2-METHYL-4',5'-DIHYDROPYRO[PIPERIDINE-4,7'-THIENO[2,3-C]PYRAN] DERIVATIVES AS APOL1 INHIBITORS AND METHODS OF USING SAME - Patent application

Abstract

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

Description

[Technical Field]

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

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

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

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

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

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

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

[0008] Although normal plasma concentrations of APOL1 are relatively high and can vary by at least 20-fold in humans, circulating APOL1 is not causally associated with renal disease. However, renal APOL1 is thought to contribute to the development of renal diseases, including FSGS and NDKD. Under certain circumstances, APOL1 protein synthesis can be increased by approximately 200-fold by proinflammatory cytokines, such as interferon or tumor necrosis factor-α. In addition, APOL1 protein is associated with the cell membrane via a pH-gated Na+ channel. + / K + pores, resulting in intracellular K + Several studies have shown that a net excretion of inflammatory cytokines occurs, ultimately leading to activation of local and systemic inflammatory responses, cell swelling, and death.

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

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

[0011] Corticosteroids, alone or in combination with other immunosuppressants, induce remission (e.g., remission of proteinuria in a minority of patients) in a minority of patients, but are associated with numerous side effects. However, even in patients who initially respond to corticosteroid and / or immunosuppressive treatment, remission is often short-lived. As a result, patients, particularly those of modern sub-Saharan African descent who carry two APOL1 risk alleles, experience rapid disease progression and end-stage renal disease (ESRD). Therefore, there is an unmet medical need for treatments for FSGS and NDKD. Specifically, given evidence that APOL1 plays a causative role in the induction and accelerated progression of renal disease, APOL1 inhibition should have a beneficial effect on patients with APOL1-mediated renal disease, particularly those who carry two APOL1 risk alleles (i.e., homozygous or compound heterozygous for the G1 or G2 allele). Furthermore, APOL1 is a gene that is aberrantly expressed in multiple cancers (Lin et al., Cell Death and Disease (2021), 12:760). Recently, APOL1 has been found to be abnormally elevated in human pancreatic cancer tissue compared with adjacent tissue and is associated with poor prognosis in pancreatic cancer patients. In vivo and in vitro experiments have shown that knockdown of APOL1 inhibits cancer cell proliferation and promotes apoptosis of pancreatic cancer cells. [Prior art documents] [Non-patent literature]

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

[0013] One aspect of the present disclosure provides at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, tautomers of Formula I, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, which can be used to treat diseases mediated by APOL1, such as FSGS and NDKD. For example, in some embodiments, the at least one compound is represented by Formula I: [ka] or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 and X 2 are -S-, -S(=O)2-, -S(=O)-, and -CR 2 is selected from: X 1 and X 2 is selected from -S-, -S(=O)-, and -S(=O)-; X 1 is -S-, -S(=O)2-, or -S(=O)-, X 2 Ha-CR 2 and X 2 is -S-, -S(=O)2-, or -S(=O)-, X 1 Ha-CR 2 and R 1 is selected from cyano, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl groups; R 1 wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from —OH and a C1-C4 alkoxy group; R 2 is hydrogen, C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), -C(=O)NR n R o and a halogen group, R 2 wherein the C1-C6 alkyl is optionally substituted with 1 to 3 groups independently selected from —OH, halogen, and a C1-C4 alkoxy group; and R n and R o is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, and -(C1-C4 alkylene)R p groups, wherein R p is selected from a C3-C6 cycloalkyl group, or R 1 and R 2 together with the carbon atom to which they are attached form a C6 aryl group, Each R 3a -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 are independently selected from hydrogen, C1-C4 alkyl, and —C(═O)(C1-C4 alkyl) groups; or Two R's 3a together form an oxo group, or Two R's 3a together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl group, Each R 3b are independently selected from C1-C4 alkyl groups, wherein: R 3b wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from —OH, halogen, and a C1-C4 alkoxy group; or One R3a and one R 3b together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl group, k is selected from 0, 1, and 2; m is selected from 0, 1, and 2; R 4a , R 4b , R 5a , and R 5b are each independently selected from hydrogen and a C1-C4 alkyl group; R 6 is C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), and [ka] is selected from the group R 6 wherein the C1-C6 alkyl is optionally substituted with 1 to 5 groups independently selected from 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 groups, each C aryl and -O-(C aryl) group is optionally substituted with 1 to 3 groups independently selected from halogen and C-C haloalkyl groups; Ring B is C3-C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C 10 aryl, and 5- to 10-membered heteroaryl groups, wherein ring B is selected from 1, 2, 3, 4, or 5 R a and optionally substituted with a group, wherein R ais, for each occurrence, halogen, cyano, C1-C8 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C1-C6 haloalkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Carbocyclyl, C6 and C 10 Aryl, 3-12 membered heterocyclyl, 5-10 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 i S(=O) p R k , -NRh 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) (1 to 3 R m optionally substituted with a -NR group, 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) (1 to 3 R m optionally substituted with -OR groups), 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 is independently selected from the group -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)-NRi 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 , N.R. 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 wherein the C1-C4 alkylene in each of R a C1-C8 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C2-C8 alkenyl are each 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 5-8 membered heteroaryl) (1-3 R m C-C carbocyclyl (optionally substituted with 1 to 3 R m optionally substituted with a group), C-C 10 Aryl (1 to 3 R m group), 4- to 10-membered heterocyclyl (1 to 3 R m aryl (optionally substituted with 1 to 3 R m optionally substituted with 1 to 3 groups independently selected from the group R a C3-C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl are each selected from halogen, cyano, C1-C6 alkyl (1 to 3 R m group), -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 heterocyclyl group, R h , R i , and R j are each, for each occurrence, hydrogen, C1-C6 alkyl, C6-C 10 Aryl, C3-C8 carbocyclyl (1-3 R m aryl (optionally substituted with 1 to 3 R m groups), and 5- to 10-membered heterocyclyl (1-3 R m and optionally substituted with a group, wherein R h , R i , and R j Any one of the C1-C6 alkyl groups may be selected from halogen, cyano, —OH, C1-C4 alkoxy, —C(═O)NH(C1-C4 alkyl), 5-10 membered heteroaryl (1-3 R m groups), and 5- to 10-membered heterocyclyl (1-3 R m optionally substituted with 1 to 4 groups independently selected from the group R k is, for each occurrence, independently selected from hydrogen, NH, (optionally substituted with 1 or 2 groups selected from C-C alkyl), C-C alkyl, benzyl, C aryl, C-C carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups; R k wherein any one of the C1-C6 alkyl groups is optionally substituted with 1 to 5 groups independently selected from halogen, cyano, —NH2, —OH, C1-C4 alkoxy, C3-C6 cycloalkyl (optionally substituted with 1 to 3 halogen groups), 4-10 membered heterocyclyl (optionally substituted with 1 to 3 —OH groups), 5-10 membered aryl (optionally substituted with 1 to 3 groups selected from C1-C4 alkyl and halogen), and 5-10 membered heteroaryl (optionally substituted with 1 to 3 —OH groups); and R k wherein any one of the C3-C6 carbocyclyl, benzyl, and C6 aryl is each optionally substituted by 1 to 3 groups independently selected from halogen, cyano, oxo, -OH, -C(=O)NH2, -C(=O)N(CH3)2, C1-C4 alkyl (optionally substituted with 1 to 3 OH groups), C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl (optionally substituted with 1 to 3 halogen groups), C6 aryl (optionally substituted with 1 to 3 halogen groups), and 5-10 membered heteroaryl (optionally substituted with 1 to 3 halogen groups); Rk wherein any one of the 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl is each optionally substituted by 1 to 3 groups independently selected from halogen, oxo, cyano, —C(═O)CH, —NH, —OH, C-C alkyl (optionally substituted with 1 to 3 —OH groups), C-C haloalkyl, 5- to 10-membered heterocyclyl, and C-C alkoxy; R m is, for each occurrence, 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 heterocyclyl group, R m any one of C1-C6 alkyl, C1-C6 alkoxy, and 5- to 10-membered heterocyclyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C4 alkoxy groups; p, for 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 for each occurrence.

