence of oxygen, N-hydroxyphthalamide, and a cobalt diacetate catalyst under balloon pressure. In some embodiments, the reaction is carried out in the presence of acetonitrile. The reaction can be carried out in the presence of additional heat (e.g., 60°C). Compounds of formula 2-3 can be prepared from compounds of formula 2-2 using any suitable method for reducing ketones to alcohols. For example, a Corey–Bakshi–Shibata catalyst (CBS catalyst) can be used in the presence of a reducing agent such as borane. In alternative embodiments, a transition metal-catalyzed transfer hydrogenation system can be used. In the presence of a chiral ligand, the transition metal transfer hydrogenation reaction may result in an asymmetric reduction of the ketone.

[0879] Option 2

[0880]

[0881] Scheme 3 shows a method for preparing compounds of formula 3-4. 2 is any suitable alcohol protecting group, such as THP. The heterocyclic bromide of formula 3-1 can be coupled with the trifluoroborate of formula 3-2 using any suitable method for coupling a halide with an alkyl borate. For example, in some embodiments, the reaction can be carried out in the presence of a catalyst system such as dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphine methanesulfonate palladium(II) N-methyl-2-phenyl-aniline and a base such as Cs2CO3. The reaction can be carried out in the presence of additional heat (e.g., 100°C). In some embodiments, the reaction is carried out in a solvent such as toluene. Any suitable method for removing the alcohol protecting group can be used to prepare the compound of formula 3-4. For example, when PG 2 In the case of 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.

[0882] Option 3

[0883]

[0884] Scheme 4 shows a method for preparing an alcohol of formula 4-5 from an aryl halide of formula 3-1. Any suitable reagent for lithium-halogen exchange on heteroaryl bromides (e.g., treatment with n-butyllithium) can be used to generate heteroaryl organometallic reagents in situ. The reaction can be carried out at low temperatures (e.g., 0 to -78°C) in a solvent such as THF or diethyl ether. In the presence of a Lewis acid such as trifluoroboron etherate, an organometallic reagent is added to an epoxide such as ethylene oxide to obtain an alcohol of formula 4-2. In some embodiments, the lithium halogen exchange reaction can be carried out under continuous flow conditions.

[0885] In an alternative method for preparing compounds of formula 4-2, aldehydes of formula 4-3 can be subjected to a Wittig reaction with a reagent such as a substituent of formula 4-4 to provide enol ethers of formula 4-5. In some embodiments, the reaction is carried out in the presence of a base such as potassium tert-butoxide in a solvent such as diethyl ether. In some embodiments, enol ethers of formula 4-5 can be converted to compounds of formula 4-6 by treatment with an acid such as HCl. In some embodiments, compounds of formula 4-2 can be prepared from compounds of formula 4-6 using any suitable reagent for reducing aldehydes to alcohols, for example, sodium borohydride in methanol.

[0886] Option 4

[0887]

[0888] Scheme 5 shows a method for preparing compounds of formula 1-1. 3 is any suitable nitrogen protecting group. The compound of formula 5-1 can be protected with any suitable nitrogen protecting group. For example, when PG 3 When it is a Boc group, any suitable reagent can be used to add the Boc group to the amine. The compound of formula 5-3 (Weinreb amide) can be prepared from the compound of formula 5-2 and N-methyl N-methoxyamine using any suitable amide coupling agent. For example, the reaction can be carried out in the presence of T3P and DIPEA in a solvent such as dichloromethane. The compound of formula 5-5 can be prepared from the compound of formula 5-3 by adding an organometallic reagent such as methylmagnesium iodide. The reaction can be carried out at low temperature (e.g., 0°C) in a solvent such as THF. The compound of formula 1-1 can be prepared by removing the nitrogen protecting group from the compound of formula 5-5 using any suitable method. For example, when PG 3 In the case of Boc, a solution of HCl in 1,4-dioxane can be used.

[0889] Option 5

[0890]

[0891] Scheme 6 shows an alternative method for preparing compounds of Formula 1-3 from N-protected β-amino acids of Formula 6-1. 4Can be Boc or any suitable nitrogen protecting group.Compound 6-2 dimagnesium salt can be coupled to formula 6-1 compound with reagent such as CDI in solvent such as THF.By formula 6-3 compound and the aldehyde of formula 6-4 condensation, obtain formula 6-5 compound.In some embodiments, this reaction can be by treating formula 6-3 compound with acid such as TFA in solvent such as dichloromethane, then adding the aldehyde of formula 6-4 to carry out.Formula 1-3 compound can be prepared by formula 6-5 compound by treating with acid such as methanesulfonic acid in solvent such as dichloromethane.Reaction can be carried out in the presence of additional heat (for example, reflux condition).

[0892] Option 6

[0893]

[0894] Preparation of S1

[0895] 2-(3-Thienyl)ethanol (S1)

[0896]

[0897] 2-(3-Thienyl)ethanol (S1) was obtained from a commercial source.

[0898] Preparation of S2

[0899] 2-(5-Chloro-3-thienyl)ethanol (S2)

[0900]

[0901] Step 1. Synthesis of tert-butyl-dimethyl-[2-(3-thienyl)ethoxy]silane (C1)

[0902] To a solution of 2-(3-thienyl)ethanol S1 (18 g, 140.4 mmol) in DMF (100 mL) was added imidazole (12 g, 176.3 mmol) and tert-butyl-chloro-dimethyl-silane (24 g, 159.2 mmol) in succession. An exotherm was observed. The reaction mixture was stirred at room temperature for 3 hours. 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; it 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%). 1H 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).

[0903] Step 2. Synthesis of tert-butyl-[2-(5-chloro-3-thienyl)ethoxy]-dimethyl-silane (C2)

[0904] To a solution of 2,2,6,6-tetramethylpiperidine (36 mL, 213.3 mmol) in tetrahydrofuran (200 mL) cooled to 0°C was added hexyllithium (92 mL 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 portionwise. The reaction was warmed to room temperature and stirred overnight. Reactant is quenched with saturated ammonium chloride (125mL), diluted with water (100mL), extracted with EtOAc (500mL), and stripped with EtOAc (100mL).The organic layer merging is washed with 0.5N HCl (200mL), water (300mL) and salt solution (200mL).Organic layer is dried over sodium sulfate, filtered, and concentrated to obtain crude product tert-butyl-[2-(5-chloro-3-thienyl) ethyoxyl]-dimethyl-silane C2.

[0905] Step 3. Synthesis of 2-(5-chloro-3-thienyl)ethanol (S2)

[0906] 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 1 M in THF, 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: 0-50% 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] + .

[0907] Preparation of S3

[0908] 2-[5-(Trifluoromethyl)-3-thienyl]ethanol (S3)

[0909]

[0910] Step 1. Synthesis of 2-[2-[5-(trifluoromethyl)-3-thienyl]ethoxy]tetrahydropyran (C5)

[0911] To a mixture of 4-bromo-2-(trifluoromethyl)thiophene C3 (9 g, 38.96 mmol), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphine; mesylate; N-methyl-2-phenyl-aniline palladium (2+) (1.8 g, 2.117 mmol) and potassium trifluoro(2-tetrahydropyran-2-yloxyethyl)borate C4 (10 g, 42.36 mmol) were added toluene (75 mL) and water (25 mL). Nitrogen was passed through the top of the reaction before adding Cs2CO3 (40 g, 122.8 mmol). A reflux condenser was added and the reaction was heated at 100 ° C for 48 hours. The reaction 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, filtered, and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-20% EtOAc in heptane) gave the product 2-[2-[5-(trifluoromethyl)-3-thienyl]ethoxy]tetrahydropyran C5 (9 g, 82%). 1 H NMR (300MHz, chloroform-d) δ7.37(t,J=1.3Hz,1H),7.22(d,J=1.5Hz,1H),4.62(dd,J= 4.2,2.8Hz,1H),3.96(dt,J=9.6,6.7Hz,1H),3.75(ddd,J=11.3,8.0,3.4Hz,1H ),3.62(dt,J=9.6,6.5Hz,1H),3.55-3.41(m,1H),2.93(t,J=6.6Hz,2H),1.83 (ddd,J=14.2,6.6,3.4Hz,1H),1.73(td,J=9.0,4.2Hz,1H),1.66-1.50(m,4H).

[0912] Step 2. Synthesis of 2-[5-(trifluoromethyl)-3-thienyl]ethanol (S3)

[0913] 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 hour. 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 NaHCO3 and 10 mL water) and brine (10 mL), dried over sodium sulfate, filtered, and evaporated under vacuum to give a crude compound. Purification by silica gel chromatography (gradient: 0-30% EtOAc in heptane) gave the product 2-[5-(trifluoromethyl)-3-thienyl]ethanol S3 (820 mg, 69%). 1 H NMR (400MHz, chloroform-d) δ7.35(p,J=1.3Hz,1H),7.23(dt,J=1.7,0.9Hz,1H),3.85( td,J=7.1,6.5,2.7Hz,2H), 2.87(td,J=6.4,0.8Hz,2H), 2.06(d,J=4.3Hz,1H).

[0914] Alternative preparation of S3

[0915] 2-[5-(Trifluoromethyl)-3-thienyl]ethanol (S3)

[0916]

[0917] 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 2.48 M, 225.7 mmol) was added at a rate suitable to maintain the temperature below -68°C. The reaction was stirred for 20 minutes and ethylene oxide (14 g, 317.8 mmol) was added at a rate to maintain the temperature below -70°C. BF3.OEt2 (28 mL, 226.9 mmol) was added at a rate to maintain the temperature below -68°C. The addition of BF3.OEt2 was highly exothermic. The reaction was stirred for one hour at -78°C and then poured into 500 mL 1N HCl and extracted with 500 mL Et2O. The extract was dried over MgSO4, filtered, and evaporated in vacuo. Purification by column chromatography (1600 g: isocratic gradient: 10% CH 3 CN-DCM) gave 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.

[0918] Preparation of S4

[0919] 2-(5-Ethyl-3-thienyl)ethanol (S4)

[0920]

[0921] Step 1. Synthesis of 5-bromothiophene-3-carboxaldehyde (C7)

[0922] To a stirred solution of thiophene-3-carboxaldehyde 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 hours. The reaction mixture was quenched with ice-cold water (600 mL) and extracted with EtOAc (2 x 600 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (Gradient: 0-2% EtOAc in petroleum ether) gave the product 5-bromothiophene-3-carboxaldehyde C7 (39.2 g, 44%). 1H 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).

[0923] Step 2. Synthesis of 2-bromo-4-[(E)-2-methoxyvinyl]thiophene (C8)

[0924] To a stirred solution of (methoxymethyl)triphenylphosphine chloride (115.1 g, 0.3358 mol) in diethyl ether (450.00 mL) was added potassium tert-butoxide (1 M in THF) (381 mL 1 M, 0.3810 mol) dropwise at 0°C. The reaction was stirred at 0°C for 1 hour. A solution of 5-bromothiophene-3-carboxaldehyde 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 minutes. The reaction mixture was quenched with NH4Cl solution (900 mL) at 0°C and extracted with EtOAc (2 x 700 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product, 2-bromo-4-[(E)-2-methoxyvinyl]thiophene C8 (44.1 g, 82%), was obtained by silica gel chromatography (eluent: petroleum ether). 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 a 1:1 mixture of E and Z isomers.

