2-methyl-4apos, which is used as an APOL1 inhibitor; , 5apos; -dihydrospiro [piperidine-4, 7apos; -thieno [2, 3-c] pyran] derivatives and methods of use thereof

Abstract

The present disclosure provides at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt selected from the group consisting of compounds of Formula I, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing; compositions including the same; the present invention relates to novel compounds, and methods of using the same, including the use of treating APOL1 mediated diseases, including pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and / or non-diabetic nephropathy (NDKD).

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 307,875, filed February 8, 2022, the contents of which are incorporated by reference in their entirety.

[0002] The present disclosure provides compounds that can inhibit apolipoprotein L1 (APOL1) and methods of using these compounds to treat APOL1-mediated 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 levels of APOL1 (e.g., elevated levels of APOL1 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 nephropathy. 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., Seminar in Nephrology 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 loss of renal function 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 loss of renal function. 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 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 an APOL1 risk allele (i.e., homozygous or compound heterozygous for the APOL1 G1 or APOL1 G2 allele) are at increased risk of developing FSGS and, if they develop FSGS, 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 renal disease. However, APOL1 in the kidney is thought to contribute to the development of renal 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 can form pH-gated Na+ molecules in cell membranes. + / 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 or approved medication for FSGS or NDKD. Currently, FSGS and NDKD are managed with symptomatic treatment (including the use of renin-angiotensin system blockers to control blood pressure), 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, used alone or in combination with other immunosuppressants, can induce remission in a small number of patients (e.g., a small number of patients experience remission of proteinuria), and are associated with a variety of side effects. However, even in patients who initially respond to corticosteroid and / or immunosuppressant treatment, 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 treatment of FSGS and NDKD. Illustratively, given the evidence that APOL1 plays a causal role in inducing and accelerating the progression of nephropathy, inhibition of APOL1 should have a positive impact on patients with APOL1-mediated nephropathy, particularly those carrying two APOL1 risk alleles (i.e., homozygous or compound heterozygous for the G1 or G2 allele).

[0012] Additionally, APOL1 is a gene that is abnormally expressed in various cancers (Lin et al., Cell Death and Disease (2021), 12:760). Recently, APOL1 expression was found to be abnormally elevated in human pancreatic cancer tissue compared to adjacent tissues and correlated 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, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of a compound of Formula I, a tautomer of Formula I, a deuterated derivative of these compounds or tautomers, and a pharmaceutically acceptable salt of any of the foregoing, which can be used to treat APOL1-mediated diseases, such as FSGS and NDKD. For example, in some embodiments, the at least one compound is a compound represented by Formula I:

[0014]

[0015] a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein:

[0016] X 1 and X 2 Selected from -S-, -S(=O)2-, -S(=O)- and -CR 2 ,in:

[0017] X 1 and X 2 One is selected from -S-, -S(=O)2- and -S(=O)-;

[0018] When X1 When it is -S-, -S(=O)2- or -S(=O)-, then X 2 Yes-CR 2 ;and

[0019] When X 2 When it is -S-, -S(=O)2- or -S(=O)-, then X 1 Yes-CR 2 ;

[0020] R 1 is selected from cyano, halogen, C1-C4 alkyl, C1-C4 haloalkyl and C3-C6 cycloalkyl, wherein:

[0021] R 1 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of -OH and C1-C4 alkoxy;

[0022] R 2 Selected from hydrogen, C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), -C(=O)NR n R o and halogen groups, wherein:

[0023] R 2 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of -OH, halogen, and C1-C4 alkoxy; and

[0024] R n and R o R is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl and -(C1-C4 alkylene) p Group, where R p Selected from C3-C6 cycloalkyl; or

[0025] R 1 and R 2 Together with the carbon atom to which it is attached, it forms a C6 aryl group;

[0026] Each R 3a Independently selected from -OH, -CN, -NR a1 R a2 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -OC(=O)(C1-C4 alkyl), 6- to 8-membered aryl, 6- to 8-membered heteroaryl, and halogen groups, wherein:

[0027] Each R a1 and R a2 independently selected from hydrogen, C1-C4 alkyl and -C(=O)(C1-C4 alkyl) groups; or

[0028] Two R's 3a together to form an oxo group; or

[0029] Two R's 3a Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group;

[0030] Each R 3b Independently selected from C1-C4 alkyl, wherein:

[0031] R 3b The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of -OH, halogen, and C1-C4 alkoxy; or

[0032] One R 3a and an R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group;

[0033] k is selected from 0, 1 and 2;

[0034] m is selected from 0, 1 and 2;

[0035] R 4a 、R 4b 、R 5a and R 5b are each independently selected from hydrogen and C1-C4 alkyl;

[0036] R 6 Selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl) and Group, in which:

[0037] R 6 wherein the C1-C6 alkyl radical is optionally substituted by 1 to 5 groups independently selected from the group consisting of halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C1-C4 alkoxy, C3-C6 carbocyclyl, C6 aryl, -O-(C6 aryl), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein:

[0038] The C6 aryl and -O-(C6 aryl) groups are each optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen and C1-C4 haloalkyl;

[0039] Ring B is selected from C3-C 12 Carbocyclyl, 3 to 12 membered heterocyclyl, C6 and C10 aryl and 5- to 10-membered heteroaryl, wherein ring B is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution; wherein:

[0040] R a independently selected at each occurrence from halogen, cyano, C1-C8 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C1-C6 haloalkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Carbocyclic, C6 and C 10 aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(=O)NR h R i 、-C(=O)OR k 、-C(=O)(C1-C4 alkylene)OR k 、-C(=O)R k 、-C(=O)(C1-C4 alkylene)S(=O) p R k 、-C(=O)(C1-C4 alkylene)S(=O) p NR h R i 、-C(=O)(C1-C4 alkylene)NR i S(=O) p R k 、-C(=O)(C1-C4 alkylene)NR h C(=O)R k 、-C(=O)C(=O)R k 、-NR h R i 、-NH(CH2) q CHR h R i 、-NH(CH2) q NR h R i 、-NR h C(=O)R k 、-NR h C(=O)OR k 、-NR h C(=O)(C1-C4 alkylene)OR k 、-NR h C(=O)O(C1-C4 alkylene)R k 、-NR h C(=O)NR i R j 、-NR h C(=O)(C1-C4 alkylene)NR iS(=O) p R k 、-NR h S(=O) p R k 、-NR h C(=O)(C1-C4 alkylene)S(=O) p R k 、-NR h S(=O) p (C1-C4 alkylene)C(=O)OR k 、-NR h C(=O)[O(CH2) q ] r OC(=O)NR h R i (CH2) q [O(CH2) q ] r (C1-C6 alkyl) (optionally replaced by 1 to 3 R m Group substitution), -NR h C(=O)(C1-C6 alkylene)[O(CH2) q ] r OC(=O)-NR h R i (CH2) q [O(CH2) q ] r (C1-C6 alkyl) (optionally replaced by 1 to 3 R m Group substitution), -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 and -S(=O) p NR h R i Group, in which:

[0041] The C1-C4 alkylene in each of the following is optionally substituted with 1 to 3 -OH groups: -C(=O)(C1-C4 alkylene)S(=O) p R k 、-C(=O)(C1-C4 alkylene)OR k 、-C(=O)(C1-C4 alkylene)S(=O) p NRh R i 、-C(=O)(C1-C4 alkylene)NR i S(=O) p R k 、-C(=O)(C1-C4 alkylene)-NR h C(=O)R k 、-NR h C(=O)O(C1-C4 alkylene)R k 、-NR h C(=O)(C1-C4 alkylene)-OR k NR h S(=O) p (C1-C4 alkylene)C(=O)OR k and -NR h C(=O)(C1-C4 alkylene)NR i S(=O) p R k ,

[0042] R a The C1-C8 alkyl, the C1-C6 haloalkyl, the C1-C6 alkoxy and the C2-C8 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 、-[O(CH2) q ] r OH, -OC(=O)R k 、-OC(=O)OR k 、-OC(=O)NR h R i 、-SR k 、-S(=O) p R k 、-S(=O) p NR h Ri 、-[O(CH2) q ] r O(C1-C4 alkyl), -O-(C6 aryl or 5- to 8-membered heteroaryl) (optionally substituted by 1 to 3 R m Group substituted), C3-C6 carbocyclic group (optionally substituted by 1 to 3 R m Group substitution), C6 to C 10 Aryl (optionally substituted with 1 to 3 R m substituted with a group), a 4- to 10-membered heterocyclic group (optionally substituted with 1 to 3 R m substituted with 1 to 3 R m group substitution); and

[0043] 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 by 1 to 3 groups independently selected from the group consisting of halogen, cyano, C1-C6 alkyl (optionally substituted by 1 to 3 R m Group substitution), -C(=O)R k 、C(=O)OR k 、-NR h R i 、-OR k 、-S(=O) p R k 、-S(=O) p NR h R i and a 5- to 10-membered heterocyclic group, wherein:

[0044] R h 、R i and R j Each occurrence is independently selected from hydrogen, C1-C6 alkyl, C6-C 10 Aryl, C3-C8 carbocyclic group (optionally substituted by 1 to 3 R m substituted with a group), a 5- to 10-membered heteroaryl group (optionally substituted with 1 to 3 R m and 5- to 10-membered heterocyclic groups (optionally substituted with 1 to 3 R m Group substitution), wherein:

[0045] R h 、R i and R jThe C1-C6 alkyl of any one of the groups is optionally substituted by 1 to 4 groups independently selected from the group consisting of halogen, cyano, -OH, C1-C4 alkoxy, -C(=O)NH(C1-C4 alkyl), 5- to 10-membered heteroaryl (optionally substituted by 1 to 3 R m and 5- to 10-membered heterocyclic groups (optionally substituted with 1 to 3 R m group substitution);

[0046] R k is independently selected at each occurrence from hydrogen, NH2 (optionally substituted with 1 or 2 groups selected from C1-C3 alkyl), C1-C6 alkyl, benzyl, C6 aryl, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein:

[0047] R k wherein the C1-C6 alkyl group is optionally substituted with 1 to 5 groups independently selected from the group consisting of halogen, cyano, -NH2, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl (optionally substituted with 1 to 3 halogen groups), 4 to 10-membered heterocyclyl (optionally substituted with 1 to 3 -OH groups), 5 to 10-membered aryl (optionally substituted with 1 to 3 groups selected from the group consisting of C1-C4 alkyl and halogen), and 5 to 10-membered heteroaryl (optionally substituted with 1 to 3 -OH groups); and

[0048] R k The C3-C6 carbocyclyl, the benzyl and the C6 aryl of any one of the is each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, oxo, -OH, -C(=O)NH2, -C(=O)N(CH3)2, C1-C4 alkyl (optionally substituted by 1 to 3 -OH groups), C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl (optionally substituted by 1 to 3 halogen groups), C6 aryl (optionally substituted by 1 to 3 halogen groups) and 5- to 10-membered heteroaryl (optionally substituted by 1 to 3 halogen groups);

[0049] R k wherein the 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl of any one of the following are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, oxo, cyano, -C(=O)CH3, -NH2, -OH, C1-C4 alkyl (optionally substituted by 1 to 3 -OH groups), C1-C4 haloalkyl, 5- to 10-membered heterocyclyl, and C1-C4 alkoxy;

[0050] R m is independently selected at each occurrence from halogen, cyano, oxo, -NH2, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)Rk 、-S(=O) p R k 、-OR k and a 5- to 10-membered heterocyclic group, wherein:

[0051] R m The C1-C6 alkyl, the C1-C6 alkoxy and the 5- to 10-membered heterocyclyl of any one of the following are optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH and C1-C4 alkoxy;

[0052] p is, at each occurrence, an integer independently selected from 1 and 2; and

[0053] q and r are integers independently selected from 0, 1, 2 and 3 at each occurrence.

[0054] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a compound represented by the following structural formulas: Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, as follows:

[0055]

[0056]

[0057] where R 6 As defined above for Formula I.

[0058] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 Selected from the following: wherein Ring B is a 5-membered heteroaryl group, and R a As defined for Formula I.

[0059] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 Selected from the following: wherein Ring B is a 5-membered heteroaryl group, and R a is oxo or selected from C1-C8 alkyl, C3-C 12 Carbocyclic groups and C6 and C 10Aryl, each of which may be optionally substituted with 1 to 3 groups selected from halogen and C1-C8 alkyl (wherein the C1-C8 alkyl may be optionally substituted with 1 to 3 groups selected from halogen, -OH, SO2CH3 and SO2NH2).

[0060] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 Selected from the following:

[0061]

[0062] In one aspect of the present disclosure, the compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il and Im is selected from compounds 1 to 1183, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt selected from the group consisting of compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il and Im, their tautomers, deuterated derivatives of these compounds or tautomers, and 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 1183, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0063] Another aspect of the present disclosure provides a method for treating an APOL1-mediated disease, comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0064] Another aspect of the present disclosure provides a method for treating APOL1-mediated cancer (e.g., pancreatic cancer), comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0065] Another aspect of the present disclosure provides a method for treating APOL1-mediated kidney disease (e.g., ESKD, FSGS, and / or NDKD) comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of: compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of: compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0066] In some embodiments, the method of treating comprises administering to a subject in need thereof at least one additional active agent, either in the form of a pharmaceutical composition identical to at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of: Compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or in the form of a separate composition. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of: Compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, in the same pharmaceutical composition or in a separate composition with at least one additional active agent.

[0067] Also provided are methods for inhibiting APOL1, a method for treating APOL1-mediated cancer (e.g., pancreatic cancer), comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method for inhibiting APOL1 comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.

[0068] All compounds 1 to 1183 disclosed herein have demonstrated the ability to inhibit ApoL1 in one or more assays. In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is selected from the group consisting of compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, excluding Compound 285, Compound 489, Compound 539, Compound 691, Compound 692, Compound 741, Compound 747, Compound 749, Compound 751, Compound 752, Compound 753, Compound 795, Compound 814, and Compound 868. DETAILED DESCRIPTION

[0069] definition

[0070] As used herein, the term "APOL1" means apolipoprotein L1 protein, and the term "APOL1" means apolipoprotein L1 gene.

[0071] The term "APOL1-mediated disease" refers to a disease or condition associated with abnormal APOL1 (e.g., certain APOL1 genetic variants; elevated levels of APOL1). 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 for the G1 or G2 allele or heterozygous for both). In some embodiments, the APOL1-mediated disease is associated with patients who have one APOL1 risk allele.

[0072] The term "APOL1-mediated nephropathy" refers to a disease or condition that impairs kidney function and is attributable to APOL1. In some embodiments, the APOL1-mediated nephropathy is associated with patients who have two APOL1 risk alleles (e.g., patients who are homozygous for the G1 or G2 allele or heterozygous for both). In some embodiments, the APOL1-mediated nephropathy is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1-mediated nephropathy is chronic kidney disease or proteinuria.

[0073] As used herein, the term "FSGS" means focal segmental glomerulosclerosis, a disease of the podocytes (epithelial cells lining the glomeruli) that causes proteinuria and progressive decline in kidney function and is associated with two common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0074] As used herein, the term "NDKD" means non-diabetic nephropathy, which is characterized by severe hypertension and progressive decline in kidney function and is associated with two common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0075] The terms "ESKD" and "ESRD" are used interchangeably herein and refer to end-stage kidney disease or end-stage renal disease. 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.

[0076] 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 compound and the efficiency of incorporation of the isotopes in the various synthetic steps used to prepare the compound. However, as explained above, the relative amount of all such isotopologues will be less than 49.9% of the compound. In other embodiments, the total relative amount of 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.

[0077] 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.

[0078] 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 14Compounds having the present structures except for C replacing carbon are within the scope of this disclosure.

[0079] Unless otherwise indicated, structures depicted herein are also intended to encompass all isomeric forms of the structures, e.g., racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds of the present invention are within the scope of this disclosure. Unless otherwise indicated, all tautomeric forms of the compounds of the present disclosure are within the scope of this disclosure.

[0080] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that coexist in equilibrium and are readily interchangeable by migration of atoms (eg, hydrogen atoms) or groups within the molecule.

[0081] As used herein, "stereoisomers" refer to enantiomers and diastereomers.

[0082] As used herein, "one or more deuterated derivatives" refers to compounds having the same chemical structure as the reference compound but with one or more hydrogen atoms replaced by a deuterium atom ("D" or " 2 H”) substituted compounds. It will be appreciated that, depending on the source 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 isotope substitution in the deuterated derivatives described herein. Therefore, unless otherwise indicated, when referring to a “deuterated derivative” of a compound of the present disclosure, at least one hydrogen has been replaced by 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).

[0083] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0084] As used herein, "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, the alkyl group contains 1 to 10 aliphatic carbon atoms. In some embodiments, the alkyl group contains 1 to 8 aliphatic carbon atoms. In some embodiments, the alkyl group contains 1 to 6 alkyl carbon atoms. In some embodiments, the alkyl group contains 1 to 4 alkyl carbon atoms, in other embodiments, the alkyl group contains 1 to 3 alkyl carbon atoms, and in yet other embodiments, the alkyl group contains 1 or 2 alkyl carbon atoms. In some embodiments, the alkyl group is linear or straight chain or unbranched. In some embodiments, the alkyl group is branched.

[0085] As used herein, the terms "carbocyclyl," "cycloalkyl," and "cyclic alkyl" refer to a fully saturated monocyclic C 3-8 Hydrocarbon or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14 hydrocarbons, wherein any individual ring in the bicyclic system has 3 to 7 members. In some embodiments, the cycloalkyl group is C3 to C 12 Cycloalkyl. 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, cyclopentanyl, and cyclohexyl.

[0086] As used herein, the term "carbocyclyl" or "alicyclic" encompasses the term "cycloalkyl" or "cyclic alkyl" and refers to a fully saturated or partially saturated monocyclic C 3-8 Hydrocarbon or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14 Hydrocarbons are hydrocarbons because they contain one or more unsaturated units but are not aromatic, wherein any individual ring in the bicyclic ring system has 3 to 7 members. Bicyclic carbocyclyls include combinations of monocyclic carbocycles fused to phenyl. In some embodiments, carbocyclyls are C3 to C 12 In some embodiments, the carbocyclic group is C3 to C 10 In some embodiments, the carbocyclyl group is a C3 to C8 carbocyclyl group.

[0087] The term "heteroalkyl" or "heteroaliphatic" as used herein means an alkyl or aliphatic group as defined above wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus or silicon.

[0088] As used herein, the term "alkenyl" means a straight (i.e., linear or unbranched) or branched hydrocarbon chain containing one or more double bonds. In some embodiments, the alkenyl is straight. In some embodiments, the alkenyl is branched.

[0089] As used herein, "heterocycle," "heterocyclyl," and "heterocyclic" refer to a non-aromatic (i.e., fully saturated or partially saturated, in that 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.

[0090] In some embodiments, the heterocycle includes ring atoms substituted with one or more oxo groups (eg, a C=O group, an S=O group, or an SO2 group).

[0091] In some embodiments, a "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" group has from 3 to 14 ring members, one or more of which is a heteroatom independently selected from oxygen, sulfur, nitrogen, silicon, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains from 3 to 7 ring members. In some embodiments, the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has one heteroatom independently selected from oxygen, sulfur, nitrogen, silicon, and phosphorus, a quaternized form of any basic nitrogen; or a substitutable nitrogen of the heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (such as in N-substituted pyrrolidinyl). 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 heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl, tetrahydrothiophenyl 1,1-dioxide, and the like.

[0092] 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.

[0093] As used herein, the term "alkoxy" or "thioalkyl" refers to an alkyl group as previously defined, wherein one of the carbon atoms of the alkyl group is replaced by an oxygen ("alkoxy") or sulfur ("thioalkyl") atom, respectively, provided that the oxygen and sulfur atoms are attached between two carbon atoms. "Cyclic alkoxy" refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon group that contains at least one alkoxy group but is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octyl, and oxepanyl.

[0094] As used herein, the terms "haloalkyl," "haloalkenyl," and "haloalkoxy" refer to straight or branched alkyl, alkenyl, or alkoxy groups substituted with one or more halogen atoms, respectively. 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.

[0095] The term "halogen" encompasses F, Cl, Br and I, ie, fluorine, chlorine, bromine and iodine, respectively.

[0096] The term "aminoalkyl" refers to an alkyl group substituted with or containing an amino group.

[0097] As used herein, "amino" refers to a group that is a primary, secondary, or tertiary amine.

[0098] As used herein, a "carbonyl" group refers to C=O.

[0099] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0100] As used herein, a "hydroxy" group refers to -OH.

[0101] As used herein, a "thiol" group refers to -SH.

[0102] As used herein, "tert" and "t-" each refer to tertiary.

[0103] 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.

[0104] 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 an aromatic ring 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 include phenyl (C6) and naphthyl (C8), phenyl (C9), phenyl (C10), phenyl (C12), phenyl (C13), phenyl (C14), phenyl (C16), phenyl (C17), phenyl (C18), phenyl (C19), phenyl (C20), phenyl (C31), phenyl (C42), phenyl (C51), phenyl (C64), phenyl (C76), phenyl (C81), phenyl (C97), phenyl (C19), phenyl (C19), phenyl (C19), phenyl (C19), phenyl (C21), phenyl (C19), phenyl (C22), phenyl (C33), phenyl (C19), phenyl (C19), phenyl (C19), phenyl (C23), phenyl (C19), phenyl (C24), phenyl (C35), phenyl (C19), phenyl (C19), phenyl (C25), phenyl (C19), phenyl (C26), phenyl (C19), phenyl (C27), phenyl (C36), phenyl (C19), phenyl (C19), phenyl (C27), phenyl (C33), phenyl (C19), phenyl (C19), 10 )ring.

[0105] The term "heteroaryl," used alone or as part of a larger moiety (e.g., in "heteroarylalkyl" or "heteroarylalkoxy"), refers to monocyclic or spirocyclic, fused or bridged bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, wherein 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 heteroaryls include combinations 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 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 having five ring members. In some embodiments, the heteroaryl group is a monocyclic ring system having six ring members. In some embodiments, the heteroaryl group is 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 include pyridyl, pyrimidinyl, thienyl, thiazolyl, isoxazolyl, and the like.

[0106] In some embodiments, the heteroaryl group includes ring atoms substituted with one or more oxo groups (e.g., C=O groups, S=O groups, or SO2 groups). Schematically, a non-limiting example of a heteroaryl group is a benzo[d]oxazol-2(3H)-one group.

[0107] Non-limiting examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, tert-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethylcarbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, tritylamine, benzylamine, and p-toluenesulfonamide. Methods of adding (commonly referred to as "protection") and removing (commonly referred to as "deprotection") such amine protecting groups are well known in the art and are available, for example, in PJ Kocienski, Protecting Groups, Thieme, 1994, which is incorporated herein by reference in its entirety, and in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed. (John Wiley & Sons, New York, 1999) and 4th ed. (John Wiley & Sons, New Jersey, 2014).

[0108] Non-limiting examples of suitable solvents that can be used in the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0109] Non-limiting examples of suitable bases that can be used in the present disclosure include, but are not limited to: 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (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).

[0110] The present disclosure encompasses 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.

[0111] As used herein, the term "pharmaceutically acceptable" refers to a component that is 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.

[0112] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, ditartaric 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-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfate, pyrophosphate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, caprate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, Pharmaceutically acceptable acid addition salts include, butane-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, benzoate, 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 acid addition salts formed with mineral acids such as hydrochloric acid and hydrobromic acid, and acid addition salts formed with organic acids such as maleic acid.

[0113] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium 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. Additional non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0114] The terms "patient" and "subject" are used interchangeably herein and refer to animals, including humans.

[0115] 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).

[0116] As used herein, the term "treat" and its cognates refer to slowing or stopping the progression of a disease. As used herein, "treat" and its cognates 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 of these symptoms or the alleviation of their severity can be readily assessed according to methods and techniques known in the art or subsequently developed.

[0117] When used in conjunction with a dose, amount, or weight percentage of an ingredient of a composition or dosage form, the terms "about" and "approximately" encompass a value for the specified dose, amount, or weight percentage, or a range 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.

[0118] At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, may be administered once daily, twice daily, or three times daily, for example, for the treatment of AMKD (including FSGS and / or NDKD). In some embodiments, at least one compound selected from the group consisting of compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, may be administered once daily, twice daily, or three times daily. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered once daily. In some embodiments, at least one compound selected from the group consisting of compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered once daily. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered twice daily. In some embodiments, at least one compound selected from the group consisting of compounds 1 to 1183, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered twice daily. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered three times daily. In some embodiments, at least one compound selected from the group consisting of compounds 1 to 1183, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered three times daily.

[0119] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound selected from Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily, twice daily, or three times daily. In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound selected from Compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily, twice daily, or three times daily.

[0120] One of ordinary skill in the art will recognize that when an amount of a compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. The amounts of 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 or pharmaceutically acceptable salt selected from a compound of Formula I and a pharmaceutically acceptable salt thereof" includes 1000 mg of a compound of Formula I and a pharmaceutically acceptable salt of a compound of Formula I at a concentration equivalent to 1000 mg of the compound of Formula I.

[0121] As used herein, the term "ambient conditions" means room temperature, open air conditions, and uncontrolled humidity conditions.

[0122] Compounds and compositions

[0123] In some embodiments, at least one compound selected from the following can be used to treat AMKD (including FSGS and NDKD): Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il and Im, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il and Im can be selected from Compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound selected from the group consisting of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing can be used to treat AMKD (including FSGS and NDKD). In some embodiments, the pharmaceutical composition comprises at least one compound selected from the group consisting of Compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0124] In some embodiments of Formula I:

[0125]

[0126] VARIABLE X 1 is selected from S, S(=O) and S(=O)2, and the variable X 2 Yes-CR 2 In some embodiments of Formula I, the variable X 1 is S, and the variable X 2 Yes-CR 2 In some embodiments of Formula I, the variable X 2 is selected from S, S(=O) and S(=O)2, and the variable X 1 Yes-CR 2 In some embodiments of Formula I, the variable X 2 is S, and the variable X 1 Yes-CR 2 .

[0127] In some embodiments (including the above-defined variable X 1 and X 2 embodiment), R 2 is selected from hydrogen, C1-C6 alkyl (optionally substituted by 1 to 3 groups independently selected from: -OH, halogen and C1-C4 alkoxy), -C(=O)O(C1-C4 alkyl), -C(=O)NRn R o and halogen groups, where R n and R o R is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl and -(C1-C4 alkylene) p group, and wherein R p Selected from C3-C6 cycloalkyl.

[0128] In some embodiments (including the above-defined variable X 1 and X 2 embodiment), R 2 Selected from hydrogen, halogen, -CH2OH, -CH2(OH)CH3 and -C(=O)NR n R o In some embodiments, R 2 is hydrogen. In some embodiments (comprising the above-defined variable X 1 and X 2 embodiment), R 2 In some embodiments (including the above-defined variable X 1 and X 2 embodiment), R 2 is Br. In some embodiments, R 2 In some embodiments (including the above-defined variable X 1 and X 2 embodiment), R 2 is CH3. In some embodiments (including the above-defined variable X 1 and X 2 embodiment), R 2 In some embodiments, R 2 is CH2(OH)CH3. In some embodiments, R 2 It is -C(=O)OCH3.

[0129] In some embodiments (including the above-defined variable X 1 and X 2 embodiment), R 2 is -C(=O)NR n R o and halogen groups, where R n and R o R is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl and -(C1-C4 alkylene) p group, and wherein R p In some embodiments (including the above-defined variable X 1 and X2 embodiment), R 2 is -C(=O)NR n R o (where R n is hydrogen and R o is CH3). In some embodiments (comprising the above-defined variable X 1 and X 2 embodiment), R 2 is -C(=O)NR n R o (where R n is hydrogen and R o is cyclopropyl substituted CH3). In some embodiments (comprising the above-defined variable X 1 and X 2 embodiment), R 2 is -C(=O)NHCH2CH2CH3 (ie, wherein R n is hydrogen and R o In some embodiments (including the above-defined variable X 1 and X 2 embodiment), R 2 is -C(=O)NHCH2CF2 (ie, wherein R n is hydrogen and R o is -CH2CF2).

[0130] In Formula I (including the above-defined variables X 1 、X 2 and R 2 In some embodiments of the embodiment of the present invention, the variable R 1 is selected from cyano, halogen, -C1-C4 alkyl, -C1-C4 haloalkyl and -C3-C6 cycloalkyl, wherein: R 1 The -C1-C4 alkyl group is optionally substituted with 1 to 3 groups independently selected from the group consisting of -OH and -C1-C4 alkoxy.

[0131] In Formula I (including the above-defined variables X 1 、X 2 and R 2 In some embodiments of the embodiment of the present invention, the variable R 1 is selected from -CN, -Br, -Cl, -C1-C4 alkyl, -CH2OH, -CH2CF2, -CF2CF2, -CF2, -CF3, -CH2OCH3, -CH2OCH2CH3, cyclopropyl and cyclobutyl. 1 、X 2 and R 2 In some embodiments of the embodiment of the present invention, the variable R1 is selected from -CH3, -CH2OH, -CH2CH3, -CH2CH2CH3, tert-butyl, -Cl, -CH2-CF2, -CF2CF3 and -CF3. 1 、X 2 and R 2 In some embodiments of the embodiment of the present invention, the variable R 1 It is deuterated, for example -CDOCH2CH3.

[0132] In Formula I (including the above-defined variables X 1 、X 2 and R 2 In some embodiments of the embodiment of the present invention, the variable R 1 Is CF3. In Formula I (containing the above-defined variable X 1 、X 2 and R 2 In some embodiments of the embodiment of the present invention, the variable R 1 Is Cl. In Formula I (containing the above-defined variable X 1 、X 2 and R 2 In some embodiments of the embodiment of the present invention, the variable R 1 Is -CH2OH. In Formula I (containing the above-defined variable X 1 、X 2 and R 2 In some embodiments of the embodiment of the present invention, the variable R 1 Is -CH2CF3. In Formula I (containing the above-defined variable X 1 、X 2 and R 2 In some embodiments of the embodiment of the present invention, the variable R 1 Is -CF2CF3. In formula I (containing the above-defined variable X 1 、X 2 and R 2 In some embodiments of the embodiment of the present invention, the variable R 1 It is -CH2(OH)CH3.

[0133] In Formula I (including the above-defined variables X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 and R 2 Together with the carbon atom to which it is attached, it forms a C6 aryl group.

[0134] In Formula I (including the above-defined variables X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is -Cl and the variable R2 Is -CH2OH. In Formula I (containing the above-defined variable X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is Cl and the variable R 2 Is -CH3. In Formula I (containing the above-defined variable X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is Cl and the variable R 2 Is hydrogen. In Formula I (containing the above-defined variable X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is -Cl and the variable R 2 It is -Cl.

[0135] In Formula I (including the above-defined variables X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is -CF3 and the variable R 2 Is hydrogen. In Formula I (containing the above-defined variable X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is -CF2CF3 and the variable R 2 Is hydrogen. In Formula I (containing the above-defined variable X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is -CH2CF3 and the variable R 2 Is hydrogen. In Formula I (containing the above-defined variable X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is -CF2 and the variable R 2 Is -CH2OH. In Formula I (containing the above-defined variable X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is -CF3 and the variable R 2 Is -CH2OH. In Formula I (containing the above-defined variable X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is -CF3 and the variable R 2 Is -CH2(OH)CH3. In Formula I (containing the above-defined variable X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R1 is -CF3 and the variable R 2 It is -Cl.

[0136] In Formula I (including the above-defined variables X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is CH3 and the variable R 2 Is hydrogen. In Formula I (containing the above-defined variable X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is CH2CH3 and the variable R 2 Is hydrogen. In Formula I (containing the above-defined variable X 1 and X 2 In some embodiments of the embodiment of the present invention, the variable R 1 is CH2OH and the variable R 2 It's hydrogen.

[0137] In some embodiments of Formula I, the variables m and k are both zero, resulting in the variable R 3a and R 3b In some embodiments of Formula I, the variable m is zero, resulting in the variable R 3b does not exist, and the variable k is one, resulting in the existence of an R 3a In some embodiments of Formula I, the variable m is zero, resulting in the variable R 3b does not exist, and the variable k is two, resulting in two R 3a The variables present in Formula I are:

[0138] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 In some embodiments of the embodiment of the present invention, each R 3a Independently selected from -OH, -CN, -NR a1 R a2 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -OC(=O)(C1-C4 alkyl), 6- to 8-membered aryl, 6- to 8-membered heteroaryl, and halogen groups, wherein:

[0139] Each R a1 and R a2 independently selected from hydrogen, C1-C4 alkyl and -C(=O)(C1-C4 alkyl) groups; or

[0140] Two R's 3a together to form an oxo group; or

[0141] Two R's3a Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group.

[0142] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 In some embodiments of the embodiment of the present invention, each R 3a Selected from -OH, F, F2, CF2, -OCH3, -OCH2CH3, -OCH2(CH3)2, -OC(=O)CH3, NH2, NHC(=O)CH3, CN, In some embodiments of Formula I, the variable k is one, and the variable R 3a Selected from -OH, F, F2, CF2, -OCH3, -OCH2CH3, -O-CH2(CH3)2, -OC(=O)CH3, NH2, NH-C(=O)CH3, CN, In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 In some embodiments of the present invention, the variable m is zero, the variable k is one, and the variable R 3a Selected from -OH, F, F2, CF2, -OCH3, -OCH2CH3, -O-CH2(CH3)2, -OC(=O)CH3, NH2, NH-C(=O)CH3, CN, In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 In some embodiments of the present invention, the variable m is zero, the variable k is one, and the variable R 3a Is -OH. In Formula I (containing the above-defined variable X 1 and X 2 、R 1 、R 2 In some embodiments of the present invention, the variable m is zero, the variable k is one, and the variable R 3a Selected from -OCH3 and -OCH2CH3.

[0143] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 In some embodiments of the embodiment of the present invention, the variable k is two, and the two R 3aThe variables are selected from (a) -CF2 and -OH; (b) -CH3 and -OH; and (c) -OH and phenyl. 1 and X 2 、R 1 、R 2 In some embodiments of the present invention, the variable m is zero, the variable k is two, and the two R 3a The variables are selected from (a) -CF2 and -OH; (b) -CH3 and -OH; and (c) -OH and phenyl.

[0144] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 In some embodiments of the embodiment of the present invention, the variable R 3a In some embodiments, the deuterated R 3a Yes-O-CD3.

[0145] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 In some embodiments of the embodiment) two R 3a Together they form an oxo group.

[0146] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 In some embodiments of the embodiment) two R 3a Together they form a C3-C6 cycloalkyl group.

[0147] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 and R 3a In some embodiments of the embodiment of the present invention, the variable R 3b is selected from C1-C3 alkyl optionally substituted by -OH or halogen. 1 and X 2 、R 1 、R 2 and R 3a In some embodiments of the embodiment), R 3b is CH3. In Formula I (containing the above-defined variable X 1 and X 2 、R 1 、R 2 and R 3aIn some embodiments of the embodiment), R 3b Selected from CF2 and CF3.

[0148] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 ,k,m,R 3a and R 3b In some embodiments of the embodiment of the present invention, the variable R 4a 、R 4b 、R 5a and R 5b In some embodiments of Formula I, the variable R 4a 、R 4b 、R 5a and R 5b In some embodiments of Formula I, the variable R is hydrogen and the remaining variables are selected from methyl, ethyl, cyclopropyl, fused cyclopropyl, and fused cyclobutyl. 4a 、R 4b and R 5b is hydrogen and the variable R 5a is selected from the group consisting of methyl, ethyl, cyclopropyl, fused cyclopropyl, and fused cyclobutyl. In some embodiments of Formula I, the variable R 4b 、R 5a and R 5b is hydrogen and the variable R 4a is selected from the group consisting of methyl, ethyl, cyclopropyl, fused cyclopropyl, and fused cyclobutyl. In some embodiments of Formula I, the variable R 4a 、R 4b 、R 5a and R 5b Three of the variables are hydrogen and the remaining variable is CH3.