[0014] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a compound represented by structural formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, as follows: [ka] [ka] In the formula, R 6 is as defined above as Formula I.

[0015] 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 teeth, [ka] Ring B is a 5-membered heteroaryl, and R a is as defined for formula I.

[0016] 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 teeth, [ka] wherein ring B is a 5-membered heteroaryl, and R a is oxo or C1-C8 alkyl, C3-C 12 Carbocyclyl 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 (C1-C8 alkyl may be optionally substituted with 1 to 3 groups selected from halogen, —OH, SO2CH3, and SO2NH2).

[0017] 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 teeth, [ka] is selected from.

[0018] In one aspect of the present disclosure, the compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im are selected from compounds 1-1183, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions can include at least one compound selected from compounds 1-1183, tautomers thereof, deuterated derivatives of those 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.

[0019] Another aspect of the present disclosure provides methods 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 compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-1183, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0020] Another aspect of the present disclosure provides a method for treating an APOL1-mediated cancer (e.g., pancreatic cancer), comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-1183, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0021] Another aspect of the present disclosure provides a method for treating APOL1-mediated kidney cancer (e.g., ESKD, FSGS, and / or NDKD), comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-1183, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0022] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition or as a separate composition, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method comprises administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-1183, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, together with the at least one additional active agent, either in the same pharmaceutical composition or as a separate composition.

[0023] Also provided are methods for inhibiting APOL1, comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those 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 selected from compounds 1-1183, tautomers thereof, deuterated derivatives of those 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.

[0024] All of compounds 1-1183 disclosed herein demonstrated the ability to inhibit ApoL1 in one or more assays. In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts selected from 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, do not include 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 OF THE INVENTION

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

[0026] The term "APOL1-mediated disease" refers to a disease or condition associated with abnormal APOL1 (e.g., a particular APOL1 genetic variant, elevated APOL1 levels). In some embodiments, the APOL1-mediated disease is an APOL1-mediated renal disease. In some embodiments, the APOL1-mediated disease is associated with patients with two APOL1 risk alleles, e.g., homozygous or compound heterozygous for the G1 allele or the G2 allele. In some embodiments, the APOL1-mediated disease is associated with patients with one APOL1 risk allele.