[0925] Step 3. Synthesis of 2-(5-bromo-3-thienyl)acetaldehyde (C9)

[0926] 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) at 0°C was added HCl (60.200 mL of 4 M in dioxane, 0.2408 mol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated NaHCO₃ at 0°C and extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated to afford 2-(5-bromo-3-thienyl)acetaldehyde C9 (13.1 g, 89%). 1H 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).

[0927] Step 4. Synthesis of 2-(5-bromo-3-thienyl)ethanol (C10)

[0928] 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 reactant was stirred for 1 hour. 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 (3x300 mL). The separated organic layer was dried over Na2SO4, filtered, and concentrated. Purification by column chromatography using neutral alumina (eluent: 35% EtOAc in petroleum ether) gave the product 2-(5-bromo-3-thienyl)ethanol C10 (30.2 g, 84%) as a light yellow liquid. 1 H NMR (300MHz, DMSO-d6) δ7.20 (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).

[0929] Step 5. Synthesis of 2-[2-(5-bromo-3-thienyl)ethoxy]tetrahydropyran (C11)

[0930] 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 then stirred at room temperature for 16 hours. The reaction mixture was quenched with a saturated aqueous solution of K2CO3 (300 mL) and extracted with EtOAc (2 x 600 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purified by silica gel chromatography (gradient: 0-5% EtOAc in petroleum ether) to obtain the product 2-[2-(5-bromo-3-thienyl)ethoxy]tetrahydropyran C11 (10.1 g, 90%). 1H NMR (400MHz, chloroform-d) δ6.95(d,J=1.6Hz,1H),6.92(d,J=0.8,1H),4.59(t,J=2.8Hz,1 H),3.94-3.74(m,2H),3.60-3.46(m,2H),2.85(q,J=6.4Hz,2H),1.80-1.61(m,6H). LCMS m / z 291.03[M+H] + .

[0931] Step 6. Synthesis of 2-[2-(5-ethyl-3-thienyl)ethoxy]tetrahydropyran (C12)

[0932] To a stirred solution of 2-[2-(5-bromotetrahydrothiophene-3-yl)ethoxy]tetrahydropyran C11 (25 g, 0.0719 mol) in THF (250.00 mL) was added n-BuLi (2.5 M in hexane) (46.1 mL 2.5 M, 0.1153 mol) at -76 ° C. The reactant was stirred for 1 hour. Iodoethane (24.832 g, 12.8 mL, 0.1592 mol) was added at -76 ° C. and the reaction temperature was slowly increased to room temperature, and then stirred for 16 hours. The reaction mixture was quenched with NH4Cl solution (500 mL) and extracted with EtOAc (2 x 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] + .

[0933] Step 7. Synthesis of 2-(5-ethyl-3-thienyl)ethanol (S4)

[0934] 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 hours. The reaction mixture was quenched with saturated NaHCO solution (150 mL), extracted with EtOAc (2 x 150 mL), dried over NaSO, filtered, and concentrated. Purification by column chromatography using neutral alumina (eluent: 10% EtOAc in petroleum ether) gave the product, 2-(5-ethyl-3-thienyl)ethanol S4 (1.1 g, 45%). 1H NMR(400MHz,DMSO-d6)δ6.90(d,J=1.2Hz,1H),6.71(d,J=1.2Hz,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).

[0935] Preparation of S5

[0936] 2-(5-Ethyl-2-thienyl)ethanol (S5)

[0937]

[0938] Step 1. Synthesis of 2-(5-ethyl-2-thienyl)ethanol (S5)

[0939] To a solution of 2-ethylthiophene C13 (54 g, 466.9 mmol) in anhydrous THF (1 L) was added n-BuLi (255 mL 2.2 M, 561.0 mmol) in hexane at 0 ° C within 45 minutes. A light yellow / orange solution was obtained. The temperature range was 0-10 ° C during the addition. The mixture was stirred at room temperature for 30 minutes. After cooling to 0 ° C, a solution of ethylene oxide (200 mL 2.9 M, 580.0 mmol) was added within 30 minutes. The reactants were stirred at 0 ° C for 2 hours and then warmed to room temperature. The reaction mixture was quenched with water (700 mL) and saturated NH4Cl (200 mL) and THF was evaporated. The product was extracted with EtOAc (1 x 400 mL; 2 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The organic layer was passed through a plug of silica gel and washed with DCM (1000 mL), 80% EtOAc / heptane (2 x 200 mL) and DCM (2 x 250 mL) to afford 2-(5-ethyl-2-thienyl)ethanol S5 (71.25 g, 93%). 1 H NMR (300MHz, chloroform-d) δ6.69 (dt, J=3.4, 0.9Hz, 1H), 6.64 (dt, J=3.3, 1.0Hz, 1H), 3.84 (t ,J=6.3Hz,2H),3.08-2.97(m,2H),2.82(qd,J=7.5,1.0Hz,2H),1.31(t,J=7.5Hz,4H).

[0940] Preparation of S6

[0941] 2-[5-(Trifluoromethyl)-2-thienyl]ethanol (S6)

[0942]

[0943] Step 1. Synthesis of 2-(5-iodo-2-thienyl)ethanol (C15)

[0944] To a stirred solution of NIS (104.83 g, 0.4680 mol) in DCM (1000 mL) at 0°C was added 2-(2-thienyl)ethanol C14 (50 g, 0.3900 mol). The reaction was warmed to room temperature and stirred for 16 hours. 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] + .

[0945] Step 2. Synthesis of 2-[2-(5-iodo-2-thienyl)ethoxy]tetrahydropyran (C16)

[0946] 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 (400MHz, DMSO-d6) δ7.14(d,J=3.6Hz,1H),6.64(d,J=3.6Hz,1H),4.59(t,J=3.6Hz,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=6Hz,2H),1.75-1.69(m,1H),1.61-1.59(m,1H),1.51-1.42(m,4H).

[0947] Step 3. Synthesis of 2-[2-[5-(trifluoromethyl)-2-thienyl]ethoxy]tetrahydropyran (C17)

[0948] To a stirred solution of 2-[2-(5-iodo-2-thienyl)ethoxy]tetrahydropyran C16 (10 g, 0.0219 mol) and 2,2-difluoro-2-fluorosulfonyl-acetic acid methyl ester (12.63 g, 0.0657 mol) in DMF (40 mL) was added copper(I) bromide dimethyl sulfide complex 99% (2.241 g, 0.0109 mol). The reaction was stirred at 100°C for 16 hours. The reaction was warmed to room temperature, diluted with EtOAc (100 mL), filtered, and washed with EtOAc (50 mL). The filtrate was washed with a 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 HNMR (400MHz, chloroform-d) δ7.25 (s, 1H), 6.82-6.81 (m, 1H), 4.63 (t, J = 3.6Hz, 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=6.4Hz,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] + .

[0949] Step 4. Synthesis of 2-[5-(trifluoromethyl)-2-thienyl]ethanol (S6)

[0950] 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 using neutral alumina (eluent: 10% EtOAc in petroleum ether) gave the product 2-[5-(trifluoromethyl)-2-thienyl]ethanol S6 (2.3 g, 61%). 1H NMR (400MHz, DMSO-d6) δ7.52-7.51(m,1H),6.99-6.98(m,1H),4.92(t,J=4.8Hz,1H),3.65-3.61(m,2H),2.98(t,J=6Hz,2H). 19 F NMR (376.22MHz, DMSO-d6) δ-53.53 (s, 3F). GCMS: 88.56%m / z: 196.0[M] + .

[0951] Preparation of S7

[0952] 2-[5-(Trifluoromethyl)-2-thienyl]propan-1-ol (S7)

[0953]

[0954] Step 1. Synthesis of ethyl 2-(2-thienyl) ethyl ethanol (C19)

[0955] To a stirred solution of 2-(2-thienyl)acetic acid C18 (100 g, 703.35 mmol) in ethanol (2000 mL) was added HCl (aqueous solution) (50 mL 36% (w / v), 493.68 mmol) at room temperature. The reaction mixture was stirred at 70 ° C for 12 hours. The mixture was concentrated, and the resulting crude material was diluted with EtOAc (1000 mL) and washed with 5% Na2CO3 aqueous solution (3 x 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%). 1 H 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 = 7.2 Hz, 3H). LCMS m / z 171.26 [M+H] + .

[0956] Step 2. Synthesis of ethyl 2-(2-thienyl)propionate (C20)

[0957] To a solution of ethyl 2-(2-thienyl)acetate C19 (1.36 g, 7.99 mmol) in THF (20 mL) was added (diisopropylamino) lithium (8 mL 1M, 8.000 mmol) at -78 ° C. After 15 minutes, MeI (500 μL, 8.032 mmol) was added and the reaction mixture was stirred at -78 ° C for 2 hours. The reactant was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc. The organic layer was dried and concentrated to give an oil. Purified by silica gel chromatography (gradient: 0 to 25% EtOAc in heptane) to give 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).

[0958] Step 3. Synthesis of ethyl 2-(5-iodo-2-thienyl)propionate (C21)

[0959] 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 one hour. 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. Purification by silica gel chromatography (eluent: 3% EtOAc in petroleum ether) 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] + .

[0960] Step 4. Synthesis of ethyl 2-[5-(trifluoromethyl)-2-thienyl]propanoate (C22)

[0961] 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 nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 12 hours. The mixture was filtered and the The pad was washed with ether (2x 100mL). The filtrate was quenched with cold water (100mL). The two layers were separated and the aqueous layer was extracted with ether (2x 50mL). The combined organic layers were washed with brine (30mL), dried, and concentrated. Purified by silica gel chromatography (eluent: 3% EtOAc in petroleum ether) to obtain product ethyl 2-[5-(trifluoromethyl)-2-thienyl] propanoate C22 (2g, 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] +

[0962] Step 5. Synthesis of 2-[5-(trifluoromethyl)-2-thienyl]propan-1-ol (S7)

[0963] 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 25% (w / v), 62.5 mmol) dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The mixture was slowly quenched with saturated NH4Cl solution (300 mL) at 0°C and washed with water. The suspension was filtered and The pad was washed with EtOAc (2x 200mL). The filtrate was separated into layers. The aqueous layer was extracted with EtOAc (2x 200mL). The combined organic layers were washed with brine (200mL), dried over Na2SO4, and concentrated. Purification by silica gel chromatography (eluent: 3% EtOAc in petroleum ether) gave a crude product. The racemic compound 2-[5-(trifluoromethyl)-2-thienyl]propan-1-ol (1.6g, 7.3067mmol) was separated from the dimethyl overalkylation by-product using chiral SFC separation. Column: Daicel 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 (400MHz, chloroform-d) δ7.52 (m, 1H), 7.00 (m, 1H), 4.97 (t, J = 5.6Hz, 1H), 3.51 (t, J = 6.0Hz, 2H) 3.17 (m, 1H), 1.27 (d, J = 6.8Hz, 3H). GCMS: m / z: 210.0[M] + .