[0149] In the above definition of variable X 1 and X 2 、R 1 、R 2 ,k,m,R 3a 、R 3b 、R 4a 、R 4b 、R 5a and R 5b In some embodiments of, and in embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im,

[0150] R 6 Selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl) and Group, in which:

[0151] R 6 wherein the C1-C6 alkyl group is optionally substituted by 1 to 5 groups independently selected from the group consisting of halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C1-C4 alkoxy, C3-C6 carbocyclyl, C6 aryl (optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen and C1-C4 haloalkyl), -O-(C6 aryl) (optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen and C1-C4 haloalkyl), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl;

[0152] Ring B 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 B is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution; wherein:

[0153] R a independently selected at each occurrence from halogen, cyano, C1-C8 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C1-C6 haloalkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Carbocyclic, C6 and C 10 aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(=O)NR h R i 、-C(=O)OR k 、-C(=O)(C1-C4 alkylene)OR k 、-C(=O)R k 、-C(=O)(C1-C4 alkylene)S(=O) p R k 、-C(=O)(C1-C4 alkylene)S(=O) p NR h R i 、-C(=O)(C1-C4 alkylene)NR i S(=O) p R k 、-C(=O)(C1-C4 alkylene)NR h C(=O)R k 、-C(=O)C(=O)R k 、-NRh R i 、-NH(CH2) q CHR h R i 、-NH(CH2) q NR h R i 、-NR h C(=O)R k 、-NR h C(=O)OR k 、-NR h C(=O)(C1-C4 alkylene)OR k 、-NR h C(=O)O(C1-C4 alkylene)R k 、-NR h C(=O)NR i R j 、-NR h C(=O)(C1-C4 alkylene)NR i S(=O) p R k 、-NR h S(=O) p R k 、-NR h C(=O)(C1-C4 alkylene)S(=O) p R k 、-NR h S(=O) p (C1-C4 alkylene)C(=O)OR k 、-NR h C(=O)[O(CH2) q ] r OC(=O)NR h R i (CH2) q [O(CH2) q ] r (C1-C6 alkyl) (optionally replaced by 1 to 3 R m Group substitution), -NR h C(=O)(C1-C6 alkylene)[O(CH2) q ] r OC(=O)-NR h R i (CH2) q [O(CH2) q ] r (C1-C6 alkyl) (optionally replaced by 1 to 3 R m Group substitution), -OR k 、-OC(=O)Rk 、-OC(=O)OR k 、-OC(=O)NR h R i 、-[O(CH2) q ] r O(C1-C6 alkyl), -S(=O) p R k and -S(=O) p NR h R i Group, in which:

[0154] The C1-C4 alkylene in each of the following is optionally substituted with 1 to 3 -OH groups: -C(=O)(C1-C4 alkylene)S(=O) p R k 、-C(=O)(C1-C4 alkylene)OR k 、-C(=O)(C1-C4 alkylene)S(=O) p NR h R i 、-C(=O)(C1-C4 alkylene)NR i S(=O) p R k 、-C(=O)(C1-C4 alkylene)-NR h C(=O)R k 、-NR h C(=O)O(C1-C4 alkylene)R k 、-NR h C(=O)(C1-C4 alkylene)-OR k NR h S(=O) p (C1-C4 alkylene)C(=O)OR k and -NR h C(=O)(C1-C4 alkylene)NR i S(=O) p R k ,

[0155] R a The C1-C8 alkyl, the C1-C6 haloalkyl, the C1-C6 alkoxy and the C2-C8 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 hC(=O)R k 、-NR h C(=O)OR k 、-NR h C(=O)NR i R j 、-NR h S(=O) p R k 、-OR k 、-[O(CH2) q ] r OH, -OC(=O)R k 、-OC(=O)OR k 、-OC(=O)NR h R i 、-SR k 、-S(=O) p R k 、-S(=O) p NR h R i 、-[O(CH2) q ] r O(C1-C4 alkyl), -O-(C6 aryl or 5- to 8-membered heteroaryl) (optionally substituted by 1 to 3 R m Group substituted), C3-C6 carbocyclic group (optionally substituted by 1 to 3 R m Group substituted), -C6 to C 10 Aryl (optionally substituted with 1 to 3 R m substituted with a group), a 4- to 10-membered heterocyclic group (optionally substituted with 1 to 3 R m substituted with 1 to 3 R m group substitution); and

[0156] 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 by 1 to 3 groups independently selected from the group consisting of halogen, cyano, C1-C6 alkyl (optionally substituted by 1 to 3 R m Group substitution), -C(=O)R k 、C(=O)OR k 、-NR h R i 、-OR k 、-S(=O) p R k 、-S(=O) p NR h R iand a 5- to 10-membered heterocyclic group, wherein:

[0157] R h 、R i and R j Each occurrence is independently selected from hydrogen, C1-C6 alkyl (optionally substituted by 1 to 4 R m Group substitution), C6-C 10 Aryl, C3-C8 carbocyclic group (optionally substituted by 1 to 3 R m substituted with a group), a 5- to 10-membered heteroaryl group (optionally substituted with 1 to 3 R m and 5- to 10-membered heterocyclic groups (optionally substituted with 1 to 3 R m Group substitution), wherein:

[0158] R h 、R i and R j The C1-C6 alkyl of any one of the groups is optionally substituted by 1 to 4 groups independently selected from the group consisting of halogen, cyano, -OH, C1-C4 alkoxy, -C(=O)NH(C1-C4 alkyl), 5- to 10-membered heteroaryl (optionally substituted by 1 to 3 R m and 5- to 10-membered heterocyclic groups (optionally substituted with 1 to 3 R m group substitution);

[0159] R k is independently selected at each occurrence from hydrogen, NH2 (optionally substituted with 1 or 2 groups selected from C1-C3 alkyl), C1-C6 alkyl, benzyl, C6 aryl, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein:

[0160] R k wherein the C1-C6 alkyl group is optionally substituted with 1 to 5 groups independently selected from the group consisting of halogen, cyano, -NH2, -OH, C1-C6 alkoxy, C3-C6 cycloalkyl (optionally substituted with 1 to 3 halogen groups), 4 to 10-membered heterocyclyl (optionally substituted with 1 to 3 -OH groups), 5 to 10-membered aryl (optionally substituted with 1 to 3 groups selected from the group consisting of C1-C4 alkyl and halogen), and 5 to 10-membered heteroaryl (optionally substituted with 1 to 3 -OH groups); and

[0161] R kThe C3-C6 carbocyclyl, the benzyl and the C6 aryl of any one of the is each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, oxo, -OH, -C(=O)NH2, -C(=O)N(CH3)2, C1-C4 alkyl (optionally substituted by 1 to 3 -OH groups), C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl (optionally substituted by 1 to 3 halogen groups), C6 aryl (optionally substituted by 1 to 3 halogen groups) and 5- to 10-membered heteroaryl (optionally substituted by 1 to 3 halogen groups);

[0162] R k wherein the 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl of any one of the following are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, oxo, cyano, -C(=O)CH3, -NH2, -OH, C1-C4 alkyl (optionally substituted by 1 to 3 -OH groups), C1-C4 haloalkyl, 5- to 10-membered heterocyclyl, and C1-C4 alkoxy;

[0163] R m is independently selected at each occurrence from halogen, cyano, oxo, -NH2, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)R k 、-S(=O) p R k 、-OR k and a 5- to 10-membered heterocyclic group, wherein:

[0164] R m The C1-C6 alkyl, the C1-C6 alkoxy and the 5- to 10-membered heterocyclyl of any one of the following are optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH and C1-C4 alkoxy;

[0165] p is, at each occurrence, an integer independently selected from 1 and 2; and

[0166] q and r are integers independently selected from 0, 1, 2, and 3 at each occurrence.

[0167] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 ,k,m,R 3a 、R 3b 、R 4a 、R 4b 、R 5a and R 5bIn some embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, -R 6 C1-C6 alkyl optionally substituted by 1 to 5 groups independently selected from the following: halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C1-C4 alkoxy, C3-C6 carbocyclyl, C6 aryl (which is optionally substituted by 1 to 3 groups independently selected from the following: halogen and C1-C4 haloalkyl), -O-(C6 aryl) (which is optionally substituted by 1 to 3 groups independently selected from the following: halogen and C1-C4 haloalkyl), 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl.

[0168] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 ,k,m,R 3a 、R 3b 、R 4a 、R 4b 、R 5a and R 5b In some embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 is an optionally substituted C1-C6 alkyl group selected from the following:

[0169] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 ,k,m,R 3a 、R 3b 、R 4a 、R 4b 、R 5a and R 5b In some embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 Selected from -C(=O)O(C1-C4 alkyl).

[0170] In Formula I (including the above-defined variables X 1 and X2 、R 1 、R 2 ,k,m,R 3a 、R 3b 、R 4a 、R 4b 、R 5a and R 5b In some embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 Selected from As defined above for Formula I. In some of these embodiments, Ring B is selected from the group consisting of optionally substituted with 1, 2, 3, 4, or 5 R a C3-C 12 In some of these embodiments, Ring B is selected from a 3- to 12-membered heterocyclyl group. In some of these embodiments, Ring B is selected from a carbocyclyl group, as defined for Formula I. In some of these embodiments, Ring B is selected from a 3- to 12-membered heterocyclyl group, optionally substituted with 1, 2, 3, 4, or 5 R a C6 and C 10 Aryl is as defined for Formula I. In some of these embodiments, Ring B is selected from optionally substituted with 1, 2, 3, 4 or 5 R a The 5- to 10-membered heteroaryl group substituted by a group is as defined for formula I.

[0171] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 ,k,m,R 3a 、R 3b 、R 4a 、R 4b 、R 5a and R 5b In some embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 Selected from and Ring B is selected from optionally substituted by 1, 2, 3, 4 or 5 R a Group substituted Groups are as defined for formula I.

[0172] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 ,k,m,R 3a 、R3b 、R 4a 、R 4b 、R 5a and R 5b In some embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 Selected from and Ring B is selected from the following:

[0173] A group optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution.

[0174] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 ,k,m,R 3a 、R 3b 、R 4a 、R 4b 、R 5a and R 5b In some embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 Selected from the following: wherein Ring B is a 5-membered heteroaryl group, and R a As defined for Formula I.

[0175] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 ,k,m,R 3a 、R 3b ,、R 4a 、R 4b 、R 5a and R 5b In some embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 Selected from: wherein Ring B is a 5-membered heteroaryl group, and R a is oxo or selected from C1-C8 alkyl, C3-C 12 Carbocyclic groups and C6 and C 10Aryl, each of which may be optionally substituted with 1 to 3 groups selected from halogen and C1-C8 alkyl (wherein the C1-C8 alkyl may be optionally substituted with 1 to 3 groups selected from halogen, -OH, SO2CH3 and SO2NH2).

[0176] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 ,k,m,R 3a 、R 3b 、R 4a 、R 4b 、R 5a and R 5b In some embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 Selected from the following:

[0177]

[0178] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 ,k,m,R 3a 、R 3b 、R 4a 、R 4b 、R 5a 、R 5b and R 6 In some embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R a is selected from C1-C4 alkyl, halogen, -OH and C1-C4 alkoxy, wherein R a The C1-C4 alkyl group is optionally substituted with 1 to 3 polar groups, for example, sulfone, sulfonamide and alcohol.

[0179] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 ,k,m,R 3a 、R 3b 、R 4a 、R 4b 、R 5a 、R 5b and R 6In some embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R a is C1-C6 alkyl, optionally substituted as defined for Formula I. In some embodiments, R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups selected from the following groups: -OH, -SO2CH3, C1-C3 alkoxy, C(=O)NHCH3, -SO2NHCH2CH2OH, -SCF 3、 -SCH2C(CH2)2OH, -SO2phenyl, 4 to 6 membered heterocyclic ring (optionally with 1 to 3 R m substituted with a group), a 4- to 6-membered heteroaryl group (optionally substituted with 1 to 3 R m group-substituted), cyano, NHC(═O)-4 to 6-membered heteroaryl.

[0180] In Formula I (including the above-defined variables X 1 and X 2 、R 1 、R 2 ,k,m,R 3a 、R 3b 、R 4a 、R 4b 、R 5a 、R 5b and R 6 In some embodiments of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R a is selected from a 4- to 6-membered carbocycle, a 4- to 6-membered heterocycle, and a 4- to 6-membered heteroaryl, any of which is optionally substituted as defined above for Formula I.

[0181] In some embodiments, the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is selected from compounds 1 to 1183 depicted in Table 1, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. The wavy lines (i.e., ) depicts a bond between two atoms and indicates the position of mixed stereochemistry of a collection of molecules, such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. Asterisks near atoms in the compounds in Table 1 (e.g., ) indicates the chiral position in the molecule.

[0182] In some embodiments, the compound of formula (I) is selected from the compounds presented in Table 1 below, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0183] Table 1: Compounds 1 to 1183

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316] Some embodiments of the present disclosure include derivatives of compounds 1 to 1183 or compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the derivative is a silicon derivative, wherein at least one carbon atom selected from the group consisting of compounds 1 to 1183 or compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing has been replaced with silicon. In some embodiments, the derivative is a boron derivative, wherein at least one carbon atom selected from the group consisting of compounds 1 to 1183 or compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts thereof has been replaced by boron. In other embodiments, the derivative is a phosphorus derivative, wherein at least one carbon atom selected from the group consisting of compounds 1 to 1183 or compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts thereof has been replaced by phosphorus.

[0317] In some embodiments, the derivative is a silicon derivative in which one carbon atom selected from the group consisting of compounds 1 to 1183 or compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is replaced by silicon or a silicon derivative (e.g., -Si(CH3)2- or -Si(OH)2-). The carbon replaced by silicon may be a non-aromatic carbon. In other embodiments, 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 by deuterium. In some embodiments, a silicon derivative selected from the group consisting of compounds 1 to 1183 or compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing can incorporate silicon into a heterocycle.

[0318] In some embodiments, the derivative is a boron derivative, wherein one carbon atom in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from Compounds 1 to 1183 or compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing has been replaced by boron or a boron derivative.

[0319] In some embodiments, the derivative is a phosphorus derivative, wherein one carbon atom in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of Compounds 1 to 1183 or compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing has been replaced with phosphorus or a phosphorus derivative.

[0320] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from any one of the following formulae, tautomers, deuterated derivatives, or pharmaceutically acceptable salts: compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, and compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound selected from the following formulae, tautomers, deuterated derivatives, or pharmaceutically acceptable salts: compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, and compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered to a patient in need thereof.

[0321] The pharmaceutical composition may further include 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.

[0322] It should also be understood that the pharmaceutical compositions of the present disclosure can be used in combination therapy; that is, the pharmaceutical compositions described herein can further include at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the following can be used as a separate composition simultaneously with, before, or after the composition comprising at least one other active therapeutic agent: Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im compounds, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the following can be used as a separate composition simultaneously with, before, or after the composition comprising at least one other active therapeutic agent: Compounds 1 to 1183, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0323] As mentioned above, pharmaceutical compositions disclosed herein may optionally further include 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, suspension 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 DB Troy, Lippincott Williams & Wilkins Publishing Company of Philadelphia (Troy, Lippincott Williams & Wilkins, Philadelphia) and Encyclopedia of Pharmaceutical Technology, edited by J.Swarbrick and JC Boylan, 1988 to 1999, Marcel Dekker, New York discloses various carriers for preparing pharmaceutical compositions and the known technology 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 components 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), saturated vegetable fatty acids, water, partial glyceride mixtures of 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., sodium carboxymethylcellulose, ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., 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, fragrances, preservatives and antioxidants.

[0324] Compounds and compositions for use in therapy

[0325] 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.

[0326] In some embodiments of the present disclosure, the compounds and pharmaceutical compositions described herein are used to treat cancer. In some embodiments, the cancer is mediated by APOL1.

[0327] In some embodiments of the present disclosure, the compounds and pharmaceutical compositions described herein are used to treat pancreatic cancer. In some embodiments, pancreatic cancer is mediated by APOL1.

[0328] In some embodiments, the methods of the present disclosure comprise administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is selected from compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the patient in need thereof has the APOL1 genetic variants G1:S342G:I384M and G2:N388del:Y389del.

[0329] Another aspect of the present disclosure provides a method of inhibiting APOL1 activity, comprising contacting APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method of inhibiting APOL1 activity comprises contacting APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds 1 to 1183, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0330] Examples

[0331] 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.

[0332] 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 description of the preparation of compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il and Im selected from compounds 1 to 1183, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, the following abbreviations are used:

[0333] abbreviation

[0334] AcOH = acetic acid

[0335] ARP = assay ready plate

[0336] Boc2O=di-tert-butyl decarbonate

[0337] n-BuLi = n-butyllithium

[0338] CFL = Compact Fluorescent Lamp

[0339] 18-Crown-6=1,4,7,10,13,16-hexaoxacyclooctadecane

[0340] DAST = diethylaminosulfur trifluoride

[0341] DBDMH=1,3-dibromo-5,5-dimethylhydantoin

[0342] DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

[0343] DCE = 1,2-dichloroethane

[0344] DCM = dichloromethane

[0345] Deoxo-fluor = bis(2-methoxyethyl)aminosulfur trifluoride

[0346] DIBAL-H = Diisobutylaluminum hydride

[0347] DIPEA or DIEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propane-2-amine

[0348] DMAP = dimethylaminopyridine

[0349] DMA = dimethylacetamide

[0350] DME = dimethoxyethane

[0351] DMEM = Dulbecco's modified Eagle's medium

[0352] DMF = dimethylformamide

[0353] DMPU=N,N′-dimethylpropyleneurea

[0354] DMSO = dimethyl sulfoxide

[0355] dppf = 1,1′-bis(diphenylphosphino)ferrocene

[0356] ESI = electrospray ionization

[0357] EtOAc = ethyl acetate

[0358] EtOH = ethanol

[0359] Et2O = ether

[0360] Et2NH=diethylamine

[0361] Et3N=triethylamine

[0362] FA = Formamide

[0363] FBS = fetal bovine serum

[0364] GF-AFC = Glycyl-phenylalanylaminofluorocoumarin

[0365] HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphorus hexafluoride ion)

[0366] HDMC = N-[(5-chloro-3-oxo-1H-benzotriazol-1-yl)-4-morpholinomethylene]-N-methylmethanium hexafluorophosphate

[0367] HPLC = High Performance Liquid Chromatography

[0368] IPA = Isopropyl alcohol

[0369] (Ir[dF(CF3)ppy]2(dtbpy))PF6=[4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridyl-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III) hexafluorophosphate

[0370] [Ir{dFCF3ppy}2(bpy)]PF6=(2,2′-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-kN][phenyl-kC]iridium(III) hexafluorophosphate

[0371] LDA = lithium diisopropylamide

[0372] LED = Light Emitting Diode

[0373] MeCN or ACN = acetonitrile

[0374] MeI = methyl iodide

[0375] MeMgCl = methylmagnesium chloride

[0376] MeOH = methanol

[0377] MsOH = methanesulfonic acid

[0378] MTBE or TBME = methyl tert-butyl ether

[0379] n-BuLi = n-butyllithium

[0380] n-BuOH=1-butanol

[0381] NaOtBu=Sodium tert-butoxide

[0382] NBS = N-bromosuccinimide

[0383] NCS = N-chlorosuccinimide

[0384] NHPI = N-hydroxyphthalimide

[0385] NIS = N-iodosuccinimide

[0386] NMM = N-methylmorpholine

[0387] NMP = N-methylpyrrolidine

[0388] PBS = Phosphate-buffered saline

[0389] Pd(dppf)2Cl2=[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0390] PdCl2(PPh3)2=Bis(triphenylphosphine)palladium(II) dichloride

[0391] pet = petroleum

[0392] PP = Polypropylene

[0393] PPh3=triphenylphosphine

[0394] PhMgCl = Phenylmagnesium chloride

[0395] PSCBH = polymer supported cyanoborohydride

[0396] PTSA = p-toluenesulfonic acid monohydrate

[0397] RBF = Round Bottom Flask

[0398] SFC = Supercritical Fluid Chromatography

[0399] SPE = Solid Phase Extraction

[0400] STAB = sodium triacetoxyborohydride

[0401] T3P=2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphaninane-2,4,6-trioxide

[0402] TBAF = Tetra-n-butylammonium fluoride

[0403] TBS = tert-butyldimethylsilyl

[0404] TBSCl = tert-butyldimethylsilyl chloride

[0405] TBTA = tris((1-benzyl-4-triazolyl)methyl)amine

[0406] TBuONO = tert-butyl nitrite

[0407] tBuXPhos Pd G1=[2-(di-tert-butylphosphine)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride

[0408] tBuOH = tert-butyl alcohol

[0409] TEA = triethylamine

[0410] tet = tetracycline

[0411] TFA or TFAA = trifluoroacetic acid

[0412] TfOH = trifluoromethanesulfonic acid

[0413] THF = Tetrahydrofuran

[0414] T3P=2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphaninane-2,4,6-trioxide

[0415] 2-Me-THF = 2 = methyltetrahydrofuran

[0416] THP = Tetrahydropyran

[0417] TLC = Thin Layer Chromatography

[0418] TMS-OTf = trimethylsilyl trifluoromethanesulfonate

[0419] TMSCl = trimethylsilyl chloride

[0420] TMSCF3 = trifluoromethyltrimethylsilane

[0421] XPhos Pd G3 = (2-dicyclohexylphosphino-2′4′6′-triisopropyl-1,1′-biphenyl)-[2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II)

[0422] Example 1: Synthesis of compounds

[0423] All specific and generic compounds and intermediates disclosed for the preparation of those compounds are considered to be part of the disclosure disclosed herein.

[0424] Preparation S1

[0425] (2′S,4R)-2-Ethyl-2′-methyl-1′-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](S1)

[0426]

[0427] Step 1: Synthesis of (2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine (C1)

[0428] To a solution of (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (10g, 46.89mmol) and 2-(5-ethyl-2-thienyl) ethanol (7g, 42.56mmol) in dioxane (80mL) was added a solution of trifluoromethanesulfonic acid (12.4mL, 140.1mmol) in dioxane (20mL) at 0°C in 15 minutes. The reactant was stirred at the same temperature for 1 hour, and then warmed to ambient temperature and stirred for 3.5 hours. The mixture was diluted with water (300mL) and ethyl acetate (200mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100mL×2). The combined organic extracts were dried over NaSO, filtered and concentrated in vacuo. The crude product was dissolved in DCM and filtered through a silica gel plug (250g), eluted with DCM, then eluted with 25% MeOH / DCM to obtain the desired product. The product was dissolved in Et2O (500 mL) and heated at reflux for 15 minutes. After cooling to ambient temperature, heptane (500 mL) was added and the solid was filtered, washed with heptane and dried to provide the title compound (triflate) as a grey solid (11.36 g, 67%). 1 H NMR(400MHz,DMSO-d6)δ6.46(d,J=1.1Hz,1H),3.96-3.79(m,2H),3.42-3.34(m,1H),3.27-3.00 (m,2H),2.80-2.63(m,4H),2.01-1.87(m,3H),1.79(dd,J=14.5,12.2Hz,1H),1.24-1.16(m,6H). LCMS m / z 252.01[M+H] + .

[0429] Step 2: Synthesis of (2′S,4R)-2-ethyl-2′-methyl-1′-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (S1)

[0430] To a mixture of (2'S, 4R) -2-ethyl-2'-methyl-spiro [6,7-dihydrothieno [3,2-c] pyran-4,4'-piperidine] C1 (trifluoromethanesulfonate) (76.7 g, 187.7 mmol) and K2CO3 (46 g, 332.8 mmol) in THF (900 mL) was added propargyl bromide (21 mL, 188.5 mmol, 80% w / w solution in toluene). The resulting mixture was heated at 45 ° C for 5 hours and then cooled to room temperature and stirred overnight. The reactants were diluted with EtOAc (350 mL), brine (150 mL) and 2M Na2S2O3 aqueous solution (25 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was triturated with Et2O. The resulting colorless solid was filtered and dried to afford S1 (55.7 g, 92%). 1 H NMR (300MHz, chloroform-d) δ6.47(d,J=1.1Hz,1H),4.05-3.85(m,2H),3.67(dd,J=17.3,2.4Hz,1H),3.44(dd,J=17.3,2.4Hz,1H),3.00-2 .64(m,7H),2.25(t,J=2.4Hz,1H),2.03-1.81(m,3H),1.68(dd,J=13.8,11.5Hz,1H),1.28(t,J=7.5Hz,3H),1.10(d,J=6.3Hz,3H). LCMS m / z 290.11[M+H] + .

[0431] Preparation S2

[0432] (2′S,4R)-1′-[[1-(azetidin-3-yl)triazol-4-yl]methyl]-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](S2)

[0433]

[0434] Compound S2 was prepared from S1 and 3-azidoazetidine using the same procedure as described for compound 1.

[0435] Compound 1

[0436] 2-[3-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]triazol-1-yl]azetidin-1-yl]sulfonylethanol (1)

[0437]

[0438] Preparation of 2-[3-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]triazol-1-yl]azetidin-1-yl]sulfonylethanol (1)

[0439] To a solution of (2′S, 4R)-1′-[[1-(azetidin-3-yl)triazol-4-yl]methyl]-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]S2 (10 mg, 0.026 mmol) in DCM (0.65 mL) was added 2-hydroxyethane-1-sulfonyl chloride (4.1 mg, 0.028 mmol) and DIPEA (9.0 μL, 0.052 mmol). The reactants were stirred at room temperature for 2 hours. The volatiles were then removed and the crude product was purified by reverse phase chromatography (C18 column; gradient: H2O containing MeCN with 0.1% TFA) to give 1 (3.1 mg, 24%). 1 H NMR (300MHz, methanol-d4) δ8.44(s,1H),6.51(s,1H),5.57(ddd,J=13.5,7.8,5.7Hz,1H),4.80–4.37(m,6H),3.97(t,J=5.9Hz,2H),3.88(p,J=6.0,5. 5Hz,2H),3.57(d,J=7.9Hz,1H),3.40(q,J=6.4,5.9Hz,4H),2.88–2.56(m,4H),2.28–1.85(m,4H),1.58(d,J=6.4Hz,3H),1.25(t,J=7.5Hz,3H). LCMS m / z496.14[M+H] + .

[0440] Compounds 2-5

[0441] Compound 2-5 (see Table 2) was prepared from S2 using the same method as described for compound 1 using the appropriate sulfonyl chloride. Unless otherwise stated, all sulfonyl chlorides were obtained from commercial sources. Any modifications to the method are noted in Table 2 and the accompanying footnotes.

[0442] Table 2: Structural and physicochemical data of compounds 2-5

[0443]

[0444]

[0445] Preparation of S3

[0446] 2-Azido-N-(2-hydroxyethyl)ethane-1-sulfonamide (S3)

[0447]

[0448] To a solution of 2-azidoethanesulfonyl chloride (60 mg, 0.35 mmol) in DCM (2 mL) was added pyridine (60 μL, 0.7418 mmol) and 2-aminoethanol (30 μL, 0.50 mmol). The mixture was stirred at room temperature ("rt") for 2 hours ("h"). Volatiles were removed to give the title compound. The crude product was used directly without further purification.

[0449] Preparation of S4

[0450] 2-Azido-N-(2-hydroxypropyl)ethane-1-sulfonamide (S4)

[0451]

[0452] Compound S4 was prepared from 2-azidoethanesulfonyl chloride and 1-aminopropan-2-ol using the same procedure as described for S3. The crude title compound was used directly without further purification.

[0453] Compound 6

[0454] 2-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]triazol-1-yl]-N-(2-hydroxyethyl)ethanesulfonamide (6)

[0455]

[0456] Preparation of 2-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-yl]methyl]triazol-1-yl]-N-(2-hydroxyethyl)ethanesulfonamide (6)

[0457] To a solution of 2-azido-N-(2-hydroxyethyl)ethane-1-sulfonamide (67.9 mg, 0.35 mmol) in MeOH (2 mL) and H2O (0.2 mL) was added (2'S)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]S1 (50 mg, 0.17 mmol), sodium ascorbate (37 mg, 0.21 mmol) and CuSO4 (1 mg, 0.006 mmol). The mixture was heated at 50 ° C for 1 hour. After cooling to room temperature, the mixture was diluted with DCM and H2O. The pH of the aqueous layer was adjusted to pH 10. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic extracts were concentrated in vacuo. The crude product was purified by reverse phase chromatography (C18 column; gradient: MeCN in H2O with 0.1% HCl) to afford the title compound (13.9 mg, 17%). 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),7.53(s,2H),7.05(s,1H),5.29(t,J=7.3Hz,2H),4 .45-4.08(m,5H),3.73(s,6H),3.26-3.04(m,5H),2.36-1.96(m,4H),1.73-1.61(m,6H). LCMS m / z 484.12[M+H] + .

[0458] Compound 7

[0459] 2-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-

[0460] 1-Yl]methyl]triazol-1-yl]-N-(2-hydroxypropyl)ethanesulfonamide (7)

[0461]

[0462] Preparation of 2-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-yl]methyl]triazol-1-yl]-N-(2-hydroxypropyl)ethanesulfonamide (7)

[0463] Compound 7 was prepared from (2'S)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] and 2-azido-N-(2-hydroxypropyl)ethane-1-sulfonamide using the same method as described for compound 6. The crude product was purified by reverse phase chromatography (C18 column; gradient: MeCN in HO with 0.1% HCl) to give the title compound (7.1 mg, 8%). 1 H NMR(400MHz, DMSO-d6)δ8.53(d,J=3.5Hz,1H),7.71(t,J=6.1Hz,1H),7.05(s,1H),5.26(q,J=6.9Hz, 2H),4.40-4.06(m,6H),3.45-3.25(m,2H),3.46-2.92(m,7H),2.35-1.93(m,5H),1.75-1.53(m,9H). LCMS m / z 498.19[M+H] + .

[0464] Compound 8

[0465] (2′S,4R)-2-ethyl-2′-methyl-1′-(1H-triazol-4-ylmethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](8)

[0466]

[0467] Preparation of (2′S,4R)-2-ethyl-2′-methyl-1′-(1H-triazol-4-ylmethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](8)

[0468] To a solution of (2'S,4R)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (40 mg, 0.14 mmol) in DMF (2 mL) was added sodium azide (30 mg, 0.46 mmol) and CuI (30 mg, 0.16 mmol). The mixture was stirred at rt overnight. The mixture was filtered and the filtrate was concentrated. The crude product was purified by reverse phase chromatography (C18 column; gradient: MeCN in HO with 0.1% HCl) to give the title compound (4.6 mg, 9%). 1H NMR(400MHz, DMSO-d6)δ8.53(d,J=3.5Hz,1H),7.71(t,J=6.1Hz,1H),7.05(s,1H),5.26(q,J=6.9Hz, 2H),4.40-4.06(m,6H),3.45-3.25(m,2H),3.46-2.92(m,7H),2.35-1.93(m,5H),1.75-1.53(m,9H). LCMS m / z333.16[M+H] + .

[0469] Preparation of S5 and S6

[0470] (2′R,4R)-2-Ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](S5)

[0471] (2′R,4S)-2-Ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](S6)

[0472]

[0473] Preparation of (2′R,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (S5) and (2′R,4S)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (S6)

[0474] To a solution of 2-(5-ethyl-2-thienyl)ethanol (1.0 g, 6.4 mmol) and (2R)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 7.03 mmol) in dioxane (15 mL) was slowly added a solution of trifluoromethanesulfonic acid (1.8 mL, 20.34 mmol) in dioxane (5 mL). The mixture was stirred overnight at rt. The mixture was diluted with H2O and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc (x2). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified to obtain the title compounds S5 (2.0 g, purity: 23%, 18%) and S6 (2.0 g, purity: 77%, 60%) as trifluoromethanesulfonates. LCMS m / z 252.11[M+H] + .

[0475] Compound 9

[0476] (2′R,4R)-2-ethyl-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](9)

[0477]

[0478] Step 1: Synthesis of (2R,4R)-2′-ethyl-2-methyl-1-(prop-2-yn-1-yl)-6′,7′-dihydrospiro[piperidin-4,4′-thieno[3,2-c]pyran] (C2)

[0479] To a solution of (2'R, 4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]S5 (trifluoromethanesulfonate) (3.0 g, 7.473 mmol) in THF (35 mL) was added K2CO3 (2.0 g, 14.47 mmol) and propargyl bromide (930 μL, 80% w / w solution in toluene, 8.35 mmol). The mixture was heated at 45 ° C for 8 hours and then cooled to room temperature and stirred overnight. The reactant was diluted with EtOAc (350 mL), brine (150 mL) and 2M aqueous sodium thiosulfate solution (25 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with Et2O. The resulting colorless solid was filtered off and the filtrate was concentrated in vacuo to give the title compound as a light brown oil (2.1 g, 74%). The product was used directly without further purification. LCMS m / z 290.11 [M+H] + .

[0480] Step 2: Synthesis of (2′R,4R)-2-ethyl-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (9)

[0481] To a solution of (2'R)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]C2 (1.0 g, 3.46 mmol, purity: 23%) in MeOH (12.75 mL) and H2O (4.25 mL) was added CuSO4 (30 mg, 0.19 mmol), TBTA (110 mg, 0.21 mmol) and sodium ascorbate (619 mg, 3.52 mmol). The mixture was stirred at room temperature, and then a solution of 1-azido-2-methylsulfonyl-ethane (600 mg, 4.02 mmol) in MeOH (2 mL) was added dropwise. After the addition, the mixture was stirred for 90 minutes. The mixture was concentrated in vacuo. The residue was suspended in EtOAc and filtered. The filtrate was washed with a mixture of saturated NaHCO solution and H O (1:1, 50 mL). The water washings were back-extracted with EtOAc (25 mL). The combined organic extracts were dried over Na SO , filtered, and concentrated in vacuo. The crude product was purified by MPLC on silica gel (0-10% MeOH in DCM) to give the title compound (40 mg, 48%) as a colorless glass. 1 H NMR (300 MHz, chloroform-d) δ 8.18 (s, 1H), 6.51 (s, 1H), 4.92 (t, J = 6.6 Hz, 2H), 4.13 (s, 2H), 3.91 (td, J = 6.6, 5.9, 3.3 Hz, 2H), 3.77 (t, J = 6.6 Hz, 2H), 3.57-3.37 (m, 1H), 3.35-3. 17(m,1H),2.99(d,J=12.0Hz,1H),2.87(s,3H),2.82-2.64(m,4H),2.26(td,J=15.7 ,15.3,4.8Hz,2H),2.07-1.80(m,2H),1.49(d,J=6.8Hz,3H),1.26(t,J=7.5Hz,3H). LCMSm / z 440.27[M+H] + .

[0482] Compound 10

[0483] (2′R,4S)-2-ethyl-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](10)

[0484]

[0485] Step 1: Synthesis of (2′S,4S)-2-ethyl-2′-methyl-1′-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (C2)

[0486] To a solution of (2'R, 4S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](trifluoromethanesulfonate) S6 (1.14 g, 2.460 mmol) in DMF (2 mL) and THF (8 mL) was added potassium carbonate (1 g, 7.24 mmol) and 4-methylbenzenesulfonic acid prop-2-ynyl ester (500 μL, 2.90 mmol). The mixture was stirred at 30 ° C overnight. The reactant was diluted with EtOAc (30 mL), H2O (20 mL) and brine (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using silica gel chromatography (10-35% EtOAc in hexanes) to give C2 (350 mg, 44%). 1 H NMR (300MHz, chloroform-d) δ6.41 (d, J=1.1Hz, 1H), 3.96-3.74 (m, 2H), 3.47 (ddd, J=71.3, 17.3, 2.4Hz, 2H), 2.98-2 .48(m,7H),1.92-1.72(m,3H),1.60(dd,J=13.8,11.5Hz,1H),1.21(t,J=7.5Hz,4H),1.03(d,J=6.3Hz,3H). LCMS m / z 290.11[M+H] + .