[0027] The term "APOL1-mediated renal disease" refers to a disease or condition that impairs kidney function and can be caused by APOL1. In some embodiments, the APOL1-mediated renal disease is associated with a patient who has two APOL1 risk alleles, for example, who is homozygous or compound heterozygous for the G1 allele or the G2 allele. In some embodiments, the APOL1-mediated renal disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arteriosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1-mediated renal disease is chronic kidney disease or proteinuria.

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

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

[0030] The terms "ESKD" and "ESRD" are used interchangeably herein and refer to end-stage renal disease or end-stage renal disease. ESKD / ESRD refers to end-stage renal disease, i.e., kidney failure, where the kidneys do not function well enough to prevent the patient from surviving without dialysis or a kidney transplant. In some embodiments, ESKD / ESRD is associated with two APOL1 risk alleles.

[0031] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having identical chemical structures, unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic variations may exist among the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom shown also includes lesser amounts of isotopic substitutions having hydrogen atoms at one or more of the designated deuterium positions in the structure. The relative amounts of such isotopic substitutions in the compounds of the present disclosure will depend on several factors, including the isotopic purity of the reagents used to make the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as noted above, the relative amount of such isotopic substitutions overall will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitution overall will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0032] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally," refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

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

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

[0035] The term "tautomer" as used herein refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by migration of atoms, e.g., hydrogen atoms, or groups, within the molecule.

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

[0037] As used herein, a "deuterated derivative" has the same chemical structure as a reference compound, but contains a deuterium atom ("D" or " 2"Deuterated derivatives" refers to compounds having one or more hydrogen atoms replaced by deuterium at a level well above its natural isotopic abundance (typically about 0.015%). It will be recognized that some variation in natural isotopic abundance will occur in synthesized compounds depending on the source of the chemicals used in their synthesis. The concentration of naturally occurring stable hydrogen isotopes, despite this variation, is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Thus, unless otherwise specified, when reference is made to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen is replaced with deuterium at a level well above its natural isotopic abundance, which is typically about 0.015%. In some embodiments, deuterated derivatives of the present disclosure have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).

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

[0039] As used herein, the term "alkyl" or "aliphatic" refers to a straight-chain (i.e., linear or unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated. Unless otherwise specified, an alkyl group contains 1-20 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-10 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1-8 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1-6 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-4 alkyl carbon atoms, in other embodiments, an alkyl group contains 1-3 alkyl carbon atoms, and in still other embodiments, an alkyl group contains 1 or 2 alkyl carbon atoms. In some embodiments, an alkyl group is linear or straight-chain or unbranched. In some embodiments, an alkyl group is branched.

[0040] As used herein, the terms "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 In some embodiments, cycloalkyl refers to a hydrocarbon, and any individual ring within the aforementioned bicyclic ring system has 3 to 7 members. In some embodiments, cycloalkyl refers to a C3-C 12 In some embodiments, the cycloalkyl is a C-C cycloalkyl. In some embodiments, the cycloalkyl is a C-C cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0041] As used herein, the term "carbocyclyl" or "cycloaliphatic" encompasses the terms "cycloalkyl" or "cyclic alkyl" and refers to a monocyclic C alkyl group that is fully saturated or partially saturated so as to contain one or more saturated units, but is not aromatic. 3-8 hydrocarbon, or spirocyclic, fused, or bridged bicyclic or tricyclic C 8-14

[0023] refers to a hydrocarbon, and any individual ring of the bicyclic ring system has 3 to 7 members. Bicyclic carbocyclyl includes a combination of a monocyclic carbocycle fused to a phenyl. In some embodiments, carbocyclyl is a C3-C 12 In some embodiments, the carbocyclyl is C-C 10 In some embodiments, the carbocyclyl is a C3-C8 carbocyclyl.

[0042] As used herein, the term "heteroalkyl" or "heteroaliphatic" means an alkyl or aliphatic group, as defined above, in which one or two carbon atoms are independently replaced by one or more oxygen, sulfur, nitrogen, phosphorus, or silicon.

[0043] As used herein, the term "alkenyl" means a straight-chain (i.e., linear or unbranched) or branched hydrocarbon chain containing one or more double bonds. In some embodiments, an alkenyl group is straight-chain. In some embodiments, an alkenyl group is branched.

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

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

[0046] In some embodiments, a "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" group has 3 to 14 ring members, with one or more ring members being heteroatoms independently selected from oxygen, sulfur, nitrogen, silicon, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, a heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, a heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, a heterocycle has one heteroatom independently selected from oxygen, sulfur, nitrogen, silicon, and phosphorus, a quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (in the case of 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.

[0047] The term "unsaturated," as used herein, means that a moiety has one or more units or degrees of unsaturation. Unsaturation is a situation in which not all of the available valence bonds in a compound are satisfied by substituents, thus causing the compound to contain double or triple bonds.

[0048] The term "alkoxy" or "thioalkyl" as used herein refers to an alkyl group, as previously defined, in which one carbon of the alkyl group is replaced by an oxygen ("alkoxy") or sulfur ("thioalkyl") atom, respectively, provided that the oxygen and sulfur atoms are connected between two carbon atoms. "Cyclic alkoxy" refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group but is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl.

[0049] As used herein, the terms "haloalkyl," "haloalkenyl," and "haloalkoxy" mean straight-chain or branched alkyl, alkenyl, or alkoxy, respectively, substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF, -CHF, -CF, -CF-, and perhaloalkyl, such as -CFCF. Non-limiting examples of haloalkoxy groups include -OCHF, -OCHF, -OCF, and -OCF.