[0964] Preparation of S8

[0965] 2-Methyl-2-[5-(trifluoromethyl)-2-thienyl]propan-1-ol (S8)

[0966]

[0967] S8 was obtained as a by-product during the SFC purification of S7 due to overalkylation in step 2 described above.

[0968] Preparation of S9, S10, and S11

[0969] 2-Methyl-2-[5-(chloro)-2-thienyl]propan-1-ol (S9)

[0970] 2-[5-(Chloro)-2-thienyl]propan-1-ol (S10[ENANT-1], S11[ENANT-2])

[0971]

[0972] Step 1. Synthesis of ethyl 2-(5-chloro-2-thienyl)propionate (C24)

[0973] 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 hour. The mixture was concentrated and the resulting crude material was diluted with EtOAc (25 mL), 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 Na2SO4, 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] +

[0974] 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)

[0975] 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 25% (w / v), 130.32 mmol) dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The mixture was slowly quenched with saturated NH4Cl solution (300 mL) at 0°C and washed with water. The suspension was filtered and The pad was washed with EtOAc (2x 200mL). The filtrate was separated into two layers. The aqueous layer was extracted with EtOAc (2x 200mL). The combined organic layers were washed with brine (200mL), dried over sodium sulfate, and concentrated. Purified by silica gel chromatography (eluent: 3% EtOAc in petroleum ether) to obtain S9 2-(5-chloro-2-thienyl)-2-methyl-propan-1-ol (410mg, 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: A dimethyl compound (S9) was obtained as a by-product during the synthesis of C20 due to overalkylation.

[0976] Step 3. Synthesis of 2-(5-chloro-2-thienyl)propan-1-ol (S10) and (S11)

[0977] The racemic compound 2-(5-chloro-2-thienyl)propan-1-ol C25 (12 g, 62.492 mmol) was separated into the constituent enantiomers by chiral SFC separation. Column: Daicel AD-H, 30x250mm; Mobile phase: 10% methanol / hexane mixture (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, 400MHz) δ6.76-6.75 (d, J=4Hz, 1H), 6.66-6.65 (dd, J=3.6Hz, 1H), 3.73-3.61 (m, 2H), 3.15-3.10 (q, J=6.8Hz, 1H), 1.51-1.48 (t, J=5.6Hz, 1H), 1.33-1.30 (d, J=7.2Hz, 3H). GCMS: m / z: 176.0[M] + .

[0978] Preparation of S12 and S13

[0979] 2-(5-Ethyl-2-thienyl)propan-1-ol (S12 ENANT-1) and (S13 ENANT-2)

[0980]

[0981] Step 1. Synthesis of ethyl 2-(5-acetyl-2-thienyl)propionate (C26)

[0982] 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 AlCl (67.388 g, 505.38 mmol) at 0 ° C. The reaction mixture was stirred for 2 hours 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 (2x500 mL). The combined organic layers were washed with brine (500 mL) and dried over sodium sulfate. Purified by silica gel chromatography (gradient: 0-5% EtOAc in petroleum ether) to give 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), 4.01-3.96 (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] + .

[0983] Step 2. Synthesis of ethyl 2-(5-ethyl-2-thienyl)propionate (C27)

[0984] To a stirred solution of ethyl 2-(5-acetyl-2-thienyl)propanoate C26 (60g, 245.79mmol) in TFA (400mL) was added triethyl-silane (42.870g, 58.9mL, 368.69mmol) dropwise at 0°C. The reaction mixture was stirred at room temperature for 4 hours. The reactant was concentrated and quenched with ice water (500mL) and extracted with EtOAc (3x 500mL). The combined organic layer was washed with brine (250mL), dried over sodium sulfate, and concentrated to give a crude product. Purified by silica gel chromatography (gradient: 0-3% EtOAc in petroleum ether) to give the product ethyl 2-(5-ethyl-2-thienyl)propanoate C27 (50g, 82%). 1 H 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]+ .

[0985] Step 3. Synthesis of 2-(5-ethyl-2-thienyl)propan-1-ol (C28)

[0986] 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) (227.75 mL 25% (w / v), 400.36 mmol) dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The mixture was slowly quenched with saturated NH4Cl solution (500 mL) at 0°C and extracted with EtOAc (2 x 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] + .

[0987] Step 4. Synthesis of 2-(5-ethyl-2-thienyl)propan-1-ol (S12) and (S13)

[0988] The racemic compound 2-(5-ethyl-2-thienyl)propan-1-ol C28 (31 g, 178.06 mmol) was separated into the constituent enantiomers by chiral SFC separation. Column: Daicel AD-H, 30x250 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%). 1H 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 HNMR (chloroform-d, 400MHz): δ6.68-6.67(d,J=3.6Hz,1H), 6.63(d,J=3.6Hz,1H), 3.73-3.61(m,2 H),3.20-3.12(m,1H),2.83-2.77(q,J=7.6Hz,2H),1.54-1.45(m,1H),1.33-1.27(m,6H). LCMS m / z 171.1[M+H] + .

[0989] Preparation of S14

[0990] 2-(5-Methyl-3-thienyl)ethanol (S14)

[0991]

[0992] 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 KCO (4.9 g, 0.036 mol) in a sealed tube at room temperature. The reaction mixture was degassed with argon for 10 minutes. Xphos Pd G (457 mg, 580.83 μmol) was added and degassed again for 5 minutes. Trimethylboroxane (50% solution in THF) (24.605 mL 50% (w / v), 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 x 150 mL). The combined organic layers were dried over NaSO, 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. 1H NMR (400MHz, DMSO-d6) δ6.87 (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).

[0993] Preparation of S15

[0994] 2-(5-Methyl-2-thienyl)ethanol (S15)

[0995]

[0996] Step 1. Synthesis of 2-(5-bromo-2-thienyl)ethanol (C30)

[0997] 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 reactant was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with 6% KOH solution, ice water (2 x 150 mL) and brine (150 mL). The organic layer was dried over sodium sulfate and concentrated. Purified by column chromatography (eluent: 10% EtOAc in petroleum ether) to obtain 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).

[0998] Step 2. Synthesis of 2-[2-(5-bromo-2-thienyl)ethoxy]tetrahydropyran (C31)

[0999] 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 hours. 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) gave 2-[2-(5-bromo-2-thienyl)ethoxy]tetrahydropyran C31 (18.5 g, 64%). 1 HNMR (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).

[1000] Step 3. Synthesis of 2-[2-(5-methyl-2-thienyl)ethoxy]tetrahydropyran (C32)

[1001] 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 dropwise n-BuLi (33.320 mL 2.5 M, 0.0833 mol) at -78 ° C. The reaction was stirred for one hour at -78 ° C. Iodomethane (15.755 g, 6.9101 mL, 0.1110 mol) was added dropwise at -78 ° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NH4Cl solution and diluted with water. The aqueous layer was extracted with EtOAc (2 x 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).

[1002] Step 4. Synthesis of 2-(5-methyl-2-thienyl)ethanol (S15)

[1003] 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 hours. 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 solution (2 x 100 mL). The aqueous layer was extracted again with EtOAc (2 x 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(400MHz,DMSO-d6)δ6.61(d,J=3.6Hz,1H),6.58-6.57(d,J=4.0Hz,1H),4 .73(t,J=5.2Hz,1H),3.58-3.53(m,2H),2.82(t,J=6.8Hz,2H),2.36(s,3H).

[1004] Preparation of S16

[1005] [4-(2-Hydroxyethyl)-2-(trifluoromethyl)-3-thienyl]methyl acetate (S16)

[1006]

[1007] Step 1. Synthesis of tert-butyl-dimethyl-[2-[5-(trifluoromethyl)-3-thienyl]ethoxy]silane (C33)

[1008] 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) to immediately precipitate a white solid. The solid was filtered and the organic layer was washed with 1N HCl (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (gradient: 0-30% EtOAc in heptane) gave the product tert-butyl-dimethyl-[2-[5-(trifluoromethyl)-3-thienyl]ethoxy]silane C33, which was assumed to be quantitative and used without further purification.

[1009] Step 2. Synthesis of tert-butyl-dimethyl-[2-[5-(trifluoromethyl)-2-trimethylsilyl-3-thienyl]ethoxy]silane (C34)

[1010] 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 1.4 M, 3.220 mmol) was added, followed by TMSCl (3 mL 1 M, 3.000 mmol). After 5 minutes, 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 by silica gel chromatography (gradient: 0-10% EtOAc in heptane) gave 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).

[1011] Step 3. Synthesis of 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(trifluoromethyl)-5-trimethylsilyl-thiophene-3-carbaldehyde (C35)

[1012] To a mixture of tert-butyl-dimethyl-[2-[5-(trifluoromethyl)-2-trimethylsilyl-3-thienyl]ethoxy]silane C34 (400 mg, 1.024 mmol) in THF (10 mL) cooled to -78 ° C was added sec-butyllithium (1.2 mL 1.4 M, 1.680 mmol) followed by DMF (3 mL 1 M, 3.000 mmol). After 5 minutes, 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) gave the product 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(trifluoromethyl)-5-trimethylsilyl-thiophene-3-carboxaldehyde 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.

[1013] Step 4. Synthesis of [4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(trifluoromethyl)-5-trimethylsilyl-3-thienyl]methanol (C36)

[1014] 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 minutes, the mixture was concentrated and redissolved in heptane (2 mL) and water (2 mL). The organic layer was separated and the aqueous layer was extracted with heptane again. 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 HNMR (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).

[1015] Step 5. Synthesis of [4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(trifluoromethyl)-5-trimethylsilyl-3-thienyl]methyl acetate (C37)

[1016] To [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 produce the product, which was carried on to the next step.

[1017] Step 6. Synthesis of [4-(2-hydroxyethyl)-2-(trifluoromethyl)-3-thienyl]methyl acetate (S16)

[1018] [4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-(trifluoromethyl)-5-trimethylsilyl-3-thienyl]methyl acetate C37 from step 5 was diluted with EtOAc (2 mL) and a THF solution of TBAF (1 mL 1M, 1.000 mmol) was added to the mixture and the mixture was stirred. The reactant was stirred for 48 hours. The mixture was further diluted with EtOAc (3 mL), washed with water, passed through a phase separator, and concentrated. Purification by silica gel chromatography (gradient: 0-60% EtOAc in heptane) gave the product [4-(2-hydroxyethyl)-2-(trifluoromethyl)-3-thienyl]methyl acetate S16 (35 mg, 12%). 1 HNMR (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] + .