[0487] Step 2: Synthesis of (2′R,4S)-2-ethyl-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (10)

[0488] To a solution of (2'R, 4S) -2-ethyl -2'-methyl -1'-prop-2-ynyl -spiro [3a, 6, 7, 7a- tetrahydrothieno [3, 2-c] pyran -4, 4'-piperidine] C2 (350 mg, 1.20 mmol) in MeOH (8 mL) and H2O (2 mL) was added CuSO4 (5 mg, 0.031 mmol), TBTA (25 mg, 0.047 mmol) and sodium ascorbate (300 mg, 1.70 mmol). The mixture was stirred at rt, and a solution of 1- azido -2- methylsulfonyl - ethane (200 mg, 1.34 mmol) in MeOH (2 mL) was then added dropwise via an addition funnel. The mixture was stirred at room temperature for 2 hours. The reactant was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (150 mL) and H2O (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (150 mL x 2). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to yield a tan solid. Purification by silica gel chromatography (0-40% EtOAc in hexanes) gave 10 (448 mg, 81%). 1 H NMR (300MHz, chloroform-d) δ7.66(s,1H),6.40(d,J=1.2Hz,1H),4.81(t,J=6.4Hz,2H),3.98(d,J= 14.6Hz,1H),3.89-3.65(m,5H),2.72-2.46(m,10H),1.85-1.57(m,4H),1.26-1.11(m,6H). LCMS m / z 439.17[M+H] + .

[0489] Compound 11

[0490] (2′S,4R)-2-ethyl-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](11)

[0491]

[0492] Preparation of (2′S,4R)-2-ethyl-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](11)

[0493] Compound 11 was prepared from (2'S, 4R)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] and 1-azido-2-methylsulfonyl-ethane using the same method as described for 10. The crude product was suspended in EtOAc and heated at 50 ° C for 10 minutes. The mixture was diluted with Et2O, cooled to 0 ° C, and stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with Et2O and dried to give the title compound (595 mg, 70%). 1 HNMR(400MHz, DMSO-d6)δ8.08(s,1H),6.58(d,J=1.1Hz,1H),4.80(t,J=6.9Hz,2H),3.91-3.65(m,6H),2.92(s,3H),2.70(qd,J=7.5,0.9Hz ,2H),2.65-2.53(m,3H),2.48-2.36(m,2H),1.82-1.62(m,3H),1.54(dd,J=13.6,11.2Hz,1H),1.19(t,J=7.5Hz,3H),1.13(d,J=6.1Hz,3H). LCMS m / z 439.56[M+H] + .

[0494] Compound 12

[0495] 2-[4-[[(2′S)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]triazol-1-yl]-N-methyl-ethanesulfonamide (12)

[0496]

[0497] Preparation of 2-[4-[[(2′S)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]triazol-1-yl]-N-methyl-ethanesulfonamide (12)

[0498] To a solution of 2-amino-N-methyl-ethanesulfonamide (HCl salt) (55 mg, 0.31 mmol) in THF (2.5 mL) and H2O (1 mL) was added CuSO4 (1 mg, 0.0063 mmol) and K2CO3 (30 mg, 0.2171 mmol), followed by the addition of N-diazideethane-1-sulfonamide (tetrafluoroborate) (120 mg, 0.46 mmol). The reactants were stirred at room temperature overnight. TBTA (10 mg, 0.019 mmol), sodium ascorbate (40 mg, 0.23 mmol) and (2'S, 4R)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]S1 (HCl salt) (56 mg, 0.17 mmol) were then added to the reactants. The resulting mixture was stirred at 55 ° C for 30 minutes. The reaction was cooled to room temperature and volatiles were removed. The crude product was purified by reverse phase chromatography (C18 column; gradient: H2O containing MeCN with 0.1% TFA) to produce the desired product as a TFA salt. The product was dissolved in DCM and treated with saturated NaHCO3 solution. The organic layer was separated and concentrated in vacuo to give 12 (53.5 mg, 70%) as a free base. 1 H NMR (400MHz, chloroform-d) δ7.54(s,1H),6.38(s,1H),4.74(t,J=6.3Hz,2H),4.63(s,1H),3.93(s,2H),3.86-3.69(m,2H),3.60(q,J=6.4 Hz,2H),2.76-2.58(m,5H),2.56(s,3H),2.52-2.37(m,2H),1.89-1.71(m,3H),1.61(dd,J=13.8,11.3Hz,1H),1.24-1.10(m,6H). LCMS m / z 454.45[M+H] + .

[0499] Preparation of S7

[0500] Azido(methylsulfonyl)methane (S7)

[0501]

[0502] Preparation of Azido(methylsulfonyl)methane (S7)

[0503] To a solution of bromo(methylsulfonyl)methane (100mg, 0.58mmol) in DMF (3mL) was added sodium azide (150mg, 2.31mmol). The resulting mixture was heated at 80°C overnight. After cooling to room temperature, the mixture was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo. The crude product was dissolved in DCM (5mL) and filtered again. The filtrate was concentrated in vacuo to give the title compound (75mg, 82%) as a red oil. The crude product can be used directly without further purification. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.20 (s, 2H), 2.98 (t, J = 0.9 Hz, 3H).

[0504] Preparation of S8

[0505] 1-(Azidomethylsulfonyl)ethane (S8)

[0506]

[0507] Preparation of 1-(azidomethylsulfonyl)ethane (S8)

[0508] Compound S8 was prepared from 1-(bromomethylsulfonyl)ethane using the same procedure as described for S7. The crude title compound was isolated as a red oil (300 mg, 88%) and used directly without further purification.

[0509] Compound 13

[0510] (2′S)-2-Ethyl-2′-methyl-1′-[[1-(methylsulfonylmethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](13)

[0511]

[0512] Preparation of (2′S)-2-ethyl-2′-methyl-1′-[[1-(methylsulfonylmethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](13)

[0513] To a mixture of azido(methylsulfonyl)methane (75 mg, 0.47 mmol), (2'S, 4R)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (50 mg, 0.16 mmol) in MeOH (3 mL) and H2O (2 mL) was added CuSO4 (0.6 mg, 0.004 mmol), TBTA (4 mg, 0.008 mmol) and sodium ascorbate (28 mg, 0.16 mmol). The resulting mixture was heated at 50 ° C for 10 minutes. After cooling to rt, the mixture was concentrated. The crude product was purified using silica gel chromatography (DCM containing 0-10% MeOH) to give the title compound (59 mg, 85%). 1 H NMR (400MHz, chloroform-d) δ7.81(s,1H),6.45(d,J=1.1Hz,1H),5.61-5.47(m,2H),4.08(d,J=14.7Hz,1H),3.92-3.76(m,3H),2.89(d,J =0.9Hz,3H),2.79-2.51(m,7H),1.94-1.76(m,3H),1.68(dd,J=14.0,11.3Hz,1H),1.25(t,J=7.5Hz,3H),1.21(d,J=6.2Hz,3H). LCMSm / z 425.52[M+H] + .

[0514] Compound 14

[0515] (2′S)-2-Ethyl-1′-[[1-(ethylsulfonylmethyl)triazol-4-yl]methyl]-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](14)

[0516]

[0517] Preparation of (2′S)-2-ethyl-1′-[[1-(ethylsulfonylmethyl)triazol-4-yl]methyl]-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](14)

[0518] 14 was prepared from (2′S,4R)-2-ethyl-2′-methyl-1′-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] and 1-(azidomethylsulfonyl)ethane using the same procedure as described for 13. The crude product was purified using silica gel chromatography (0-100% EtOAc in heptane) to give 14 (46 mg, 67%) as a clear oil. 1H NMR (400MHz, chloroform-d) δ7.81 (s, 1H), 6.50-6.41 (m, 1H), 5.63-5.44 (m, 2H), 4.06 (d, J = 14.7Hz, 1H), 3.94-3.74 (m, 3H), 2.96 (q, J = 7.5Hz, 2H), 2.78-2.52(m,7H),1.93-1.77(m,3H),1.68(dd,J=14.0,11.3Hz,1H),1.37(t,J=7.5Hz,3H),1.25(t,J=7.5Hz,3H),1.21(d,J=6.2Hz,3H). LCMS m / z 439.56[M+H] + .

[0519] Compound 15

[0520] (3R)-3-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-yl]methyl]triazol-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (15)

[0521]

[0522] Preparation of (3R)-3-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]triazol-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (15)

[0523] To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (9.1 μL, 0.054 mmol) in MeOH (600 μL) was added a solution of CuSO (0.15 mg, 0.026 mmol) in H O (75 μL) and a solution of NaHCO in H O (75 μL). Then a solution of trifluoromethanesulfonic acid azide (0.15 mL, 0.45 mmol) in DCM was added. After the mixture was stirred at rt for 1 hour, a solution of (2'S, 4R)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (10 mg, 0.036 mmol) in MeOH (100 μL) was added, followed by a solution of sodium ascorbate (7 mg, 0.040 mmol) in H2O (50 μL) and a solution of TBTA (2 mg, 0.004 mmol) in MeOH (100 μL). The resulting mixture was heated at 50 ° C overnight. After cooling to room temperature, the volatiles were removed and the crude product was purified by reverse phase chromatography (C18 column; gradient: H2O containing MeCN with 0.1% TFA) to give 15 (5.3 mg, 30%). 1 H NMR (300MHz, methanol-d4) δ8.01(s,1H),6.49(d,J=1.1Hz,1H),5.26(tt,J=6.1,4.2Hz,1H),4.04(d,J=14.5Hz,1H),3 .96–3.70(m,5H),3.57(d,J=7.9Hz,2H),2.83–2.36(m,9H),2.01–1.57(m,4H),1.47(s,8H),1.38–1.10(m,7H). LCMS m / z 502.38[M+H] + .

[0524] Compound 16

[0525] 5-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]triazol-1-yl]pyridin-3-ol (16)

[0526]

[0527] Preparation of 5-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]triazol-1-yl]pyridin-3-ol (16)

[0528] To a solution of 5-aminopyridin-3-ol (18 mg, 0.16 mmol) in MeCN (2 mL) was added tBuONO (0.28 mL, 0.24 mmol) and TMS azide (0.025 mL, 0.19 mmol) dropwise. After stirring at rt for 2 hours, (2'S, 4R)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (35 mg, 0.11 mmol) was added, followed by an aqueous solution of CuSO4 (1.2 mg, 0.008 mmol) and sodium ascorbate (30 mg, 0.17 mmol) in H2O (0.2 mL). The resulting mixture was stirred at 65 ° C overnight. After cooling to rt, the crude product was purified by reverse phase chromatography (C18 column; gradient: MeCN in H O with 0.1% TFA) to give the desired product as a TFA salt. The product was dissolved in DCM (2 mL) and treated with saturated aqueous NaHCO (2 mL). The organic layer was separated and concentrated in vacuo to give the title compound (15.4 mg, 33%) as a free base. 1 H NMR (400MHz, chloroform-d) δ8.44(s,1H),8.36(dd,J=10.0,2.2Hz,2H),8.10(s,1H),6.40(d,J=1.1Hz,1H),4.22(d,J=14 .5Hz,1H),3.97-3.71(m,3H),2.94-2.53(m,8H),1.98-1.62(m,4H),1.27(d,J=6.2Hz,3H),1.19(t,J=7.5Hz,3H). LCMS m / z 426.17[M+H] + .

[0529] Compound 17-197

[0530] Compounds 17-197 (see Table 3) were prepared from S1 using the appropriate amines using General Methods B or C. Unless otherwise stated, all amines were obtained from commercial sources. Any modifications to the methods are noted in Table 2 and the accompanying footnotes.

[0531] Table 3: Structural and physicochemical data of compounds 17-197

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595] Compound 198

[0596] (2′S,4R)-1′-[(2-chloropyrimidin-5-yl)methyl]-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](198)

[0597]

[0598] Step 1: 2-Chloro-5-(chloromethyl)pyrimidine (C4)

[0599] In bottom flask, pack (2-chloropyridine-5-yl) methanol (1g, 6.92mmol) and thionyl chloride (12.5mL, 171mmol).In suspension, add DMF (32.5 μ L, 0.42mmol), and gained mixture is heated under reflux for 5 hours.After heating, mixture dissolves and forms clear yellow homogeneous solution.After complete conversion, reactant is cooled to ambient temperature, and then concentrated in vacuum.Crude product is azeotroped with ethylene dichloride (x2), and dried to constant mass under high vacuum, to obtain C4 (1.08g, 92%). 1 H NMR (300 MHz, chloroform-d) δ 8.67 (s, 2H), 4.57 (d, J = 0.6 Hz, 2H). LCMS m / z 331.25 [M+H] + .

[0600] Step 2: (2′S,4R)-1′-[(2-chloropyrimidin-5-yl)methyl]-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (198)

[0601] A solution of (2′S, 4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](trifluoromethanesulfonate) (2 g, 4.99 mmol), 2-chloro-5-(chloromethyl)pyrimidine (3 g, 6.07 mmol), KCO (2.2 g, 15.92 mmol) and NaI (750 mg, 5.00 mmol) in THF (18 mL) and DMF (2 mL) was heated at 40°C overnight. The mixture was diluted with HO (30 mL) and extracted with EtOAc (50 mL×2). The combined organic extracts were washed with 2N NaS0 (20 mL) and brine (20 mL), dried over NaSO, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 0 to 33% EtOAc / hexanes to afford 198 (1.34 g, 70%). 1 H NMR (300MHz, chloroform-d) δ8.62(s,2H),6.48(d,J=1.1Hz,1H),4.12(d,J=14.2Hz,1H),4.01-3.67(m,2H),3.19(d,J=14 .2Hz,1H),2.89-2.61(m,5H),2.57-2.30(m,2H),2.00-1.53(m,4H),1.29(t,J=7.5Hz,3H),1.17(d,J=6.2Hz,3H). LCMS m / z 378.07[M+H] + .

[0602] Compound 199

[0603] (2′S,4R)-1′-[(6-chloro-pyrimidin-3-pyridinyl)methyl]-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](199)

[0604]

[0605] Preparation of (2′S,4R)-1′-[(6-chloro-pyrimidin-3-pyridinyl)methyl]-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](199)

[0606] A mixture of (2′S, 4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](trifluoromethanesulfonate) S1 (2 g, 4.99 mmol), 2-chloro-5-(chloromethyl)pyridine (900 mg, 5.56 mmol), KCO (2.2 g, 15.92 mmol) and NaI (750 mg, 5.00 mmol) in THF (18 mL) and DMF (2 mL) was heated at 30°C overnight. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL×2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 0 to 33% EtOAc / hexane to give 199 (2.00 g, 92%). 1 H NMR (300MHz, chloroform-d)8.30(d,J=2.4Hz,1H),7.65(dd,J=8.2,2.4Hz,1H),7.23(d,J=8.2Hz,1H),6.45(d,J=1.1Hz,1H),4.06(d,J=13.8Hz,1H),3.84(tdd, J=11.3,8.8,4.9Hz,2H),3.11(d,J=13.8Hz,1H),2.87-2.55(m,5H),2.57-2 .24(m,2H),1.96-1.58(m,4H),1.23(t,J=7.5Hz,3H),1.12(d,J=6.1Hz,3H). LCMS m / z 377.13[M+H] + .

[0607] Compound 200

[0608] [(1R,4S)-4-[[5-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]pyrimidin-2-yl]amino]cyclopent-2-en-1-yl]methanol (200)

[0609]

[0610] Preparation of [(1R,4S)-4-[[5-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]pyrimidin-2-yl]amino]cyclopent-2-en-1-yl]methanol (200)

[0611] A mixture of (2'S, 4R)-1'-[(2-chloropyrimidin-5-yl)methyl]-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (14.5 mg, 0.037 mmol), ((1R, 4S)-4-aminocyclopent-2-en-1-yl)methanol (5.89 mg, 0.052 mmol), tBuXPhosPdG1 (2.41 mg, 0.0037 mmol) in tBuOH (560 μL) was degassed with N2, and then a 2M solution of NaOtBu in tBuOH (48 μL) was added. The resulting mixture was heated at 85 °C for 3 hours. After cooling to ambient temperature, the reaction was quenched with MeOH. The solvent was removed in vacuo and the crude product was purified by reverse phase chromatography (C18 column; gradient: MeCN in H2O with 0.1% TFA) to afford 200 (2.2 mg, 8.3%). LCMS m / z 455.58 [M+H] + .

[0612] Compound 201

[0613] 2-[[5-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]pyrimidin-2-yl]amino]-2-methyl-propan-1-ol (201)

[0614]

[0615] Preparation of 2-[[5-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]pyrimidin-2-yl]amino]-2-methyl-propan-1-ol (201)

[0616] To a mixture of 2-amino-2-methyl-propan-1-ol (50 mg, 0.56 mmol) and (2′S, 4R)-1′-[(2-chloropyrimidin-5-yl)methyl]-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] 198 (30 mg, 0.069 mmol) in NMP (2 mL) was added DIPEA (51 mg, 0.39 mmol). The reactants were heated at 230° C. in a microwave for 6 hours. After cooling to rt, the reactants were diluted with DCM and washed with H2O (x3). The organic layer was separated and concentrated in vacuo. The crude product was purified by reverse phase chromatography (C18 column; gradient: H2O containing MeCN with 0.1% TFA) to give 201 (3.6 mg, 9%) as a TFA salt. 1H NMR (300MHz, methanol-d4) δ8.24(s,2H),6.49(d,J=1.0Hz,1H),3.97(d,J=13.6Hz,1H),3.92-3.81(m,2H),3.67(s,2H),3.21 (d,J=13.6Hz,1H),2.78-2.61(m,6H),2.44(td,J=10.9,5.3Hz,1H),1.87-1.66(m,4H),1.38(s,6H),1.27-1.20(m,6H). LCMS m / z 431.49[M+H] + .

[0617] Compound 202

[0618] 5-[[(2′S)-2-Ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]-N-methyl-pyridin-2-amine (202)

[0619]

[0620] Preparation of 5-[[(2′S)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]-N-methyl-pyridin-2-amine (202)

[0621] A mixture of (2'S)-1'-[(6-chloro-3-pyridinyl)methyl]-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 199 (15 mg, 0.038 mmol), ((1R,4S)-4-aminocyclopent-2-en-1-yl)methanol (5.21 mg, 0.046 mmol), tBuXPhosPdG1 (2.50 mg, 0.0038 mmol) in tBuOH (500 μL) was degassed with N2, and then a 2M solution of NaOtBu in tBuOH (42 μL) was added. The resulting mixture was heated at 60 °C for 3 hours. After cooling to ambient temperature, the reaction was quenched with MeOH. The solvent was removed in vacuo, and the crude product was purified by reverse phase chromatography (C18 column; gradient: MeCN in H2O with 0.1% TFA) to afford 202 (11.9 mg, 49%). 1H NMR (300 MHz, chloroform-d) δ 8.29 (dd, J = 18.9, 9.3 Hz, 1H), 7.99 (s, 1H), 7.03 (d, J = 9.6 Hz, 1H), 6.49 (s, 1H), 6.12-6.02 (m, 1H), 5.95 (s, 1H), 5.91-5.81 (m, 1H), 4.84-4.62 (m, 2H), 4.45 (s, 1H), 4.02-3.49 (m, 6H), 3.26-2.88(m,3H),2.77(q,J=7.7Hz,4H),2.58(dt,J=14.1,8.7Hz,1H),2.36(q,J=13.4,12.3Hz,2H) ,2.12-1.91(m,2H),1.83(dt,J=14.2,3.2Hz,1H),1.60(dd,J=6.5,3.6Hz,3H),1.27(t,J=7.5Hz,3H).

[0622] Compounds 203-231

[0623] Compounds 203-231 (see Table 4) were prepared from 198 or 199 using the appropriate amines according to the general method of 200-202. Unless otherwise stated, all amines were obtained from commercial sources. Any modifications to the methods are noted in Table 4 and the accompanying footnotes.

[0624] Table 4: Structural and physicochemical data of compounds 203-231

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632] Compound 232

[0633] 4-[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]tetrahydrofuran-3-ol (232) and 4-[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]tetrahydrofuran-3-ol (233)

[0634]

[0635] Preparation of 4-[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]tetrahydrofuran-3-ol (232) and 4-[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]tetrahydrofuran-3-ol (233)

[0636] To a solution of (2′S, 4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](trifluoromethanesulfonate) S1 (36 mg, 0.088 mmol) in MeOH (1 mL) was added DIPEA (100 μL, 0.57 mmol) and 3,6-dioxabicyclo[3.1.0]hexane (43 mg, 0.50 mmol). The mixture was heated in a microwave at 150 ° C for 6 hours. After cooling to ambient temperature, the volatiles were removed in vacuo, and the crude product was purified by reverse phase chromatography (C18 column; gradient: H 2 O containing MeCN with 0.2% formic acid) to give 232 (11.5 mg, 38%) and the corresponding trans diastereomer 233 (10 mg, 33%), compound 232: 1 H NMR (300MHz, chloroform-d) δ9.16 (s, 1H), 6.51 (d, J = 1.1Hz, 1H), 4.91 (t, J = 6.6Hz, 1H), 4.36 ( dd,J=10.2,7.2Hz,1H),4.21(d,J=11.9Hz,1H),4.12(d,J=5.9Hz,1H),4.05-3.79(m, 2H),3.60(dd,J=10.2,5.9Hz,1H),3.51-3.31(m,1H),2.92-2.72(m,4H),2.59(s,4H) ,2.44-2.24(m,1H),2.21-1.99(m,2H),1.46(d,J=6.6Hz,3H),1.29(t,J=7.5Hz,3H). LCMS m / z 338.21[M+H] + Compound 233:1 H NMR (300 MHz, chloroform-d) δ 8.56 (s, 1H), 6.54 (d, J = 1.0 Hz, 1H), 4.73 (t, J = 6.3 Hz, 1H), 4.35-4.01 (m, 3H), 3.99-3.79 (m, 2H), 3.60 (dd, J = 9.8, 5.9 Hz, 1H), 3.49 (d, J = 10.3 Hz, 1H), 3.18 (d,J=10.9Hz,1H),2.98(t,J=12.4Hz,1H),2.86-2.71(m,5H),2.40-2.20(m,1H),2.13( d, J=12.0Hz, 1H), 1.98 (d, J=14.4Hz, 2H), 1.43 (d, J=6.4Hz, 3H), 1.28 (t, J=7.6Hz, 3H). LCMS m / z 338.21[M+H] + .

[0637] Compounds 234-263

[0638] Compounds 234-263 (see Table 5) were prepared from C1 using the appropriate epoxides, following the epoxide ring-opening method described for 232 and 233. Unless otherwise stated, all epoxides were obtained from commercial sources. Any modifications to the methods are noted in Table 5 and the accompanying footnotes.

[0639] Table 5: Structural and physicochemical data of compounds 234-263

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647] Preparation of S9

[0648] (2′S,4S)-2-Ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](S9)

[0649]

[0650] Step 1: (2′S,4S)-2-Ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylic acid tert-butyl ester (C6)

[0651] A solution of 2-(5-ethyl-2-thienyl)ethanol (103 mg, 0.622 mmol), (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (144 mg, 0.675 mmol) in DCM (1 mL) was cooled to -78 ° C. MsOH (0.1 mL, 1.54 mmol) was added dropwise, and the resulting solution was stirred for 2 hours. Trifluoromethanesulfonic acid (0.1 mL, 1.13 mmol) was added, and the reactants were stirred at -78 ° C for 1 hour. Water (15 mL) and DCM (15 mL) were added, and the pH was adjusted to about 10 using 2N NaOH. The aqueous layer was extracted with DCM (3 × 15 mL) and filtered to produce a yellow gel. The crude product was dissolved in DCM (1 mL), and Et3N (0.2 mL, 1.43 mmol) was added, followed by boc anhydride (0.2 mL, 0.870 mmol). The reaction mixture was stirred at rt for 3 hours. The solution was diluted with DCM and washed with water (10 mL). The aqueous layer was extracted with DCM (2 × 10 mL), dried over Na SO dried, and filtered. Purified by silica gel chromatography (gradient: heptane containing 0-60% EtOAc), produce (2'S, 4S)-2-ethyl-2'-methyl-spiro [6,7-dihydrothieno [3,2-c] pyrans-4,4'-piperidine] -1'-t-butyl formate C6 (117 mg, 50%). 1H NMR (300 MHz, methanol-d4) δ 6.46 (s, 1H), 4.43-4.29 (m, 1H), 3.97-3.83 (m, 3H), 2.84-2.61 (m, 4H), 1.94-1.76 (m, 4H), 1.48 (s, 9H), 1.33 (d, J = 7.1 Hz, 3H), 1.24 (t, J = 7.5 Hz, 3H). (1H below the MeOH peak).

[0652] Step 2: (2′S,4S)-2-Ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]S9

[0653] To a stirred solution of (2′S,4S)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylic acid tert-butyl ester C6 (105 mg, 0.299 mmol) in DCM (1 mL) was added 4M HCl in dioxane (0.16 mL of 4M, 0.660 mmol) and the reaction was stirred at rt for 4 h. The mixture was concentrated and purified by preparative HPLC (mobile phase A: −0.1% FA (aqueous), mobile phase B: −acetonitrile) to yield (2′S,4S)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] S9 (65 mg, 72%). 1 H NMR (300MHz, methanol-d4) δ6.56(d,J=1.6Hz,1H),3.94(t,J=5.4Hz,2H),3.81-3.70(m,1H),3.50(td,J=12.4,3.6Hz,1H),3.19(dt,J=13.0,4 .1Hz,1H),2.82-2.70(m,4H),2.15(td,J=14.7,14.2,4.8Hz,2H),2.02(d,J=15.2Hz,2H),1.55(d,J=7.1Hz,3H),1.25(t,J=7.5Hz,3H).

[0654] Preparation of S10

[0655] 2-(4-Formylpyrazol-1-yl)-N-methyl-ethanesulfonamide (S10)

[0656]

[0657] Step 1: 2-(4-Formylpyrazol-1-yl)-N-methyl-ethanesulfonamide (S10)

[0658] A solution of 1H-pyrazole-4-carboxaldehyde C8 (250 mg, 2.60 mmol), N-methylethanesulfonamide C7 (350 mg, 2.88 mmol) and potassium carbonate (700 mg, 5.06 mmol) in 2-methyltetrahydrofuran (10 mL) was stirred at 60 ° C. After stirring for 4 hours, the mixture was cooled to room temperature and the reactants were quenched with water (10 mL). The organic layer was diluted with EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 30 mL), followed by extraction with DCM (2 × 20 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (gradient: DCM containing 0-10% methanol) produced 2-(4-formylpyrazolyl-1-yl)-N-methyl-ethanesulfonamide S10 (565 mg, 54%).1 H NMR(400MHz, DMSO-d6)δδ9.80(s,1H),8.53(d,J=0.7Hz,1H),8.03(d,J=0.7Hz,1H),7.15(d,J =4.3Hz, 1H), 4.53 (dd, J = 7.4, 6.5Hz, 2H), 3.60 (dd, J = 7.4, 6.5Hz, 2H), 2.56 (d, J = 3.5Hz, 3H). LCMS m / z 218.42[M+H] + .

[0659] Preparation of S11

[0660] 1-(2-Methylsulfonylethyl)pyrazole-4-carbaldehyde (S11)

[0661]

[0662] Step 1: 1-(2-Methylsulfonylethyl)pyrazole-4-carbaldehyde (S11)

[0663] A solution of 1H-pyrazole-4-carboxaldehyde C8 (1 g, 10.4 mmol), 1-methylsulfonylethene C9 (1.2 g, 11.4 mmol) and potassium carbonate (2.4 g, 18.1 mmol) in 2-methyltetrahydrofuran (20 mL) was stirred at 60 ° C. After stirring overnight, the mixture was cooled to room temperature and the reactant was quenched with water (10 mL). The organic layer was diluted with EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 30 mL), then extracted with DCM (2 × 20 mL), dried over Na2SO4, filtered and concentrated. Purified by silica gel chromatography (gradient: DCM containing 0-10% methanol) to produce 1- (2-methylsulfonylethyl) pyrazole-4-carboxaldehyde S11 (1.3 g, 58%). 1H NMR (400 MHz, chloroform-d) δ 9.90 (s, 1H), 8.10 (d, J = 0.7 Hz, 1H), 8.06 (d, J = 0.6 Hz, 1H), 4.75-4.63 (m, 2H), 3.70 (tdd, J = 6.0, 1.4, 0.7 Hz, 2H), 2.66 (t, J = 0.7 Hz, 3H). LCMS m / z 203.34 [M+H] + .

[0664] Preparation of S12

[0665] 1-[3-[tert-Butyl(dimethyl)silyl]oxy-2-[[tert-Butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (S12)

[0666]

[0667] Step 1: 2-(Bromomethyl)-2-methyl-propane-1,3-diol (C11)

[0668] To a solution of (3-methyloxetane-3-yl)methanol C10 (10 mL, 100.3 mmol) in THF (70 mL) was added hydrogen bromide (14 mL of 48% w / w, 123.7 mmol) at 0 ° C and stirred for 24 hours. The mixture was concentrated and diluted in dichloromethane / methanol. Excess hydrogen bromide was quenched with saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was dried over Na2SO4, filtered, rinsed with methanol and concentrated to produce 2-(bromomethyl)-2-methyl-propane-1,3-diol C11 (13.6 g, 74%). 1 H NMR (400 MHz, methanol-d4) δ 3.47 (d, J = 1.1 Hz, 6H), 0.96 (s, 3H).

[0669] Step 2: [2-(Bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propyloxy]-tert-butyl-dimethyl-silane (C12)

[0670] To a solution of 2- (bromomethyl) -2- methyl -propane -1,3- diol C11 (10g, 54.1mmol) in DCM (200mL) was added imidazole (7.7g, 113.1mmol), followed by TBSCl (17g, 112.8mmol). After 5 minutes, the solid was filtered and washed with DCM. The filtrate was diluted with heptane (25mL), and the solid was filtered and washed with heptane (10mL). The filtrate was concentrated to produce [2- (bromomethyl) -3- [tert-butyl (dimethyl) silyl] oxy-2-methyl-propoxy] -tert-butyl-dimethyl-silane C12 (22.2g, 99%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.44 (s, 4H), 3.40 (s, 2H), 0.94 (s, 3H), 0.89 (s, 18H), 0.04 (d, J = 1.2 Hz, 12H).

[0671] Step 3: 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (S12)

[0672] To a solution of 1H-pyrazole-4-carboxaldehyde C8 (2 g, 20.8 mmol) in acetonitrile (20 mL) was added potassium carbonate (4 g, 28.9 mmol) and [2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propyloxy]-tert-butyl-dimethyl-silane C12 (9.5 g, 23.1 mmol) and stirred at 110 ° C for 35 minutes. The mixture was cooled to rt, filtered, rinsed with acetonitrile and concentrated. Purified by silica gel chromatography (gradient: heptane containing 30-60% EtOAc) to produce 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carboxaldehyde (S12) (2.39 g, 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] + .

[0673] Compound 264

[0674] 2-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]pyrazol-1-yl]-N-methyl-ethanesulfonamide

[0675]

[0676] Step 1: 2-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]pyrazol-1-yl]-N-methyl-ethanesulfonamide (264)

[0677] A mixture of 2-(4-formylpyrazol-1-yl)-N-methyl-ethanesulfonamide S10 (100 mg, 0.460 mmol), (2'S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] C1 (100 mg, 0.338 mg), sodium acetoxyborohydride (250 mg, 1.18 mmol) and acetic acid (0.025 mL, 0.439 mmol) in 1,2-dichloroethane (5 mL) was stirred at 50 ° C overnight. The mixture was diluted with saturated sodium bicarbonate and dichloromethane (10 mL), and the layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (Gradient: 0-10% methanol in DCM) yielded 2-[4-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]pyrazol-1-yl]-N-methyl-ethanesulfonamide (264) (71 mg, 45%). 1 HNMR (400MHz, chloroform-d) δ7.60-7.44(m,2H),6.54-6.41(m,1H),4.57(t,J=6.0Hz,3H),3.99-3.75(m,3H),3 .75-3.42(m,5H),2.94-2.24(m,12H),2.09-1.65(m,4H),1.27(t,J=7.5Hz,3H),1.22(d,J=6.2Hz,3H). LCMS m / zm / z453.46[M+H] + .

[0678] Compounds 265-277

[0679] Compounds 265-277 (Table 6) were prepared from the intermediate piperidine selected from C1, S5, S6, or S9 and the appropriate aldehyde using the appropriate reagents described in the method for compound 264. The aldehydes were prepared by the methods described above or obtained from commercial sources. Any modifications to the methods are noted in Table 6 and the accompanying footnotes.

[0680] Table 6: Structural and physicochemical data of compounds 265-277

[0681]

[0682]

[0683]

[0684]

[0685]

[0686] footnote:

[0687] 1) Reductive amination was performed using 2 equivalents of polymer-supported cyanoborohydride instead of sodium acetoxyborohydride.

[0688] After the reductive amination was completed, the product was stirred with aqueous HCl and MeOH for five minutes to deprotect the TBS group. The precipitated white solid was collected and dried to obtain the final product.

[0689] Compound 278

[0690] (2′S,4R)-2-ethyl-1′-(2-methoxyethyl)-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]

[0691]

[0692] Step 1: (2′S,4R)-2-ethyl-1′-(2-methoxyethyl)-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (278)

[0693] To a stirred solution of (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] C1 (100 mg, 0.236 mmol) and 1-bromo-2-methoxy-ethane C13 (99 mg, 0.712 mmol) in DMF (1 mL) containing MeCN (8 mL) was added potassium carbonate (180 mg, 13.0 mmol) followed by KI (8 mg, 0.048 mmol) and stirred at 60° C. for 48 h. The mixture was diluted with MeCN (20 mL) and filtered. The filtrate was concentrated and purified by preparative HPLC (conditions: mobile phase A: -0.01 M ammonium bicarbonate (aqueous), mobile phase B: -acetonitrile) and the pure fractions were collected to yield (2′S,4R)-2-ethyl-1′-(2-methoxyethyl)-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] 278 (28 mg, 38%). 1H NMR (400MHz, DMSO-d6): δ6.60(s,1H),3.83-3.79(q,J=5.2Hz,2H),3.42-3.39(t,J=6.0Hz,2H),3.23(s,3H),2.89-2.86( m,1H),2.73-2.63(m,5H),2.54-2.32(m,3H),1.70-1.49(m,4H),1.20-1.17(t,J=7.6Hz,3H),0.98-0.97(d,J=6.0Hz,3H). LCMSm / z 310.2[M+H] + .