[0050] The term "halogen" includes F, Cl, Br, and I, ie, fluoro, chloro, bromo, and iodo, respectively.

[0051] The term "aminoalkyl" refers to an alkyl group that is substituted with or contains an amino group.

[0052] As used herein, "amino" refers to a group that is a primary, secondary, or tertiary amine.

[0053] As used herein, a "carbonyl" group refers to C=O.

[0054] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0055] As used herein, a "hydroxy" group refers to an --OH group.

[0056] As used herein, a "thiol" group refers to -SH.

[0057] As used herein, "tert" and "t-" each refer to tertiary.

[0058] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system having delocalized pi orbitals consisting of [4n+2]p electrons, where n is an integer ranging from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0059] The term "aryl," used alone or as part of a larger moiety, as in "arylalkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic, or spirocyclic, fused, or bridged bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, in which all rings in the system are aromatic rings containing only carbon atoms, and in which each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C6) and naphthyl (C 10 ) rings.

[0060] The term "heteroaryl," used alone or as part of a larger moiety, such as "heteroarylalkyl" or "heteroarylalkoxy," refers to a monocyclic, spirocyclic, fused, or bridged bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and at least one ring in the system contains one or more heteroatoms, and each ring in the bicyclic and tricyclic ring systems contains 3 to 7 ring members. Bicyclic heteroaryls include the following combinations of monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl. In some embodiments, a heteroaryl group has one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group has one heteroatom. In some embodiments, a heteroaryl group has two heteroatoms. In some embodiments, a heteroaryl group is a monocyclic ring system having five ring members. In some embodiments, a heteroaryl group is a monocyclic ring system having six ring members. In some embodiments, heteroaryl is a 3- to 12-membered heteroaryl. In some embodiments, heteroaryl is a 3- to 10-membered heteroaryl. In some embodiments, heteroaryl is a 3- to 8-membered heteroaryl. In some embodiments, heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, heteroaryl is a 5- to 8-membered heteroaryl. In some embodiments, heteroaryl is a 5- or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls include pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, and the like.

[0061] In some embodiments, the heteroaryl includes one or more ring atoms substituted with one or more oxo groups (e.g., C=O, S=O, or SO groups). Illustratively, a non-limiting example of a heteroaryl group is a benzo[d]oxazol-2(3H)-one group.

[0062] Non-limiting examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethylcarbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods for adding (a process commonly referred to as "protecting") and removing (a process commonly referred to as "deprotecting") such amine protecting groups are well known in the art, and are described, for example, in P.J. Kocienski, Protecting Groups, Thieme, 1994, and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999), which are incorporated herein by reference in their entireties. th Edition (John Wiley & Sons, New Jersey, 2014).

[0063] Non-limiting examples of suitable solvents that may be used in the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0064] Non-limiting examples of suitable bases that can be used in the present disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (KCO), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropyl-ethylamine (i-PrEtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH).

[0065] The present disclosure includes pharmaceutically acceptable salts of the disclosed compounds, which are formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0066] As used herein, the term "pharmaceutically acceptable" refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0067] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, and the like. benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0068] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4(Alkyl)4 salts are also included. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable, non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0069] The terms "patient" and "subject" are used interchangeably herein and refer to animals, including humans.

[0070] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of the compound that produces the desired effect for which it is administered (e.g., amelioration of symptoms of FSGS and / or NDKD, reduction in the severity of FSGS and / or NDKD, or alleviation of symptoms of FSGS and / or NDKD, and / or slowing the progression of FSGS and / or NDKD, or slowing the progression of symptoms of FSGS and / or NDKD). The exact amount of the effective dose will depend on the purpose of treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0071] As used herein, the term "treatment" and its cognate terms refer to the slowing or stopping of disease progression.As used herein, "treatment" and its cognate terms include, but are not limited to, complete or partial remission, lower risk of renal failure (e.g., ESRD), and disease-related complications (e.g., edema, susceptibility to infection, or thromboembolic events).The improvement or reduction in severity of any of these symptoms can be easily assessed according to methods and techniques known in the art or subsequently developed.

[0072] The terms "about" and "approximately," when used in reference to a dose, amount, or weight percent of a component of a composition or dosage form, include a particular dose, amount, or weight percent value, or a range of doses, amounts, or weight percent, that would be recognized by one of skill in the art as providing an equivalent pharmacological effect to that obtained from the particular dose, amount, or weight percent.

[0073] At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from 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 and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can 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 compounds 1-1183, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can 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, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those 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 compounds 1-1183, tautomers thereof, deuterated derivatives of those 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 compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those 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 compounds 1-1183, tautomers thereof, deuterated derivatives of those 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 compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those 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 compounds 1-1183, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered three times daily.

[0074] 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 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 1-1183, 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.

[0075] Those skilled in the art will recognize that when the amount of a compound is disclosed, the relative amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. The amounts of compounds, pharmaceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based on the free base form of the reference compound. For example, "1000 mg of at least one compound or pharmaceutically acceptable salt selected from the compound of Formula I and its pharmaceutically acceptable salts" includes 1000 mg of the compound of Formula I and a pharmaceutically acceptable salt of the compound of Formula I at a concentration equivalent to 1000 mg of the compound of Formula I.