[1019] Preparation of S17

[1020] 1-Methyltriazole-4-carbaldehyde (S17)

[1021]

[1022] 1-Methyltriazole-4-carbaldehyde S17 was obtained from a commercial source

[1023] Preparation of S18

[1024] 1-(2-Methylsulfonylethyl)triazole-4-carbaldehyde (S18)

[1025]

[1026] Step 1. Synthesis of 1-azido-2-methylsulfonyl-ethane (C40)

[1027] 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 minutes and DBU (5.5 g, 5.42 mL, 0.04 mol) was added dropwise at 0 ° C over 10 minutes and the reactants were stirred at room temperature for 16 hours. The reaction mixture was quenched with water (25 mL) and EtOAc (100 mL) and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted again with EtOAc (2 x 100 mL). The organic layer was dried over Na2SO4 and concentrated. Purification by silica gel chromatography (gradient: 0-100% ethyl acetate in petroleum ether) gave 1-azido-2-methylsulfonyl-ethane C40 (5.2 g, 86%). 1 H NMR (400MHz, DMSO-d6) δ3.77-3.73 (t, J = 8.8 Hz, 2H), 3.44-3.42 (t, J = 8.8 Hz, 2H), 3.03 (s, 3H).

[1028] Step 2. Synthesis of 1-(2-methylsulfonylethyl)triazole-4-carbaldehyde (S18)

[1029] A mixture of 3,3-diethoxyprop-1-yne (555 μL, 3.897 mmol), 1-azido-2-methylsulfonyl-ethane C40 (600 mg, 4.022 mmol), CuSO 4 (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 hours. The reaction was cooled to room temperature, concentrated, and diluted in EtOAc (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The layers were combined and dried, diluted in 1N HCl (20 mL), and stirred overnight. At this time, the solution was concentrated to yield 1-(2-methylsulfonylethyl)triazole-4-carbaldehyde (hydrochloride) 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] + .

[1030] Preparation of S19

[1031] 1-(2-Methylsulfonylethyl)pyrazole-4-carbaldehyde (S19)

[1032]

[1033] 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 suspended in diethyl ether (100 mL), triturated, and stirred for 2 hours. The product was filtered and dried overnight to yield 11-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde S19 (20.28 g, 83%). 1 HNMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 8.54 (d, J = 0.7Hz, 1H), 8.05 (d, J = 0.7Hz, 1H), 4.64 (t, J = 6.8Hz, 2H), 3.80-3.67 (m, 2H), 2.96 (d, J = 0.7Hz, 3H). LCMS m / z 203.01[M+H] + .

[1034] Preparation of S20

[1035] 1-[2-[tert-Butyl(dimethyl)silyl]oxyethyl]pyrazole-4-carbaldehyde (S20)

[1036]

[1037] Step 1. Synthesis of tert-butyl-(2-iodoethoxy)-dimethyl-silane (C44)

[1038] 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 reactants were warmed to room temperature and stirred for 4 hours. The reaction mixture was diluted with DCM (100 mL), washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated under reduced pressure to give tert-butyl-(2-iodoethoxy)-dimethyl-silane C44 (2.5 g, 68%). 1 H 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).

[1039] Step 2. Synthesis of 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazole-4-carbaldehyde (S20)

[1040] To a solution of 1H-pyrazole-4-carboxaldehyde 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 reactants were heated to 80 ° C. The reactants were stirred for 5 hours. The reactants were cooled to 50 ° C and stirred for 16 hours. The reaction mixture was allowed to reach ambient temperature, filtered, and the solid was washed with MeCN (200 mL). The solid was discarded and the filtrate was concentrated. The residue was distributed between EtOAc (400 mL) and water (400 mL). The organic layer was separated, washed with water (400 mL) and brine (400 mL), dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (800 g column, 0-80% EtOAc in hexanes) gave the product, 1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazole-4-carbaldehyde S20 (46 g, 87%), as a light yellow oil. 1 H NMR (300MHz, chloroform-d) δ9.86 (s, 1H), 7.98 (s, 2H), 4.25 (dd, J = 5.5, 4.5Hz, 2H), 3.96 (dd, J = 5.5, 4.5Hz, 2H), 0.83 (s, 9H), -0.06 (s, 6H). LCMS m / z 255.14[M+H] + .

[1041] Preparation of S21

[1042] 1-[3-[tert-Butyl(dimethyl)silyl]oxy-2-[[tert-Butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (S21)

[1043]

[1044] Step 1. Synthesis of 2-(bromomethyl)-2-methyl-propane-1,3-diol (C46)

[1045] 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 48% (w / w), 123.7 mmol). After stirring for 24 hours, the mixture was concentrated to a minimum volume, diluted in DCM / MeOH, and the excess HBr was quenched with saturated sodium bicarbonate. The layers were separated and the organic layer was dried over NaSO, filtered, rinsed with methanol, and concentrated to yield 2-(bromomethyl)-2-methyl-propane-1,3-diol C46 (13.6682 g, 74%). 1 HNMR (400 MHz, methanol-d4) δ 3.47 (d, J = 1.1 Hz, 6H), 0.96 (s, 3H).

[1046] Step 2. Synthesis of [2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propyloxy]-tert-butyl-dimethyl-silane (C47)

[1047] 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, a white crystalline solid precipitated from the mixture. The mixture was filtered, rinsed with DCM, and concentrated. The mixture was diluted with heptane (25 mL) to further precipitate imidazole / imidazole HCl, filtered, and the solid was rinsed with heptane (10 mL). The mixture was concentrated to precipitate additional 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-propyloxy]-tert-butyl-dimethyl-silane C47 (22.246 g, 100%) 1 HNMR (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).

[1048] Step 3. Synthesis of 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (S21)

[1049] To a vial was added 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-propyloxy]-tert-butyl-dimethyl-silane C47 (9.5 g, 23.08 mmol) in DMF (20 mL). The mixture was heated to 130°C. After 3 hours, the mixture was cooled to room temperature and diluted with water (100 mL) and heptane (100 mL). The layers were combined and the aqueous layer was washed with heptane (2 x 100 mL). The combined organic layers were 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) gave 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] + .

[1050] Preparation of S22

[1051] 2-[(2-Hydroxy-1,1-dimethyl-ethyl)amino]pyrimidine-5-carbaldehyde (S22)

[1052]

[1053] Step 1. Synthesis of ethyl 2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]pyrimidine-5-carboxylate (C49)

[1054] 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 by silica gel chromatography (eluent: 70% EtOAc in petroleum ether) gave ethyl 2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]pyrimidine-5-carboxylate C49 (18 g, 55%).1 H NMR (400MHz, DMSO-d6) δ 8.70 (s, 2H), 7.39 (s, 1H), 4.86 (t, J = 6Hz, 1H), 4.25 (q, J = 6.8Hz, 2H), 3.52 (d, J = 6Hz, 2H), 1.32 (s, 6H), 1.28 (t, J = 6.8Hz, 3H). LCMS m / z 240.27[M+H] + .

[1055] Step 2. Synthesis of ethyl 2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidine-5-carboxylate (C50)

[1056] 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) at room temperature, followed by DMAP (1.0018 g, 0.0082 mol) and stirred for 16 hours. The reactants were 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 (400MHz, DMSO-d6) δ 8.70 (s, 2H), 7.46 (s, 1H), 4.25 (q, J = 7.2Hz, 2H), 3.77 (s, 2H), 1.30 (s, 6H), 1.28 (t, J = 7.6Hz, 3H), 0.82 (s, 9H), -0.06 (s, 6H). LCMS m / z 354.3[M+H] + .

[1057] Step 3. Synthesis of [2-[[2-[tert-Butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidin-5-yl]methanol (C51)

[1058] 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) was slowly added DIBAL-H (1M in toluene) (205.50 mL 1M, 0.2055 mol) at -78 ° C under nitrogen. The reactant was stirred at -78 ° C for 30 minutes and 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 x 500 mL). The organic layer was washed with 1N 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 (400MHz, DMSO-d6) δ8.19(s,2H),6.25(s,1H),4.99(t,J=5.6Hz,1H),4.27(d,J=5.6Hz,2H),3.71(s,2H),1.30(s,6H),0.84(s,9H),-0.03(s,6H). LCMS m / z 312.23[M+H] + .

[1059] Step 4. Synthesis of 2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidine-5-carbaldehyde (C52)

[1060] 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 MnO2 (851.98 mg, 0.0098 mol) at room temperature and stirred for 6 hours. The reaction was filtered and washed with DCM (10 mL).The filtrate was concentrated under reduced pressure to provide 2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]amino]pyrimidine-5-carbaldehyde C52 (90 mg, 99%). 1H NMR (400MHz, DMSO-d6) δ9.71 (s, 1H), 8.71 (d, J = 11.6Hz, 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] + .

[1061] Step 5. Synthesis of 2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]pyrimidine-5-carbaldehyde (S22)

[1062] 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) was added TBAF (1 M in THF) (21.700 mL of 1 M, 0.0217 mol) at room temperature and stirred for 2 hours. 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%). 1 H NMR (400MHz, DMSO-d6) δ9.72 (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] + .

[1063] Preparation of S23

[1064] (3S)-3-Aminobutyric acid (S23)

[1065]

[1066] (3S)-3-Aminobutyric acid (S23) was obtained from a commercial source.

[1067] Preparation of S24

[1068] 4-Aminopentan-2-one hydrochloride (S24)

[1069]

[1070] 4-Aminopentan-2-one hydrochloride (S24) was obtained from a commercial source.

[1071] Preparation of S25

[1072] (4S)-4-Aminopentan-2-one hydrochloride (S25)

[1073]

[1074] Step 1. Synthesis of (3S)-3-(tert-butoxycarbonylamino)butanoic acid (C53)

[1075] To a solution of (3S)-3-aminobutyric acid S23 (100 g, 969.7 mmol) in dioxane (600 mL) was added an aqueous NaOH solution (950 mL 1M, 950.0 mmol) followed by Boc2O (300 g, 1.375 mol) over 15 minutes. The reaction mixture was stirred at room temperature for 12 hours. The reactants were partitioned between MTBE (1 L) and water (300 mL). The layers were separated and the aqueous layer was extracted again with MTBE (500 mL). The aqueous layer was then acidified with 1N HCl until pH = 2 and extracted with DCM (3 x 600 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to produce (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).

[1076] Step 2. Synthesis of tert-butyl N-[(1S)-3-[methoxy(methyl)amino]-1-methyl-3-oxo-propyl]carbamate (C54)

[1077] To a solution of (3S)-3-(tert-butoxycarbonylamino)butanoic acid C53 (160 g, 787.3 mmol) in DCM (1.5 L) was added N-methoxymethylamine (hydrochloride) (81 g, 830.4 mmol), followed by DIPEA (560 mL, 3.215 mol) over 10 minutes. The reaction mixture was cooled to 0°C and T3P (600 g of 50% (w / w) in EtOAc, 942.9 mmol) was added over 45 minutes. After the addition, the cooling bath was removed and the reaction was stirred at room temperature for 1 hour. The reaction mixture was cooled to 10°C and 1N aqueous NaOH (700 mL) was added and the solution was stirred for 15 minutes. The organic phase was separated, washed with saturated aqueous ammonium chloride solution (200 mL) and brine (200 mL), dried, filtered through a plug of silica gel, 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. 1 H 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).