[0694] Compound 279

[0695] (2′S,4R)-2-Ethyl-1′-(isoxazol-3-ylmethyl)-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]

[0696]

[0697] Step 1: (2′S,4R)-2-ethyl-1′-(isoxazol-3-ylmethyl)-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (279)

[0698] To a solution of (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] C1 (100 mg, 0.397 mmol) in DMF (2 mL) was added triethylamine (0.16 mL, 1.19 mmol) followed by 3-(chloromethyl)isoxazole C14 (56 mg, 0.477 mmol). The mixture was stirred at room temperature overnight. It was diluted with EtOAc (20 mL) and washed with water (2 x 10 mL) and brine (2 x 5 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. Purification by preparative HPLC yielded (2'S,4R)-2-ethyl-1'-(isoxazol-3-ylmethyl)-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 279 (9 mg, 7%). 1H NMR (400MHz, DMSO-d6)8.85(s,1H),6.60(s,1H),6.52(s,1H),3.91(d,J=14.55 Hz,2H),3.80-3.76(m,2H),3.63(d,J=14.36Hz,1H),2.70(q,J=7.44Hz,14.92Hz 2H),2.62(bs,,2H),2.49-2.43(m,2H),1.77–1.69(m,3H),1.58(t,J=12.16Hz 1H),1.19(t,J=7.44Hz,3H),1.10(d,J=6.08Hz,3H). LCMS m / z333.0[M+H] + .

[0699] Compounds 280-298

[0700] Compounds 280-298 were prepared from intermediate C1 and the corresponding commercial alkyl halides using the procedures described for compounds 278 and 279. Any modifications to the procedures are noted in Table 7 and the accompanying footnotes.

[0701] Table 7: Structural and physicochemical data of compounds 280-298

[0702]

[0703]

[0704]

[0705]

[0706]

[0707] footnote:

[0708] 1) Epoxide ring opening using NaCN in DMF

[0709] 2) Stir the alcohol and trifluoromethanesulfonic anhydride at 80°C and then add them to the reaction mixture

[0710] 3) Preparation of Compound 299 by Chiral SFC Purification and Separation of Stereoisomers of Compounds 295-298

[0711] 3-[[(2′S,4R)-2-Ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-yl]methyl]cyclobutanamine (299)

[0712]

[0713] Step 1: Synthesis of tert-butyl N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-yl]methyl]cyclobutyl]carbamate (1039)

[0714] A microwave tube was charged with (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]trifluoromethanesulfonate (C1) (2.468 g, 6.163 mmol), tert-butyl N-(3-formylcyclobutyl)carbamate (6.54 g, 32.82 mmol), polymer-supported cyanoborohydride (11.4 g of 2 mmol / g, 22.80 mmol) and acetic acid (3 mL, 52.75 mmol) in DCM (45 mL). The reaction was heated to 110 ° C under microwave irradiation for 30 minutes. After cooling to room temperature, the reaction was filtered and the filtrate was diluted with DCM (150 mL). The organic phase was washed with 1N NaOH (2×100 mL), dried over Na2SO4, filtered, and evaporated in vacuo. Purification by silica gel chromatography (120 g column, 0-5% MeOH in DCM) afforded the product tert-butyl N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]carbamate (1042) (2.170 g, 79%). 1 H NMR (300MHz, chloroform-d) δ6.49(s,1H),4.84-4.45(bs,1H),4.17-3.76(m,3H),2.90-2.72(m,5H),2.69-2.33(m,6H),2.28-2.15( m,1H),2.00-1.76(m,3H),1.76-1.62(m,1H),1.60-1.45(m,2H),1.45(s,9H),1.28(t,J=7.5Hz,3H),1.08(d,J=6.2Hz,3H). ss LCMS m / z 435.4[M+H] + .

[0715] Step 3: Synthesis of 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-yl]methyl]cyclobutanamine (299)

[0716] Tert-butyl N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]carbamate (1042) (2.04 g, 4.600 mmol) was dissolved in dioxane (10 mL, 40.00 mmol) containing 4M HCl solution, and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to give the crude product 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutylamine (hydrochloride) (299) (1.7 g, 96%). LCMS m / z 334.68 [M+H] + .

[0717] Compound 300

[0718] N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]-3,3-difluoro-cyclobutanecarboxamide (300)

[0719]

[0720] Preparation of N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]-3,3-difluoro-cyclobutanecarboxamide (300). 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutylamine (hydrochloride) 299 (20 mg, 0.05979 mmol) and 3,3-difluorocyclobutanecarboxylic acid (8.1 mg, 0.05979 mmol) were dissolved in DMF, and HDMC (32.7 mg, 0.07175 mmol) and 4-methylmorpholine (20 μL, 0.1794 mmol) were added. The reaction was stirred at room temperature for 1 hour. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H 2 O with 0.1% trifluoroacetic acid to afford the product N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]-3,3-difluoro-cyclobutanecarboxamide (trifluoroacetate) (300) (17 mg, 50%). LCMS m / z 453.24 [M+H] +.

[0721] Compound 301

[0722] N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]-2-(2,2,2-trifluoroethoxy)acetamide (301)

[0723]

[0724] Preparation of N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]-2-(2,2,2-trifluoroethoxy)acetamide (301)

[0725] 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutanamine (hydrochloride) 299 (20 mg, 0.05979 mmol) and 2-(2,2,2-trifluoroethoxy)acetic acid (9.5 mg, 0.05979 mmol) were dissolved in DMF (1 mL), and T3P (38.5 mg, 0.1210 mmol) and DIPEA (21 μL, 0.1206 mmol) were added. The reaction was stirred at room temperature overnight. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid to give N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]methyl]cyclobutyl]-2-(2,2,2-trifluoroethoxy)acetamide (trifluoroacetate) (6.8 mg, 24%) (301). LCMS m / z 475.19 [M+H] + .

[0726] Compound 302

[0727] Methyl N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]carbamate (302)

[0728]

[0729] Preparation of methyl N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]carbamate (302)

[0730] 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutanamine (hydrochloride) 299 (18 mg, 0.03962 mmol) was dissolved in DCM (1 mL), and methyl chloroformate (5 μL, 0.06471 mmol) and triethylamine (15 μL, 0.1076 mmol) were added. The reaction was stirred at room temperature for 2 hours, and then the solvent was evaporated in vacuo. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid to give the product, methyl N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]methyl]cyclobutyl]carbamate (trifluoroacetate) (302) (9.7 mg, 45%). LCMS m / z 393.23 [M+H] + .

[0731] Compounds 303-384

[0732] Compounds 303-384 (see Table 8) were prepared from intermediate 299 using appropriate reagents and the amide formation method described for compounds 300-302. Coupling partners were obtained from commercial sources. Any modifications to the methods are noted in Table 8 and the accompanying footnotes.

[0733] Table 8: Preparation methods, structures and physicochemical data of compounds 303-384

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754] 1) DIPEA was used as a base compound 385

[0755] 6-[2-[2-[2-(6-chlorohexyloxy)ethoxy]ethoxy]ethoxy]-N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-yl]methyl]cyclobutyl]hexanamide (385)

[0756]

[0757] Preparation of 6-[2-[2-[2-(6-chlorohexyloxy)ethoxy]ethoxy]ethoxy]-N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]hexanamide (385)

[0758] 3-[[(2′S,4R)-2-Ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutanamine (trifluoroacetate) (299) (30 mg, 0.05333 mmol) was dissolved in DMF (1 mL), and 6-[2-[2-[2-(6-chlorohexyloxy)ethoxy]ethoxy]ethoxy]hexanoic acid (25 mg, 0.06529 mmol), DIPEA (50 μL, 0.2871 mmol) and HATU (24 mg, 0.06312 mmol) were added thereto, and the reaction mixture was stirred at room temperature for 1 hour. Purification by reverse phase chromatography (column: C18. Gradient: 0-100% MeCN in water with 0.1% TFA) gave the product 6-[2-[2-[2-(6-chlorohexyloxy)ethoxy]ethoxy]ethoxy]-N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]hexanamide (trifluoroacetate salt) (385) (24 mg, 55%). LCMS m / z 699.24 [M+H] + .

[0759] Compound (386)

[0760] 2-[2-[2-[[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]carbamoyloxy]ethoxy]ethoxy]N-[2-[2-(6-chlorohexyloxy)ethoxy]ethyl]carbamic acid ethyl ester (386)

[0761]

[0762] Preparation of ethyl 2-[2-[2-[[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]carbamoyloxy]ethoxy]ethoxy]N-[2-[2-(6-chlorohexyloxy)ethoxy]ethyl]carbamate (386)

[0763] 3-[[(2′S,4R)-2-Ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutanamine (trifluoroacetate) (299) (49 mg, 0.08710 mmol) was dissolved in DMF (1 mL), and 2-[2-[2-[2-[2-(6-chlorohexyloxy)ethoxy]ethylaminoformyloxy]ethoxy]ethoxy](4-nitrophenyl)ethyl carbonate (59 mg, 0.1044 mmol) and DIPEA (75 μL, 0.4306 mmol) were added thereto, and the reaction was stirred at room temperature for 12 hours. Purification by reverse phase chromatography (column: C18. Gradient: 0-100% MeCN in water with 0.1% formic acid) gave the product ethyl 2-[2-[2-[[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]carbamoyloxy]ethoxy]ethoxy]N-[2-[2-(6-chlorohexyloxy)ethoxy]ethyl]carbamate (formate salt) (386) (25 mg, 35%). LCMS m / z 760.27 [M+H] + .

[0764] Compound 387

[0765] N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-

[0766] [methyl]cyclobutyl]-2,2,2-trifluoro-acetamide (387)

[0767]

[0768] Preparation of N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]-2,2,2-trifluoro-acetamide (387)

[0769] 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutanamine (hydrochloride) (299) (20 mg, 0.05391 mmol) was dissolved in DCM (1 mL) and (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (9 μL, 0.06475 mmol) and DIPEA (19 μL, 0.1091 mmol) were added. The reaction was stirred at room temperature for 2 hours and then the solvent was evaporated. Purification by reverse phase chromatography (column: C18. Gradient: 0-100% MeCN in water with 0.1% TFA) gave the product N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]-2,2,2-trifluoro-acetamide (387) (8.5 mg, 32%). LCMS m / z 431.15 [M+H] + .

[0770] Compound 388

[0771] N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]-2-hydroxy-ethanesulfonamide (388)

[0772]

[0773] Preparation of N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]-2-hydroxy-ethanesulfonamide (388)

[0774] 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]methyl]cyclobutanamine and 2-hydroxyethanesulfonyl chloride were dissolved in DCM (1 mL) and TEA (20 μL, 0.1435 mmol) was added. The reaction was stirred at room temperature for 2 hours, then the solvent was evaporated and the crude material was redissolved in minimal MeOH. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid to give the product N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]methyl]cyclobutyl]-2-hydroxy-ethanesulfonamide (trifluoroacetate) (388) (5.6 mg, 20%). LCMS m / z 443.14 [M+H] + .

[0775] Compounds 389-417

[0776] Compounds 389-417 (see Table 9) were prepared in a single step from intermediate 299 using the coupling methodology of 388. Sulfonyl chlorides were obtained from commercial sources.

[0777] Table 9: Structural and physicochemical data of compounds 389-417

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787] Preparation of S13

[0788] Tert-butyl N-(3-formylcyclobutyl)carbamate (S13)

[0789]

[0790] Preparation of tert-butyl N-(3-formylcyclobutyl)carbamate (S13)

[0791] N-[3-(hydroxymethyl) cyclobutyl] t-butyl carbamate (263mg, 1.269mmol) is dissolved in DCM (4mL), adds Dai Si-Martin periodate (1.211g, 2.855mmol) wherein.Reactant is at room temperature stirred 3 hours, then passes through SiO with the DCM eluent Plug filters, and evaporates in vacuo.By silica gel chromatography purifying (4g post, containing the heptane of 0-40%EtOAc), obtain product N-(3-formylcyclobutyl) t-butyl carbamate (S13) (117mg, 46%). 1 H NMR (300 MHz, chloroform-d) δ 9.84 (d, J = 1.9 Hz, 1H), 4.75 (s, 1H), 4.25-4.00 (m, 1H), 3.12-2.94 (m, 1H), 2.75-2.60 (m, 2H), 2.28-2.07 (m, 2H), 1.45 (s, 9H). LCMS m / z 200.14 [M+H] + .

[0792] Preparation of Compound 419 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-yl]methyl]cyclobutanamine (419)

[0793]

[0794] Step 1: Synthesis of tert-butyl N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-yl]methyl]cyclobutyl]carbamate (418)

[0795] A microwave tube was charged with (2'S, 4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]trifluoromethanesulfonate (C1) (116 mg, 0.2887 mmol), tert-butyl N-(3-formylcyclobutyl)carbamate (S13) (110 mg, 0.5571 mmol), polymer-supported cyanoborohydride (455 mg of 2 mmol / g, 0.9104 mmol) and acetic acid (100 μL, 1.758 mmol) in DCM (2 mL). The reaction was heated to 110 ° C under microwave irradiation for 30 minutes. After cooling to room temperature, the reactant was filtered and the filtrate was diluted with DCM (10 mL). The organic phase was washed with 1 M NaOH (10 mL), dried over Na2SO4, filtered, and evaporated in vacuo. Purification by silica gel chromatography (4 g column, 0-10% MeOH in DCM) afforded the product tert-butyl N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]cyclobutyl]carbamate (418) (19 mg, 15%). 1 H NMR (300 MHz, chloroform-d) δ 6.49 (s, 1H), 4.91-4.55 (bs, 1H), 4.31-4.03 (m, 1H), 4.01-3.80 (m, 2H), 3.07-2.88 (m, 1H), 2.86

[0796] -1.59(m,17H),1.46(s,9H),1.28(t,J=7.5Hz,3H),1.10(d,J=6.2Hz,3H). LCMSm / z 435.40[M+H] + .

[0797] Step 2: Synthesis of 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-yl]methyl]cyclobutanamine (trifluoroacetic acid (2)) (419)

[0798] Tert-butyl N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]methyl]cyclobutyl]carbamate (418) (16 mg, 0.03706 mmol) was dissolved in DCM (300 μL) and TFA (100 μL, 1.298 mmol) was added. The reaction was stirred at room temperature for 3 hours, and then the reaction mixture was filtered. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid to give the product 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]methyl]cyclobutanamine (trifluoroacetic acid (2)) (419) (13 mg, 62%). LCMS m / z 335.21 [M+H] + .

[0799] Preparation of Compound 421

[0800] (2′S,4R)-1′-(azetidin-3-ylmethyl)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](421)

[0801]

[0802] Step 1: Synthesis of tert-butyl 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-yl]methyl]azetidine-1-carboxylate (420)

[0803] A microwave tube was charged with (2'S, 4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] trifluoromethanesulfonate (C1) (2.5 g, 6.243 mmol), tert-butyl 3-formylazetidine-1-carboxylate (4.65 g, 25.11 mmol), polymer-supported cyanoborohydride (12.5 g of 2 mmol / g, 25.00 mmol) and acetic acid (2.5 mL, 43.96 mmol) in DCM (50 mL). The reaction was heated to 110 ° C under microwave irradiation for 30 minutes. After cooling to room temperature, the reactants were filtered and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (120 g column, 0-5% MeOH in DCM) afforded the product tert-butyl 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]azetidine-1-carboxylate (420) (1.838 g, 67%). 1 H NMR (300MHz, chloroform-d) δ6.48 (s, 1H), 4.05 (td, J = 8.4, 4.3Hz, 2H), 3.98-3.82 (m, 2H) ,3.66(dd,J=8.6,5.7Hz,1H),3.59(dd,J=8.5,5.7Hz,1H),3.07(dd,J=12.9,7.8H z,1H),2.86-2.70(m,5H),2.70-2.53(m,2H),2.53-2.40(m,2H),1.91-1.77(m,3 H), 1.70-1.58 (m, 1H), 1.46 (s, 9H), 1.28 (t, J = 7.5Hz, 3H), 1.09 (d, J = 6.2Hz, 3H). LCMS m / z 421.5[M+H] + .

[0804] Step 2: Synthesis of (2′S,4R)-1′-(azetidin-3-ylmethyl)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](421)

[0805] TFA (3.0 mL, 38.94 mmol) was added to a solution of tert-butyl 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]azetidine-1-carboxylate (420) (1.8 g, 4.205 mmol) in DCM (12 mL), and the reaction was stirred at room temperature for 3 hours. The resulting solution was concentrated in vacuo to give the crude product (2′S,4R)-1′-(azetidin-3-ylmethyl)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin](trifluoroacetic acid (2) salt) (421) (3.657 g, 95%). LCMS m / z 321.22 [M+H] + .

[0806] Compound 422

[0807] (4-Amino-1,2,5-oxadiazol-3-yl)-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]azetidin-1-yl]methanone (422)

[0808]

[0809] Preparation of (4-amino-1,2,5-oxadiazol-3-yl)-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]azetidin-1-yl]methanone (422)

[0810] (2'S,4R)-1'-(azetidin-3-ylmethyl)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](trifluoroacetic acid (2) salt) 421 (34 mg, 0.03719 mmol) was dissolved in DMF (300 μL) and DIPEA (50 μL, 0.285 mmol), to which was added 4-amino-1,2,5-oxadiazole-3-carboxylic acid (16 mg, 0.1228 mmol) and HATU (40 mg, 0.1052 mmol). The reaction was stirred at room temperature for 16 hours, then the solution was diluted with MeOH (500 μL) and filtered. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 5 mM HCl to afford the product (4-amino-1,2,5-oxadiazol-3-yl)-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]methyl]azetidin-1-yl]methanone (hydrochloride) (422) (7.4 mg, 49%). LCMS m / z 432.19 [M+H] + .

[0811] Compound 423

[0812] [3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]azetidin-1-yl]-(3-hydroxy-2-pyridinyl)methanone (423)

[0813]

[0814] Preparation of [3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]azetidin-1-yl]-(3-hydroxy-2-pyridinyl)methanone (423)

[0815] (2'S,4R)-1'-(azetidin-3-ylmethyl)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 421 (20 mg, 0.0624 mmol) was dissolved in DMF (2 mL) and pyridine (50 μL, 0.6182 mmol), to which was added T3P (40 mg, 0.1257 mmol) and 3-hydroxypyridine-2-carboxylic acid (25 mg, 0.1797 mmol). The reaction was stirred at room temperature overnight. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid to afford [3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]methyl]azetidin-1-yl]-(3-hydroxy-2-pyridinyl)methanone (2.8 mg, 10%) (423). LCMS m / z 442.16 [M+H] + .

[0816] Compound 424

[0817] 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-yl]methyl]azetidine-1-carboxylic acid methyl ester (424)

[0818]

[0819] Preparation of methyl 3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]azetidine-1-carboxylate (424)

[0820] (2'S,4R)-1'-(azetidin-3-ylmethyl)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](trifluoroacetic acid (2) salt) 421 (34 mg, 0.03719 mmol) was dissolved in DMF (300 μL) and DIPEA (50 μL, 0.285 mmol), and methyl chloroformate (9.5 μL, 0.1228 mmol) was added. The reaction was stirred at room temperature for 10 minutes and then filtered. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 5 mM HCl to give the product 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]methyl]azetidine-1-carboxylic acid methyl ester (hydrochloride) (424) (13.4 mg, 86%). LCMS m / z 379.22 [M+H] + .

[0821] Compounds 425-490

[0822] Compounds 425-490 (see Table 10) were prepared from intermediate 421 using appropriate reagents and the amide formation method described for compounds 422-424. Coupling partners were obtained from commercial sources.

[0823] Table 10: Preparation methods, structures and physicochemical data of compounds 425-490

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840] Compound 491

[0841] (2′S,4R)-2-Ethyl-1′-[(1-ethylsulfonylazetidin-3-yl)methyl]-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](491)

[0842]

[0843] Preparation of (2′S,4R)-2-ethyl-1′-[(1-ethylsulfonylazetidin-3-yl)methyl]-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](491)

[0844] (2'S,4R)-1'-(azetidine-3-ethanesulfonyl chloride)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](trifluoroacetic acid (2) salt) 421 (50 mg, 0.05502 mmol) was dissolved in DMF (800 μL) and DIPEA (100 μL, 0.5740 mmol), and ethanesulfonyl chloride (14 μL, 0.1500 mmol) was added. The reaction was stirred at room temperature for 3 hours, then diluted with MeOH (800 μL) and filtered. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 5 mM HCl to give the product (2'S,4R)-2-ethyl-1'-[(1-ethylsulfonylazetidin-3-yl)methyl]-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (hydrochloride) (491) (14.5 mg, 63%). LCMS m / z 413.20 [M+H] + .

[0845] Compounds 492-496

[0846] Compounds 492-496 (see Table 11) were prepared in a single step from intermediate 421 using the coupling methodology of 491. Sulfonyl chlorides were obtained from commercial sources.

[0847] Table 11: Structural and physicochemical data of compounds 492-496

[0848]

[0849]

[0850] Compound 497

[0851] (2′S,4R)-2-Ethyl-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] 1,1-dioxide

[0852]

[0853] Step 1: Synthesis of tert-butyl (2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate (C16)

[0854] To a mixture of (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (200 mg, 0.7956 mmol) CI in DCM (6 mL) was added Boc2O (211 μL, 0.9185 mmol) and DIPEA (160 μL, 0.9186 mmol). After 1 hour, the reaction mixture was diluted with saturated aqueous ammonium chloride. The layers were separated, and the organic layer was passed through a phase separator and used in the next step without further purification.

[0855] Step 2: Synthesis of tert-butyl (2′S,4R)-2-ethyl-2′-methyl-1,1-dioxo-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate (C17)

[0856] To the mixture of (2'S, 4R) -2- ethyl -2'- methyl - spiro [6,7- dihydrothieno [3,2-c] pyrans -4,4'- piperidine] -1'- tert-butyl formate C16 in DCM (6mL) from the previous step, mCPBA (200mg, 0.8692mmol) was added, and the reactant was stirred at rt. The mixture was then divided into two halves, and half of the mixture was stirred at reflux for 3 hours with mCPBA (300mg, 1.74mmol). Now, the mixture was cooled to rt, diluted with saturated sodium bicarbonate (20mL) and other DCM (20mL). The layers were separated, and the aqueous layer was washed with DCM (10mL), and the combined organic layer was then washed with other saturated sodium bicarbonate (10mL), followed by washing with brine (10mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (Gradient: 0-100% EtOAc in heptane) afforded tert-butyl (2′S,4R)-2-ethyl-2′-methyl-1,1-dioxo-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate C17 (46 mg, 26%). 1 HNMR (400 MHz, chloroform-d3) δ 6.14 (t, J = 2.1 Hz, 1H), 4.01 (tt, J = 11.8, 6.5 Hz, 1H), 3.95-3.67 (m, 3H), 3.24 (ddd, J = 14.0, 9.3, 5.4 Hz, 1H), 2.63-2.40 (m, 4H), 1.95-1.74 (m, 2H), 1.70-1.56 (m, 2H), 1.46 (d, J = 14.0 Hz, 9H), 1.31-1.23 (m, 6H). LCMS m / z 383.85 [M+H] + .

[0857] Step 3: Synthesis of (2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] 1,1-dioxide (C18)

[0858] To (2'S,4R)-2-ethyl-2'-methyl-1,1-dioxo-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylic acid tert-butyl ester C17 (46 mg, 0.12 mmol) was added dioxane containing HCl (500 μL of 4M, 2.000 mmol). The mixture was stirred at rt. After 1 hour, the mixture was concentrated in vacuo to provide (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 1,1-dioxide C18 (hydrochloride salt) (33 mg, 25%). LCMS m / z 284.03 [M+H] + It was used in the next step without further purification.

[0859] Step 4: Synthesis of (2′S,4R)-2-ethyl-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] 1,1-dioxide (497)

[0860] To a mixture of (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]1,1-dioxide C (hydrochloride) (33 mg, 0.1032 mmol) in acetonitrile (3 mL) was added potassium carbonate (30 mg, 0.2171 mmol) and 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (30 mg, 0.1155 mmol). After stirring for 60 hours, the reaction mixture was blown dry, diluted with water / DMSO, and the mixture was purified by reverse phase HPLC (C18 column, gradient: 10-100% MeCN in water with TFA as a modifier). The product-containing fractions were combined, concentrated, and diluted with 6N NaOH / DCM. The layers were separated, and the aqueous layer was extracted with additional DCM. The organic layer was passed through a phase separator and concentrated to give (2'S,4R)-2-ethyl-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 1,1-dioxide 497 (12 mg, 23%). 1H NMR (400MHz, chloroform-d3) δ7.64(s,1H),6.24(t,J=2.2Hz,1H),4.92-4.83(m,2H),4.04(d,J=14.7Hz,1H),3.88(d,J=14.7Hz,1H),3 .84-3.78(m,1H),3.78-3.70(m,3H),2.73(s,3H),2.63-2.46(m,6H),1.83-1.62(m,4H),1.61-1.48(m,1H),1.30-1.23(m,6H). LCMS m / z 471.09[M+H] + .

[0861] Compound 498

[0862] 2-Ethyl-2′,2′-dimethyl-1′-[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]

[0863]

[0864] Step 1: Synthesis of 2-ethyl-2′,2′-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](C19)

[0865] 2,2-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (90.9 mg, 0.4 mmol), 2-(5-ethyl-2-thienyl)ethanol (75 mg, 0.48 mmol) and dioxane (2 mL) were added to the vial. Trifluoromethanesulfonic acid (100 μL, 1.13 mmol) was then added at 0 ° C. and stirred at rt for 4 hours. The reaction mixture was concentrated in vacuo to provide 2-ethyl-2′, 2′-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] C19, which was used in the next step without purification.

[0866] Step 2: Synthesis of 2-ethyl-2′,2′-dimethyl-1′-[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](498)

[0867] To DCM containing the crude material from the previous step was added AcOH (114 μL, 2.0 mmol), 1-methylpyrazole-4-carbaldehyde (88 mg, 0.8 mmol), and polymer-supported cyanoborohydride (500 mg, 1 mmol). The reaction mixture was heated at 110° C. in a microwave reactor for 20 minutes. The reaction mixture was then filtered and concentrated in vacuo. Purification was by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H 2 O with 0.1% trifluoroacetic acid. The product was isolated as 2-ethyl-2′,2′-dimethyl-1′-[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (trifluoroacetate) (20.5 mg, 11%). LCMS m / z 360.23 [M+H] + .

[0868] Preparation of S15

[0869] 2-(4,5-Dimethyl-2-thienyl)ethanol (S15)

[0870]

[0871] Preparation of 2-(4,5-dimethyl-2-thienyl)ethanol (S15)

[0872] To a solution of 2,3-dimethylthiophene (2 g, 17.826 mmol) in Et2O (50 mL) was added n-BuLi (8.5564 mL of 2.5 M, 21.391 mmol) at 0 ° C. within 15 minutes. The mixture was stirred at rt for 30 minutes. After cooling to 0 ° C., a solution of ethylene oxide (7.1303 mL of 3 M, 21.391 mmol) was added. The reactant was stirred at 0 ° C. for 3 hours, then quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purified by silica gel chromatography (gradient: hexane containing 20-25% EtOAc) to obtain 2- (4,5-dimethyl-2-thienyl) ethanol S15 (2 g, 67%). 1 HNMR (400MHz, DMSO-d6) δ6.51 (s, 1H), 4.71 (s, 1H), 3.54 (s, 2H), 2.77 (t, J = 6.4Hz, 2H), 2.21 (s, 3H), 2.00 (s, 3H). LCMS m / z157.1[M+H] + .

[0873] Intermediates S16-S17

[0874] Intermediates S16-S17 (see Table 12) were prepared in a single step using the method described for S15. Any modifications to the method are noted in Table 11 and the accompanying footnotes.

[0875] Table 12: Structural and physicochemical data of compounds S16-S17

[0876]

[0877] Preparation of S18

[0878] (2′S,4R)-2,2′-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](S18)

[0879]

[0880] Preparation of (2′S,4R)-2,2′-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](S18)

[0881] A solution of 2-(5-methyl-2-thienyl)ethanol (12.8g, 85.50mmol) and (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (20g, 93.78mmol, 1.1 equivalents) in dioxane (158mL) was prepared in a flask. The flask was cooled with an ice methanol bath and allowed to balance for 10 minutes to reach an internal temperature of about 0°C. Trifluoromethanesulfonic acid (17mL, 192.1mmol, 2.2 equivalents) was added dropwise via an addition funnel over 30 minutes. After addition, the mixture was stirred for another 30 minutes with an ice bath. The ice bath was then removed, and the reactant was warmed to rt and stirred overnight. The mixture was diluted with a 1:1 mixture of water and saturated sodium bicarbonate aqueous solution (500mL) and EtOAc (400mL). The layers were separated and the aqueous layer was re-extracted with EtOAc (200mL). The combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo.Then at rt, the solid is suspended in Et2O (about 250mL), and then heated to reflux. Dissolve the mixture while refluxing, and then cool. Add heptane, then add more Et2O. A portion of solvent is removed. Filter the solid, and wash with 1: 1Et2O-heptane (3 × 75mL), and further dry under high vacuum. The solid is suspended in Et2O (250mL), and stirred and heated to reflux 30 minutes. Now, the mixture is cooled to 0 ° C and stirred 10 minutes, filtered, and then rinsed with ice-cold Et2O, produce a colorless solid, which is dried in air for 5 minutes, and then dried overnight under high vacuum. (2'S,4R)-2,2'-Dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](trifluoromethanesulfonate) S18 (19.3 g, 57%). 1 H NMR (300MHz, chloroform-d) δ7.78(bs,1H),7.48(bs,1H),6.52(d,J=1.3Hz,1H),3.89(hept,J=5.8Hz,2H),3.75-3.54(m,1H),3.40(dq,J=10.9,4.7,3 .8Hz,2H),2.77(td,J=5.2,2.8Hz,2H),2.43(d,J=1.1Hz,3H),2.21(ddd,J=15.0,11.5,6.4Hz,1H),2.09-1.92(m,3H),1.42(d,J=6.6Hz,3H). LCMS m / z 238.14[M+H] + .

[0882] Key intermediates S19-S21

[0883] Intermediates S19-S21 (see Table 13) were prepared in a single step from (S)-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate and the appropriate thiophene alcohol reagents S15-S17 using a Pictet-Spengler reaction, as in the preparation of intermediate S18. Any modifications to the method are noted in Table 13 and the accompanying footnotes.

[0884] Table 13: Structural and physicochemical data of compounds S19-S21

[0885]

[0886] footnote:

[0887] 1) (2S)-2-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.9 eq.) and trifluoromethanesulfonic acid (2.8 eq.) were used.

[0888] 2) (2S)-2-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.8 eq.) and trifluoromethanesulfonic acid (3.0 eq.) were used.

[0889] 3) (2S)-2-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.9 eq.) and trifluoromethanesulfonic acid (2.8 eq.) were used.

[0890] Preparation of S21

[0891] Tert-butyl (2′S)-2′-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidinyl]-1′-carboxylate (S21)

[0892]

[0893] Step 1: (2′S)-2′-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (S20)

[0894] By 2- (2- thienyl) ethanol (1.028g, 7.618mmol) and (2S) -2- methyl -4- oxo - piperidine -1- tert-butyl formate (1.8g, 8.440mmol) in dioxane (15mL) solution cooling ice bath. In 5 minutes, trifluoromethanesulfonic acid (2.5mL, 28.25mmol) was added to the solution. The resulting solution was slowly warmed to rt and stirred overnight, and then the reactant was basified to pH 8 with 1N NaOH. The mixture was distributed with EtOAc, and the organic matter merged was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, to provide an amber thick oil. Purification by HPLC: 10-90% ACN in water (TFA modifier) ​​on a C18 column followed by lyophilization gave (2'S)-2'-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](trifluoromethanesulfonate) (1.40 g). 1 H NMR (300MHz, chloroform-d) δ7.13(d,J=5.2Hz,1H),6.87(d,J=5.3Hz,1H),3.97-3.86(m,2H),3.62(d,J=15.1Hz,1H),3 .39(d,J=8.4Hz,2H),2.84(td,J=5.3,2.0Hz,2H),2.31-2.18(m,1H),2.07-1.97(m,3H),1.41(d,J=6.6Hz,3H). LCMS m / z 224.18[M+H] + .

[0895] Step 2: tert-Butyl (2′S)-2′-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate (S21)

[0896] The obtained material was dissolved in DCM (20 mL) and treated with Boc2O (1.9 mL, 8.270 mmol) and subsequently treated with DIPEA (2.7 mL, 15.50 mmol). The resulting solution was stirred overnight at rt. The reactant was distributed between 1N NaOH and DCM. The organic matter was collected by a phase separator tube, concentrated in vacuo, and then purified by silica gel chromatography (gradient: heptane containing 0-50% EtOAc) to obtain (2'S)-2'-methylspiro[6,7-dihydrothieno[3,2-c]pyrans-4,4'-piperidine]-1'-tert-butyl formate S21 (786.4 mg, 32%). 1H NMR (300 MHz, chloroform-d) δ 7.10 (dd, J = 5.2, 0.7 Hz, 1H), 6.73 (d, J = 5.2 Hz, 1H), 4.06-3.95 (m, 1H), 3.93-3.88 (m, 2H), 3.81-3.72 (m, 1H), 3.37 (ddd, J = 14.0, 8.8, 5.4 Hz, 1H), 2.82 (q, J = 5.2 Hz, 2H), 2.11

[0897] -1.93(m,2H),1.86-1.73(m,2H),1.50(s,9H),1.28(d,J=6.6Hz,3H).

[0898] Preparation of S22

[0899] (2′R,4R)-2,2′-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](S22)

[0900]

[0901] Step 1: Synthesis of tert-butyl (2′R,4R)-2,2′-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate (C20)

[0902] A solution of 2-(5-methyl-2-thienyl)ethanol (107 mg, 0.7524 mmol) and (2R)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (170 mg, 0.7971 mmol) in DCM (1.4 mL) was cooled to -78 ° C. Trifluoromethanesulfonic acid (130 μL, 1.469 mmol) was added to the reaction mixture and the reactants were stirred at -78 ° C for 1.5 hours. The reactants were quenched into a two-phase mixture of saturated NaHCO (15 mL) and DCM (15 mL), and the pH of the aqueous layer was adjusted to >10 using 2N NaOH. The aqueous layer was then extracted with DCM (3 × 15 mL), filtered through a phase separation cartridge, and concentrated. The crude material was dissolved in DCM (1.4 mL) and triethylamine (250 μL, 1.794 mmol), and di-tert-butyl dicarbonate (250 μL, 1.088 mmol) was added to the reactant in this order. The reactant was stirred at rt for 18 hours. The solution was diluted with DCM and washed with water (10 mL). The aqueous layer was extracted with DCM (2 × 10 mL), dried over sodium sulfate, filtered through a phase separation filter, and concentrated in vacuo. The crude mixture was concentrated and purified by silica gel chromatography (gradient: heptane containing 0-30% EtOAc) to produce (2′R, 4R)-2,2′-dimethylspiro[6,7-dihydrothieno[3,2-c]pyrans-4,4′-piperidine]-1′-tert-butyl formate C20 (138.3 mg, 54%). 1 H NMR (300 MHz, methanol-d4) δ 6.42 (d, J = 1.2 Hz, 1H), 4.35 (d, J = 7.2 Hz, 1H), 3.99-3.82 (m, 3H), 2.83-2.60 (m, 2H), 2.37 (s, 3H), 1.89 (d, J = 4.3 Hz, 2H), 1.85-1.75 (m, 2H), 1.48 (s, 9H), 1.33 (d, J = 7.1 Hz, 3H).

[0903] Step 2: Synthesis of (2′R,4R)-2,2′-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (S22)

[0904] To a stirred solution of (2′R,4R)-2,2′-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylic acid tert-butyl ester C20 (135 mg, 0.4000 mmol) in DCM (1.3 mL) was added dioxane containing hydrogen chloride (500 μL of 4 M, 2.000 mmol), and the reaction was stirred at rt for 2.5 hours. The reaction was concentrated under a stream of nitrogen. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in HO with 0.1% HCl. (2′R,4R)-2,2′-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (hydrochloride) S22 (84.9 mg, 71%). 1 H NMR (300MHz, methanol-d4) δ6.52(s,1H),3.94(t,J=5.4Hz,2H),3.83-3.67(m,1H),3.50(td,J=12.5,3.9Hz,1H),3.1 9(dt,J=13.0,4.1Hz,1H),2.83-2.63(m,2H),2.41(d,J=1.1Hz,3H),2.24-1.96(m,4H),1.55(d,J=7.1Hz,3H). LCMS m / z 238.0[M+H] + .