[0076] As used herein, the term "ambient conditions" means room temperature, outside air conditions, and uncontrolled humidity conditions.

[0077] Compounds and Compositions In some embodiments, 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 and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be used to treat AMKD, including FSGS and NDKD. 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 1-1183, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, pharmaceutical compositions comprising at least one compound selected from Formulas 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, can be used to treat AMKD, including FSGS and NDKD. In some embodiments, the pharmaceutical compositions comprise at least one compound selected from Compounds 1-1183, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0078] Formula I: [ka] In some embodiments of 1 is selected from S, S(=O), and S(=O)2, and the variable X 2 -CR 2 In some embodiments of Formula I, the variable X 1 is S and the variable X 2 -CR 2 In some embodiments of Formula I, the variable X 2is selected from S, S(=O), and S(=O)2, and the variable X 1 -CR 2 In some embodiments of Formula I, the variable X 2 is S and the variable X 1 -CR 2 is.

[0079] In some embodiments, (variable X 1 and X 2 (including the embodiments discussed above, which define 2 is selected from hydrogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from —OH, halogen, and C1-C4 alkoxy groups), —C(═O)O(C1-C4 alkyl), —C(═O)NR n R o and a halogen group, R n and R o is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, and -(C1-C4 alkylene)R p independently selected from the group R p is selected from C3-C6 cycloalkyl groups.

[0080] In some embodiments, (variable X 1 and X 2 (including the embodiments discussed above, which define 2 are hydrogen, halogens, -CH2OH, -CH2(OH)CH3, and -C(=O)NR n R o In some embodiments, R 2 is hydrogen. In some embodiments, the variable X 1 and X 2 (including the embodiments discussed above, which define 2 is a halogen. In some embodiments, the variable X 1 and X 2 (including the embodiments discussed above, which define 2 is Br. In some embodiments, R 2 is Cl. In some embodiments, (variable X1 and X 2 (including the embodiments discussed above, which define 2 is CH3. In some embodiments, (variable X 1 and X 2 (including the embodiments discussed above, which define 2 is —CHOH. In some embodiments, R 2 is CH2(OH)CH3. In some embodiments, R 2 is -C(=O)OCH3.

[0081] In some embodiments, (variable X 1 and X 2 (including the embodiments discussed above, which define 2 is -C(=O)NR n R o , and a halogen group, R n and R o is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, and -(C1-C4 alkylene)R p independently selected from the group R p is selected from C3-C6 cycloalkyl groups. In some embodiments, the variable X 1 and X 2 (including the embodiments discussed above, which define 2 is -C(=O)NR n R o (R n is hydrogen and R o is CH3). In some embodiments, (variable X 1 and X 2 (including the embodiments discussed above, which define 2 teeth, -C(=O)NR n R o (R n is hydrogen and R o is CH substituted with a cyclopropyl group). In some embodiments, (variable X 1 and X 2 (including the embodiments discussed above, which define 2 teeth, -C(=O)NH CH2CH2CH3 (i.e., R n is hydrogen and R o is -CH2CH2CH3). In some embodiments, (variable X 1 and X 2 (including the embodiments discussed above), R 2 is -C(=O)NH CH2CF2 (i.e., R n is hydrogen and R o is -CH2CF2).

[0082] In some embodiments of Formula I, (variable X 1 , X 2 , and R 2 (including the embodiment described above), the variable R 1 is selected from cyano, halogen, —C1-C4 alkyl, —C1-C4 haloalkyl, and —C3-C6 cycloalkyl groups, wherein R 1 The -C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from -OH and -C1-C4 alkoxy groups.

[0083] In some embodiments of Formula I, (variable X 1 , X 2 , and R 2 (including the embodiment described above), the variable R 1 -CN, -Br, -Cl, -C1-C4 alkyl, -CH2OH, -CH2CF2, In some embodiments of Formula I, the variable X is selected from -CFCF, -CF, -CF, -CHOCH, -CHOCHCH, cyclopropyl, and cyclobutyl. 1 , X 2 , and R 2 (including the embodiment described above), the variable R 1 is selected from -CH, -CHOH, -CHCH, -CHCHCH, tert-butyl, -Cl, -CH-CF, -CFCF, and -CF. In some embodiments of Formula I, the variable X 1 , X 2 , and R2 (including the embodiment described above), the variable R 1 is deuterated, for example, -CDOCH2CH3.

[0084] In some embodiments of Formula I, (variable X 1 , X 2 , and R 2 (including the embodiment described above), the variable R 1 is CF3. In some embodiments of Formula I, the variable X 1 , X 2 , and R 2 (including the embodiment described above), the variable R 1 is Cl. In some embodiments of Formula I, the variable X 1 , X 2 , and R 2 (including the embodiment described above), the variable R 1 is —CH OH. In some embodiments of Formula I, the variable X 1 , X 2 , and R 2 (including the embodiment described above), the variable R 1 is —CH2CF3. In some embodiments of Formula I, the variable X 1 , X 2 , and R 2 (including the embodiment described above), the variable R 1 is -CF2CF3. In some embodiments of Formula I, (variable X 1 , X 2 , and R 2 (including the embodiment described above), the variable R 1 is -CH2(OH)CH3.