[1078] Step 3. Synthesis of tert-butyl N-[(1S)-1-methyl-3-oxo-butyl]carbamate (C55)

[1079] 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) was added iodine (methyl) magnesium (900 mL 3M, 2.700 mol) at 0 ° C within 40 minutes. The resulting reaction mixture was stirred at 0 ° C for 4 hours. The reactant was quenched with saturated ammonium chloride solution (2 L) and subsequently quenched with MTBE (1 L) and water (2 L). The mixture was stirred for 30 minutes and the organic layer was separated. The aqueous phase was extracted with MTBE (1 L) and the combined organic layer was washed with saturated ammonium chloride solution (1 L), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-70% EtOAc in heptane) gave the product tert-butyl N-[(1S)-1-methyl-3-oxo-butyl]carbamate C55 (115 g, 64%) as a white solid. 1H 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).

[1080] Step 4. Synthesis of (4S)-4-aminopentan-2-one (hydrochloride) (S25)

[1081] 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 4 M in dioxane, 200.0 mmol) over 3 minutes. The reaction was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was co-evaporated with EtOH (2 x 30 mL) and dried under vacuum to afford (4S)-4-aminopentan-2-one (hydrochloride) 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).

[1082] Preparation of S26 (Method A)

[1083] (2S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S26)

[1084]

[1085] Step 1. Synthesis of (2S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (C56)

[1086] 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: 0-60% of 20% MeOH / DCM in DCM) gave the product (2S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one C56 (6.7 g, 44%) in a 5:1 cis to trans ratio. In addition, the er from the stereocenter of S25 was reduced to 85%.

[1087] 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).

[1088] NMR rationalization of stereoisomer assignments in C56: It should be noted that the major component in C56 was assigned as the cis stereoisomer using the NMR coupling constant data for the peak at 4.26 ppm (C5-methylene protons). The triazole at C6 was assumed to occupy the equatorial axis position in the lowest energy configuration. The coupling between the axial C-H at C4 and one of the C-H protons at C5 (J = 10.3 Hz) indicated a 180° relationship as defined by the Karplus equation. Traces of trans product were removed in a subsequent recrystallization step to afford S26.

[1089] Step 2. Synthesis of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S26)

[1090] A solution of (2S)-2-methyl-6-(1-methyltriazole-4-yl)piperidin-4-one C56 (6.7 g) in MTBE (100 mL) with a ratio of 5:1 cis to trans was heated to reflux for 30 minutes. Ethanol was slowly added until all solids dissolved (20 mL). The solution was refluxed for 30 minutes and allowed to slowly cool overnight. Solid was crystallized, diluted with MTBE (30 mL), filtered, and dried under vacuum to give (2S, 6S)-2-methyl-6-(1-methyltriazole-4-yl)piperidin-4-one S26 (3.2 g, 48%) as a white solid. Its enantiomeric ratio was >85%, and all other compounds were obtained using S26 as starting material, unless otherwise mentioned (excluding the embodiment of SFC purification). 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).

[1091] Alternative preparation of S26 (Method B)

[1092] ((2S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S26)

[1093]

[1094] Step 1. Synthesis of bis[(3-tert-butoxy-3-oxo-propionyl)oxy]magnesium (C109)

[1095] A solution of 3-tert-butoxy-3-oxo-propionic 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 cooling bath and stirred at room temperature overnight. The reaction was filtered through a plug and the plug was washed with THF. The clear colorless filtrate was evaporated in vacuo to give a pasty solid. The solid was ground with 1 L of ether and filtered. The filter cake was washed with Et2O and dried in vacuo. The filtrate was evaporated again in vacuo and then ground with a small volume of Et2O and filtered to give a second batch of product. The batches were combined and dried in vacuo to give bis[(3-tert-butoxy-3-oxo-propionyl)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.

[1096] Step 2. Synthesis of tert-butyl (5S)-5-(tert-butoxycarbonylamino)-3-oxo-hexanoate (C111)

[1097] 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). The milky suspension became clear over the next few minutes. Gas evolution was observed. The reactants were stirred at room temperature for 3 hours. Bis[(3-tert-butoxy-3-oxo-propionyl)oxy]magnesium C109 (172.19 g, 502.6 mmol) was added. Another milky suspension was formed, which became clear after stirring for 30 minutes. The reactants were stirred for 48 hours. The reactants were poured into 1.5 L of 1N HCl and extracted with MTBE (1 L). The pH was confirmed to be approximately pH 3. The extract was washed with saturated aqueous NaHCO 3 , separated, dried over MgSO 4 , filtered, and evaporated in vacuo to give (5S)-5-(tert-butoxycarbonylamino)-3-oxo-hexanoic acid tert-butyl ester C111 (248.5 g, 98.5%). 1 HNMR (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.

[1098] Step 3. Synthesis of (2S,3R,6S)-6-methyl-2-(1-methyltriazol-4-yl)-4-oxo-piperidine-3-carboxylic acid tert-butyl ester (C112)

[1099] To a solution of (5S)-5-(tert-butoxycarbonylamino)-3-oxo-tert-butyl 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 reactant was evaporated in vacuo at 25 ° C. The retained solid was ground with 500 mL of pentane and filtered. The filter cake was washed with pentane and most of the solvent was squeezed out from the filter cake. The cake was transferred back to the reaction flask and dissolved in 1 L of DCM.

[1100] 1-Methyltriazole-4-carboxaldehyde S17 (120.7 g, 1.086 mol) was added. The reaction was stirred at room temperature overnight. Brine (100 mL) was added and 6N NaOH was added until the aqueous layer remained alkaline when the funnel was shaken. The organic layer was separated and the aqueous layer was extracted with DCM (1 L). The organic layers were combined, dried over MgSO4, and filtered through a silica gel plug. The plug was eluted with 10% MeOH in EtOAc. The filtrate was evaporated in vacuo to give a solid, which was ground with MTBE (500 mL) and filtered. The filter cake was washed with MTBE and dried in vacuo to give a batch of products. The mother liquor from the grinding was concentrated. The precipitated solid was filtered to provide a second batch of products. The batches were combined to give (2S, 3R, 6S)-6-methyl-2-(1-methyltriazole-4-yl)-4-oxo-piperidine-3-carboxylate C112 (105.45 g, 43%). 1 H NMR (300MHz, chloroform-d) δ7.48(s,1H),4.52(d,J=11.0Hz,1H),4.09(s,3H),3.61(dd,J=11.0,1.0Hz,1H),3.21(ddd,J=11.7 ,6.1,2.9Hz,1H),2.55(dd,J=13.7,2.9Hz,1H),2.37-2.13(m,1H),1.98(s,1H),1.39(s,9H),1.29(d,J=6.3Hz,3H)ppm.

[1101] Step 4. Synthesis of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one (S26)

[1102] To a solution of (2S,3R,6S)-6-methyl-2-(1-methyltriazol-4-yl)-4-oxo-piperidine-3-carboxylic acid tert-butyl ester C112 (70.59 g, 239.8 mmol) in DCM (750 mL) was added MsOH (62 mL, 955.4 mmol) and the reactants were heated to reflux for 6 hours. The reactants were 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 solution was extracted with DCM (2 x 500 mL). The organic layers were combined, dried over MgSO4, 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.

[1103] Preparation of S27-S29

[1104] Intermediates S27-S29 (see Table 1) were prepared from intermediate S25 in a single step using the appropriate aldehyde and the method described for intermediate S26 (Method A). The aldehydes were prepared by the methods described above or obtained from commercial sources. With respect to intermediate S26 (prepared by Method A), partial stereochemical elimination of the enantiomerically pure starting material (4S)-4-aminopentan-2-one (hydrochloride) S25 was observed in Step 1, resulting in an unseparated mixture of stereoisomers in Step 1. In each case, the cis product was the major isomer. This mixture is represented by the use of a wavy bond. Any modifications to the method are identified in Table 1 and the accompanying footnotes.

[1105] Table 1. Preparation methods, structures and physicochemical data of intermediates S27-S29

[1106]

[1107]

[1108] 1. Stir the reaction over the weekend (step 1)

[1109] 2. The crude residue was diluted with water and saturated sodium bicarbonate solution and extracted with DCM (5x) via a phase separator. (Step 1)

[1110] 3. Purify by silica gel chromatography (gradient: 0-50% of 20% MeOH / DCM in DCM) to give the product. (Step 1)

[1111] 4. Purge minor isomers through chromatography and do not proceed with step 2.

[1112] 5. Purify by silica gel chromatography (gradient: 0-100% of 20% MeOH / DCM in DCM) to give the product. (Step 1)

[1113] Compound 1

[1114] (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)

[1115]

[1116] 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 minutes, at which time it was cooled to room temperature and quenched with 2N NaOH until the pH reached 14. 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% of 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 ratio >8:1. It was inferred that the minor isomer observed was the enantiomer of compound 1, as S26 prepared by Method A contained a minor amount of the other cis enantiomer. It should be noted that the relative stereochemistry of compound 1 was assigned by NOE NMR studies. 1H 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=13.6,2.6Hz,1H), 2.06(dt,J=13.7,2.5Hz,1H), 1.79(dd,J=13.6,11. 8Hz, 1H), 1.42 (dd, J = 13.7, 11.3Hz, 1H), 1.31-1.19 (m, 1H), 1.12 (d, J = 6.4Hz, 3H). LCMSm / z 339.0[M+H] + .

[1117] Alternative preparation of compound 1 (HCl salt)

[1118] (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)

[1119] To (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 minutes, at which time it was 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% of 20% MeOH / DCM in DCM) gave the product, which was immediately dissolved in a small amount of DCM and treated with HCl (100 μL 4M 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 as a pale yellow solid (171.6 mg, 43%). 1H NMR (300MHz, DMSO-d6) δ9.46(s,1H),9.24(d,J=8.3Hz,1H),8.29(s,1H),6.95(s,1H),4.67(t,J=11.1Hz,1H),4.09(s,3H),3.95(t,J =5.4Hz,2H),3.72(s,1H),2.61(t,J=5.3Hz,2H),2.46-2.32(m,2H),2.25(d,J=15.1Hz,1H),2.01-1.86(m,1H),1.29(d,J=6.5Hz,3H). LCMSm / z 339.0[M+H] +

[1120] Compound 2

[1121] (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)

[1122]

[1123] To a solution of (2S, 6S) -2- methyl -6- (1- methyltriazole -4- bases) 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 μ L, 7.705 mmol) and the reactant was heated to 40 ° C. After 16 hours, additional MsOH (200 μ L, 3.082 mmol) was added and the reactant was continued to be heated overnight. The mixture was diluted with water (4 mL) and DCM (5 mL) and quenched with the NaOH aqueous solution (2 mL 6M, 12.00 mmol). The mixture was separated, extracted with DCM (2x 5 mL), passed through a phase separator, and organic matter was concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-10% MeOH in DCM) gave (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 as a white solid (445 mg, 93%). Note that the relative stereochemistry of compound 2 was assigned by NOE NMR studies. 1H NMR (300MHz, chloroform-d) δ7.46(s,1H),7.14(s,1H),4.47(d,J=11.6Hz,1H),4.08(d,J=3.3Hz,3H),4.00(s,2H),3.36(s,1H),2.72(d,J= 5.6Hz, 2H), 2.41 (d, J = 14.2Hz, 1H), 2.12 (d, J = 13.7Hz, 1H), 1.86 (t, J = 12.7Hz, 1H), 1.49 (d, J = 12.8Hz, 1H), 1.15 (d, J = 6.3Hz, 3H). LCMS m / z 373.07[M+H] +

[1124] Compound 3-16

[1125] Compounds 3-16 (see Table 2) were prepared by a single Oxa-Pictet Spengler step using isolated piperidones (S26, S29, or C56) and the related thiophene alcohols described for compounds 1 and 2. The thiophene alcohols and piperidones were prepared by the methods described above or obtained from commercial sources. In the examples using S26, S26 was prepared by Method A, so the piperidone used may contain small amounts of other cis-isomers. Any modifications to the method are identified in Table 2 and the accompanying footnotes.