[0905] Preparation of S23

[0906] (2′S,4S)-2,2′-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](S23)

[0907]

[0908] (2'S,4S)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] S23 was prepared using the same procedure as that of S22. 1 H NMR (300MHz, methanol-d4) δ6.51(s,1H),3.94(t,J=5.4Hz,2H),3.81-3.69(m,1H),3.50(td,J=12.2,3.6Hz,1H),3.1 9(dt,J=13.0,4.1Hz,1H),2.74(td,J=5.5,1.7Hz,2H),2.41(s,3H),2.22-1.96(m,4H),1.55(d,J=7.1Hz,3H). LCMS m / z 238.0[M+H] + .

[0909] Preparation of S24

[0910] (2′S)-2-Chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](S24)

[0911]

[0912] A solution of (2'S)-2'-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylic acid tert-butyl ester S21 (286 mg, 0.8842 mmol) in ACN (4.5 mL) was treated with NCS (112 mg, 0.8387 mmol) and DMAP (1.1 mg, 0.009004 mmol). The resulting solution was stirred overnight and then purified by silica gel chromatography (gradient: 10-100% EtOAc in heptane) to give (2'S)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylic acid tert-butyl ester (210 mg, 66%). LCMS m / z 358.22 [M+H]+.

[0913] The product was dissolved in DCM (4 mL) and treated with TFA (210 μL, 2.726 mmol). The resulting solution was stirred at rt for 3 hours, then concentrated in vacuo and co-evaporated with MeOH to give (2'S)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] S24 (trifluoroacetate salt) (180 mg, 46%). LCMS m / z 258.21 [M+H] + .

[0914] Compounds 499 [ENANT-1] and 500 [ENANT-2]

[0915] 4-[(2′S,4R)-2,2′-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]tetrahydrofuran-3-ol

[0916]

[0917] Preparation of 4-[(2′S,4R)-2,2′-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]tetrahydrofuran-3-ol (499[ENANT-1] and 500[ENANT-2])

[0918] (2'S,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](trifluoromethanesulfonate) S23 (54 mg, 0.1397 mmol), DIPEA (210 μL, 1.206 mmol, 8.6 equiv) and 3,6-dioxabicyclo[3.1.0]hexane (43 μL, 0.60 mmol, 4.3 equiv) were mixed with n-BuOH (1 ml). The resulting mixture was heated at 210°C for 1 hour. The crude reaction mixture was evaporated. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O with 0.1% formic acid. The two products were separated:

[0919] 4-[(2'S,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]tetrahydrofuran-3-ol (499[ENANT-1])(formic acid) (16 mg, 62%). 1 H NMR (300 MHz, methanol-d4) δ 8.44 (s, 1H), 6.50 (d, J = 1.3 Hz, 1H), 4.69 (t, J = 6.1 Hz, 1H), 4.20 (dd, J = 9.6, 6.6 Hz, 1H), 4.15-4.02 (m, 3H), 4.02-3.87 (m, 2H), 3.61 (dt, J = 10.8, 4.1 Hz, 1 H),3.49(dd,J=9.6,5.5Hz,1H),3.30-3.21(m,1H),3.09(td,J=12.0,4.2Hz,1H),2.73( td,J=5.3,2.1Hz,2H),2.40(d,J=1.0Hz,3H),2.19-1.89(m,4H),1.40(d,J=6.4Hz,3H). LCMS m / z 324.26[M+H] + ;and

[0920] 4-[(2'S,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]tetrahydro-furan-3-ol (500[ENANT-2])(formic acid) (12 mg, 46%). 1H NMR (300MHz, methanol-d4) δ8.38(s,1H),6.53(q,J=1.1Hz,1H),4.70(t,J=5.3Hz,1H),4.30-4.07(m,2H),4.07-3.88(m,4H),3.70-3.48(m,2H) ,3.28-3.20(m,1H),3.15(dd,J=12.2,2.7Hz,1H),2.73(t,J=5.4Hz,2H),2.40(d,J=1.0Hz,3H),2.24-1.90(m,4H),1.36(d,J=6.5Hz,3H). LCMS m / z 324.26[M+H] + .

[0921] Compounds 501-507

[0922] Compounds 501-507 (see Table 14) were prepared in a single step from intermediate S23 or S24, as in the preparation of compounds 499 and 500. Epoxides were obtained from commercial sources. Any modifications to the methods are noted in Table 14 and the accompanying footnotes.

[0923] Table 14: Structural and physicochemical data of compounds 501-507

[0924]

[0925]

[0926] footnote:

[0927] 1) Use oxirane-2-carboxamide (1.6 eq) and DIPEA (5.2 eq). Use IPA instead of n-BuOH. Heat the reaction at 150°C for 2 hours. Purify using silica gel chromatography (gradient: 0 to 20% MeOH in DCM).

[0928] 2) The mixture is separated into its constituent enantiomers by chiral SFC separation. Column: Daicel OJ-H, 10 x 250 mm; Mobile phase: 30% MeOH (containing 5 mM ammonia), 70% carbon dioxide. Flow rate: 15 ml / min. 3) Using 6-oxabicyclo[3.1.0]hexane (4.2 equiv.) and DIPEA (8.5 equiv.), the reaction was heated at 200°C for 4 hours.

[0929] 4) Use the corresponding ethylene oxide (3.1 equivalents) and DIPEA (5.0 equivalents). Use MeOH instead of n-BuOH. Heat the reaction at 90°C for 2 hours. Purify using silica gel chromatography (gradient: 0 to 15% MeOH in DCM).

[0930] Compound 508

[0931] (2S)-3-[(2′S,4R)-2-chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]-2-hydroxy-propionamide (508)

[0932]

[0933] Preparation of (2S)-3-[(2′S,4R)-2-chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]-2-hydroxy-propionamide (508)

[0934] (2′S,4R)-2-chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]S24 (78 mg, 0.3026 mmol) and (2S)-oxirane-2-carboxylic acid methyl ester (260 μL, 2.970 mmol) were added to a microwave vial, and MeOH (1.5 mL) containing NH3 (400 μL of 7 M, 2.800 mmol) was added. DIPEA (260 μL, 1.493 mmol) was added, and the reaction was heated at 120°C for 3 hours. An additional 200 μL of (2S)-oxirane-2-carboxylate and NH3 (400 μL of 7 M, 2.800 mmol)) were added, and the reaction was stirred at 120°C for 7 hours. The reaction mixture was concentrated in vacuo. Purification was by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H 2 O with 0.1% trifluoroacetic acid. Further purification was performed using silica gel chromatography (gradient: 1-16% MeOH in DCM) to provide (2S)-3-[(2′S,4R)-2-chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]-2-hydroxy-propionamide (8.5 mg, 7%). 1H NMR (300MHz, chloroform-d) δ11.37(s,1H),8.30(s,1H),7.20(s,1H),6.68(s,1H),5. 58(s,1H),4.69(d,J=9.8Hz,1H),4.07-3.84(m,2H),3.65(s,1H),3.49(d,J=1 1.8Hz,1H),3.29(s,0H),2.92(t,J=11.9Hz,1H),2.76(q,J=5.5Hz,2H),2.37( dd, J = 32.2, 15.7 Hz, 2H), 2.00 ( dd, J = 14.9, 8.1 Hz, 2H), 1.49 ( d, J = 6.4 Hz, 3H). LCMS m / z 345.21 [M+H] + .

[0935] Compound 509

[0936] (2R)-3-[(2′S,4R)-2-Chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]-2-hydroxy-propionamide

[0937]

[0938] Step 1: Synthesis of (2R)-3-[(2′S,4R)-2-chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]-2-hydroxy-propionic acid methyl ester (C22)

[0939] (2R)-3-[(2′S,4R)-2-chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]-2-hydroxy-propionic acid methyl ester C22 was prepared from S24 and (2R)-oxirane-2-carboxylate following the epoxide ring-opening method described in 508.

[0940] Step 2: Synthesis of (2R)-3-[(2′S,4R)-2-chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]-2-hydroxy-propionamide (509)

[0941] (2R)-3-[(2′S,4R)-2-chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]-2-propionic acid methyl ester (66 mg, 0.1834 mmol) was added to a microwave vial and MeOH (100 μL) containing NH (1.3 mL of 7 M, 9.100 mmol) was added. The reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (gradient: 0-12% MeOH in DCM) to provide (2R)-3-[(2′S,4R)-2-chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]-2-hydroxy-propionamide 509 (21.1 mg, 31%). 1 H NMR (300MHz, chloroform-d) δ7.01(d,J=3.9Hz,1H),6.59(s,1H),5.92(s,1H),4.19(dd,J=9.9,4.9Hz,1H),3.89(h,J=6.1Hz,2H),3.15-2.86(m,3 H), 2.80-2.59 (m, 3H), 1.84 (dt, J = 14.9, 4.7Hz, 3H), 1.65 (dd, J = 14.2, 11.4Hz, 1H), 1.44 (dd, J = 17.0, 7.0Hz, 1H), 1.10 (d, J = 6.2Hz, 3H).

[0942] Compound 510

[0943] (2′S)-2,2′-dimethyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]

[0944]

[0945] Preparation of (2′S)-2,2′-dimethyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](510)

[0946] In a reaction vial were added (2'S)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](trifluoromethanesulfonate) S23 (260 mg, 0.6148 mmol), 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (151 mg, 0.6751 mmol), K2CO3 (255 mg, 1.845 mmol) and DMF (1.5 mL). The reaction mixture was heated to 60°C and stirred for 6 hours, then cooled to rt and stirred overnight. The reaction was diluted with DCM, washed with NaHCO3, and extracted with DCM. The combined organic layers were concentrated in vacuo and then purified by silica gel chromatography (Gradient: 0-10% MeOH in DCM) to provide (2'S)-2,2'-dimethyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 510 (157.4 mg, 57%). 1 H NMR (300MHz, chloroform-d) δ7.81(s,1H),6.45(d,J=1.3Hz,1H),4.87(t,J=6.4Hz,2H),4.17(d,J=14.7Hz,1H),3.96(d,J=14.5Hz,1H),3.89-3.78 (m,2H),3.73(t,J=6.4Hz,2H),2.71(d,J=11.4Hz,8H),2.39(d,J=1.0Hz,3H),2.00(s,1H),1.85(d,J=10.0Hz,3H),1.31(d,J=6.3Hz,3H). LCMS m / z 425.32[M+H] + .

[0947] Compounds 511-514

[0948] Compounds 511-514 (see Table 15) were prepared in a single step from the appropriate intermediate piperidine and alkyl halide using the same alkylation method as for compound 510. Alkyl halides were obtained from commercial sources or as described previously. Any modifications to the method are noted in Table 15 and the accompanying footnotes.

[0949] Table 15: Structural and physicochemical data of compounds 511-514

[0950]

[0951] footnote:

[0952] 1) Purification by silica gel chromatography (Gradient: 10-100% EtOAc in heptane).

[0953] 2) Purification by reverse phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid.

[0954] Compound 515

[0955] 2-[[5-[[(2′S,4R)-2-chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]pyrimidin-2-yl]amino]-2-methyl-propan-1-ol

[0956]

[0957] Step 1: Synthesis of (2′S,4R)-2-chloro-1′-[(2-chloropyrimidin-5-yl)methyl]-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (C23)

[0958] A microwave vial was charged with (2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]S24 (trifluoromethanesulfonate) (250 mg, 0.6011 mmol), 2-chloro-5-(chloromethyl)pyrimidine (118 mg, 0.7239 mmol), K2CO3 (965 mg, 1.930 mmol) and NaI (91 mg, 0.6071 mmol), followed by THF (2.2 mL) and DMF (250 μL). The resulting mixture was heated at 40 ° C overnight and then partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 10-100% EtOAc in heptane) provided (2'S,4R)-2-chloro-1'-[(2-chloropyrimidin-5-yl)methyl]-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] C23 ​​(143.7 mg, 59%). LCMS m / z 384.01 [M+H] + .

[0959] Step 2: Synthesis of N-[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]-5-[[(2′S,4R)-2-chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]pyrimidin-2-amine (C24)

[0960] A mixture of (2'S,4R)-2-chloro-1'-[(2-chloropyrimidin-5-yl)methyl]-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] C23 ​​(143.7 mg, 0.3519 mmol), 1-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propan-2-amine (108 mg, 0.5310 mmol), tBuXPhosPdG1 (15 mg, 0.02303 mmol) in t-BuOH (3.5 mL) was degassed under nitrogen for 10 minutes before the addition of NaOtBu (388 μL of 2M, 0.7760 mmol). The resulting mixture was sealed and heated at 60 °C for 45 minutes. It was partitioned between EtOAc and water. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give N-[2-[tert-butyl(dimethyl)silyl]oxy-1,1-dimethyl-ethyl]-5-[[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]methyl]pyrimidin-2-amine. LCMS m / z 551.28 [M+H] + .

[0961] Step 3: Synthesis of 2-[[5-[[(2′S,4R)-2-chloro-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-1′-yl]methyl]pyrimidin-2-yl]amino]-2-methyl-propan-1-ol (515)

[0962] The crude product from step 2 was dissolved in THF (3 mL) and treated with TBAF (1.8 mL of 1 M THF, 1.800 mmol). The reaction was stirred at rt for 2 hours and then partitioned between EtOAc and water. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by HPLC: water containing 10-90% ACN (HCl modifier) ​​gave 2-[[5-[[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]pyrimidin-2-yl]amino]-2-methyl-propan-1-ol (hydrochloride) (6.3 mg, 4%). 1H NMR (300MHz, methanol-d4) δ8.43(s,2H),6.81(s,1H),4.56(s,1H),3.96(h,J=6.1Hz,3H),3.69(s,2H),3.56(s ,1H),3.18(s,2H),2.74(td,J=5.3,1.9Hz,2H),2.09(dd,J=23.2,8.1Hz,4H),1.56(s,3H),1.39(s,6H). LCMS m / z 437.11[M+H] + .

[0963] Compound 516

[0964] (2′S,4S)-2,2′-dimethyl-1′-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](516)

[0965]

[0966] Preparation of (2′S,4S)-2,2′-dimethyl-1′-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](516)

[0967] (2'S, 4S) -2,2'- dimethylspiro [6,7- dihydrothieno [3,2-c] pyran -4,4'- piperidine] S23 (27.6 mg, 0.1163 mmol) and 1- (2- methylsulfonylethyl) pyrazole -4- carbaldehyde (41 mg, 0.2027 mmol) were dissolved in DCM (750 μ L), and acetic acid (40 μ L, 0.7034 mmol) was added to the solution, followed by polymer-loaded cyanoborohydride (186 mg of 2 mmol / g, 0.3720 mmol). The solution was heated to 90 ° C in a microwave reactor for 95 minutes. Another portion of polymer-loaded cyanoborohydride (67 mg, 0.5930 mmol) was added, and the reactants were stirred at rt overnight. The suspension was stirred in 1.5 mL of MeOH for 10 minutes, and then the resin was filtered off. The solvent is removed, and the residue is dissolved in water (2mL) and DCM (2mL). The pH of the aqueous layer is adjusted to pH>10 with 2M NaOH. Each phase is separated by a phase separator, the aqueous layer is extracted with DCM (2×10mL), and the combined organic matter is concentrated in a vacuum. The crude residue is purified by silica gel chromatography (gradient: DCM containing 0-20% MeOH) to produce (2′S, 4S) -2,2′- dimethyl -1′- [[1- (2- methylsulfonylethyl) pyrazol-4-yl] methyl] spiro [6,7- dihydrothieno [3,2-c] pyrans -4,4′- piperidine] (32.1 mg, 62%). 1 HNMR (300MHz, chloroform-d) δ7.54(s,1H),7.49(s,1H),6.46(d,J=1.3Hz,1H),4.58(t,J=6.8Hz,2H),4.00-3.80(m,2H),3.64(t,J=6.1Hz,2H),3.55( s,2H),3.06(q,J=5.9,5.3Hz,1H),2.91-2.58(m,3H),2.56-2.43(m,1H ), 2.47 (s, 3H), 2.40 (s, 3H), 2.03-1.76 (m, 4H), 1.17 (d, J = 6.8Hz, 3H).

[0968] Compounds 517-518

[0969] Compounds 517-518 (see Table 16) were prepared in a single step from intermediates S22 and S24 using the reductive amination procedure as for compound 516. The aldehydes were as described above. Any modifications to the procedures are noted in Table 16 and the accompanying footnotes.

[0970] Table 16: Structural and physicochemical data of compounds 517-518

[0971]

[0972]

[0973] footnote:

[0974] 1) Different amounts of reagents were used: 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (2.2 equivalents), acetic acid (7.0 equivalents), polymer-supported cyanoborohydride (4.7 equivalents).

[0975] 2) Different amounts of reagents were used: 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (1.5 equivalents), acetic acid (5.0 equivalents), polymer-supported cyanoborohydride (2.8 equivalents) and the reaction was carried out at 110° C. for 1 hour.

[0976] Compound 519

[0977] (2′S,4R)-2,2′,3-trimethyl-1′-[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](519)

[0978]

[0979] Preparation of (2′S,4R)-2,2′,3-trimethyl-1′-[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](519)

[0980] To a stirred solution of (2'S, 4R)-2,2', 3-trimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] S19 (150 mg, 0.5967 mmol) in MeOH (2 mL) was added 1-methylpyrazole-4-carboxaldehyde (131.41 mg, 1.1934 mmol) and titanium isopropoxide (508.77 mg, 0.5283 mL, 1.7901 mmol) and stirred at 50 ° C for 2 hours. Sodium cyanoborohydride (112.49 mg, 1.7901 mmol) was added to the reaction mixture and stirred at 50 ° C for 24 hours. The reaction mixture was concentrated in vacuo and washed with water (4 ml) and extracted with EtOAc (3×5 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo and purified by reverse phase HPLC chromatography. Method: YMC Triart Actus C18 (250×20 mm, 5 microns). Gradient: MeCN in H2O with 20 mM ammonium bicarbonate. The product was isolated as (2′S,4R)-2,2′,3-trimethyl-1′-[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (56.3 mg, 27%). 1H NMR (400MHz, DMSO-d6) δ7.57(s,1H),7.29(s,1H),3.80(bs,3H),3.77-3.65(m,3H),3.45(d,J=14.52Hz,1H),2.60(bs,2H),2.43- 2.32(m,3H),2.21(s,3H),2.09(s,3H),2.02-1.97(m,1H),1.75(t,J=11.6Hz,1H),1.59(d,J=13.8Hz,2H),1.09(d,J=5.8Hz,3H). LCMS m / z 346.3[M+H] + .

[0981] Compounds 520-521

[0982] Compounds 520-521 (see Table 17) were prepared in a single step from the appropriate piperidine selected from intermediate S20 or S21 using the reduction protocol described for compound 519. Aldehydes were obtained from commercial sources. Any modifications to the procedures are noted in Table 17 and the accompanying footnotes.

[0983] Table 17: Structural and physicochemical data of compounds 520-521

[0984]

[0985] Preparation of S25

[0986] (2′S,4R)-2-Bromo-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylic acid tert-butyl ester (S25)

[0987]

[0988] Preparation of (2′S,4R)-2-bromo-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylic acid tert-butyl ester (S25)

[0989] To a stirred solution of (2′S, 4R)-2′-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylic acid tert-butyl ester S21 (220 mg, 564.54 μmol) in ACN (4 mL) was added NBS (100 mg, 561.85 μmol) and DMAP (0.6 mg, 4.9113 μmol) at rt. The reaction mixture was then heated to 65° C. and stirred overnight. The reaction mixture was diluted with 1N NaOH (25 mL) and extracted with EtOAc (2×50 ml). The organic layer was washed with saturated aqueous sodium thiosulfate solution (50 ml), then with brine solution (50 ml) and dried over Na 2 SO 4 . The organic layer was concentrated in vacuo to provide a crude material. The crude compound was purified by silica gel chromatography (Gradient: 10-15% EtOAc in petroleum ether) to yield (2′S,4R)-2-bromo-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylic acid tert-butyl ester S25 (140 mg, 59%). 1 HNMR (400 MHz, chloroform-d) δ 6.55 (s, 1H), 5.30 (s, 1H), 3.98-3.88 (m, 1H), 3.87-3.85 (m, 1H), 3.74-3.71 (m, 1H), 3.32-3.28 (m, 1H), 2.71-2.66 (m, 2H), 1.96-1.91 (m, 2H), 1.76-1.64 (m, 2H), 1.48 (s, 9H), 1.24 (d, J = 6.4 Hz, 3H). LCMS m / z 404.24 [M+H] + .

[0990] Compound 522

[0991] (2′S,4R)-2-Bromo-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](522)

[0992]

[0993] Preparation of (2′S,4R)-2-bromo-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](522)

[0994] To a mixture of (2'S, 4R)-2-bromo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylic acid tert-butyl ester S25 (50 mg, 0.1156 mmol) in DCM (1 mL) was added trifluoroacetic acid (200 μL, 2.596 mmol). After stirring for 5 minutes, the mixture was dried and redissolved in acetonitrile (2 mL), and 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (hydrochloride) (45 mg, 0.1730 mmol) and potassium carbonate (50 mg, 0.3618 mmol) were added thereto. The mixture was stirred at 70 ° C for 3 hours. The mixture was cooled to rt, diluted with water (3 mL) and EtOAc (5 mL), the layers were mixed and the aqueous layer was removed. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (Gradient: 0-10% MeOH in DCM) to yield (2'S,4R)-2-bromo-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 522 (33 mg, 58%). 1 H NMR (400 MHz, chloroform-d) δ 7.55 (s, 1H), 6.65 (s, 1H), 4.83-4.75 (m, 2H), 4.00-3.71 (m, 5H), 3.66 (t, J = 6.3 Hz, 2H), 2.68-2.55 (m, 6H), 2.48 (s, 2H), 1.80-1.71 (m, 3H), 1.58 (d, J = 12.7 Hz, 1H), 1.16 (d, J = 6.1 Hz, 3H). LCMS m / z 488.97 [M+H] + .

[0995] Compound 523

[0996] (2′S,4R)-2-(2,2-difluoroethyl)-2′-methyl-1′-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](523)

[0997]

[0998] Step 1: Synthesis of (2′S,4R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](C25)

[0999] [Ir{dFCFppy}2(bpy)]PF6 (4 mg, 0.003962 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridinyl)pyridine (10 mg, 0.03726 mmol) and dichloronickel; 1,2-dimethoxyethane (10 mg, 0.04551 mmol) were added to a 1 dram vial, which was evacuated and refilled with nitrogen three times. Under nitrogen, bis(trimethylsilyl)silyl-trimethyl-silane (190 μL, 0.6159 mmol), 2,6-lutidine (90 μL, 0.7769 mmol), 2-bromo-1,1-difluoro-ethane (50 μL) and (2′S, 4R)-2-bromo-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-tert-butyl carboxylate (150 mg, 0.3728 mmol) were dissolved in 1,2-dimethoxyethane (2 mL). The reactants were irradiated for 2 hours with 100% LED power and 4700 RPM fan in a Merck photoreactor. The reactants were diluted with 3 mL of EtOAc and 1 mL of water. The reactants were extracted, and the organic layer was dried, and the volatiles were then evaporated. The crude residue was dissolved in HCl (1000 μL of 4 M, 4.000 mmol) and stirred for 1 hour before removing the volatiles. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H 2 O with 0.1% trifluoroacetic acid. This gave (2′S,4R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] C25 (trifluoroacetate salt) (33.2 mg, 22%). 1H NMR (400MHz, DMSO-d6) δ8.91 (s, 2H), 6.66 (s, 1H), 6.40-6.02 (m, 1H), 3.89 (hept, J = 6.0, 5.5Hz, 2H), 3.70-3 .37(m,3H),3.12(dd,J=54.9,12.4Hz,2H),2.74(t,J=5.4Hz,2H),2.10-1.83(m,4H),1.24(d,J=6.4Hz,3H). LCMS m / z 288.48[M+H] + .

[1000] Step 2: Synthesis of (2′S,4R)-2-(2,2-difluoroethyl)-2′-methyl-1′-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](523)

[1001] (2'S, 4R) -2- (2,2- difluoroethyl) -2'- methyl - spiro [6,7- dihydrothieno [3,2-c] pyran -4,4'- piperidine] C25 (30 mg) was dissolved in ACN (1 mL) and 4- (chloromethyl) -1- (2-methylsulfonylethyl) pyrazole (hydrochloride) (17 mg, 0.06560 mmol) and K2CO3 (100 mg, 0.7236 mmol) were added. The mixture was heated to 65 ° C overnight under nitrogen. The reaction was then diluted with water and DCM, and the layers were separated on a phase separator and the aqueous layer was extracted with DCM (x2). The organic layer was concentrated in vacuo and purified by silica gel chromatography (Gradient: 0-20% MeOH in DCM) to yield (2′S,4R)-2-(2,2-difluoroethyl)-2′-methyl-1′-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (6.1 mg, 19%). 1 H NMR (400MHz, DMSO-d6) δ7.71(s,1H),7.39(s,1H),6.77(s,1H),6.19(tt,J=56.2,4.2Hz,1H),4.51(t,J=6.8Hz,2H),3.82 -3.65(m,5H),3.51-3.26(m,4H),2.77(s,3H),2.65(s,2H),2.44-2.25(m,2H),1.76-1.46(m,4H),1.09(d,J=6.1Hz,3H). LCMS m / z474.02[M+H] + .

[1002] Compound 524

[1003] (2′S,4R)-2-(Difluoromethyl)-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]

[1004]

[1005] Step 1: Synthesis of tert-butyl (2′S,4R)-2-formyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate (C26)

[1006] A solution of (2'S, 4R)-2-bromo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-tert-butyl formate S25 (50 mg, 0.1243 mmol) in THF (1 mL) was cooled to -78 ° C. At this time, hexane containing butyllithium (50 μL of 2.5 M, 0.1250 mmol) was added dropwise. After stirring at this temperature for 60 minutes, DMF (10 μL, 0.1291 mmol) was added. After another 50 minutes, the mixture was slowly warmed to rt. The reactant was quenched with saturated ammonium chloride and diluted with 1 mL of water and 5 mL of EtOAc. The layers were mixed and separated, and the organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (Gradient: 0-50% EtOAc in heptane) to provide (2′S,4R)-2-formyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylic acid tert-butyl ester C26 (29 mg, 65%). 1 H NMR (400 MHz, chloroform-d) δ 9.82 (s, 1H), 7.42 (s, 1H), 4.05-3.85 (m, 3H), 3.76 (ddd, J = 13.8, 6.1, 4.8 Hz, 1H), 3.37 (ddd, J = 14.0, 8.9, 5.4 Hz, 1H), 2.96-2.80 (m, 2H), 2.10 (dddd, J = 14.7, 8.2, 6.0, 1.8 Hz, 1H), 1.99 (ddd, J = 14.2, 5.2, 1.9 Hz, 1H), 1.83-1.73 (m, 2H), 1.49 (s, 9H), 1.27 (d, J = 6.6 Hz, 3H). LCMS m / z 351.93 [M+H] + .

[1007] Step 2: Synthesis of tert-butyl (2′S,4R)-2-(difluoroethyl)-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate (C27)

[1008] A mixture of (2'S, 4R)-2-formyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylic acid tert-butyl ester C26 (29 mg, 0.08040 mmol) in DCM (500 μL) was stirred at rt. N-ethyl-N-(trifluoro-λ4-thiol)ethanamine (30 μL, 0.2271 mmol) and the mixture were stirred at reflux. After stirring for 20 hours, the mixture was cooled to rt, diluted with water, and the layers were separated. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (Gradient: 0-50% EtOAc in heptane) to provide (2′S,4R)-2-(difluoromethyl)-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylic acid tert-butyl ester C27 (18 mg, 59%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.90 (d, J = 2.1 Hz, 1H), 6.75 (t, J = 56.2 Hz, 1H), 4.03-3.83 (m, 3H), 3.74 (ddd, J = 13.9, 6.0, 4.8 Hz, 1H), 3.33 (ddd, J = 14.1, 8.9, 5.4 Hz, 1H), 2.88-2.72 (m, 2H), 2.05 (dddd, J = 14.8, 9.0, 6.1, 1.8 Hz, 1H), 1.95 (ddd, J = 14.2, 5.2, 1.8 Hz, 1H), 1.80-1.67 (m, 2H), 1.48 (s, 9H), 1.25 (d, J = 6.5 Hz, 3H). LCMS m / z 373.99[M+H] + .

[1009] Step 3: Synthesis of (2′S,4R)-2-(difluoromethyl)-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](524)

[1010] To a mixture of (2'S, 4R)-2-(difluoromethyl)-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylic acid tert-butyl ester C27 (18 mg, 0.04775 mmol) in DCM (400 μL) was added trifluoroacetic acid (40 μL, 0.5192 mmol) (11:30). After stirring for 60 minutes, the mixture was dried and redissolved in acetonitrile (1,000 μL), and 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (hydrochloride) (15 mg, 0.05766 mmol) and potassium carbonate (20 mg, 0.1447 mmol) were added thereto, and the mixture was stirred at 60 ° C overnight. The mixture was diluted with EtOAc (5 mL) and water (2 mL), and the organic layers were mixed and separated. The organic layer was then washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (Gradient: 0-10% MeOH in DCM) to provide (2'S,4R)-2-(difluoromethyl)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 524 (10 mg, 45%). 1 H NMR (400MHz, chloroform-d) δ7.57(s,1H),6.90(t,J=2.1Hz,1H),6.68(t,J=56.1Hz ,1H),4.86-4.74(m,2H),3.97(d,J=14.7Hz,1H),3.91-3.71(m,3H),3.71-3 .62(m,2H),2.82-2.64(m,3H),2.62(d,J=0.7Hz,3H),2.52(dt,J=11.5,5. 9Hz, 2H), 1.86-1.72 (m, 3H), 1.61 (t, J = 12.6Hz, 1H), 1.17 (d, J = 6.2Hz, 3H). LCMS m / z 461.1[M+H] + .

[1011] Compound 525

[1012] (2′S,4R)-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]

[1013]

[1014] Step 1: Synthesis of (2′S)-2-iodo-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylic acid tert-butyl ester (C28)

[1015] (2'S)-tert-Butyl 2'-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate S21 (200 mg, 0.6183 mmol) was dissolved in CH3CN (4 mL) and NIS (168 mg, 0.7467 mmol) was added. The reaction mixture was stirred at rt overnight and then diluted with 1N NaOH / EtOAc, and the organic layer was dried and concentrated, which was purified by silica gel chromatography (gradient: 0 to 40% EtOAc / heptane) to provide (2'S)-tert-butyl 2-iodo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate C28 (222 mg, 80%). LCMS m / z 449.94 [M+H] + .

[1016] Step 2: Synthesis of tert-butyl (2′S)-2′-methyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate (C29)

[1017] (2'S)-2-iodo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylic acid tert-butyl ester C28 (215 mg, 0.4785 mmol) was dissolved in DMF (4 mL) and copper bromide, methylsulfonylmethane (30 mg, 0.1459 mmol) and ethyl 2,2-difluoro-2-fluorosulfonyl-formate (150 μL, 1.178 mmol) were added. The reaction mixture was heated to 100 ° C in a microwave for 40 minutes. Additional ethyl 2,2-difluoro-2-fluorosulfonyl-formate (75 μL, 0.5891 mmol) was added and the reaction mixture was heated to 100 ° C in a microwave again for 40 minutes. The reaction mixture was diluted with EtOAc / 1N NaOH and filtered through The organic layer was dried and concentrated to an oil, which was purified by silica gel chromatography (Gradient: 0 to 25% EtOAc in heptane) to yield tert-butyl (2′S)-2′-methyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate C28 (87 mg, 46%). 1H NMR (300 MHz, chloroform-d) δ7.07 (s, 1H), 4.07-3.96 (m, 1H), 3.96-3.86 (m, 2H), 3.84-3.70 (m, 1H), 3.41-3.28 (m, 1H), 2.88-2.78 (m, 2H), 2.15-1.91 (m, 2H), 1.83-1.67 (m, 2H), 1.48 (s, 9H), 1.28 (d, J = 6.5 Hz, 3H).

[1018] Step 3: Synthesis of (2′S,4R)-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](525)

[1019] Tert-butyl (2'S)-2'-methyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate C29 (42 mg, 0.1073 mmol) was dissolved in DCM (1 mL) and TFA (500 μL, 6.490 mmol) was added. After 20 minutes, the solvent was removed and the residue was redissolved in DCE (1 mL) and 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (40 mg, 0.1788 mmol), NaI (3 mg, 0.02001 mmol) and DIPEA (60 μL, 0.3445 mmol) were added. The reaction mixture was heated to 60 °C for 20 hours. The reaction mixture was concentrated, dissolved in 1 mL of MeOH and re-purified using a reverse phase C18 column (gradient: CH3CN / H2O, TFA modifier). Pure fractions were diluted with EtOAc / 1N NaOH and the organic layer was dried and concentrated to yield (2′S,4R)-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] 525 (27 mg, 52%). 1H NMR (300MHz, chloroform-d) δ7.65(s,1H),7.14(s,1H),4.88(t,J=6.3Hz,2H),4.12-3.82(m,4H),3.75(t,J=6. 3Hz,2H),2.91-2.75(m,3H),2.71(s,3H),2.66-2.51(m,2H),1.96-1.68(m,4H),1.25(d,J=6.2Hz,3H). LCMS m / z 479.11[M+H] + .

[1020] Compounds 526 and 527

[1021] (2′S,4R)-3-Bromo-2-ethyl-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](526) and (2′S,4R)-3-deuterio-2-ethyl-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](527)

[1022]

[1023] Step 1: Synthesis of 3,5-dibromo-2-ethyl-thiophene (C30)

[1024] To a solution of N-isopropylpropan-2-amine (1.2mL, 8.562mmol) in THF (50mL) was added hexyllithium (4.2mL of 2.3M, 9.660mmol) at 0°C under nitrogen within 5 minutes, and the reactants were stirred for another 30 minutes. After the solution was cooled to -78°C, 2,5-dibromothiophene (900 μL, 7.987mmol) was added. Iodoethane (1.3mL, 16.25mmol) was then added and stirred overnight, slowly warming to rt. The reactants were quenched with saturated ammonium chloride solution, then extracted with DCM (3×100mL), and the combined organics were washed with saturated bicarbonate solution and saturated brine solution. The combined organic layers were evaporated in vacuo to produce 3,5-dibromo-2-ethyl-thiophene (1.1g, 52%). 1 H NMR (300 MHz, CHLOROFORM-d) δ 6.79 (s, 1H), 2.68 (q, J = 7.5 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H).

[1025] Step 2: Synthesis of (2′S)-3-bromo-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (C31)

[1026] At -78 DEG C, 3,5-dibromo-2-ethyl-thiophene C30 (500mg, 1.852mmol) is dissolved in THF (10mL).Hexanedione (900 μ L of 2.3M, 2.070mmol) is added, and stirred for 30 minutes, then ethylene oxide (1000 μ L of 2.5M, 2.500mmol) is added. The reaction mixture is warmed to rt and stirred for 2 days. Reactant is quenched with saturated ammonium chloride solution and extracted with DCM (x3). The organic layer merged is concentrated in a vacuum, and by silica gel chromatography purification (gradient: containing 0 to 60% EtOAc heptane), produce 2- (4-bromo-5-ethyl-2-thienyl) ethanol (200mg, 46%). 1 H NMR (300 MHz, CHLOROFORM-d) δ 6.62 (s, 1H), 3.78 (m, 2H), 2.91 (t, J = 6.1 Hz, 2H), 2.73-2.61 (m, 2H), 1.18 (td, J = 7.5, 1.4 Hz, 3H).