[0085] In some embodiments of Formula I, (variable X 1 and X 2 (including the embodiment described above), the variable R 1 and R 2 together with the carbon atom to which they are attached form a C6 aryl group.

[0086] In some embodiments of Formula I, (variable X 1 , X 2 (including the embodiment described above), the variable R 1 is -Cl, and the variable R 2 is —CHOH. In some embodiments of Formula I, the variable X 1 , X 2 (including the embodiment described above), the variable R 1 is Cl and the variable R 2 is —CH3. In some embodiments of Formula I, the variable X 1 , X 2 (including the embodiment described above), the variable R 1 is Cl and the variable R 2 is hydrogen. In some embodiments of Formula I, the variable X 1 , X 2 (including the embodiment described above), the variable R 1 is -Cl, and the variable R 2 is -Cl.

[0087] In some embodiments of Formula I, (variable X 1 , X 2 (including the embodiment described above), the variable R 1 is -CF3 and the variable R 2 is hydrogen. In some embodiments of Formula I, the variable X 1 , X 2 (including the embodiment described above), the variable R 1 teeth -CF2CF3, and variable R 2 is hydrogen. In some embodiments of Formula I, the variable X 1 , X 2 (including the embodiment described above), the variable R 1 is -CH2CF3 and the variable R 2 is hydrogen. In some embodiments of Formula I, the variable X 1 , X 2 (including the embodiment described above), the variable R 1 is -CF2 and the variable R 2 is —CHOH. In some embodiments of Formula I, the variable X 1 , X2 (including the embodiment described above), the variable R 1 is -CF3 and the variable R 2 is —CHOH. In some embodiments of Formula I, the variable X 1 , X 2 (including the embodiment described above), the variable R 1 is -CF3 and the variable R 2 is —CH2(OH)CH3. In some embodiments of Formula I, the variable X 1 , X 2 (including the embodiment described above), the variable R 1 is -CF3 and the variable R 2 is -Cl.

[0088] In some embodiments of Formula I, (variable X 1 , X 2 (including the embodiment described above), the variable R 1 is CH3 and the variable R 2 is hydrogen. In some embodiments of Formula I, the variable X 1 , X 2 (including the embodiment described above), the variable R 1 is CH2CH3 and the variable R 2 is hydrogen. In some embodiments of Formula I, the variable X 1 , X 2 (including the embodiment described above), the variable R 1 is CH2OH, and the variable R 2 is hydrogen.

[0089] In some embodiments of Formula I, the variables m and k are both zero, and the variable R 3a and R 3b In some embodiments of Formula I, the variable m is zero and the variable R 3b , the variable k is 1, and one R 3a In some embodiments of Formula I, the variable m is zero and the variable R 3b and the variable k is 2, and the two R 3a Brings about the existence of a variable.

[0090] In some embodiments of Formula I, (variable X 1 and X 2 , R 1 , R 2 Each R (including the embodiment described above) defines 3a are independently -OH, -CN, or -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, Each R a1 and R a2 are independently selected from hydrogen, C1-C4 alkyl, and —C(═O)(C1-C4 alkyl) groups; or Two R's 3a together form an oxo group, or Two R's 3a together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl group.

[0091] In some embodiments of Formula I, (variable X 1 and X 2 , R 1 , R 2 Each R (including the embodiment described above) defines 3a -OH, F, F2, CF2, -OCH3, -OCH2CH3, -OCH2(CH3)2, -OC(=O)CH3, NH2, NHC(=O)CH3, CN, [ka] In some embodiments of Formula I, the variable k is 1 and the variable R 3a -OH, F, F2, CF2, -OCH3, -OCH2CH3, -O-CH2(CH3)2, -OC(=O)CH3, NH2, NH-C(=O)CH3, CN, [ka] In some embodiments of Formula I, the variable X 1 and X 2 , R 1 , R 2 (including the embodiment described above that defines 3a -OH, F, F2, CF2, -OCH3, -OCH2CH3, -O-CH2(CH3)2, -OC(=O)CH3, NH2, NH-C(=O)CH3, CN, [ka] In some embodiments of Formula I, the variable X 1 and X 2 , R 1 , R 2 (including the embodiment described above that defines 3a is —OH. In some embodiments of Formula I, the variable X 1 and X 2 , R 1 , R 2 (including the embodiment described above), where the variable m is zero, the variable k is one, and the variable R 3a are -OCH3 and -OCH2CH3.

[0092] In some embodiments of Formula I, (variable X 1 and X 2 , R 1 , R 2 (including the embodiment described above that defines 3a The variables are selected from (a) —CF and —OH, (b) —CH and —OH, and (c) —OH and phenyl. In some embodiments of Formula I, the variable X 1 and X 2 , R 1 , R 2 (including the embodiment described above that defines 3a The variables are selected from: (a) -CF2 and -OH, (b) -CH3 and -OH, and (c) -OH and phenyl.

[0093] In some embodiments of Formula I, (variable X 1 and X 2 , R 1 , R 2 (including the embodiment described above), the variable R 3a is deuterated. In some embodiments, deuterated R 3a teeth, -O-CD3.

[0094] In some embodiments of Formula I, (variable X 1 and X 2 , R 1 , R 2 (including the embodiment described above), two R 3a together form an oxo group.