[1126] Table 2. Preparation methods, structures and physicochemical data of compounds 3-16.

[1127]

[1128]

[1129]

[1130]

[1131] 1. Stir the reaction for 30 minutes.

[1132] 2. Upon completion, the mixture was concentrated and diluted in MeOH. No further work was performed.

[1133] 3. Purification by reverse phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O with 5 mM HCl) gave the product as the HCl salt.

[1134] 4. The organic layer was collected through a phase separator and dried under nitrogen.

[1135] 5. After purification, the product was dissolved in 0.6 mL of water, cooled, and lyophilized overnight to obtain.

[1136] 6. Stir the reaction overnight.

[1137] 7. Once the reaction was complete, the organic layer was separated, dried over Na2SO4, filtered, and concentrated.

[1138] 8. Purification by silica gel chromatography (Gradient: 0-20% MeOH in DCM) gave the product.

[1139] 9. The reaction was run with C56, enriching the mixture of two isomers from the purification of S26. Compound 7 was isolated as a single diastereomer as a minor product of the Pictet-Spangler reaction. As described in Method A for S26, epimerization of the S25 stereocenter was observed, providing this compound as a mixture of enantiomers.

[1140] After 10.50 minutes, the reaction was quenched with saturated NaHCO 3 solution and extracted with DCM (6×). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated.

[1141] Compound 17

[1142] [(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)

[1143]

[1144] Step 1. 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]methyl acetate (C57)

[1145] To a mixture of (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one S26 (10 mg, 0.05148 mmol) and [4-(2-hydroxyethyl)-2-(trifluoromethyl)-3-thienyl]methyl 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 hours, the reaction was quenched with saturated NaHCO solution, the layers were separated and the mixture was concentrated to dryness to give crude C57.

[1146] 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)

[1147] The crude material C57 was diluted with MeOH (2 mL) and NaOH (20 μL 6M, 0.1200 mmol) was added to the mixture. The reaction was stirred for 5 minutes. The mixture was concentrated, diluted 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 17 as the parent.

[1148] The deprotected 17 (mother compound) was diluted with ether (1 mL) and HCl (13 μL 4M in dioxane, 0.05200 mmol) was added, immediately precipitating a white solid. The mixture was concentrated and azeotroped three times with ether to yield [(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(300MHz,DMSO-d6)δ9.35(d,J=9.8Hz,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=13.5Hz,1H),1.29(d,J=6.5Hz,3H). LCMS m / z 403.13[M+H] + .

[1149] Compound 18

[1150] 2-[4-[(2S,6S)-2-Chloro-6'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidinyl]-2'-yl]pyrazol-1-yl]-N,N-dimethyl-acetamide (18)

[1151]

[1152] 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 CsCO (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 hour. The reaction was quenched with saturated NaHCO solution and extracted with EtOAc (4x). The combined organic layers were dried over NaSO, filtered, and concentrated. Purification by reverse phase HPLC (method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O) 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%). 1 H NMR (300MHz, chloroform-d) δ7.50(s,2H),6.57(s,1H),4.92(s,2H),4.17(dd,J=11.6,2.5Hz,1H),3.93(t,J=5.5Hz,2H),3.25(d,J=9.1Hz,1H),3.06(s,3H ),2.97(s,3H),2.60(td,J=5.4,1.8Hz,2H),2.25(d,J=13.6Hz,1H),2.01 (s, 1H), 1.70 (d, J = 12.5Hz, 1H), 1.47-1.32 (m, 1H), 1.11 (d, J = 6.4Hz, 3H). LCMS m / z 409.19[M+H] + .

[1153] Compound 19

[1154] (2S)-2-Chloro-2'-methyl-6'-(1-methylpyrazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine](19)

[1155]

[1156] 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), MgSO4 (25 mg, 0.2077 mmol) and L-proline (5 mg, 0.043 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated at 40 ° C. via Genevac until dryness 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 (750.0 μL), followed by a solution of TfOH (80 μL, 0.90 mmol) in dioxane (750.0 μL). The mixture was stirred at room temperature for 30 minutes. Additional trifluoromethanesulfonic acid (50 μL, 0.5650 mmol) was added and stirring continued for 10 minutes. The reactants were placed under a nitrogen stream until the volume was reduced by half. The remaining solution was quenched with NaOH (1.5 mL 2M, 3.000 mmol) and diluted with DCM (1.500 mL). The resulting biphasic mixture was stirred for a few minutes and then passed through a phase separator. The organic layer was purged with nitrogen. Purified by reverse phase HPLC (method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid) to obtain (2S)-2-chloro-2'-methyl-6'-(1-methylpyrazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]19 as a trifluoroacetate salt (6.6 mg, 11%). Compound 19 was determined to be 88% er by chiral SFC analysis (method: AD-H column (4.6 x 100 mm). Gradient: 10% MeOH and 90% CO2 with 5 mM ammonia). 1 H NMR(400MHz,DMSO-d6)δ8.91(d,J=10.8Hz,1H),8.49(d,J=11.3Hz,1H),7.86( s,1H),7.59(s,1H),6.94(s,1H),4.49(t,J=11.2Hz,1H),3.93(t,J=5.5Hz,2H) ,3.84(s,3H),2.93(td,J=13.9,6.9Hz,1H),2.60(t,J=5.5Hz,2H),2.35(d,J= 17.2Hz, 1H), 2.21 (q, J = 13.9Hz, 2H), 1.84-1.73 (m, 1H), 1.24 (d, J = 6.6Hz, 3H). LCMS m / z 338.17[M+H] +

[1157] Compound 20

[1158] 2-Chloro-2'-methyl-6'-(3-pyridyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine](20)

[1159]

[1160] A solution of 4-aminopentan-2-one hydrochloride S24 (25 mg, 0.1817 mmol) in EtOH (1 mL) was added to pyridine-3-carboxaldehyde (19.5 mg, 17.06 μL, 0.1817 mmol), MgSO4 (25 mg, 0.2077 mmol) 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 more than 3 days. The reaction mixture was evaporated under a stream of nitrogen to give crude C59. A solution of 2-(5-chloro-3-thienyl)ethanol S2 (25 μL, 0.2075 mmol) in dioxane (750 μL) was added thereto, 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 minutes. The reactant was placed under a nitrogen stream until the volume was reduced by half. The remaining solution was quenched with NaOH (1.5mL 2M, 3.000mmol) and diluted with DCM (1.500mL). The resulting biphasic mixture was stirred for a few minutes and then passed through a phase separator. The organic layer was bubbled with nitrogen. Purified by reverse phase HPLC (method: C18 Waters Sunfire column (30x 150mm, 5 microns). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid), 2-chloro-2'-methyl-6'-(3-pyridyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]20 was obtained as trifluoroacetate salt (34.4mg, 56%). Compound 20 was determined by chiral SFC analysis to be 94% cis enantiomer and 6% trans enantiomer (method: AD-H column (4.6 x 100 mm). Gradient: 10% MeOH and 90% CO2 with 5 mM ammonia). 1H 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 = 5.5H z,2H),3.90(dqd,J=13.4,6.7,3.1Hz,1H),2.67(t,J=5.6Hz,2H),2.51(dt,J=14.5, 2.9Hz, 1H), 2.46-2.30 (m, 2H), 1.93 (dd, J = 14.8, 12.2Hz, 1H), 1.41 (d, J = 6.6Hz, 3H). LCMS m / z 335.14[M+H] + .

[1161] Compound 21

[1162] (2S)-2-Chloro-2'-methyl-6'-(2-methyl-4-pyridinyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine](21)

[1163]

[1164] 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 between 35-40 ° C via Genevac 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 minutes. The reaction mixture was evaporated at 40 ° C via Genevac. The residue was quenched with NaOH (1.7 mL 2M, 3.400 mmol) and diluted with DCM (1.7 mL). The resulting biphasic mixture was stirred for a few minutes and then passed through a phase separator. The organic layer was purged with nitrogen. Purified by reverse phase HPLC (method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid) to obtain (2S)-2-chloro-2'-methyl-6'-(2-methyl-4-pyridyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] 21 (19.3 mg, 21%) as a trifluoroacetate salt. Compound 21 was determined to be 77% er by chiral SFC analysis (method: AD-H column (4.6 x 100 mm). Gradient: 10% MeOH and 90% CO2 with 5 mM ammonia). 1 H NMR (400 MHz, DMSO-d6) δ9.28 (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 (hidden under the water peak of 1H), 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]+

[1165] Compound 22-172

[1166] Compound 22-172 (see Table 3) follows the method for compound 19, 20 or 21 in a two-step one-pot procedure to prepare trifluoroacetate. Intermediate S24 or S25, appropriate aldehyde and thiophene ethanol S2 are used. Aldehydes are prepared by the methods described above or obtained from commercial sources. Partial stereochemical elimination of (4S)-4-aminopentan-2-one (hydrochloride) S25 of the enantiomerically pure starting material is observed under the reaction conditions of step 1, resulting in an unseparated mixture of 2,6-trans piperidine enantiomers. This is produced by a mixture of cis-piperidone intermediates (as previously described in Method A for preparing S26) and subsequent 2,6-trans piperidine final products, in which 2 and 6 substituents are cis, and 2 and 4 substituents are trans. Any modifications to the method are identified in Table 3 and the accompanying footnotes.

[1167] Table 3. Preparation methods, structures and physicochemical data of compounds 22-172

[1168]

[1169]

[1170]

[1171]

[1172]

[1173]

[1174]

[1175]

[1176]

[1177]

[1178]

[1179]

[1180]

[1181]

[1182]

[1183]

[1184]

[1185]

[1186]

[1187]

[1188]

[1189]

[1190]

[1191]

[1192]

[1193]

[1194]

[1195]

[1196] 1. The product is obtained in the form of a free base.

[1197] 2. The product was isolated as a 3:2 mixture of diastereomers with unknown absolute stereochemistry.

[1198] 3. The mixture from step 1 was bubbled with nitrogen at 40°C.

[1199] 4. Purification by silica gel chromatography (Gradient: 0-100% of 20% MeOH in DCM / DCM) gave the product.

[1200] 5. TBS was deprotected during the reaction (step 2).

[1201] 6. The product was impure after purification and was repurified by reverse phase HPLC (method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O with 10 mM ammonium hydroxide).

[1202] 7. The product was isolated as a 4.5:1 mixture of diastereomers with unknown absolute stereochemistry.