[1027] The material from step 2 is dissolved in dioxane (5mL) and (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (400mg, 1.876mmol) is added under nitrogen. Trifluoromethanesulfonic acid (400 μL, 4.520mmol) is added and stirred overnight. The reaction mixture is quenched with saturated bicarbonate solution, diluted with DCM, and extracted on a phase separator (x3). The solvent is evaporated under positive nitrogen pressure to produce (2'S)-3-bromo-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](trifluoromethanesulfonic acid (1)) C31 (510mg, 37%). LCMS m / z 330.05[M+H] + .

[1028] Step 3: Synthesis of (2′S,4R)-3-bromo-2-ethyl-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](526)

[1029] To a solution of (2'S)-3-bromo-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](trifluoromethanesulfonic acid (1)) C31 (120 mg, 0.1593 mmol) in DMF (1 mL) was added K2CO3 (88 mg, 0.6367 mmol) and 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (hydrochloride) (42 mg, 0.1615 mmol). The reaction was stirred at 60 ° C overnight. The reaction mixture was quenched with water and extracted with DCM (x 3). The combined organic layers were concentrated in vacuo and then purified by silica gel chromatography (Gradient: 0-20% MeOH in DCM) to yield (2'S,4R)-3-bromo-2-ethyl-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 526 (60 mg, 71%). LCMS m / z 517.1 [M+H] + .

[1030] Step 4: Synthesis of (2′S,4R)-3-deuterio-2-ethyl-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](527)

[1031] (2'S,4R)-3-bromo-2-ethyl-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 526 (10 mg) was dissolved in MeOH (2 mL) and Pd / C (10 mg, 0.09397 mmol) was added under nitrogen. The reaction was allowed to stand under deuterium overnight. The flask was then purged with nitrogen and the Pd / C was filtered off to produce (2'S,4R)-3-deuterio-2-ethyl-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 527 (6.0 mg, 73%). LCMS m / z 440.12[M+H] + .

[1032] Preparation of S26

[1033] 1-(5-Chloro-2-thienyl)propan-2-ol (S26)

[1034]

[1035] Step 1: 1-(5-chloro-2-thienyl)propan-2-ol (S26)

[1036] To a stirred solution of 2-chlorothiophene (1.5 g, 12.6 mmol) in THF (20 mL) was added LDA (9.45 mL of a 2M solution in THF, 18.9 mmol) at -78 ° C, and the reaction mixture was stirred for 1 hour. 2-Methyloxirane (731 mg, 12.6 mmol) was added and continued to stir at -78 ° C for 2 hours. The reactant was quenched with saturated NH4Cl aqueous solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated. Purified by silica gel chromatography (gradient: heptane containing 5% EtOAc) to produce 1- (5-chloro-2-thienyl) propan-2-ol S26 (1.3 g, 52%). 1 H NMR (300MHz, DMSO-d6) δ6.90 (d, J = 3.6 Hz, 1H), 6.70 (d, J = 3.9 Hz, 1H), 4.82 (d, J = 4.8 Hz, 1H), 3.77 (m, 1H), 2.84-2.68 (m, 2H), 1.06 (d, J = 5.7 Hz, 3H). LCMS m / z272.19[M+H] + .

[1037] Intermediates S27-S29

[1038] Intermediates S27-S29 (Table 18) were prepared from 2-chlorothiophene and the appropriate epoxide as described for compound S26.

[1039] Table 18: Structure and LCMS data of thiophene cores S27-S29

[1040]

[1041]

[1042] Preparation of S30

[1043] (2′S)-2-Chloro-2′,6-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](S30)

[1044]

[1045] Step 1: Synthesis of (2′S)-2-chloro-2′,6-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (S30)

[1046] To a stirred solution of 1-(5-chloro-2-thienyl)propan-2-ol S30 (1.3 g, 0.0066 mol), (2S)-2-methylpiperidin-4-one (trifluoroacetic acid (1)) (1.5 g, 0.0059 mol) in toluene (15 mL) was added methanesulfonic acid (701.58 mg, 0.4737 mL, 0.0073 mol) at room temperature. The reaction mixture was stirred at 120° C. for 4 hours. The pH was adjusted to 8-9 using a saturated aqueous solution of Na2CO3 and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Purification was performed by reverse phase HPLC. Method Xbridge C18 column (19×150 mm, 5 microns). Gradient: MeCN in H2O with 10 mM ammonium bicarbonate to produce the product. The collected fractions were lyophilized to give (2'S)-2-chloro-2',6-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] S30 (370 mg, 20%). 1H NMR (300MHz, DMSO-d6) δ6.92 (s, 1H), 3.87 (d, J = 9.6Hz, 1H), 2.95-2.78 (m, 2H), 2.71-2.62 (m, 2H), 2.42-2.3 3(m,1H),1.91-1.79(m,2H),1.46-1.36(m,2H),1.23(d,J=6.3Hz,3H),1.15-1.07(m,1H),0.94-0.91(m,3H). LCMS m / z 272.11[M+1] + .

[1047] Compounds S31-S33

[1048] Compounds S31-S33 (Table 19) were prepared from (2S)-2-methylpiperidin-4-one and the appropriate thiophene reagent as described for compound S30.

[1049] Table 19: Structure and LCMS data of spiropiperidine cores S31-S33

[1050]

[1051] footnote:

[1052] 1) Trifluoromethanesulfonic acid (1 equivalent) was used as acid.

[1053] Compound 528

[1054] (2′S)-2-Chloro-2′,6-dimethyl-1′-[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (528[DIAST-1] and 529[DIAST-2])

[1055]

[1056] Preparation of (2′S)-2-chloro-2′,6-dimethyl-1′-[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (528 and 529)

[1057] To a stirred solution of (2'S)-2-chloro-2',6-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] S30 (300 mg, 0.993 mmol) and 4-(chloromethyl)-1-methyl-pyrazole (115 mg, 0.792 mmol) in MeCN (6 mL) was added potassium carbonate (691 mg, 5.0 mmol) followed by KI (33 mg, 0.198 mmol) and stirred at room temperature for 16 hours. After completion, the solvent was evaporated. Purification by reverse phase HPLC. Method: XSelect phenylhexyl column (19 x 250 mm, 5 microns). Gradient: MeCN in H2O with 0.1% formic acid. Subsequent purification by SFC produced two diastereomers:

[1058] (2'S)-2-Chloro-2',6-dimethyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 528[DIAST-1] (39.7 mg, 11%). 1 H NMR (400MHz, DMSO-d6) δ7.54(s,1H),7.28(s,1H),6.98(s,1H),3.82-3.79(m,4H),3.73(d,J=14Hz,1H),3.25(d,J=13.6Hz,1H),2.63(dd,J=3.2Hz and 16Hz,1H),2.55-2.45(m,2H),2.39-2.28(m,2H),1.87(dd,J=2.4Hz and 14Hz,1H),1.75-1.69(m,1H),1.57-1.56(m,1H),1.46-1.42(m,1H),1.18(d,J=6Hz,3H),1.07(d,J=6Hz,3H). LCMS m / z 366.1[M+1] + ;and

[1059] (2'S)-2-Chloro-2',6-dimethyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 529[DIAST-2] (10.3 mg, 3%). 1H NMR (400MHz, DMSO-d6) δ7.54(s,1H),7.28(s,1H),6.98(s,1H),3.90-3.85(m,1H),3.79-3.72(m,4H),3.32-3.23(m,1H),2.64(dd,J=2.8Hz and 16Hz,1H),2.56-2.49(m,1H),2.41-2.32(m,3H),1.97-1.90(m,2H),1.44-1.34(m,2H),1.18(d,J=6Hz,3H),1.09(d,J=6Hz,3H). LCMS m / z 366.1[M+1] + .

[1060] Compounds 530-533

[1061] Using the method of compounds 528 and 529, compounds 530-533 (Table 20) were prepared from appropriately selected piperidines and 4-(chloromethyl)-1-methyl-pyrazoles.

[1062] Table 20: Structural and physicochemical data of compounds 530-533

[1063]

[1064]

[1065] Preparation of S34

[1066] (2′S)-2′,7-dimethyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine](S34)

[1067]

[1068] Step 1: Synthesis of (2′S)-2′,7-dimethyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine] (S34)

[1069] 2-[5-(Trifluoromethyl)-2-thienyl]propan-1-ol (250 mg, 1.18 mmol) and (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (362 mg, 1.69 mmol) were dissolved in 1,2-dioxane (3 mL). Trifluoromethanesulfonic acid (375 μL, 4.24 mmol) was added and stirred at rt overnight. The reactants were quenched with NaHCO3 and the solvent was evaporated. DCM and water were added and the organic layer was collected by phase separator. The solvent was evaporated to produce (2'S)-2',7-dimethyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S34) (600 mg, 146%). LCMS m / z 306.24 [M+H] + .

[1070] Compounds S35-S41

[1071] Using the method for compound S34, compounds S35-S41 (Table 21) were prepared from (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester and the appropriate thiophene.

[1072] Table 22: Structural and physicochemical data of compounds S35-S41

[1073]

[1074]

[1075] footnote:

[1076] 1) (2'S)-2-ethyl-2',7-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] was separated into its constituent diastereomers (cis and trans) by chiral SFC separation. Column: Phenomenex Cellulose-2, 20 x 250 mm. Mobile phase: 40% MeOH (containing 5 mM ammonia), 60% CO2 Compound 534

[1077] (2S,4R)-2,7′-dimethyl-1-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-2′-(trifluoromethyl)-6′,7′-dihydrospiro[piperidin-4,4′-thieno[3,2-c]pyran]

[1078]

[1079] Step 1: (2S,4R)-2,7′-dimethyl-1-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-2′-(trifluoromethyl)-6′,7′-dihydrospiro[piperidin-4,4′-thieno[3,2-c]pyran] (534)

[1080] To a stirred solution of (2S,4R)-2,7′-dimethyl-2′-(trifluoromethyl)-6′,7′-dihydrospiro[piperidine-4,4′-thieno[3,2-c]pyran] S34 (71 mg, 0.111 mmol) and 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (25 mg, 0.111 mmol) in DMF was added potassium carbonate (15 mg, 0.111 mmol) and the reaction was stirred overnight at 60° C. Water and dichloromethane were added and the organic layer was collected by phase separator. Purification by silica gel chromatography (gradient: 0-20% methanol in DCM) yielded (2S,4R)-2,7′-dimethyl-1-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-2′-(trifluoromethyl)-6′,7′-dihydrospiro[piperidin-4,4′-thieno[3,2-c]pyran] 534 (10 mg, 18%). LCMS m / z 493.56 [M+H] + .

[1081] Compounds 535-541

[1082] Using the method of compound 534, compounds 535-541 (Table 23) were prepared from the intermediate piperidine and 4-(chloromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazole.

[1083] Table 23: Structural and physicochemical data of compounds 535-541

[1084]

[1085]

[1086]

[1087] Compound 542

[1088] (2′S,4R)-2′-Methyl-1′-[(1-ethylmethylpyrazol-4-yl)methyl]-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-7-ol

[1089]

[1090] Step 1: Synthesis of tert-butyl (2′S,4R)-7-hydroxy-2′-methyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate (S43)

[1091] Tert-butyl (2'S,4R)-2'-methyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate S42 (670 mg, 1.71 mmol), 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (390 mg, 1.36 mmol) and 2-(1-cyano-1-methyl-ethyl)azo-2-methyl-propionitrile (20 mg, 0.121 mmol) were combined in dichloromethane (10 mL) and the mixture was stirred at 35° C. for 4 hours. Sodium thiosulfate was added and the reaction mixture was diluted with water and ethyl acetate. The organic layer was concentrated and purified by silica gel chromatography (gradient: 0-30% EtOAc in heptane) to produce the bromide intermediate (2′S,4R)-7-bromo-2′-methyl-2-(trifluoromethyl)-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylic acid tert-butyl ester. The intermediate was dissolved in THF and treated with saturated NaHCO (2 mL), and the mixture was heated to 60° C. overnight. The mixture was diluted with water and EtOAc, and the organic layer was dried and concentrated. Purification by silica gel chromatography (gradient: 0-50% EtOAc in heptane) gave (2′S,4R)-7-hydroxy-2′-methyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylic acid tert-butyl ester S43 (48 mg, 7%). 1 H NMR(300MHz, chloroform-d)δ7.09(s,1H),4.74-4.61(m,1H),4.05-3.69(m,4H),3.44-3.24( m, 1H), 2.39 (t, J = 9.0Hz, 1H), 2.26-1.73 (m, 3H), 1.50 (s, 9H), 1.28 (d, J = 6.6Hz, 3H).

[1092] Step 2: (2′S,4R)-2′-methyl-1′-[(1-methylpyrazol-4-yl)methyl]-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidin]-7-ol (542)

[1093] Tert-butyl (2′S,4R)-7-hydroxy-2′-methyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate (48 mg, 0.117 mmol) was dissolved in dichloromethane (1 mL) and TFA (0.5 mL, 6.490 mmol) was added. The reaction mixture was stirred for 30 minutes and then concentrated to an oil. The oil was dissolved in dichloromethane (1 mL) and 1-methylpyrazole-4-carboxaldehyde (20 mg, 0.181 mmol), AcOH (35 μL, 0.615 mmol) and (trimethylammonium)methyl(cyanoborohydride) (180 mg of 2 mmol / g, 0.3600 mmol) resin were added. The reaction mixture was heated to 110° C. in a microwave for 60 minutes. The reactants were filtered and the filtrate was concentrated. Purification by silica chromatography (gradient: 0-20% methanol in DCM) afforded (2′S,4R)-2′-methyl-1′-[(1-methylpyrazol-4-yl)methyl]-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-7′-ol 542 (23 mg, 48%). 1 H NMR (300MHz, chloroform-d) δ7.40(s,1H),7.30(s,1H),7.15(s,1H),4.76-4.58(m,1H),4.06-3.76(m,6H) ,3.62-3.48(m,1H),3.05-2.36(m,4H),2.09-1.69(m,3H),1.67-1.43(m,1H),1.23-1.14(m,3H). LCMS m / z402.04[M+H] + .

[1094] Preparation of S44 (2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] (S44)

[1095]

[1096] Step 1: Synthesis of tert-butyl (2′S,7R)-2-formyl-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate (C22)

[1097] To a solution of tert-butyl (2'S,7R)-2'-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate S21 (81.4 g, 251.7 mmol) in THF (740 mL) cooled to -78 ° C was added a solution of hexyllithium in hexane (120 mL of 2.6 M, 312.0 mmol) via an addition funnel under nitrogen over the course of 20 minutes. After stirring for 70 minutes after the addition of hexyllithium was complete, DMF (100 mL. 1.291 mol) was added over the course of 5 minutes. The solution was stirred at -78 ° C for 30 minutes, and then the reaction was warmed to 0 ° C and stirred for 45 minutes. The reaction was then quenched by the addition of saturated aqueous ammonium chloride (600 mL). The mixture was partitioned between EtOAc (1 L) and water (500 mL). The organic layer was separated and washed with saturated aqueous ammonium chloride, water, and brine (600 mL each). The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield tert-butyl (2'S,7R)-2-formyl-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate C22 (88 g, 99%) as a viscous amber oil, which was used without further purification. 1 H NMR (300 MHz, CHLOROFORM-d) δ 9.83 (s, 1H), 7.42 (s, 1H), 4.01 (ddd, J = 11.5, 6.7, 5.3 Hz, 1H), 3.94-3.82 (m, 2H), 3.75 (ddd, J = 14.0, 6.1, 4.7 Hz, 1H), 3.35 (ddd, J = 14.1, 8.8, 5.4 Hz, 1H), 2.71 (td, J = 5.5, 2.8 Hz, 2H), 2.28-2.06 (m, 2H), 1.90-1.65 (m, 2H), 1.47 (s, 9H), 1.26 (d, J = 6.6 Hz, 3H).

[1098] Step 2: Synthesis of tert-butyl (2′S,7R)-2-(2,2-difluorovinyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate (C23)

[1099] To a solution of dibromo(difluoro)methane (33 mL, 361.3 mmol) in THF (600 mL) was added N-[bis(dimethylamino)phosphino]-N-methyl-methylamine (140 mL, 770.3 mmol) via an addition funnel over 45 minutes in a dry ice-acetone cooling bath. The dry ice-acetone bath was then replaced with an ice-water bath and stirred for 45 minutes. A solution of (2'S,7R)-2-formyl-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylic acid tert-butyl ester C22 (88 g, 250.4 mmol) in THF (500 mL) was added over 30 minutes, at which point the ice-water bath was removed. After 2 hours, the reaction was cooled in an ice-water bath and then quenched by the addition of water (300 mL) over 5 minutes. 10% sodium bisulfite aqueous solution (300mL) is added. The mixture is stirred for 30 minutes, and the organic layer is then separated. The organic layer is washed with 1M HCl aqueous solution (1L). The organic layer is diluted with MTBE (500mL), washed with saturated sodium bicarbonate aqueous solution (1L), then washed with 50% saturated brine solution (1L), dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel chromatography (gradient: heptane containing 0-50% EtOAc, to obtain (2'S, 7R) -2- (2,2- difluorovinyl) -2'- methyl - spiro [4,5- dihydrothieno [2,3-c] pyran -7,4'- piperidine] -1'- tert-butyl carboxylate C23 (54g, 56%) as a viscous, clear light yellow oil. 1 HNMR (300 MHz, chloroform-d) δ 6.62 (s, 1H), 5.44 (dd, J = 25.8, 2.0 Hz, 1H), 4.00 (dp, J = 12.2, 6.4 Hz, 1H), 3.86 (t, J = 5.5 Hz, 2H), 3.74 (ddd, J = 13.9, 6.0, 4.7 Hz, 1H), 3.32 (ddd, J = 14.1, 8.9, 5.4 Hz, 1H), 2.71-2.51 (m, 2H), 2.26-2.03 (m, 2H), 1.91-1.65 (m, 2H), 1.48 (s, 9H), 1.25 (d, J = 6.5 Hz, 3H). 19F NMR (282 MHz, chloroform-d) δ -80.93 (d, J = 28.1 Hz), -87.47 (d, J = 27.9 Hz).

[1100] Step 3: Synthesis of tert-butyl (2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate (C24)

[1101] To Pd / carbon (8.2g of 5% w / w, 3.853mmol) in a 2L Parr bottle was added a solution of (2'S, 7R) -2- (2,2- difluorovinyl) -2'- methyl - spiro [4,5- dihydrothieno [2,3-c] pyran -7,4'- piperidine] -1'- carboxylic acid tert-butyl ester C23 (54g, 140.1mmol) in EtOH (700mL) under nitrogen. The Parr oscillator was charged with 50psi of H2. After 24 hours, the reaction mixture was filtered through a pad of celite, and the filtrate was treated with fresh catalyst Pd / carbon (10g of 5% w / w, 4.698mmol) under nitrogen. The Parr oscillator was charged with 50psi of H2, and the reaction was continued for another 16 hours. The reactant was then filtered through a pad of celite and washed with EtOH (200mL). The filtrate was concentrated to a yellow oil, which was purified by silica gel chromatography (Gradient: 0-50% EtOAc in heptane) to give tert-butyl (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate (45.5 g, 84%) as a clear, colorless, viscous oil. 1 H NMR (300 MHz, chloroform-d) δ 6.58 (s, 1H), 5.90 (tt, J = 56.5, 4.4 Hz, 1H), 3.99 (ddd, J = 11.5, 6.7, 5.3 Hz, 1H), 3.86 (t, J = 5.5 Hz, 2H), 3.79-3.66 (m, 1H), 3.40-3.16 (m, 3H), 2.72-2.51 (m, 2H), 2.24-2.03 (m, 2H), 1.90-1.65 (m, 2H), 1.48 (s, 9H), 1.25 (d, J = 6.5 Hz, 3H). 19F NMR (282 MHz, chloroform-d) δ -115.12.

[1102] Step 4: Synthesis of (2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] (S44)

[1103] To a solution of (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylic acid tert-butyl ester (32 g, 82.58 mmol) C23 in dichloromethane (300 mL) was added 2,6-lutidine (18 mL, 155.4 mmol) followed by trimethylsilyl trifluoromethanesulfonate (15.4 mL, 85.23 mmol) via an addition funnel at 0°C (ice-water bath) over the course of 12 minutes. After stirring for 50 minutes, the reaction was quenched with 1 M aqueous sodium hydroxide solution (150 mL) and stirred for 10 minutes. The layers were then separated. The organic layer was washed with 1 M aqueous sodium hydroxide solution (2 x 200 mL), dried over magnesium sulfate, filtered and concentrated to give (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] S44 (23.8 g, 100%) as a viscous light amber oil. 1 H NMR (300MHz, chloroform-d) δ6.60 (s, 1H), 5.90 (tt, J = 56.5, 4.5Hz, 1H), 3.91 (td, J = 5.6 ,2.9Hz,2H),3.26(td,J=16.7,4.5Hz,2H),3.17-2.99(m,2H),2.92(ddd,J=12.1 ,4.8,2.0Hz,1H),2.63(td,J=5.5,2.9Hz,2H),2.01(dt,J=13.9,2.2Hz,2H),1.7 0 (td, J = 13.3, 4.8 Hz, 1H), 1.39 ( dd, J = 13.6, 11.3 Hz, 2H), 1.06 ( d, J = 6.4 Hz, 3H). 19F NMR (282 MHz, chloroform-d) δ -115.07. LCMS m / z 288.1 [M+1] + .

[1104] Preparation of S45 (2′S)-2-(2,2-difluoroethyl)-2′-methyl-1′-prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] (S45)

[1105]

[1106] Preparation of (2′S)-2-(2,2-difluoroethyl)-2′-methyl-1′-prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](S45)

[1107] A mixture of (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]S44 (700 mg, 2.436 mmol) and potassium carbonate (440 mg, 3.184 mmol) in tetrahydrofuran (14 mL) was heated to 50 ° C and stirred. At this time, toluene containing propargyl bromide (353 μL, 3.961 mmol) was added and the mixture was stirred at 50 ° C overnight. The reactant was quenched with saturated sodium bicarbonate aqueous solution and DCM. The layers were separated by a phase separator. The organic matter was concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-10% MeOH-DCM) yielded (2'S)-2-(2,2-difluoroethyl)-2'-methyl-1'-prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (S45) (537 mg, 67%). 1H NMR (400MHz, methanol-d4) δ6.64(s,1H),5.96(tt,J=56.6,4.3Hz,1H),3.91(td,J=5.6,2.2Hz,2H),3.64(dd,J=17.4,2.4Hz,1H),3.41(dd,J=17.3,2.4Hz,1 H),3.25(ddd,J=17.2,4.3,0.9Hz,2H),3.04-2.82(m,2H),2.77-2.54(m,4H ), 2.13-1.83 (m, 3H), 1.61 (dd, J = 13.9, 11.6Hz, 1H), 1.07 (d, J = 6.4Hz, 3H). LCMS m / z 326.04[M+1] + .

[1108] Preparation of 543

[1109] 1-[4-[[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidinyl]-1′-yl]methyl]triazol-1-yl]propan-2-ol (543)

[1110]

[1111] Preparation of 1-[4-[[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidinyl]-1′-yl]methyl]triazol-1-yl]propan-2-ol (543)

[1112] To a solution containing 1-aminopropan-2-ol (20.8 mg, 150 μmol) dissolved in DMSO (0.3 mL) was added an aqueous solution of bicarbonate (sodium salt) (0.25 mL of a 1 M solution, 0.25 mmol). To this mixture was added 0.550 mL of a fluorosulfonyl azide solution (containing approximately 0.45 M MTBE, approximately 250 μmol, prepared according to the protocol in Nature, 574, 2019, 86-89), and the reactants were stirred at room temperature for 20 minutes. A solution of (2′S, 7R)-2-(2,2-difluoroethyl)-2′-methyl-1′-prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] S45 (30 mg, 0.092 mmol) dissolved in DMSO (1.0 mL) was added to the reactants. To this mixture was added CuSO4 aqueous solution (0.085 mL of a 0.1 M solution, 0.0085 mmol), a solution of 4-[bis[4-hydroxy-1-(1H-triazol-4-yl)butyl]amino]-4-(1H-triazol-4-yl)butan-1-ol in DMSO (0.085 mL of a 0.1 M solution, 0.0085 mmol), and an aqueous solution of sodium ascorbate (0.085 mL of a 0.2 M solution, 0.017 mmol). The resulting reaction mixture was heated at 50 ° C in the open air overnight. Additional portions of CuSO4 (0.1 mL of a 0.1 M aqueous solution, 0.01 mmol) and sodium ascorbate (0.1 mL of a 0.2 M aqueous solution, 0.02 mmol) were added, and the reactants were heated at 50 ° C overnight. The reactants were cooled to room temperature, diluted with 2 mL of water and 1 mL of DCM, and stirred for several minutes. The mixture was passed through parallel filter plates and washed with 1 mL of DCM. The organic layer was used and evaporated. The resulting residue was dissolved in 1 mL of DMSO and purified by reverse phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: H2O containing MeCN with 10 mM ammonium hydroxide to produce 1-[4-[[(2'S, 7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]methyl]triazol-1-yl]propan-2-ol (543). 1HNMR (300MHz, methanol-d4) δ7.94 (s, 1H), 6.62 (s, 1H), 5.95 (tt, J = 56.6, 4.3Hz, 1H), 4.52-3.67 (m, 7H), 3.2 4(dd,J=17.1,4.3Hz,2H),2.84-2.37(m,5H),2.12-1.78(m,3H),1.75-1.48(m,1H),1.34-0.95(m,6H). LCMS m / z 427.16[M+1] + .

[1113] Preparation of compounds 544-548

[1114] Compounds 544-548 (see Table 23) were prepared from intermediate S45 using azide transfer and click chemistry methods using appropriate reagents as described for compound 543. Amines were purchased from commercial sources.

[1115] Table 23: Preparation methods, structures and physicochemical data of compounds 544-548

[1116]

[1117]

[1118] Preparation of S46 3-[[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidinyl]-1′-yl]methyl]cyclobutanamine (S46)

[1119]

[1120] Step 1: Synthesis of tert-butyl N-[3-[[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidinyl]-1′-yl]methyl]cyclobutyl]carbamate (C25)

[1121] To a solution of tert-butyl N-(3-formylcyclobutyl)carbamate (177 mg, 0.8883 mmol) and (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]S44 (170 mg, 0.5916 mmol) in DCM (5 mL) was added triacetoxyborohydride (sodium salt) (376 mg, 1.774 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with NaHCO (saturated) and the mixture was extracted with DCM (3 x 5 mL). The combined organics were washed respectfully with H2O and brine and then dried over Na2SO4. The solvent was removed in vacuo to give tert-butyl N-[3-[[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]methyl]cyclobutyl]carbamate C25 (270 mg, 87%). LCMS m / z 471.68 [M+H] + .

[1122] Step 2: Synthesis of 3-[[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidinyl]-1′-yl]methyl]cyclobutanamine (S47)

[1123] Tert-butyl N-[3-[[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]methyl]cyclobutyl]carbamate C25 was treated with dioxane containing HCl (3 mL of 4 M, 12.00 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed to give 3-[[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]methyl]cyclobutylamine (189 mg, 83%). LCMS m / z 371.18 [M+H] + .

[1124] Compound 549

[1125] 1-Cyano-N-((1R,3s)-3-(((2S,4R)-2′-(2,2-difluoroethyl)-2-methyl-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)cyclobutyl)methanesulfonamide (549)

[1126]

[1127] Synthesis of 1-cyano-N-((1R,3s)-3-(((2S,4R)-2′-(2,2-difluoroethyl)-2-methyl-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)cyclobutyl)methanesulfonamide (549)

[1128] 3-[[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]methyl]cyclobutanamine S47 (20 mg) and cyanomethanesulfonyl chloride (7.2 mg, 0.052 mmol) were mixed in DCM (1 mL) and Et3N (22 uL) was added. The mixture was stirred at room temperature for 2 hours. The solvent was removed. The resulting residue was redissolved in MeOH and purified by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid to give 3-[[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]methyl]-N-oxo-cyclobutanamine (4.7 mg). LCMS m / z 474.02 [M+H] + .

[1129] Preparation of compounds 550-558

[1130] Compounds 550-558 (see Table 24) were prepared from intermediate S47 using appropriate acyl chloride or sulfonyl chloride reagents according to the procedure described for compound 549. Acid chlorides or sulfonyl chlorides were purchased from commercial sources.

[1131] Table 24: Preparation methods, structures and physicochemical data of compounds 550-558

[1132]

[1133]

[1134]

[1135] Compound 559

[1136] (2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-1′-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]

[1137]

[1138] Preparation of (2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-1′-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](559)

[1139] (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]S44 (295 mg, 0.8864 mmol) and 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (323 mg, 1.597 mmol) were dissolved in THF (4 mL). Triacetoxyborohydride (sodium salt) (470 mg, 2.218 mmol) was added to the solution and the reaction was heated to 60 ° C and stirred for 4 hours. The reaction was then cooled to room temperature, at which time the reaction was quenched with brine (20 mL) and extracted with EtOAc (20 mL). The organic matter was dried, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by reverse phase column chromatography (Isco 150 g gold C-18, gradient: 5-95% ACN / water 0.2% FA modifier) ​​to yield (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] 559 (142.9 mg, 31%). 1 H NMR (400 MHz, methanol-d4) δ8.42 (s, 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.71 (d, J = 0.7 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 5.97 (tt, J = 56.6, 4.2 Hz, 1H), 4.75-4.65 (m, 2H), 4.46 (d, J = 14.1 Hz, 1H), 4.2 3(d,J=14.1Hz,1H),3.89(dt,J=6.2,5.3Hz,2H),3.76-3.66(m,3H),2.85(d,J=0.7Hz,3H) ,2.63(td,J=5.4,1.5Hz,2H),2.36-2.13(m,3H),2.13-1.89(m,2H),1.50(d,J=6.5Hz,3H). LCMS m / z 474.38[M+H] + .

[1140] Compound 560

[1141] 2-[[4-[[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidinyl]′-1′-yl]methyl]pyrazol-1-yl]methyl]-2-methyl-propane-1,3-diol

[1142]

[1143] Preparation of 2-[[4-[[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]methyl]pyrazol-1-yl]methyl]-2-methyl-propane-1,3-diol (560)

[1144] (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]S44 (55 mg, 0.19 mmol) was placed in a microwave vial and 5-((1-cyano-2-methylpropan-2-yl)amino)pyrimidine-2-carbaldehyde (37 mg, 0.19 mmol), acetic acid (52 uL, 0.92 mmol), dichloromethane (1.6 mL) were added, and polymer-supported cyanoborohydride (295 mg, 0.59 mmol) was added. The solution was capped and heated to 95 ° C in a microwave reactor for 120 minutes. MeOH was added and the solution was stirred for ten minutes to wash the beads. The solution was filtered and the solvent was removed in vacuo. Purification was performed by reverse phase HPLC. C18 Waters Sunfire column (30×150 mm, 5 microns) was added. Gradient: MeCN in H2O with 10 mM ammonium hydroxide to produce the product 2-[[4-[[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]methyl]pyrazol-1-yl]methyl]-2-methyl-propane-1,3-diol. 1H NMR (300MHz, chloroform-d) δ8.23 (s, 2H), 6.60 (d, J = 9.5Hz, 2H), 5.92 (tt, J = 56.5, 4.4Hz, 1H),5.24(s,1H),4.05-3.59(m,6H),3.28(td,J=16.7,4.5Hz,2H),3.06(d,J=13. 6Hz,1H),2.64(hept,J=4.4Hz,4H),2.39(td,J=12.2,11.7,2.6Hz,1H),2.01(ddt ,J=14.2,5.3,2.8Hz,2H),1.91-1.68(m,2H),1.38(s,7H),1.21(d,J=6.1Hz,4H). LCMS m / z 467.18 [M+H] + .

[1145] Compound 561

[1146] 2-[[4-[[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]methyl]pyrazol-1-yl]methyl]-2-methyl-propane-1,3-diol

[1147]

[1148] Preparation of 2-[[4-[[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]methyl]pyrazol-1-yl]methyl]-2-methyl-propane-1,3-diol (561)

[1149] To a microwave elution containing (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]S44 (55 mg, 0.19 mmol) was added 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (82 mg, 0.19 mmol), acetic acid (52 uL, 0.92 mmol), dichloromethane (1.6 mL) and polymer-supported cyanoborohydride (295 mg, 0.59 mmol). The solution was capped and heated to 95 ° C in a microwave reactor for 120 minutes. MeOH was added and the solution was stirred for ten minutes to wash the beads. The reaction was stirred with dioxane containing HCl 4M (0.5 mL) for 10 minutes. The solution was filtered and the solvent removed in vacuo. Purification by reverse phase HPLC. Method: A C18 Waters Sunfire column (30 x 150 mm, 5 microns) (Basic Methods) yielded the product (2'S,7R)-2-(2,2-difluoroethyl)-1'-ethyl-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]. 1H NMR (300 MHz, chloroform-d) δ 7.46 (s, 1H), 7.37 (s, 1H), 6.61 (s, 1H), 5.92 (tt, J = 56.4, 4.5 Hz, 1H), 4.26 (s, 2H), 4.00-3.74 (m, 3H), 3.74-3.06 (m, 9H), 2.86-2.41 (m, 5H), 2.16-1.64 (m, 5H), 1.21 (d, J = 6.2 Hz, 3H), 0.84 (s, 3H). ESI-MS m / z 470.24.

[1150] Compounds 562-593

[1151] Compounds 562-593 were prepared by a reductive amination step, with a deprotection step in some cases using the method for intermediate S44, compounds 559-561, and the relevant aldehydes or ketones. Aldehydes or ketones were obtained from commercial sources or synthesized as described above. Any modifications to the methods are noted in Table 25 and the accompanying footnotes.

[1152] Table 25: Preparation methods, structures and physicochemical data of compounds 562-593.

[1153]

[1154]

[1155]

[1156]

[1157]

[1158]

[1159]

[1160]

[1161]

[1162] footnote:

[1163] 1. DCM was used as solvent instead of THF, and the reaction was carried out at room temperature for 2 hours.

[1164] 2. DCM was used as solvent instead of THF, and Et3N (1 equivalent) was used in addition to the standard reagents. The reaction was stirred at 50° C. for 30 minutes. Sodium triacetoxyborohydride was added after cooling to room temperature before addition and stirred overnight, and then the reaction was quenched. Separately, the compound was purified on silica gel (Redi-Sep cartridge, 4 g) using 0-10% DCM in MeOH (with 7N NH3) as eluent to give the product.

[1165] 3. DCM was used as solvent instead of THF, and DIPEA (1 equivalent) was used in addition to the standard reagents. The reaction was stirred at reflux for 30 minutes. Before adding sodium triacetoxyborohydride, it was cooled to room temperature and added to the reaction and stirred overnight, and then the reaction was quenched. Separately, the compound was purified on silica gel (Redi-Sep cartridge, 4 g) eluting with 0-10% DCM in MeOH (with 7N NH3) to give the product.

[1166] 4. HCl was not used for TBS deprotection.