[0095] In some embodiments of Formula I, (variable X 1 and X 2 , R 1 , R 2 (including the embodiment described above), two R 3a together form a C3-C6 cycloalkyl group.

[0096] In some embodiments of Formula I, (variable X 1 and X 2 , R 1 , R 2 , and R 3a (including the embodiment described above), the variable R 3b is selected from C1-C3 alkyl optionally substituted with -OH or halogen. In some embodiments of Formula I, the variable X 1 and X 2 , R 1 , R 2 , and R 3a (including the embodiment described above), R 3b is CH3. In some embodiments of Formula I, the variable X 1 and X 2 , R 1 , R 2 , and R3a (including the embodiment described above), R 3b is selected from CF2 and CF3.

[0097] In some embodiments of Formula I, (variable X 1 and X 2 , R 1 , R 2 , k, m, R 3a , and R 3b (including the embodiment described above), the variable R 4a , R 4b , R 5a , and R 5b In some embodiments of Formula I, three of the variables R are hydrogen and the remaining variables are selected from C1-C4 alkyl groups. 4a , R 4b , R 5a , and R 5b In some embodiments of Formula I, three of the variables R are hydrogen and the remaining variables are selected from methyl, ethyl, cyclopropyl, fused cyclopropyl, and fused cyclobutyl. 4a , R 4b , and R 5a is hydrogen, and the variable R 5b is selected from methyl, ethyl, cyclopropyl, fused cyclopropyl, and fused cyclobutyl. In some embodiments of Formula I, the variable R 4a , R 5a , and R 5b is hydrogen, and the variable R 4b is selected from 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.

[0098] Variable X 1 and X 2 , R 1 , R 2 , k, m, R 3a , R 3b , R4a , R 4b , R 5a , and R 5b In the foregoing embodiments defining R 6 is C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), and [ka] is selected from the group R 6 wherein the C1-C6 alkyl is optionally substituted with 1 to 5 groups independently selected from 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 with 1 to 3 groups independently selected from halogen and C1-C4 haloalkyl groups), —O—(C6 aryl) (optionally substituted with 1 to 3 groups independently selected from halogen and C1-C4 haloalkyl groups), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups; Ring B is C3-C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C 10 aryl, and 5- to 10-membered heteroaryl groups, wherein ring B is selected from 1, 2, 3, 4, or 5 R a and optionally substituted with a group, wherein R a is, for each occurrence, halogen, cyano, C1-C8 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C1-C6 haloalkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Carbocyclyl, C6 and C 10Aryl, 3-12 membered heterocyclyl, 5-10 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 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) (1 to 3 R m optionally substituted with a -NR group, 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) (1 to 3 R m optionally substituted with -OR groups), 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 is independently selected from the group -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)-NRh C(=O)R k , -NR h C(=O)O(C1-C4 alkylene)R k , -NR h C(=O)(C1-C4 alkylene)-OR k , N.R. 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 wherein the C1-C4 alkylene in each of R a C1-C8 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C2-C8 alkenyl are each 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 5-8 membered heteroaryl) (1-3 R m C-C carbocyclyl (optionally substituted with 1 to 3 R m optionally substituted with a -C-C group), 10 Aryl (1 to 3 R m group), 4- to 10-membered heterocyclyl (1 to 3 R m aryl (optionally substituted with 1 to 3 R m optionally substituted with 1 to 3 groups independently selected from the group R a C3-C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl are each selected from halogen, cyano, C1-C6 alkyl (1 to 3 R m group), -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 heterocyclyl group, R h , R i , and R j Each occurrence of R is selected from hydrogen, C1-C6 alkyl (1 to 4 R m optionally substituted with a group), C-C 10 Aryl, C3-C8 carbocyclyl (1-3 R m aryl (optionally substituted with 1 to 3 R m groups), and 5- to 10-membered heterocyclyl (1-3 R mand optionally substituted with a group, wherein R h , R i , and R j Any one of the C1-C6 alkyl groups may be selected from halogen, cyano, —OH, C1-C4 alkoxy, —C(═O)NH(C1-C4 alkyl), 5-10 membered heteroaryl (1-3 R m groups), and 5- to 10-membered heterocyclyl (1-3 R m optionally substituted with 1 to 4 groups independently selected from the group R k is, for each occurrence, independently selected from hydrogen, NH, (optionally substituted with 1 or 2 groups selected from C-C alkyl), C-C alkyl, benzyl, C aryl, C-C carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups; R k wherein any one of the C1-C6 alkyl groups is optionally substituted with 1 to 5 groups independently selected from halogen, cyano, -NH2, -OH, C1-C6 alkoxy, C3-C6 cycloalkyl (optionally substituted with 1 to 3 halogen groups), 4-10 membered heterocyclyl (optionally substituted with 1 to 3 -OH groups), 5-10 membered aryl (optionally substituted with 1 to 3 groups selected from C1-C4 alkyl and halogen), and 5-10 membered heteroaryl (optionally substituted with 1 to 3 -OH groups); and R kwherein any one of the C3-C6 carbocyclyl, benzyl, and C6 aryl is each optionally substituted by 1 to 3 groups independently selected from halogen, cyano, oxo, -OH, -C(=O)NH2, -C(=O)N(CH3)2, C1-C4 alkyl (optionally substituted with 1 to 3 OH groups), C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl (optionally substituted with 1 to 3 halogen groups), C6 aryl (optionally substituted with 1 to 3 halogen groups), and 5-10 membered heteroaryl (optionally substituted with 1 to 3 halogen groups); R k wherein any one of the 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl is each optionally substituted by 1 to 3 groups independently selected from halogen, oxo, cyano, —C(═O)CH3, —NH2, —OH, C1-C4 alkyl (optionally substituted with 1 to 3 —OH groups), C1-C4 haloalkyl, 5- to 10-membered heterocyclyl, and C1-C4 alkoxy; R m is, for each occurrence, 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 heterocyclyl group, R m any one of C1-C6 alkyl, C1-C6 alkoxy, and 5- to 10-membered heterocyclyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C4 alkoxy groups; p, for 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 for each occurrence.