[1203] 8. Stir step 1 at room temperature for one week.

[1204] 9. The pH was carefully adjusted to about pH 7 with 2N NaOH before extraction with DCM.

[1205] 10. The product was isolated as a 2:1 mixture of diastereomers with unknown absolute stereochemistry.

[1206] 11. The product was isolated as a 3:1 mixture of diastereomers with unknown absolute stereochemistry.

[1207] 12. The product was isolated as a 5:1 mixture of diastereomers with unknown absolute stereochemistry.

[1208] 13. The product was isolated as a 3.5:1 mixture of diastereomers with unknown absolute stereochemistry.

[1209] 14. The product was impure after purification and was repurified by reverse phase HPLC (method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O with 0.2% formic acid). The product was obtained as a formate salt.

[1210] 15. The product was obtained as a bis-TFA salt.

[1211] 16. The product was isolated as a 4:1 mixture of diastereomers with unknown absolute stereochemistry.

[1212] 17. A complex mixture of stereoisomers is obtained.

[1213] Compound 173

[1214] (2S)-2-Chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](173)

[1215]

[1216] 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)

[1217] 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 to 40 ° C for 40 minutes. More methanesulfonic acid (800 μL, 12.33 mmol) was added and the reaction was heated for another 30 minutes. The reaction was cooled to room temperature, diluted with water, and basified with 2N NaOH solution. The mixture was extracted with DCM (3 x 20 mL) through a phase separator 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]

[1218] A solution of crude (2S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] in DCM (9 mL) with DIPEA (600 μL, 3.445 mmol) was cooled to 0°C. TFAA (390 μL, 2.806 mmol) was added slowly over 2 minutes and the reaction was stirred at 0°C. After 15 minutes, the reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM (3x). The organics were dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-50% EtOAc in heptane) gave a 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-trifluoro-ethanone 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).

[1219] 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)

[1220] 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-trifluoro-ethanone C61 (20 mg, 0.04415 mmol) in MeOH (1 mL) was treated with NaOH (400 μL 2M, 0.8000 mmol). The solution was heated to 50° C. for 3 hours, at which point it was cooled to room temperature and stirred overnight. The reaction was extracted with DCM (3x) through a phase separator and the organics were concentrated in vacuo to afford (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 approximate er of 85%. 1 H NMR (300MHz, chloroform-d) δ7.41 (s, 1H), 6.61 (s, 1H), 4.40 (dd, J = 11.8, 2.7Hz, 1H), 4. 05(s,3H),3.96(td,J=5.7,2.0Hz,2H),3.28(dtd,J=12.6,6.3,2.5Hz,1H),2.85 -2.60(m,2H),2.18(dt,J=13.5,2.6Hz,1H),1.89(dt,J=13.7,2.5Hz,1H),1.80 (dd, J=13.6, 11.9Hz, 1H), 1.44 (dd, J=13.7, 11.4Hz, 1H), 1.11 (d, J=6.3Hz, 3H). LCMS m / z 339.1[M+H] +

[1221] Preparation of S32

[1222] (2S,4S,6S)-2-Methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)-2'-(trifluoromethyl)spiro[piperidin-4,7'-thieno[2,3-c]pyran]-4'-one (S32)

[1223]

[1224] 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)

[1225] 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) dissolved in DCM (25 mL) and cooled to -15°C was added DIPEA (800 μL, 4.593 mmol) followed by TFAA (550 μL, 3.957 mmol). After 5 minutes, the mixture was quenched with 1N HCl (25 mL) and the phases were separated. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (Gradient: 0-50% 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 (400MHz, methanol-d4) δ7.93(s,1H),7.27(d,J=1.3Hz,1H),5.63(s,1H),4.46(h,J=7.1Hz,1H),4.11(d,J=1.4Hz,3H),3.96(t d,J=5.6,1.7Hz,2H),3.04(s,1H),2.79-2.70(m,3H),2.51(s,1H),2.09(dd,J=14.7,7.3Hz,1H),1.23(q,J=9.6,8.4Hz,3H). LCMS m / z 469.14[M+H] + .

[1226] Step 2. Synthesis of (2S,4S,6S)-2-methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)-2'-(trifluoromethyl)spiro[piperidin-4,7'-thieno[2,3-c]pyran]-4'-one (S32)

[1227] To 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 added N-hydroxyphthalimide (165 mg, 1.011 mmol) and cobalt diacetate tetrahydrate (35 mg, 0.1405 mmol) and the mixture was then purged with an oxygen balloon under vacuum three times. The mixture was heated to 60 ° C and filtered. After one and a half hours, the reactants were cooled to room temperature. The mixture was purged with nitrogen under vacuum three times and then diluted with MTBE (25 mL) and a saturated aqueous bicarbonate solution (25 mL). The layers were separated and the organic layer was washed with aqueous NaHCO3 (2x50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (gradient: 0-50% EtOAc in heptane) gave (2S,4S,6S)-2-methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)-2'-(trifluoromethyl)spiro[piperidin-4,7'-thieno[2,3-c]pyran]-4'-one S32 (207 mg, 26%). 1 H NMR (300MHz, methanol-d4) δ7.98(s,1H),7.80(d,J=1.4Hz,1H),5.70(s,1H),4.48(s,1H),4.45(s,2H),4.12(s,3H), 2.95(dd,J=14.8,9.8Hz,1H),2.73(s,1H),2.22(dd,J=14.8,8.4Hz,1H),1.29(s,1H),1.19(d,J=14.9Hz,3H). LCMS m / z 483.45[M+H] + .

[1228] Preparation of intermediates S33-S36

[1229] Intermediate ketones S33-S36 (see Table 4) were prepared in two steps from related compounds using TFAA protection and benzylic oxidation as described for intermediate S32. Any modifications to the methods are identified in Table 4 and the accompanying footnotes.

[1230] Table 4. Preparation methods, structures, and physicochemical data of ketone intermediates S33-S36

[1231]

[1232] 1. Add TFAA at 0°C (step 1)

[1233] 2. Stir the reaction at 45°C (step 2)

[1234] 3. The mixture was quenched with water (10 mL) and the layers were separated. The organic layer was washed with 1N HCl (10 mL), brine (10 mL), dried over magnesium sulfate, filtered, and concentrated. (Step 1)

[1235] 4. Stir the reaction for 18 hours (step 2)

[1236] 5. Purify by silica gel chromatography (0-100% EtOAc:heptane) to give the product (step 1)

[1237] 6. Quench with water, followed by 1N HCl (step 1)

[1238] 7. Stir the reaction for 45 minutes (step 1)

[1239] 8. The reaction was diluted with DCM, water and saturated sodium bicarbonate. Extracted with DCM (3x) and collected through a phase separator (step 1)

[1240] 9. The reaction was diluted with DCM, water and saturated sodium bicarbonate. Extracted with DCM (3x) and collected through a phase separator (step 2)

[1241] 10. Purification by silica gel chromatography (0-100% EtOAc in heptane) gave the product (step 2)

[1242] 11. Purification by silica gel chromatography (0-80% EtOAc in heptane) gave the product (step 2)

[1243] 12. Purification by silica gel chromatography (0-45% EtOAc in heptane) gave the product (step 2)

[1244] 13. Stir the reaction overnight (step 2)

[1245] 14.S36 has about 85% er

[1246] Preparation of S33

[1247]

[1248] 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)

[1249] 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 was added TFAA (6.4 mL, 46.04 mmol). After 5 minutes, the mixture was quenched with 1N HCl (100 mL) and the phases 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 heated to reflux. After 30 minutes, the mixture was cooled to 0 ° C, and after 10 minutes, the material was filtered and rinsed with additional cold TBME. The product was dried to yield 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] + .

[1250] Step 2. Synthesis of (2S,4S,6S)-2'-chloro-2-methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)spiro[piperidin-4,7'-thieno[2,3-c]pyran]-4'-one (S33)

[1251] To a mixture of 1-[(2'S, 6'S, 7S)-2-chloro-2'-methyl-6'-(1-methyltriazole-4-yl) spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]-2,2,2-trifluoro-ethanone (C154) (4.5g, 10.24mmol) in acetonitrile (70mL) was added N-hydroxyphthalimide (1.2g, 7.36mmol) and cobalt diacetate tetrahydrate (550mg, 0.216mmol) and the mixture was then purged three times with an oxygen balloon under vacuum. The mixture was heated to 45°C and stirred for 18 hours, then cooled to room temperature. The reactant was diluted with DCM, water and saturated sodium bicarbonate, then extracted with DCM (3x150mL) and collected by a phase separator. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (Gradient: 0-50% EtOAc in heptane) afforded (2S,4S,6S)-2′-chloro-2-methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)spiro[piperidin-4,7′-thieno[2,3-c]pyran]-4′-one S33 (3.50 g, 68%).1 HNMR (300MHz, chloroform-d) δ7.61(s,1H),7.19(s,1H),5.61(s,1H),4.44(q,J=7.1Hz,1H),4.31(s,2H),4.12(s,3H),3. 34(dd,J=15.1,6.2Hz,1H),2.78(dd,J=15.1,8.3Hz,1H),2.70-2.43(m,1H),2.16(s,1H),1.27(d,J=7.3Hz,3H). LCMS m / z 449.12[M+H] + .

[1252] Compound 174

[1253] (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)

[1254]

[1255] 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)

[1256] To (2S,4S,6S)-2'-chloro-2-methyl-6-(1-methyltriazol-4-yl)-1-(2,2,2-trifluoroacetyl)spiro[piperidin-4,7'-thieno[2,3-c]pyran]-4'-one S33 (3.5 g, 7.025 mmol) in DCM (60 mL) was added 1,2,3,4,5-pentamethylcyclopentane rhodium tetrachloride (2+) (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 equipped with an air balloon to capture the CO2 off-gas byproduct. After two hours, the mixture was washed with saturated aqueous sodium bicarbonate solution (150 mL). The organic phase was separated, passed through a phase separator, and concentrated. Purification on silica gel (column: 120 g silica gel, gradient: 0-45% EtOAc in heptane) gave 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'-piperidine]-1'-yl]-2,2,2-trifluoro-ethanone C63 (3.3 g, 86%) as a pale off-white foam. 1 H NMR (300MHz, chloroform-d) δ7.59 (s, 1H), 6.83 (s, 1H), 5.53 (s, 1H), 4.46 (dt, J = 9.1, 3.1Hz, 2H), 4.10 (s, 3H), 4.03-3.80 (m, 2H), 3.10 (dd, J=15.1,7.3Hz,1H),2.65(ddd,J=15.1,8.1,2.2Hz,1H),2.47(s,1H),2.21-2.08(m,1H),2.08(d,J=9.2Hz,1H),1.40-1.19(m,3H). LCMS m / z 451.05[M+H] + .

[1257] It should be noted that the stereochemistry of alcohol C63 was assigned using NMR NOE studies and reduced literature understanding using this catalyst and ligand system (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).