[1167] Compound 594

[1168] 2-[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-1-phenyl-ethanol (594)

[1169]

[1170] Preparation of 2-[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-1-phenyl-ethanol (594)

[1171] To a solution of (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine](hydrochloride) (9.8 mg, 0.02875 mmol) in methanol (1 ml) was added Hunig's base (40 μL, 0.2296 mmol) and 2-phenyloxirane (10 μL, 0.08748 mmol) in a microwave vial. The reaction was carried out in a microwave at 100 ° C for 15 minutes. The solvent was evaporated. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 0.2% trifluoroacetic acid to afford 2-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-1-phenyl-ethanol 594 (6.5 mg, 55%). LCMS m / z 408.16 [M+1] + .

[1172] Compounds 595-609

[1173] Compounds 595-609 and intermediates S48 and S49 were prepared by an epoxide ring-opening procedure as described for the preparation of compound 594 from intermediate S44 and the related epoxide. The epoxide was obtained from a commercial source. Any modifications to the method are noted in Table 26 and the accompanying footnotes.

[1174] Table 26: Preparation methods, structures and physicochemical data of compounds 595-609 and intermediates S48 and S49

[1175]

[1176]

[1177]

[1178]

[1179]

[1180] footnote:

[1181] 1. IPA (1 mL) was used as solvent,

[1182] 2. After heating at 150°C for two hours, another 3 equivalents of epoxide were added.

[1183] 3. Heat the reaction in a microwave to 150°C for eight hours

[1184] 4. The product was re-purified by silica gel chromatography (gradient: 0-20% MeOH in DCM)

[1185] 5. Product submitted as formate

[1186] 6. Two diastereomers were separated during purification

[1187] 7. Heat the reaction in a microwave to 90°C for 1.5 hours

[1188] 8. After complete reaction, the solvent was removed in vacuo, rinsed with MeOH and DCM, and the crude reaction was scaled up to the next reaction.

[1189] Compound 610

[1190] (2R)-3-[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-propionamide (610)

[1191]

[1192] Preparation of (2R)-3-[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-propionamide (610)

[1193] (2R)-3-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2-hydroxy-propionic acid methyl ester S48 (96 mg, 0.2465 mmol) was added to a microwave flask. A solution of NH3 (1.5 mL of 7M, 10.50 mmol) in MeOH (100 μL) was added and the reaction was stirred at 50 °C overnight. The solvent was removed in vacuo. Purification by silica gel chromatography (gradient: 0-10% MeOH in DCM) provided the desired product 610. 1HNMR (300MHz, chloroform-d) δ6.94 (d, J = 4.2Hz, 1H), 6.58 (s, 1H), 6.13-5.61 (m, 2H), 3.9 3-3.76(m,2H),3.24(td,J=16.8,4.4Hz,2H),2.91(dd,J=12.9,9.9Hz,1H),2.80 (ddq,J=11.5,7.0,2.5Hz,2H),2.62(tdd,J=13.1,10.3,3.7Hz,4H),1.99-1.86( m, 2H), 1.86-1.69 (m, 1H), 1.56 (dd, J = 14.0, 11.4Hz, 1H), 1.03 (d, J = 6.2Hz, 3H). LCMS m / z 375.14[M+1] + .

[1194] Compound 611

[1195] (2S)-3-[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidinyl]-1′-yl]-2-hydroxy-propionamide (611)

[1196]

[1197] Preparation of (2S)-3-[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-propionamide (611)

[1198] (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]S44 (108 mg, 0.3758 mmol) and (2S)-oxirane-2-carboxylic acid methyl ester (700 μL, 7.995 mmol) were added to a microwave vial and placed in MeOH containing NH3 (4 mL of 7M, 28.00 mmol). DIPEA (980 μL, 5.626 mmol) was added and the reaction was stirred at 120 ° C for 6 hours. The solvent was removed in vacuo and the product was rinsed with MeOH and DCM (2x). Purified by reverse phase HPLC. Method: Purification on a C18 Waters Sunfire column (30×150 mm, 5 microns) followed by silica gel chromatography (gradient: 0-20% MeOH in dichloromethane) gave the product (2S)-3-[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-propionamide 611 (17.8 mg, 12%). 1 H NMR (300MHz, chloroform-d) δ7.29(s,1H),6.61(s,1H),6.11-5.66(m,2H),4.38(s,1H),3.87(hept,J=5.9Hz,2H),3.61(s,1H), 3.26(td,J=16.7,4.4Hz,4H), 3.11(s,1H), 2.77(dd,J=13.5,8.2Hz,1H), 2.63(q,J=5.2Hz,2H), 1.29(d,J=6.4Hz,3H). LCMSm / z375.14[M+1] + .

[1199] Compound 612

[1200] (2S)-3-[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidinyl]-1′-yl]-2-hydroxy-N-methyl-propionamide (612)

[1201]

[1202] Preparation of (2S)-3-[(2′S,7R)-2-(2,2-difluoroethyl)-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-N-methyl-propionamide (612)

[1203] (S)-methyl 3-((2S,4R)-2′-(2,2-difluoroethyl)-2-methyl-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran]-1-yl)-2-hydroxypropanoate 49 (95 mg, 0.2439 mmol) was placed in dioxane (1.9 mL) and added to a microwave flask. Methylamine (250 μL of 40% w / v, 3.220 mmol) and water (45 μL, 2.498 mmol) were added, and the reaction was heated to 80° C. and stirred overnight. The solvent was removed in vacuo. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid to yield (2S)-3-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2-hydroxy-N-methyl-propionamide (trifluoroacetic acid (2)) 612 (60.1 mg, 39%). 1 H NMR (300 MHz, chloroform-d) δ7.41 (d, J = 5.8 Hz, 1H), 6.64 (d, J = 4.2 Hz, 1H), 5.91 (tt, J = 56.3, 4.4 Hz, 1H), 4.81-4.46 (m, 1H), 4.02 (s, 0H), 3.89 (dp, J = 10.6, 5.9 Hz, 2H), 3.68 (d, J = 12.1 Hz,1H),3.53(s,1H),3.27(td,J=16.7,4.4Hz,3H),3.13-2.92(m,1H),2.86(d,J=4.9H z,2H),2.71-2.60(m,2H),2.46-2.26(m,1H),2.26-2.07(m,2H),1.48(d,J=6.4Hz,2H). LCMS m / z 389.28[M+1] + .

[1204] Compound 613

[1205] 1-((2S,4R)-2′-(2,2-difluoroethyl)-2-methyl-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran]-1-yl)propan-2-ol (613)

[1206]

[1207] Preparation of 1-((2S,4R)-2′-(2,2-difluoroethyl)-2-methyl-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran]-1-yl)propan-2-ol (613)

[1208] To a solution of 1-bromopropan-2-ol (16.51 mg, 0.1188 mmol) and (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine](hydrochloride) (27 mg, 0.07921 mmol) in DMF (2 mL) was added K2CO3 (32.84 mg, 0.2376 mmol). The reaction was stirred at 110°C for 72 hours, then cooled to room temperature and filtered. The crude reaction mixture was 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 give 1-((2S,4R)-2′-(2,2-difluoroethyl)-2-methyl-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran]-1-yl)propan-2-ol (613) (8.8 mg, 31.5%). 1H NMR (300 MHz, acetonitrile-d3) δ 6.68 (d, J = 1.1 Hz, 1H), 6.04 (tt, J = 56.5, 4.2 Hz, 1H), 3.89 (tt, J = 5.7, 1.8 Hz, 2H), 3.84-3.63 (m, 1H), 3.33 (tdt, J = 17.7, 4.2, 0.8 Hz, 3H), 2.91-2.36 (m, 6H), 2.14-2.03 (m, 1H), 2.03-1.98 (m, 1H), 1.93-1.77 (m, 2H), 1.56 (ddd, J = 20.6, 13.7, 11.3 Hz, 1H), 1.13-0.97 (m, 6H). LCMS m / z 345.44 [M+H] + .

[1209] Compounds 614-624

[1210] Compounds 614-624 (Table 27) were prepared from intermediate S44 and the appropriate amine reagent using the method for compound 613. Alkyl halides were obtained from commercial sources. Any modifications to the methods are noted in Table 27 and the accompanying footnotes.

[1211] Table 27: Structural and physicochemical data of compounds 614-624

[1212]

[1213]

[1214]

[1215] footnote:

[1216] 1 The reaction was stirred at 90 °C for 18 hours.

[1217] Compound 625

[1218] (2′S,7R)-2-Chloro-2′-methyl-1′-prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]

[1219]

[1220] Preparation of (2′S,7R)-2-chloro-2′-methyl-1′-prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](625)

[1221] A mixture of (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine](trifluoroacetate) S50 (500 mg, 1.345 mmol) and propargyl bromide (267 mg, 1.796 mmol) and potassium carbonate (250 mg, 1.809 mmol) in acetonitrile (10 mL) was heated to 70 ° C for 2 minutes. The mixture was cooled to room temperature, filtered and concentrated. The crude material was diluted in dichloromethane (10 mL) and 2M NaOH. The layers were mixed, passed through a phase separator and concentrated. Purification by silica gel chromatography (1-10% MeOH in dichloromethane) afforded (2'S,7R)-2-chloro-2'-methyl-1'-prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] 625 (228 mg, 57%). 1H NMR (400 MHz, chloroform-d) δ 6.54 (s, 1H), 3.96-3.82 (m, 2H), 3.61 (dd, J = 17.4, 2.4 Hz, 1H), 3.38 (dd, J = 17.4, 2.4 Hz, 1H), 2.87 (ddd, J = 12.8, 11.5, 2.7 Hz, 1H), 2.78 (dqd, J = 12.5, 6.3, 2.6 Hz, 1H), 2.63 (ddd, J = 11 .4,4.7,2.4Hz,1H),2.60-2.49(m,2H),2.22(t,J=2.4Hz,1H),2.10-2.01(m,1H),1.98(dt,J=13.8,2 .8Hz, 1H), 1.84 (ddd, J=13.9, 12.8, 4.6Hz, 1H), 1.55 (dd, J=13.8, 11.5Hz, 1H), 1.05 (d, J=6.3Hz, 3H). LCMS m / z 296.36[M+H] + .

[1222] Compound 626

[1223] 1-(4-(((2R,4S)-2′-chloro-2-methyl-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-3-methylbutane-2,3-diol

[1224]

[1225] Preparation of 1-(4-(((2R,4S)-2′-chloro-2-methyl-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-3-methylbutane-2,3-diol (626)

[1226] To a mixture of 1-amino-3-methyl-butane-2,3-diol (40 mg, 0.3357 mmol) in MeOH (3 mL) was added CuSO4 (0.25 mg, 0.001566 mmol) in water (0.125 mL), followed by sodium bicarbonate (45 mg) in water (0.375 mL) and trifluoromethanesulfonic acid azide (1.25 mL of 0.452 M, 0.5650 mmol) in dichloromethane and the solution was stirred for 1 hour. To the reaction were added (2′S,7R)-2-chloro-2′-methyl-1′-prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] 625 (50 mg, 0.1671 mmol) in methanol (0.5 mL), sodium ascorbate (35 mg, 0.1987 mmol) in water (0.25 mL), and 1-(1-benzyltriazol-4-yl)-N,N-bis[(1-benzyltriazol-4-yl)methyl]methanamine (2 mg, 0.003769 mmol) in methanol (0.2 mL), and the mixture was heated to 60° C. and stirred for 17 hours. The reaction was concentrated and 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 give 1-(4-(((2R,4S)-2′-chloro-2-methyl-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-3-methylbutane-2,3-diol (626) (51 mg, 69%). 1 H NMR (400MHz, chloroform-d) δ7.80 (s, 1H), 6.59 (s, 1H), 4.73-4.60 (m, 1H), 4.34 (td, J = 13.8, 13.3, 9.4Hz, 1H), 3.95-3.78 (m, 4H), 2.75(d,J=78.1Hz,4H),2.65-2.54(m,2H),2.22(d,J=10.7Hz,1H),2.04(d,J=7.0Hz,3H),1.79(s,2H),1.47-1.27(m,9H). LCMS m / z 441.11[M+H] + .

[1227] Compounds 627-629

[1228] Compounds 627-629 (Table 28) were prepared from intermediate S50 and the appropriate amine reagent using the method for compound 626. Amines were obtained from commercial sources. Any modifications to the methods are noted in Table 28 and the accompanying footnotes.

[1229] Table 28: Structural and physicochemical data of compounds 627-629

[1230]

[1231] Compound 630#MZ48

[1232] (2R,4S)-2′-Chloro-2-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran]

[1233]

[1234] Step 1: Synthesis of (2R,4S)-2′-chloro-2-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran](630)

[1235] 1-Methylpyrazole-4-carbaldehyde (12 mg, 0.109 mmol) and acetic acid (15 L, 0.266 mmol) were added to a solution of (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]S50 (14 mg, 0.0290 mmol) in DMF (2 mL). NaBH3CN (81 mg, 0.162 mmol) was added and the reaction mixture was stirred at 110 ° C for 30 minutes. Purification by preparative HPLC (mobile phase A: 0.1% TFA (aqueous), mobile phase B: acetonitrile) gave (2R,4S)-2′-chloro-2-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] 630 (13 mg, 67%). 1 H NMR (300MHz, chloroform-d) δ11.80(s,1H),7.67(s,1H),7.52(s,1H),6.58(s,1H),4.51(d,J=14.2Hz,1H),3.95(s,4H),3.89-3.75(m,2H ), 3.31 (d, J = 13.0Hz, 2H), 3.02 (d, J = 9.6Hz, 1H), 2.63-2.48 (m, 2H), 2.39-2.23 (m, 2H), 2.23-2.06 (m, 2H), 1.56 (d, J = 6.5Hz, 3H). LCMS m / z352.12[M+H] + .

[1236] Compounds 631-693

[1237] Compounds 631-693 (Table 29) were prepared from intermediate S50 and the appropriate aldehyde reagent using the method of compound 630. Aldehydes were prepared by the methods described above or obtained from commercial sources. Any modifications to the methods are noted in Table 29 and the accompanying footnotes.

[1238] Table 29: Structural and physicochemical data of compounds 631-693

[1239]

[1240]

[1241]

[1242]

[1243]

[1244]

[1245]

[1246]

[1247]

[1248]

[1249]

[1250]

[1251]

[1252]

[1253]

[1254]

[1255]

[1256]

[1257] footnote

[1258] 1. Step 2: Deprotection of TBS group using methanol containing HCl

[1259] 2. Second step: SnAr was treated with cyclopropylamine (2.5 eq.), potassium carbonate (4 eq.) in DMF (0.5 mL) at 90°C overnight. The reaction was diluted in DCM and water, and the aqueous layer was collected through a phase separator. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O with 5 mM HCl, followed by purification by reverse phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O with 10 mM ammonium hydroxide to produce the product.

[1260] Preparation of S50

[1261] (2′S,7R)-2-Chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](S50)

[1262]

[1263] Step 1(i): Synthesis of (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

[1264] To a mixture of (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (25 g, 117.2 mmol) in DCM (500 mL) was added MsOH (24 mL, 369.8 mmol), and the mixture was stirred at room temperature for 40 minutes. The mixture was vacuum-purged with nitrogen five times to remove dissolved isobutylene.

[1265] Step 1(ii): Synthesis of (2′S,7R)-2′-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]

[1266] 2-(3-Thienyl)ethanol (16.5 g, 128.7 mmol) was then added to the mixture, and the reaction was stirred overnight. The mixture was concentrated to approximately 50 mL and rediluted with water (300 mL) and diethyl ether (600 mL). The organic layer was removed. The aqueous layer was adjusted to pH 14 with aqueous NaOH (64 mL of 6 M, 384.0 mmol), and then DCM (600 mL) was added to extract the free base. The organic layer was washed with pH 14 water (2×200 mL), pH 14 brine (200 mL), dried over MgSO , filtered and concentrated to produce (2′S,7R)-2′-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] (24900 mg, 95%). LCMS m / z 224.54 [M+H] + .

[1267] Step 1(iii): Synthesis of tert-butyl (2′S,7R)-2′-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate (C26)

[1268] To the mixture of the products from the first two steps in DCM (500 mL) was added DIPEA (20 mL, 114.8 mmol) followed by Boc2O (27 mL, 117.5 mmol). The reactants were stirred for 45 minutes. Imidazole (1 g, 14.69 mmol) was added to quench the excess Boc2O. 2N HCl (100 mL) was then added and the mixture was stirred for 20 minutes. The layers were separated and the organic layer was washed with 1N HCl (100 mL). The organic layer was passed through a phase separator and concentrated to produce tert-butyl (2'S, 7R)-2'-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate (37300 mg, 91%) as a yellow oil. LCMS m / z 323.11 [M+H] + .

[1269] Step 2: Synthesis of tert-butyl (2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate (C27)

[1270] Tert-butyl (2′S,7R)-2′-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate C26 (16 g, 49.47 mmol) was dissolved in acetonitrile (150 mL) and NCS (13.2 g, 98.85 mmol) was added. The reaction was heated at 65°C and stirred overnight. The reaction was diluted with 1N NaOH / EtOAc, washed with sodium thiosulfate solution and brine, dried over Na2SO4, and concentrated to an oil. Purification by silica gel chromatography (gradient: 0-30% EtOAc in heptane) produced the product. Tert-butyl (2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate (15.4 g, 83%). LCMS m / z 358.14[M+H] + .

[1271] Step 3: Synthesis of (2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](hydrochloride) (C28)

[1272] A mixture of (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylic acid tert-butyl ester (9500 mg, 26.37 mmol) in dioxane containing HCl (25 mL of 4M, 100.0 mmol) was stirred overnight at room temperature. After stirring overnight, the mixture condensed into a solid mass. Diethyl ether (200 mL in total) was added to the mixture, the mixture was filtered and rinsed with additional ether and dried to produce (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine](hydrochloride) (C28) (7.4757 g, 94%). 1 H NMR (400MHz, DMSO-d6) δ9.25-8.93(m,2H),6.92(s,1H),3.96-3.81(m,2H),3.38-3.26(m,1H),3.23-3.12(m,1H),3.04(q,J=12.2Hz,1H) ,2.58(t,J=5.5Hz,2H),2.13(t,J=15.0Hz,2H),2.01(td,J=14.1,13.7,4.6Hz,1H),1.84(dd,J=14.3,12.1Hz,1H),1.25(d,J=6.5Hz,3H). LCMS m / z 258.09[M+H] + .

[1273] Step 4: Synthesis of (2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] (S50)

[1274] (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (2.70 g) was dissolved in water, and saturated sodium bicarbonate was added to the mixture, followed by adjustment to pH>10 with NaOH. At this point, the product oiled out and dissolved in DCM (10 mL), and the aqueous layer was extracted with additional DCM (10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to yield (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] S50 (2280 mg, 93%). 1H NMR (400 MHz, chloroform-d) δ 6.57 (s, 1H), 3.98-3.81 (m, 2H), 3.18-3.00 (m, 2H), 2.94 (ddd, J = 12.2, 4.8, 2.1 Hz, 1H), 2.67-2.51 (m, 2H), 2.07-1.94 (m, 2H), 1.66 (d, J = 4.8 Hz, 1H), 1.38 (dd, J = 13.7, 11.4 Hz, 1H), 1.09 (d, J = 6.4 Hz, 3H). LCMS m / z 258.09 [M+H] + .

[1275] Preparation of S51 Preparation of (2′S,7S)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](S51)

[1276]

[1277] Step 1(i): Synthesis of (2′S)-2′-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]

[1278] A solution of 2-(3-thienyl)ethanol (1.275 g, 9.946 mmol) and (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.217 g, 10.40 mmol) in DCM (18 mL) was cooled to -78 ° C. Trifluoromethanesulfonic acid (1.5 mL, 16.95 mmol) was added to the reactants and stirred at -78 ° C for 1.5 hours. The reactants were quenched into a two-phase mixture of saturated NaHCO (75 mL) and DCM (50 mL), and the pH of the aqueous layer was adjusted to >10 using 2N NaOH. The aqueous layer was then extracted with DCM (3 × 75 mL), filtered through an SPE cartridge, and concentrated to produce a crude product (2′S)-2′-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine].

[1279] Step 1(ii): Synthesis of tert-butyl (2′S,7S)-2′-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate (C29)

[1280] The crude product from the previous step is dissolved in DCM (20mL), and triethylamine (3.1mL, 22.24mmol) is added, followed by tert-butyl carbonate (3.1mL, 13.49mmol). The reactant is stirred at room temperature for 18 hours. The solution is diluted with DCM and washed with water (50mL). The aqueous layer is extracted with DCM (2 × 50mL), dried over Na2SO4, filtered through an SPE filter, and concentrated under vacuum. Purified by silica gel chromatography (heptane containing 0 to 30% EtOAc), produce (2'S, 7S)-2'-methylspiro [4,5-dihydrothieno [2,3-c] pyrans -7,4'-piperidine] -1'- tert-butyl formate C29 (2.95g, 92%). 1 H NMR (300MHz, methanol-d4) δ7.21(d,J=5.1Hz,1H),6.77(d,J=5.1Hz,1H),4.37(p,J=7.0Hz,1H),4.03-3.84(m,3 H),3.39-3.21(m,1H),2.68(td,J=5.5,2.6Hz,2H),2.16-1.65(m,4H),1.48(s,9H),1.34(d,J=7.2Hz,3H).

[1281] Step 2: Synthesis of tert-butyl (2′S,7S)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate (C30)

[1282] To a solution of (2′S, 7S)-2′-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylic acid tert-butyl ester C29 (239 mg, 0.7389 mmol) in MeCN (3 mL) was added NCS (138 mg, 1.033 mmol) at room temperature, followed by DMAP (5 mg, 0.04093 mmol). The reactants were heated to 55° C. for 24 hours. The reactants were cooled to rt and stirred overnight, and then quenched with 15% aqueous sodium bisulfite solution (10 mL). Stirred for 15 minutes, the mixture was then distributed between brine (20 mL) and DCM (20 mL). The aqueous layer was separated and extracted with DCM (2×20 mL), and the combined organic layers were dried over Na2SO4, filtered through a phase separator, and concentrated. Purification by silica gel chromatography (0 to 30% EtOAc in heptane) gave a crude mixture with some starting material remaining.

[1283] By dissolving the crude material in MeCN (2.5 mL) and adding N-chlorosuccinimide (50 mg, 0.3744 mmol) and DMAP (5 mg, 0.04093 mmol), the crude material was subjected to reaction conditions again. The reactant was heated to 60 ° C for 6 hours, then cooled to room temperature and quenched with 15% aqueous sodium bisulfite solution (10 mL). Stirred for 15 minutes, then distributed between salt solution and DCM (each 20 mL). The aqueous layer was separated and extracted with DCM (2 × 20 mL), and the combined organic layer was dried over Na SO , filtered through a phase separator and concentrated. Purification by silica gel chromatography (0 to 30% EtOAc in heptane) gave (2'S,7S)-tert-butyl 2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate C30 (170 mg, 63%). 1 H NMR (300 MHz, methanol-d4) δ 6.66 (s, 1H), 4.35 (q, J = 6.9 Hz, 1H), 4.03-3.85 (m, 3H), 3.27 (s, 1H), 2.69-2.50 (m, 2H), 2.14-1.94 (m, 2H), 1.80 (dd, J = 14.5, 6.6 Hz, 1H), 1.68 (ddd, J = 13.7, 12.9, 4.7 Hz, 1H), 1.47 (s, 9H), 1.32 (d, J = 7.1 Hz, 3H).

[1284] Step 3: Synthesis of (2′S,7S)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] (S51)

[1285] To a stirred solution of (2'S,7S)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylic acid tert-butyl ester C30 (170 mg, 0.4750 mmol) in dioxane (2 mL) was added HCl (600 μL of 4 M, 2.400 mmol) in dioxane and the reaction was stirred at room temperature for 20 hours. The reaction was concentrated. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in HO with 5 mM HCl and lyophilization to give the product (2'S,7S)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] S51 (hydrochloride salt) (108.2 mg, 75%). 1H NMR (300MHz, methanol-d4) δ6.77(s,1H),3.98(t,J=5.8Hz,2H),3.72(h,J=6.3Hz,1H),3.53(ddd,J=13.8 ,9.7,4.0Hz,1H),3.29-3.16(m,1H),2.70-2.60(m,2H),2.25-2.05(m,4H),1.52(d,J=7.0Hz,3H). LCMS m / z 258.0[M+H] + .

[1286] Preparation of C31

[1287] 1-Methylprop-2-ynyl 4-methylbenzenesulfonate (C31)

[1288]

[1289] Synthesis of 1-methylprop-2-ynyl-4-methylbenzenesulfonate (C31)

[1290] To the stirred solution of but-3-yn-2-ol (1.5g, 0.0214mol) in DCM (15mL) was added DMAP (1g, 0.0082mol), TEA (726.00mg, 1mL, 0.0072mol) and 4-methylbenzenesulfonyl chloride (0.45g, 0.0024mol) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and at room temperature for 1 hour. Then, the reaction mixture was filtered. The filtrate was washed with saturated CuSO4 solution (200mL), saturated NaHCO3 solution (200mL) and brine (200mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purified by silica gel chromatography (gradient: petroleum ether containing 10-30% EtOAc), 4-methylbenzenesulfonic acid 1-methyl prop-2-ynyl ester C31 (1.2g, 25%) was obtained. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.83-7.80 (m, 2H), 7.34-7.26 (m, 2H), 5.19-5.13 (m, 1H), 2.44-2.41 (m, 4H), 1.58-1.56 (m, 3H).

[1291] Compound 694

[1292] (2′S,7R)-2-chloro-2′-methyl-1′-(1-methylprop-2-ynyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](694)

[1293]

[1294] Preparation of (2′S,7R)-2-chloro-2′-methyl-1′-(1-methylprop-2-ynyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](694)

[1295] To a stirred solution of (2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](trifluoroacetic acid (1))(S50) (500 mg, 0.0012 mol) in MeCN (10 mL) was added KCO (415 mg, 0.0030 mol) and 1-methylprop-2-ynyl-4-methylbenzenesulfonate (C31) (403 mg, 0.0018 mol) at room temperature. The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The reaction mixture was cooled to room temperature, quenched with water (50 ml), and extracted with EtOAc (2×100 mL). The combined organic layers were dried over 2SO 4 , filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-30% EtOAc in hexanes) followed by reverse phase chromatography (column: -xselect Phenyl hexyle (250*19) mm, 5u,. Gradient: 0-20% MeCN in water with 0.1% formic acid) gave (2′S,7R)-2-chloro-2′-methyl-1′-(1-methylprop-2-ynyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] 694 (28 mg, 8%). 1 H NMR(400MHz,DMSO-d6)δppm 6.84(s,1H),3.99-3.96(m,1H),3.86-3.82(m,2H),3.11-3.11(m,1H),2.93-2.90(m,1H),2.69-2.67(m,1H),2.58- 2.49(m,2H),2.01-1.90(m,2H),1.64-1.62(m,1H),1.44-1.38(m,1H),1.11(d,J=6.8Hz,3H),0.98(d,J=6.4Hz,3H). LCMS m / z 310.0[M+H] + .

[1296] Compound 695

[1297] (2′S,7S)-2-Chloro-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](695)

[1298]

[1299] Preparation of (2′S,7S)-2-chloro-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](695)

[1300] (2'S,7S)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (35 mg, 0.1358 mmol) (S51) was dissolved in DCE (1 mL) and DIEA (50 μL, 0.2871 mmol) and 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (34 mg, 0.1520 mmol) were added. The reaction mixture was heated at 60 ° C in a sealed tube overnight. Additional 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (10 mg, 0.04471 mmol) was added and the reaction was heated at 60 ° C overnight. The reaction mixture was concentrated. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid to afford (2'S,7S)-2-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine](695) (trifluoroacetic acid salt) (32 mg, 41%). 1 H NMR (300 MHz, chloroform-d) δ 8.26 (s, 1H), 6.60 (s, 1H), 4.94 (t, J = 6.8 Hz, 2H), 4.41 (d, J = 19.1 Hz, 2H), 3.93 (t, J = 5.1 Hz, 2H), 3.81-3.65 (m, 3H), 3.56-3.37 (m, 2H), 2.95 (s, 3H), 2.69-2.58 (m, 2H), 2.38-2.09 (m, 4H), 1.70 (d, J = 7.1 Hz, 3H). LCMS m / z 445.31 [M+H] + .

[1301] Compound 696

[1302] (2′S,7R)-2-chloro-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](696)

[1303]

[1304] Synthesis of 2′S)-2-chloro-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](696)

[1305] (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (48 mg, 0.1862 mmol) was dissolved in DCE (1 mL) and 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (45 mg, 0.2012 mmol) and DIEA (65 μL, 0.3732 mmol) were added. The reaction mixture was heated to 60°C in a sealed tube overnight. Additional 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (15 mg, 0.06706 mmol) was added and heating was continued for 24 hours. The reaction mixture was concentrated. Purification was performed 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 afford (2'S)-2-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (trifluoroacetate) (696) (46 mg, 43%). 1 H NMR (300MHz, chloroform-d) δ8.28(s,1H),6.61(s,1H),4.97(td,J=6.6,4.0Hz,2H),4.78(d,J=14.0Hz,1H),4.26(d,J=14.0Hz,1H),3.9 7-3.65(m,4H),3.65-3.55(m,1H),3.40-3.18(m,2H),2.95(s,3H),2.69-2.56(m,2H),2.28-2.09(m,4H),1.62(d,J=6.5Hz,3H). LCMS m / z 445.21[M+H] + .

[1306] Compound 697

[1307] (2′S,7R)-2-Chloro-2′-methyl-1′-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](697)

[1308]

[1309] Preparation of (2′S,7R)-2-chloro-2′-methyl-1′-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](697)

[1310] i. To a solution of (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylic acid tert-butyl ester (65 mg, 0.1780 mmol) in DCM (1 mL) was added TFA (200 μL, 2.596 mmol) and the mixture was refluxed for 5 minutes. At this time, UPLC showed complete conversion, and the mixture was concentrated to dryness, diluted in DCM and concentrated again.

[1311] ii. The oil from the first step was diluted with acetonitrile (1.5 mL) and KCO (75 mg, 0.5427 mmol) was added, followed by 4-(chloromethyl)-1-(2-methylsulfonylethyl)pyrazole (hydrochloride) (90 mg, 0.3473 mmol). The mixture was stirred at 70°C. The mixture was stirred overnight. The mixture was cooled to room temperature and diluted with water (10 mL) and EtOAc (15 mL). The phases were separated and the organic layer was washed with water (2 x 10 mL) and brine (10 mL), and the organic layer was dried over MgSO, filtered and concentrated. Purification was by silica gel chromatography (0-20% MeOH in DCM). (2'S,7R)-2-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (697) was obtained (41.6 mg, 51%). 1 H NMR (400MHz, chloroform-d) δ7.51 (d, J = 0.7Hz, 1H), 7.47 (s, 1H), 6.57 (s, 1H), 4.64-4.56 (m, 2H), 3.89-3.75 (m, 3H), 3.71-3.59 (m, 3H), 2. 69-2.43(m,8H),2.00(tt,J=14.2,2.9Hz,2H),1.82(td,J=13.3,4.6Hz,1H),1.62(dd,J=13.8,11.4Hz,1H),1.20(d,J=6.2Hz,3H). LCMS m / z 444.04[M+H] + .

[1312] Compound 698

[1313] (2′S,7R)-2-chloro-2′-methyl-1′-(1H-pyrazol-4-ylmethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](698)

[1314]

[1315] Preparation of (2′S,7R)-2-chloro-2′-methyl-1′-(1H-pyrazol-4-ylmethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine](698)

[1316] A mixture of 1H-pyrazole-4-carbaldehyde (150 mg, 1.561 mmol), (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]S50 (trifluoromethanesulfonate) (350 mg, 0.8603 mmol), cyanoborohydride (sodium salt) (1000 mg of 2 mmol / g, 2.000 mmol) in DCM (10 mL) was stirred at 110 ° C. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-20% MeOH in DCM) gave the product. (2'S,7R)-2-Chloro-2'-methyl-1'-(1H-pyrazol-4-ylmethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (72 mg, 25%). 1 H NMR (400 MHz, chloroform-d) δ 7.56 (s, 2H), 6.50 (s, 1H), 4.05 (s, 1H), 3.88-3.71 (m, 3H), 3.70-3.57 (m, 1H), 2.82 (s, 2H), 2.66-2.47 (m, 4H), 2.01-1.91 (m, 3H), 1.28 (d, J = 6.3 Hz, 3H). LCMS m / z 337.88 [M+H] + .

[1317] Compound 699

[1318] (2S,7R)-2′-chloro-1-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)methyl)-2-methyl-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran](699)

[1319]

[1320] Preparation of (2S,7R)-2′-chloro-1-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)methyl)-2-methyl-4′,5′-dihydrospiro[piperidin-4,7′-thieno[2,3-c]pyran](699)

[1321] To a mixture of (2'S,7R)-2-chloro-2'-methyl-1'-(1H-pyrazol-4-ylmethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] 698 (20 mg) in DMF (1 mL) was added NaH (3 mg, 60% w / w) followed by 1-bromo-2-methoxy-ethane (16 mL). The reaction was stirred at room temperature for 80 minutes and then heated to 60°C and stirred for 5 hours. Purification was by reverse phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO with 5 mM HCl to give the product (HCl salt) EA#6 (18.8 mg, 73.3%). 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),7.95(s,1H),7.65(s,1H),6.91(s,1H),4.35 (d,J=14.3Hz,1H),4.28(t,J=5.3Hz,2H),4.18(dd,J=14.0,5.3Hz,1H),3.82(hept ,J=6.0Hz,2H),3.68(t,J=5.2Hz,2H),3.21(s,5H),3.16(d,J=14.3Hz,1H),2.98(d ,J=15.3Hz,1H),2.56(s,1H),2.18(q,J=14.1,13.1Hz,4H),1.45(d,J=6.3Hz,3H). LCMS m / z 396.14[M+H] + .

[1322] Compounds 700-707

[1323] Compounds 700-707 (see Table 30) were prepared in a single step by alkylation of 698 and the related alkyl halides, as described for compound 699. Alkyl halides were obtained from commercial sources. Any modifications to the methods are noted in Table 30 and the accompanying footnotes.

[1324] Table 30: Preparation methods, structures and physiochemical data of compounds 700-707

[1325]

[1326]

[1327]

[1328] footnote:

[1329] 1. Stir the reaction at room temperature for 10 minutes.

[1330] 2. Purify with formic acid modifier. The product is isolated as formate compound 708

[1331] (2S)-3-[(2′S,7R)-2-Chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-propionamide

[1332]

[1333] Preparation of (2S)-3-[(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-propionamide (708)

[1334] (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]S50 (99.1 mg, 0.3844 mmol) and (2S)-oxirane-2-carboxylic acid methyl ester (100 μL, 1.142 mmol) were added to a microwave vial, and NH (3.5 mL of 7M, 24.50 mmol) and MeOH (99 μL) were added. DIPEA (340 μL, 1.952 mmol) was added, and the reaction was stirred at 120 °C for 4 hours. An additional 70 μL of ethylene oxide and 800 μL of NH / MeOH were added, and the reaction was heated at 120 °C for 2 hours. An additional 50 μL of ethylene oxide and 500 μL of NH / MeOH were added, and the reaction was heated at 120 °C for another 2 hours. The reaction mixture was concentrated by rotary evaporation, then diluted in water / DCM, and the organics were extracted (3x DCM, 3x EtOAc) and concentrated by rotary evaporation. The material was purified by normal phase chromatography (12 g HP silica gel, DCM containing 0-100% 90:10 MeOH / DCM) to give the desired product 708 (2S) -3- [(2'S, 7R) -2-chloro-2'-methyl-spiro [4, 5-dihydrothieno [2, 3-c] pyran-7, 4'-piperidin] -1'-yl] -2-hydroxy-propionamide (10.2 mg, 7%). 1H NMR (300 MHz, chloroform-d) δ 7.34 (s, 1H), 6.58 (s, 1H), 5.66 (s, 1H), 4.03 (dd, J = 7.8, 5.8 Hz, 1H), 3.95-3.76 (m, 2H), 3.18 (dd, J = 13.3, 7.8 Hz, 1H), 2.89 (dtd, J = 11.5, 6.3, 2.3 Hz, 1H), 2.82-2.72(m,2H),2.62-2.49(m,3H),2.02(d,J=2.3Hz,1H),1.97(q,J=2.8Hz,1H),1.7 7(ddd,J=13.8,10.5,6.7Hz,1H), 1.52(dd,J=14.0,11.4Hz,1H), 1.10(d,J=6.3Hz,3H). LCMS m / z 345.08[M+1] + .

[1335] Compound 709

[1336] (2R)-3-[(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-

[1337] 2-Hydroxy-propionamide

[1338]

[1339] Preparation of (2R)-3-[(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-propionamide (709)

[1340] (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]S50 (107.5 mg, 0.4170 mmol) and (2R)-oxirane-2-carboxylic acid methyl ester (360 μL, 4.112 mmol) were added to a microwave vial and MeOH (4.7 mL) containing NH (4.7 mL of 7M, 32.90 mmol) was added. DIPEA (750 μL, 4.306 mmol) was added and the reaction was stirred at 120 ° C for 5 hours. An additional 200 μL of ethylene oxide and 500 μL of NH were added and the reaction was stirred at 120 ° C for another 4 hours. The material was concentrated by rotary evaporation and rinsed with MeOH / DCM (2x). The remaining solid was insoluble in DCM to be loaded onto the post, so citric acid was added for acidification and the organic matter was extracted with EtOAc (3x). The organic layer was dried on a rotary evaporator and the material was purified by normal phase chromatography (40 g silica gel, 0-20% MeOH / DCM) to give product (2R)-3-[(2'S, 7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]-2-hydroxy-propionamide (36.9 mg, 22%). 1 H NMR (300MHz, chloroform-d) δ6.93(d,J=4.4Hz,1H),6.56(s,1H),5.88(s,1H),4.07(d,J=7.1Hz,3H),3.95-3.77(m,2H),2.92(dd,J=12.9,9.9Hz,1H),2 .85-2.75(m,2H),2.70-2.42(m,4H),1.98(p,J=2.7Hz,1H),1.73(td,J=13.4,4.6Hz,1H),1.51(dd,J=14.0,11.3Hz,1H),1.04(d,J=6.2Hz,3H). LCMS m / z 345.03[M+1] + .

[1341] Compound 710

[1342] (2S)-3-[(2′S,7R)-2-Chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-N-methyl-propionamide

[1343]

[1344] Step 1: Synthesis of (2S)-3-[(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-propionic acid methyl ester (C32)

[1345] (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] S50 (176 mg, 0.6828 mmol) was added to MeOH (3.5 mL) and added to a microwave vial. (2S)-methyl oxirane-2-carboxylate (250 μL, 2.855 mmol) and DIPEA (600 μL, 3.445 mmol) were added and the reaction was heated at 90 °C for 1 hour. The reaction mixture was concentrated by rotary evaporation and purified by normal phase chromatography (24 g silica gel, 0-80% EtOAc / heptane) to afford (2S)-3-[(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-propionic acid methyl ester C32 (147.5 mg, 57%). LCMS m / z 360.02 [M+1] + .

[1346] Step 2: Synthesis of (2S)-3-[(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-N-methyl-propionamidomethyl (710)

[1347] (2S)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2-hydroxy-propanoate C32 (35.7 mg, 0.09920 mmol) was added to dioxane (700 μL) in a microwave flask. Methylamine (100 μL of 40% w / v, 1.288 mmol) and water (17 μL, 0.9436 mmol) were added, and the reaction was heated to 80°C for 3 hours. Purification was performed by reverse phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). The product (2S)-3-[(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-N-methyl-propionamide 710 (22.4 mg, 62%) was obtained. 1H NMR (300 MHz, chloroform-d) δ 10.65 (s, 1H), 7.46 (s, 1H), 6.61 (s, 1H), 4.70 (dd, J = 9.7, 3.1 Hz, 1H), 4.04 (d, J = 13.7 Hz, 1H), 3.89 (p, J = 5.8 Hz, 3H), 3.66 (d, J = 12.0 Hz, 1H), 3.53 (d, J = 13.7 Hz, 1H). (s,1H),3.32(q,J=11.6,10.9Hz,1H),2.87(d,J=4.9Hz,3H),2.63(q,J=5.2Hz,3H) ,2.32(q,J=13.7,12.7Hz,1H),2.17(d,J=15.6Hz,2H),1.49(dd,J=6.5,2.2Hz,4H). LCMS m / z 359.42[M+1] + .

[1348] Compound 711

[1349] (2S)-3-[(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-N,N-dimethyl-propionamide

[1350]

[1351] Step 1: Synthesis of (2S)-3-[(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-propionic acid (C33)

[1352] A solution of (2S)-3-[(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-propionic acid methyl ester C32 (107 mg, 0.2973 mmol) and LiOH (31.6 mg, 1.320 mmol) in MeOH (1.1 mL) and THF (1 mL) was stirred at rt for 2 hours. The reaction mixture was concentrated by rotary evaporation, and the crude material was used without purification. (2S)-3-[(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-propionic acid (lithium salt) C33 (147 mg, 98%). LCMS m / z 344[M+1] + .

[1353] Step 2: Synthesis of (2S)-3-[(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-1′-yl]-2-hydroxy-N,N-dimethyl-propionamide (711)

[1354] (2S)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2-hydroxy-propionic acid C33 (lithium salt) (147 mg, 0.2917 mmol), N-methylmethylamine (500 μL of 2M, 1.000 mmol) and HATU (379.5 mg, 0.9981 mmol) were added to DMF (2 mL). DIPEA (200 μL, 1.148 mmol) was added and the reaction was stirred for 2 hours. Another 500 μL of DMF was added to rinse the sides of the flask. Another 500 μL of DMF and 300 μL of dimethylamine solution containing 332 mg of HATU were added and the reaction was stirred overnight. The reaction mixture was concentrated by rotary evaporation. Excess water was added, and the organics were extracted with DCM and concentrated by rotary evaporator. Purification by silica gel chromatography (0-20% MeOH / DCM) followed by silica gel chromatography (0-15% MeOH / DCM) gave (2S)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2-hydroxy-N,N-dimethyl-propionamide 711 (7.6 mg, 6%). 1H NMR (300MHz, chloroform-d) δ6.60(s,1H),4.69(dd,J=7.4,4.0Hz,1H),4.14(q,J=7.1Hz,1H),4.03–3.79(m,2H),3.33–2.94( m,11H),2.80–2.50(m,3H),2.24–2.08(m,1H),2.05–1.88(m,2H),1.71(dd,J=14.1,11.6Hz,1H),1.33–1.07(m,4H). LCMS m / z 373.12[M+1] + .

[1355] Preparation of S53

[1356] [(2′S,7R)-2-Chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-3-yl]methanol (S53)

[1357]

[1358] Step 1: Synthesis of (2′S,7R)-2-chloro-3-formyl-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-...

Claims

1. A compound represented by the following structural formula: ● Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 and X 2 Selected from -S-, -S(=O)2-, -S(=O)- and -CR 2 ,in: X 1 and X 2 one selected from -S-, -S(=O)2- and -S(=O)-; When X 1 When it is -S-, -S(=O)2- or -S(=O)-, then X 2 Yes-CR 2 ;and When X 2 When it is -S-, -S(=O)2- or -S(=O)-, then X 1 Yes-CR 2 ; R 1 is selected from cyano, halogen, C1-C4 alkyl, C1-C4 haloalkyl and C3-C6 cycloalkyl, wherein: R 1 The C1-C4 alkyl group is optionally substituted by 1 to 3 groups independently selected from the following groups: -OH and C1-C4 alkoxy; R 2 Selected from hydrogen, C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), -C(=O)NR n R o and halogen groups, wherein: R 2 The C1-C6 alkyl is optionally substituted by 1 to 3 groups independently selected from: -OH, halogen and C1-C4 alkoxy; and R n and R o R is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl and -(C1-C4 alkylene) p Group, where R p Selected from C3-C6 cycloalkyl; or R 1 and R 2 Together with the carbon atom to which it is attached, it forms a C6 aryl group; k is selected from 0, 1 and 2; m is selected from 0, 1 and 2; Each R 3a Independently selected from -OH, -CN, -NR a1 R a2 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -OC(=O)(C1-C4 alkyl), 6- to 8-membered aryl, 6- to 8-membered heteroaryl, and halogen groups, wherein: Each R a1 and R a2 independently selected from hydrogen, C1-C4 alkyl and -C(=O)(C1-C4 alkyl) groups; or Two R's 3a together to form an oxo group; or Two R's 3a Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group; Each R 3b Independently selected from C1-C4 alkyl, wherein: R 3b The C1-C4 alkyl is optionally substituted by 1 to 3 groups independently selected from the following groups: -OH, halogen and C1-C4 alkoxy; or One R 3a and an R 3b Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group; R 4a , R 4b , R 5a and R 5b Each independently selected from hydrogen and C1-C4 alkyl; R 6 Selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl) and Group, in which: R 6 The C1-C6 alkyl is optionally substituted by 1 to 5 groups independently selected from the following: halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C1-C4 alkoxy, C3-C6 carbocyclyl, C6 aryl, -O-(C6 aryl), 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein: The C6 aryl and -O-(C6 aryl) groups are each optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen and C1-C4 haloalkyl; Ring B is selected from C3-C 12 Carbocyclic group, 3 to 12 membered heterocyclic group, C6 and C 10 aryl and 5 to 10 membered heteroaryl, wherein ring B is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution; wherein: R a In each occurrence, independently selected halogen, Cyano, C1-C8 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C1-C6 haloalkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Carbocyclic group, C6 and C 10 Aryl, 3 to 12 membered heterocyclic group, 5- to 10-membered heteroaryl, -C(=O)NR h R i 、 -C(=O)OR k 、 -C(=O)(C1-C4alkylene)OR k , -C(=O)R k 、 -C(=O)(C1-C4 alkylene)S(=O) p R k , -C(=O)(C1-C4 alkylene)S(=O) p NR h R i , -C(=O)(C1-C4alkylene)NR i S(=O) p R k , -C(=O)(C1-C4alkylene)NR h C(=O)R k , -C(=O)C(=O)R k 、 -NR h R i 、 -NH(CH2) q CHR h R i 、 -NH(CH2) q NR h R i 、 -NR h C(=O)R k 、 -NR h C(=O)OR k 、 -NR h C(=O)(C1-C4 alkylene)OR k , -NR h C(=O)O(C1-C4 alkylene)R k , -NR h C(=O)NR i R j 、 -NR h C(=O)(C1-C4alkylene)NR i S(=O) p R k , -NR h S(=O) p R k 、 -NR h C(=O)(C1-C4 alkylene)S(=O) p R k , -NR h S(=O) p (C1-C4 alkylene)C(=O)OR k 、 -NR h C(=O)[O(CH2) q ] r OC(=O)NR h R i (CH2) q [O(CH2) q ] r (C1-C6 alkyl) (optionally with 1 to 3 R m Group substitution), -NR h C(=O)(C1-C6 alkylene)[O(CH2) q ] r OC(=O)NR h R i (CH2) q [O(CH2) q ] r (C1-C6 alkyl) (optionally with 1 to 3 R m Group substitution), -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 and -S(=O) p NR h R i Group, in: The C1-C4 alkylene in each of the following is optionally substituted by 1 to 3 groups independently selected from -OH: -C(=O)(C1-C4 alkylene)S(=O) p R k , -C(=O)(C1-C4alkylene)OR k 、-C(=O)(C1-C4alkylene)S(=O) p NR h R i 、-C(=O)(C1-C4alkylene)NR i S(=O) p R k 、-C(=O)(C1-C4alkylene)NR h C(=O)R k 、-NR h C(=O)O(C1-C4 alkylene)R k 、-NR h C(=O)(C1-C4 alkylene)OR k 、-NR h S(=O) p (C1-C4 alkylene)C(=O)OR k and-NR h C(=O)(C1-C4alkylene)NR i S(=O) p R k , R a The C1-C8 alkyl, the C1-C6 haloalkyl, the C1-C6 alkoxy and the C2-C8 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 、-[O(CH2) q ] r OH, -OC(=O)R k 、-OC(=O)OR k 、-OC(=O)NR h R i 、-SR k 、-S(=O) p R k 、-S(=O) p NR h R i 、-[O(CH2) q ] r O(C1-C4 alkyl), -O-(C6 aryl or 5- to 8-membered heteroaryl) (optionally substituted with 1 to 3 R m group), C3-C6 carbocyclic group (optionally substituted with 1 to 3 R m C6 to C 10 Aryl (optionally substituted with 1 to 3 R m substituted with a group), a 4- to 10-membered heterocyclic group (optionally substituted with 1 to 3 R m substituted with 1 to 3 R m group substitution); R a The C3-C 12 The carbocyclic group, the 3 to 12 membered heterocyclic group, the C6 and C 10 The aryl group and the 5- to 10-membered heteroaryl group are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, C1-C6 alkyl (optionally substituted by 1 to 3 R m Group substitution), -C(=O)R k 、C(=O)OR k 、-NR h R i 、-OR k 、-S(=O) p R k 、-S(=O) p NR h R i and a 5- to 10-membered heterocyclic group, wherein: R h , R i and R j is independently selected at each occurrence from hydrogen, C1-C6 alkyl (optionally substituted by 1 to 4 R m Group substitution), C6-C 10 Aryl, C3-C8 carbocyclic group (optionally substituted by 1 to 3 R m substituted with 1 to 3 R m substituted with 1 to 3 R m Group substitution), wherein: R h , R i and R j The C1-C6 alkyl group of any one of the following is optionally substituted by 1 to 3 groups independently selected from the following: halogen, cyano, -OH, C1-C4 alkoxy, -C(=O)NH(C1-C4 alkyl), 5- to 10-membered heteroaryl (optionally substituted by 1 to 3 R m substituted with 1 to 3 R m group substitution); R k is independently selected at each occurrence from hydrogen, NH2 (optionally substituted with 1 or 2 groups selected from C1-C3 alkyl), C1-C6 alkyl, benzyl, C6 aryl, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein: R k The C1-C6 alkyl of any one of is optionally substituted by 1 to 5 groups independently selected from the following: halogen, cyano, -NH2, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl (optionally substituted by 1 to 3 halogen groups), 4 to 10 membered heterocyclyl (optionally substituted by 1 to 3 -OH groups), 5 to 10 membered aryl (optionally substituted by 1 to 3 groups selected from the following: C1-C4 alkyl and halogen) and 5 to 10 membered heteroaryl (optionally substituted by 1 to 3 -OH groups); and R k The C3-C6 carbocyclyl, the benzyl and the C6 aryl of any one of the above are each optionally substituted by 1 to 3 groups independently selected from the following: halogen, cyano, oxo, -OH, -C(=O)NH2, -C(=O)N(CH3)2, C1-C6 alkyl (optionally substituted by 1 to 3 -OH groups), C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl (optionally substituted by 1 to 3 halogen groups), C6 aryl (optionally substituted by 1 to 3 halogen groups) and 5 to 10 membered heteroaryl (optionally substituted by 1 to 3 halogen groups); and R k The 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl of any one of the above are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, oxo, cyano, -C(=O)CH3, -NH2, -OH, C1-C4 alkyl (optionally substituted by 1 to 3 -OH groups), C1-C4 haloalkyl, 5- to 10-membered heterocyclyl, and C1-C4 alkoxy; R m is independently selected at each occurrence from halogen, cyano, oxo, -NH2, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)R k 、-S(=O) p R k 、-OR k and a 5- to 10-membered heterocyclic group, wherein: R m The C1-C6 alkyl, the C1-C6 alkoxy and the 5- to 10-membered heterocyclyl of any one of the above are optionally substituted by 1 to 3 groups independently selected from the following: halogen, cyano, -OH and C1-C4 alkoxy; p at each occurrence is an integer independently selected from 1 and 2; and q and r are integers independently selected from 0, 1, 2 and 3 at each occurrence.

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: Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein R 6 As defined in claim 1.

3. 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: Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein R 6 As defined in claim 1.

4. 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: ● Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein R 6 As defined in claim 1.

5. 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: ● Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein R 6 As defined in claim 1.

6. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 1, wherein the variable X 1 is selected from S, S(=O) and S(=O)2, and the variable X 2 Yes-CR 2 .

7. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 1, wherein the variable X 2 is selected from S, S(=O) and S(=O)2, and the variable X 1 Yes-CR 2 .

8. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1, 6 and 7, wherein the variable R 2 It's hydrogen.

9. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 1, wherein the variable X 1 is S, the variable X 2 Yes-CR 2 , and the variable R 2 It's hydrogen.

10. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 1, wherein the variable X 1 Yes-CR 2 , the variable X 2 is S, and the variable R 2 It's hydrogen.

11. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein R 2 Selected from hydrogen, halogen, -CH3, -CH2OH, -CH2(OH)CH3 and -C(=O)NR n R o ,in R n and R o R is independently selected from hydrogen, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C6 cycloalkyl and -(C1-C4 alkylene)R p group, and wherein R p Selected from -C3-C6 cycloalkyl.

12. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 10, wherein R 2 Selected from halogen.

13. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 11, wherein R 2 Selected from Br and Cl.

14. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 10, wherein the variable R 2 Selected from -CH3, -CH2OH and CH(OH)CH3.

15. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 10, wherein R 2 is -C(=O)NR n R o , and where R n is hydrogen and R o It is CH3.

16. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 10, wherein R 2 is -C(=O)NR n R o , and where R n is hydrogen and R o It is CH3 substituted by cyclopropyl.

17. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 10, wherein R 2 is -C(=O)NR n R o , and where R n is hydrogen and R o It is -CH2CH2CH3.

18. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 10, wherein R 2 is -C(=O)NR n R o , and where R n is hydrogen and R o It is -CH2CF2.

19. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 and 6 to 17, wherein R 1 Selected from cyano, halogen, C1-C4 alkyl (optionally substituted with 1 to 3 groups independently selected from: -OH and C1-C4 alkoxy), C1-C4 haloalkyl and C3-C6 cycloalkyl.

20. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 18, wherein the variable R 1 Selected from -CN, -Br, -Cl, CH3, CH2OH, -CH2CH3, -CH2CH2CH3, tert-butyl, -CH2CF2, -CF2, -CF3, -CF2CF2, -CH2OCH3, -CH2OCH2CH3, cyclopropyl and cyclobutyl.

21. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 18, wherein the variable R 1 It's CF3.

22. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 18, wherein the variable R 1 It is Cl.

23. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 18, wherein the variable R 1 It is -CH2OH.

24. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 18, wherein the variable R 1 It is -CH2CF3.

25. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 18, wherein the variable R 1 It is -CF2CF3.

26. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 18, wherein the variable R 1 It is -CH2(OH)CH3.

27. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 18, wherein the variable R 1 Including deuterium.

28. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 26, wherein the variable R 1 It is CD-OCH2CH3.

29. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1, 6 and 7, wherein the variable R 1 and R 2 Together with the carbon atom to which it is attached, it forms a C6 aryl group.

30. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1, 6 and 7, wherein the variable R 1 is -Cl, and the variable R 2 It is -CH2OH.

31. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein the variable R 1 is Cl, and the variable R 2 It is -CH3.

32. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1, 6 and 7, wherein the variable R 1 is Cl, and the variable R 2 It's hydrogen.

33. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein the variable R 1 is -Cl, and the variable R 2 It is -Cl.

34. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein the variable R 1 is -CF3, and the variable R 2 It's hydrogen.

35. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein 36. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein -CF2CF3 and the variable R 2 It's hydrogen.

37. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein -CH2CF3 and the variable R 2 It's hydrogen.

38. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein the variable R 1 is -CF2, and the variable R 2 It is -CH2OH.

39. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1, 6 and 7, wherein the variable R 1 is -CF3, and the variable R 2 It is -CH2OH.

40. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1, 6 and 7, wherein the variable R 1 is -CF3, and the variable R 2 It is -CH2(OH)CH3.

41. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein the variable R 1 is -CF3, and the variable R 2 It is -Cl.

42. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein the variable R 1 is CH3, and the variable R 2 It's hydrogen.

43. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein the variable R 1 is CH2CH3, and the variable R 2 It's hydrogen.

44. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein the variable R 1 is CH2OH, and the variable R 2 It's hydrogen.

45. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1 and 6 to 43, wherein the variables m and k are zero.

46. ​​The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1 and 6 to 43, wherein the variable m is zero and the variable k is one.

47. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1 and 6 to 43, wherein the variable m is zero and the variable k is two.

48. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1 and 6 to 43, wherein the variable m is one and the variable k is zero.

49. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1 and 6 to 43, wherein the variable m is two and the variable k is zero.

50. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 and 6 to 43, wherein the variable m is zero, the variable k is one or two, and each R 3a The variables are independently selected from -OH, F, F2, CF2, -OCH3, -OCH2CH3, -OCH2(CH3)2, -OC(=O)CH3, NH2, NHC(=O)CH3, CN, 51. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 and 6 to 43, wherein the variable m is zero, the variable k is one, and the variable R 3a independently selected from -OH, F, F2, CF2, -OCH3, -OCH2CH3, -OCH2(CH3)2, -OC(=O)CH3, NH2, NHC(=O)CH3, CN, 52. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 and 6 to 43, wherein the variable m is zero, the variable k is one, and the variable R 3a It is -OH.

53. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 and 6 to 43, wherein the variable m is zero, the variable k is one, and the variable R 3a Selected from -OCH3 and -OCH2CH3.

54. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 and 6 to 43, wherein the variable m is zero, the variable k is two, and both R 3a The variables together form =0.

55. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein two R 3a The variables are present and are selected from the following: -CF2 and -OH; -CF2 and -CH3; -OH and -CH3; and -OH and phenyl.

56. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 and 6 to 53, wherein the variable R 4a , R 4b , R 5a and R 5b Three of the variables are hydrogen and the remaining variables are selected from C1-C4 alkyl.

57. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 and 6 to 53, wherein the variable R 4a , R 4b , R 5a and R 5b Three of the variables are hydrogen and the remaining variable is CH3.

58. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 6 to 55, wherein R 6 Selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl) and Group, in which: R 6 The C1-C6 alkyl is optionally substituted by 1 to 5 groups independently selected from the following: halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C1-C4 alkoxy, C3-C6 carbocyclyl, C6 aryl, -O-(C6 aryl), 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein: The C6 aryl and -O-(C6 aryl) groups are each optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen and C1-C4 haloalkyl; Ring B is selected from C3-C 12 Carbocyclic group, 3 to 12 membered heterocyclic group, C6 and C 10 aryl and 5 to 10 membered heteroaryl, wherein ring B is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution; wherein: R a In each occurrence, independently selected halogen, Cyano, C1-C8 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C1-C6 haloalkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Carbocyclic group, C6 and C 10 Aryl, 3 to 12 membered heterocyclic group, 5- to 10-membered heteroaryl, -C(=O)NR h R i 、 -C(=O)OR k 、 -C(=O)(C1-C4alkylene)OR k , -C(=O)R k 、 -C(=O)(C1-C4 alkylene)S(=O) p R k , -C(=O)(C1-C4 alkylene)S(=O) p NR h R i , -C(=O)(C1-C4alkylene)NR i S(=O) p R k , -C(=O)(C1-C4alkylene)NR h C(=O)R k , -C(=O)C(=O)R k 、 -NR h R i 、 -NH(CH2) q CHR h R i 、 -NH(CH2) q NR h R i 、 -NR h C(=O)R k 、 -NR h C(=O)OR k 、 -NR h C(=O)(C1-C4 alkylene)OR k , -NR h C(=O)O(C1-C4 alkylene)R k , -NR h C(=O)NR i R j 、 -NR h C(=O)(C1-C4alkylene)NR i S(=O) p R k , -NR h S(=O) p R k 、 -NR h C(=O)(C1-C4 alkylene)S(=O) p R k , -NR h S(=O) p (C1-C4 alkylene)C(=O)OR k 、 -NR h C(=O)[O(CH2) q ] r OC(=O)NR h R i (CH2) q [O(CH2) q ] r (C1-C6 alkyl) (optionally with 1 to 3 R m Group substitution), -NR h C(=O)(C1-C6 alkylene)[O(CH2) q ] r OC(=O)NR h R i (CH2) q [O(CH2) q ] r (C1-C6 alkyl) (optionally with 1 to 3 R m Group substitution), -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 and -S(=O) p NR h R i Group, in: The C1-C4 alkylene in each of the following is optionally substituted by 1 to 3 groups independently selected from -OH: -C(=O)(C1-C4 alkylene)S(=O) p R k , -C(=O)(C1-C4alkylene)OR k 、-C(=O)(C1-C4alkylene)S(=O) p NR h R i 、-C(=O)(C1-C4alkylene)NR i S(=O) p R k 、-C(=O)(C1-C4alkylene)NR h C(=O)R k 、-NR h C(=O)O(C1-C4 alkylene)R k 、-NR h C(=O)(C1-C4 alkylene)OR k 、-NR h S(=O) p (C1-C4 alkylene)C(=O)OR k and-NR h C(=O)(C1-C4alkylene)NR i S(=O) p R k , R a The C1-C8 alkyl, the C1-C6 haloalkyl, the C1-C6 alkoxy and the C2-C8 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 、-[O(CH2) q ] r OH, -OC(=O)R k 、-OC(=O)OR k 、-OC(=O)NR h R i 、-SR k 、-S(=O) p R k 、-S(=O) p NR h R i 、-[O(CH2) q ] r O(C1-C4 alkyl), -O-(C6 aryl or 5- to 8-membered heteroaryl) (optionally substituted with 1 to 3 R m group), C3-C6 carbocyclic group (optionally substituted with 1 to 3 R m C6 to C 10 Aryl (optionally substituted with 1 to 3 R m substituted with a group), a 4- to 10-membered heterocyclic group (optionally substituted with 1 to 3 R m substituted with 1 to 3 R m group substitution); R a The C3-C 12 The carbocyclic group, the 3 to 12 membered heterocyclic group, the C6 and C 10 The aryl group and the 5- to 10-membered heteroaryl group are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, C1-C6 alkyl (optionally substituted by 1 to 3 R m Group substitution), -C(=O)R k 、C(=O)OR k 、-NR h R i 、-OR k 、-S(=O) p R k 、-S(=O) p NR h R i and a 5- to 10-membered heterocyclic group, wherein: R h , R i and R j is independently selected at each occurrence from hydrogen, C1-C6 alkyl (optionally substituted by 1 to 4 R m Group substitution), C6-C 10 Aryl, C3-C8 carbocyclic group (optionally substituted by 1 to 3 R m substituted with 1 to 3 R m substituted with 1 to 3 R m Group substitution), wherein: R h , R i and R j The C1-C6 alkyl group of any one of the following is optionally substituted by 1 to 3 groups independently selected from the following: halogen, cyano, -OH, C1-C4 alkoxy, -C(=O)NH(C1-C4 alkyl), 5- to 10-membered heteroaryl (optionally substituted by 1 to 3 R m substituted with 1 to 3 R m group substitution); R k is independently selected at each occurrence from hydrogen, NH2 (optionally substituted with 1 or 2 groups selected from C1-C3 alkyl), C1-C6 alkyl, benzyl, C6 aryl, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein: R k The C1-C6 alkyl of any one of is optionally substituted by 1 to 5 groups independently selected from the following: halogen, cyano, -NH2, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl (optionally substituted by 1 to 3 halogen groups), 5 to 10 membered heterocyclyl (optionally substituted by 1 to 3 -OH groups), 5 to 10 membered aryl (optionally substituted by 1 to 3 groups selected from the following: C1-C4 alkyl and halogen) and 5 to 10 membered heteroaryl (optionally substituted by 1 to 3 -OH groups); and R k The C3-C6 carbocyclyl, the benzyl and the C6 aryl of any one of the above are each optionally substituted by 1 to 3 groups independently selected from the following: halogen, cyano, oxo, -OH, -C(=O)NH2, -C(=O)N(CH3)2, C1-C4 alkyl (optionally substituted by 1 to 3 -OH groups), C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl (optionally substituted by 1 to 3 halogen groups), C6 aryl (optionally substituted by 1 to 3 halogen groups) and 5 to 10 membered heteroaryl (optionally substituted by 1 to 3 halogen groups); and R k The 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl of any one of the above are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, oxo, cyano, -C(=O)CH3, -NH2, -OH, C1-C4 alkyl (optionally substituted by 1 to 3 -OH groups), C1-C4 haloalkyl, 5- to 10-membered heterocyclyl, and C1-C4 alkoxy; R m is independently selected at each occurrence from halogen, cyano, oxo, -NH2, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)R k 、-S(=O) p R k 、-OR k and a 5- to 10-membered heterocyclic group, wherein: R m The C1-C6 alkyl, the C1-C6 alkoxy and the 5- to 10-membered heterocyclyl of any one of the above are optionally substituted by 1 to 3 groups independently selected from the following: halogen, cyano, -OH and C1-C4 alkoxy; p at each occurrence is an integer independently selected from 1 and 2; and q and r are integers independently selected from 0, 1, 2 and 3 at each occurrence.

59. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 56, wherein R 6 The invention is selected from C1-C6 alkyl which is optionally substituted by 1 to 5 groups independently selected from the following groups: halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C1-C4 alkoxy, C3-C6 carbocyclyl, C6 aryl (which is optionally substituted by 1 to 3 groups independently selected from the following groups: halogen and C1-C4 haloalkyl), -O-(C6 aryl) (which is optionally substituted by 1 to 3 groups independently selected from the following groups: halogen and C1-C4 haloalkyl), 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl.

60. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 57, wherein R 6 is a substituted C1-C6 alkyl group selected from the following:

61. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 56, wherein R 6 Selected from -C(=O)O(C1-C4 alkyl).

62. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 56, wherein R 6 Selected from R 6 Selected from the group consisting of those defined in claim 56 63. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 59, wherein Ring B is selected from C3-C 12 The C3-C12 carbocyclic group is optionally substituted by 1, 2, 3, 4 or 5 R as defined in claim 56 a Group substitution.

64. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 59, wherein Ring B is selected from a 3- to 12-membered heterocyclic group, wherein the 3- to 12-membered heterocyclic group is optionally substituted by 1, 2, 3, 4 or 5 R as defined in claim 56. a Group substitution.

65. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 59, wherein Ring B is selected from C6 and C 10 Aryl, wherein the C6 and C10 aryl groups are optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution.

66. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 59, wherein Ring B is selected from a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 R as defined in claim 56. a Group substitution.

67. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 59, wherein Ring B is selected from the group consisting of: Group, The group is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution.

68. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 64, wherein Ring B is selected from the following: A group, which is optionally substituted by 1, 2, 3, 4 or 5 R as defined in claim 56 a Group substitution.

69. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 56, wherein R 6 Selected from: wherein Ring B is a 5-membered heteroaryl group, and R a As defined for Formula I.

70. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 56, wherein R 6 Selected from: wherein Ring B is a 5-membered heteroaryl group, and R a is oxo or selected from C1-C8 alkyl, C3-C 12 Carbocyclic groups and C6 and C 10 Aryl, each of which may be optionally substituted with 1 to 3 groups selected from halogen and C1-C8 alkyl (wherein the C1-C8 alkyl may be optionally substituted with 1 to 3 groups selected from halogen, -OH, SO2CH3 and SO2NH2).

71. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 56, wherein R 6 Selected from:

72. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 59, wherein R a is selected from C1-C4 alkyl, halogen, -OH and C1-C4 alkoxy, wherein R a The C1-C4 alkyl group is optionally substituted with 1 to 3 polar groups such as sulfone, sulfonamide and alcohol.

73. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 59, wherein R a is an optionally substituted C1-C6 alkyl as defined for Formula I; in some embodiments, R a The C1-C6 alkyl group is optionally substituted by 1 to 3 groups selected from the following groups: -OH, -SO2CH3, C1-C3 alkoxy, C(=O)NHCH3, -SO2NHCH2CH2OH, -SCF 3、 -SCH2C(CH2)2OH, -SO2phenyl, 4 to 6 membered heterocyclic ring (optionally with 1 to 3 R m substituted with a group), a 4- to 6-membered heteroaryl group (optionally substituted with 1 to 3 R m group-substituted), cyano, NHC(═O)-4 to 6-membered heteroaryl.

74. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 59, wherein R a is selected from optionally substituted 4 to 6 membered carbocyclic rings, 4 to 6 membered heterocyclic rings and 4 to 6 membered heteroaryl rings.

75. A compound selected from the following: compounds 1 to 1183, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein the compound is not compound 285, compound 489, compound 539, compound 691, compound 692, compound 741, compound 747, compound 749, compound 751, compound 752, compound 753, compound 795, compound 814 or compound 868.

76. A pharmaceutical composition comprising a compound according to any one of claims 1 to 72.

77. A method of treating an ApoL1 mediated disease, the method comprising administering a compound according to any one of claims 1 to 72 or a pharmaceutical composition according to claim 73.

78. A method of treating focal segmental glomerulosclerosis (FSGS) comprising administering a compound according to any one of claims 1 to 72 or a pharmaceutical composition according to claim 73.

79. A method of treating non-diabetic nephropathy (NDKD) comprising administering a compound according to any one of claims 1 to 72 or a pharmaceutical composition according to claim 73.

80. A method of treating ApoL1 mediated cancer, the method comprising administering a compound according to any one of claims 1 to 72 or a pharmaceutical composition according to claim 73.

81. The method of treating cancer according to claim 77, wherein the cancer is pancreatic cancer.

82. The method of treatment according to any one of claims 74 to 78, wherein the patient to be treated has an APOL1 genetic variant.

83. The method of treatment of claim 79, wherein the genetic variant is selected from G1:S342G:I384M and G2:N388del:Y389del.

84. 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 claims 1 to 72 or a pharmaceutical composition according to claim 73.

85. Use of a compound according to any one of claims 1 to 72 in the manufacture of a medicament for treating an ApoL1 mediated disease.

86. Use of a compound according to any one of claims 1 to 72 in the manufacture of a medicament for the treatment of FSGS.

87. Use of a compound according to any one of claims 1 to 72 in the manufacture of a medicament for the treatment of NDKD.

88. Use of a compound according to any one of claims 1 to 72 in the manufacture of a medicament for treating ApoL1 mediated cancer.

89. Use of a compound according to any one of claims 1 to 72 in the manufacture of a medicament for treating ApoL1 mediated pancreatic cancer.

90. Use of a compound according to any one of claims 1 to 72 in the manufacture of a medicament for inhibiting ApoL1 activity in a patient in need thereof.

91. A compound according to any one of claims 1 to 72 or a pharmaceutical composition according to claim 73 for use in inhibiting ApoL1 activity in a patient in need thereof.

92. A compound according to any one of claims 1 to 72 or a pharmaceutical composition according to claim 73 for use in treating an ApoL1 mediated disorder.

93. A compound according to any one of claims 1 to 72 or a pharmaceutical composition according to claim 73 for use in the treatment of FSGS.

94. A compound according to any one of claims 1 to 72 or a pharmaceutical composition according to claim 73 for use in the treatment of NDKD.

95. A compound according to any one of claims 1 to 72 or a pharmaceutical composition according to claim 73 for use in the treatment of ApoL1 mediated cancer.

96. A compound according to any one of claims 1 to 72 or a pharmaceutical composition according to claim 73 for use in the treatment of ApoL1 mediated pancreatic cancer.

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