[1258] 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)

[1259] 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-trifluoro-ethanone C63 (3.33 g, 100%) in MeOH (50 mL) was added NaOH (40 mL 2M, 80.00 mmol) and the mixture was stirred at 60 ° C. After 40 minutes, the mixture was diluted with saturated aqueous ammonium chloride until pH 10 (about 50 mL) and extracted with MTBE (5 x 100 mL)...

Claims

1. A compound represented by the following structural formula: a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 Selected from S and -CR 2a And X 2 Selected from S and -CR 2b ,in: X 1 and X 2 One is S; When X 1 When it is S, then X 2 -CR 2b ;and When X 2 When it is S, then X 1 Yes-CR 2a ; R 1 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy and C3-C6 cycloalkyl, wherein: R 1 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen and cyano; R 1 The C1-C6 alkoxy group is optionally substituted by 1 to 3 groups independently selected from halogen; R 1 The C3-C6 cycloalkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen and cyano; R 2a is selected from hydrogen, halogen, cyano, -OH, =O and C1-C6 alkyl, wherein: R 2a The C1-C6 alkyl group is optionally substituted by 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 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH; R 3b is selected from C1-C2 alkyl, said C1-C2 alkyl being optionally substituted with 1 to 3 groups independently selected from halogen and -OH; When R 3a When selected from halogen, cyano, OH, C1-C6 alkyl or when R 3b When selected from C1-C2 alkyl, A single bond at each occurrence; or when R 3a =0, Each occurrence is a double bond; R 4 selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), C2-C6 alkynyl and in: R 4 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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- to 10-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl; Ring A is selected from C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 aryl and 5- to 10-membered heteroaryl, wherein ring A is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution; wherein: R a is independently selected at each occurrence from 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 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl; wherein: R a The C1-C6 alkyl, the C1-C6 alkoxy and the C2-C6 alkenyl are each optionally substituted by 1 to 3 groups independently selected from the following groups: C6 to C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, 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 carbocyclic group; wherein C6 to C 10 Aryl, 5- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl and C3-C6 carbocyclic group are each independently optionally substituted by 1 to 3 R m group substitution; R a The C3-C 12 Carbocyclic group, said 3 to 12 membered heterocyclic group, said C6 and C 10 Aryl and the 5- to 10-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, cyano, C1-C4 alkyl, -NR h R i AND-OR k ;in: R h 、R i and R j Each occurrence is independently selected from hydrogen, C1-C4 alkyl, C6-C 10 Aryl and C3-C6 cycloalkyl; wherein: R h 、R i and R j The C1-C4 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen, cyano and -OH; R k is independently selected at each occurrence from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl; wherein: R k The C1-C4 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen, cyano and -OH; R m is independently selected at each occurrence from halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S(=O) p R k AND-OR k ;in: R m The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and -OH; R 5 Selected from C1-C6 alkyl and C3-C 12 A carbocyclic group; wherein: R 5 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, and C1-C4 alkoxy; R 5 The C3-C 12 The carbocyclyl group is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, cyano, C1-C5 alkyl; k is an integer selected from 0, 1 and 2; wherein When R 3a When selected from halogen, cyano, -OH and C1-C6 alkyl, k is 1 or 2; and When R 3a When =O, k is 1; m is 0 or 1; p is an integer selected from 1 and 2; and q and r are each an integer selected from 1, 2, 3 and 4, and The carbocyclic and heterocyclic groups are non-aromatic rings.

2. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein the compound is represented by one of the following structural formulas: or a tautomer thereof, a deuterated derivative of said 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 The C1-C4 alkyl group is optionally substituted by 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.

3. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 4 Selected from C1-C4 alkyl and in: R 4 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of 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.

4. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 4 Selected from C1-C2 alkyl and in: R 4 The C1-C2 alkyl group is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH and 5- to 6-membered heterocyclic groups.

5. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 4 Selected from -CH3, -CH2OH and (tetrahydro-2H-pyran-4-yl)methyl.

6. The compound according to claim 1, wherein the compound is represented by one of the following structural formulas: or a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring A is selected at each occurrence from C3-C6 cycloalkyl, 5- to 10-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl; each of which is optionally substituted by 1, 2, 3, 4, or 5 R a Group substitution.

7. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein ring A is selected from cyclopropyl, 5- to 10-membered heterocyclyl, phenyl and 5- to 9-membered heteroaryl; each of which is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution.

8. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein ring A is selected from cyclopropyl, 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, phenyl and 5- to 9-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O; each of which is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution.

9. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein Ring A is selected from cyclopropyl, a 5-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a 9-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, a phenyl, a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, a 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, and a 9-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O; each of which is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution.

10. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein ring A is selected from Each of which is optionally replaced by 1, 2, 3, 4 or 5 R a Group substitution.

11. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein ring A is selected from Each of which is optionally replaced by 1, 2, 3, 4 or 5 R a replace.

12. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 4 Selected from -CH3 and Ring A; wherein Ring A is selected from Each of which is optionally replaced by 1, 2, 3, 4 or 5 R a Group substitution.

13. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 5 Selected from C1-C4 alkyl and C3-C6 cycloalkyl, wherein: R 5 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen, cyano and C1-C2 alkoxy; and R 5 The C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups independently selected from halogen, cyano and C1-C2 alkyl.

14. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 5 is selected from C1-C2 alkyl, cyclopropyl and cyclobutyl; wherein: R 5 The C1-C2 alkyl group is optionally substituted by 1 to 3 groups independently selected from F, Cl, Br, cyano and C1-C2 alkoxy; and R 5 The cyclopropyl and the cyclobutyl are each optionally substituted with 1 to 3 groups independently selected from F, Cl, Br, cyano and C1-C2 alkyl.

15. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 5 Selected from -CH3, -CH2CH3, -CH2OCH3, -CH(CH3)2, cyclopropyl and difluorocyclopropyl.

16. The compound according to claim 1, wherein the compound is represented by one of the following structural formulas: or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

17. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 1 is selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy and C3-C6 cycloalkyl; wherein: R 1 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and cyano; R 1 The C1-C4 alkoxy group is optionally substituted with 1 to 3 independently selected halogen groups; and R 1 The C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups independently selected from halogen and cyano.

18. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 1 is selected from F, Cl, Br, C1-C4 alkyl and C3-C6 cycloalkyl; wherein: R 1 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen; and R 1 The C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups independently selected from halogen.

19. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 1 Selected from Cl, Br, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH2CHF2, -CH2CH(CH3)2, difluorocyclobutyl and cyclohexyl.

20. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 1 It's Cl.

21. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 3a is selected from halogen, -OH and C1-C4 alkyl; wherein: R 3a The C1-C4 alkyl group is optionally substituted with 1 to 3 groups independently selected from halogen and -OH.

22. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 3a is selected from F, Cl, Br, -OH and C1-C2 alkyl; wherein: R 3a The C1-C2 alkyl group is optionally substituted with 1 to 3 groups independently selected from F, Cl and -OH.

23. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R 3a Selected from F, -OH, -CH3, -CHF2 and CH2OH.

24. The compound according to claim 1, wherein the compound is represented by one of the following structural formulas: or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

25. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R a independently selected at each occurrence from 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- to 10-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl; wherein: R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the following groups: 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 C3-C6 cycloalkyl; R a The C3-C6 cycloalkyl, the 5- to 10-membered heterocyclyl, the phenyl and the 5- to 8-membered heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C2 alkyl and -OR k The group substitution; in: R h 、R i and R j is independently selected at each occurrence from hydrogen, C1-C2 alkyl, cyclopropyl and cyclobutyl; wherein: R h 、R i and R j The C1-C2 alkyl group of any one of the following is optionally substituted with 1 to 3 groups independently selected from halogen and -OH; R k is independently selected at each occurrence from hydrogen and C1-C4 alkyl; wherein: R k The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH; and q and r are each an integer selected from 1, 2, and 3.

26. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R a is independently selected at each occurrence from 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 group is optionally substituted by 1 to 3 groups independently selected from cyano, -C(=O)NR h R I 、-NR h R i 、-OR k , cyclopropyl and cyclobutyl group substitution; R a The cyclopropyl, the cyclobutyl, the 5- to 6-membered heterocyclyl, the phenyl and the 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, -CH3, -OH and -OCH3; in: R h and R i is independently selected at each occurrence from hydrogen, -CH3, cyclopropyl, and cyclobutyl; wherein: R h and R i The -CH3 of any one of is optionally substituted with 1 to 3 groups independently selected from F, Cl and -OH; R k is independently selected at each occurrence from hydrogen and -CH3; wherein: R k The -CH3 is optionally substituted with 1 to 3 groups independently selected from halogen and -OH.

27. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R a independently selected at each occurrence from F, Cl, Br, cyano, C1-C6 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -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 heterocyclic group, phenyl and 6-membered heteroaryl; wherein: R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from cyano, -C(=O)NR h R i 、-OR k and cyclopropyl group substitution; R a The cyclopropyl, the cyclobutyl, the 5-membered heterocyclyl, the phenyl and the 6-membered heteroaryl are each optionally substituted with 1 to 3 groups independently selected from halogen, -CH3, -OH and -OCH3; in: R h and R i is independently selected at each occurrence from hydrogen, -CH3 and cyclopropyl; wherein: R h and R i The -CH3 of any one of is optionally substituted with 1 to 3 groups independently selected from F, Cl and -OH; R k is independently selected at each occurrence from hydrogen and -CH3; and q and r are each an integer selected from 1 and 2.

28. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein R a independently selected at each occurrence from 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)2CH2OH, -NHC(=O)CH3, -SO2CH3, -SO2NH2, cyclopropyl, 2-methoxyphenyl, N-methylpiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl and tetrahydrothiophene 1,1-dioxide.

29. The compound according to claim 1, wherein the compound is represented by one of the following structural formulas: or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

30. A compound selected from: Tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

31. A compound selected from the group consisting of: Compound 174 Tautomers of Compound 174, deuterated derivatives of Compound 174 and its tautomers, and pharmaceutically acceptable salts of any of the foregoing.

32. Compound 174: or a pharmaceutically acceptable salt of Compound 174.

33. Compound 174:

34. A compound selected from the group consisting of: Compound 181 Tautomers of Compound 181, deuterated derivatives of Compound 181 and its tautomers, and pharmaceutically acceptable salts of any of the foregoing.

35. Compound 181: or a pharmaceutically acceptable salt of Compound 181.

36. Compound 181:

37. A pharmaceutical composition comprising the compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 36 and a pharmaceutically acceptable carrier.

38. Use of a compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 36 in the manufacture of a medicament for treating focal segmental glomerulosclerosis and / or non-diabetic nephropathy.

39. Use of a compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 36 in the manufacture of a medicament for inhibiting APOL1 activity.

40. Use of a compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 36 in the manufacture of a medicament for use in a method of treating an APOL1 mediated disease comprising administering to a patient in need thereof.

41. The use according to claim 40, wherein the APOL1-mediated disease is cancer.

42. The use according to claim 40, wherein the APOL1-mediated disease is pancreatic cancer.

43. The use according to claim 40, wherein the APOL1-mediated disease is an APOL1-mediated kidney disease.

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