[0099] In some embodiments of Formula I (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 and in embodiments of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, - R 6 is 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 (halogen and and C1-C4 haloalkyl), —O—(C6 aryl) (optionally substituted with 1-3 groups independently selected from halogen and C1-C4 haloalkyl), 5- to 10-membered heterocyclyl, and C1-C6 alkyl optionally substituted with 1-5 groups independently selected from a 5- to 10-membered heteroaryl group.

[0100] In some embodiments of Formula I (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 and in embodiments of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 teeth, [ka] is an optionally substituted C1-C6 alkyl selected from:

[0101] In some embodiments of Formula I (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 and in embodiments of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 is selected from -C(=O)O(C1-C4 alkyl).

[0102] In some embodiments of Formula I (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 and in embodiments of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 is as defined above for formula I, [ka] In some of these embodiments, ring B is selected from 1, 2, 3, 4, or 5 R as defined for formula I. a C3-C optionally substituted with a group 12 In some of these embodiments, Ring B is selected from 3- to 12-membered heterocyclyl. In some of these embodiments, Ring B is selected from 1, 2, 3, 4, or 5 R as defined for Formula I. a C and C optionally substituted with groups 10 In some of these embodiments, ring B is selected from 1, 2, 3, 4, or 5 R aryl as defined for formula I. aThe heteroaryl group is selected from 5-10 membered heteroaryl groups optionally substituted with a group.

[0103] In some embodiments of Formula I (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 and in embodiments of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 teeth, [ka] and ring B is selected from 1, 2, 3, 4, or 5 R as defined for formula I. a optionally substituted with a group [ka] is selected from the group

[0104] In some embodiments of Formula I (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 and in embodiments of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 teeth, [ka] and ring B is selected from 1, 2, 3, 4, or 5 R as defined for Formula I a optionally substituted with a group [ka] is selected from the group

[0105] In some embodiments of Formula I (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 and in embodiments of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 teeth, [ka] wherein ring B is a 5-membered heteroaryl and R a is as defined for formula I.

[0106] In some embodiments of Formula I (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 and in embodiments of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 teeth, [ka] wherein ring B is a 5-membered heteroaryl and R a is oxo or C1-C8 alkyl, C3-C 12 Carbocyclyl, and C6 and C 10aryl, each of which may be optionally substituted with 1 to 3 groups selected from halogen and C1-C8 alkyl (C1-C8 alkyl may be optionally substituted with 1 to 3 groups selected from halogen, —OH, SO2CH3, and SO2NH2). In some embodiments of Formula I (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 and in embodiments of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R 6 teeth, [ka] is selected from.

[0107] In some embodiments of Formula I (variable 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 and in embodiments of formulae 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; R a The C1-C4 alkyl is optionally substituted with 1 to 3 polar groups, such as sulfone, sulfonamide, and alcohol.

[0108] The embodiments of Formula I (variable X 1 and X 2 , R 1 , R2 , k, m, R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , and R 6 and in embodiments of formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R a is C1-C6 alkyl optionally substituted as defined in Formula I. In some embodiments, R a C1-C6 alkyl is -OH, -SO2CH3, C1-C3 alkoxy, C(=O)NHCH3, -SO2NHCH2CH2OH, -SCF 3、 -S CH2C(CH2)2OH, -SO2phenyl, 4-6 membered heterocycle (1-3 R m aryl (optionally substituted with 1 to 3 R m optionally substituted with 1 to 3 groups selected from NHC(=O)-4 to 6-membered heteroaryl), cyano, and NHC(=O)-4 to 6-membered heteroaryl.

[0109] In some embodiments of Formula I (variable 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 and in embodiments of formulae 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 for formula I.

[0110] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is selected from compounds 1-1183 set forth in Table 1, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. [ka] depicts a bond between two atoms and indicates the location of mixed stereochemistry for a set of molecules such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. An asterisk (e.g., [ka] indicates a chiral position in the molecule.

[0111] In some embodiments, the compound of Formula I is selected from the compounds presented in Table I below, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 Table 1-67 Table 1-68 Table 1-69 Table 1-70 Table 1-71 Table 1-72 Table 1-73 Table 1-74 Table 1-75 Table 1-76 Table 1-77 Table 1-78 Table 1-79 Table 1-80 Table 1-81 Table 1-82 Table 1-83 Table 1-84 Table 1-85 Table 1-86 Table 1-87 Table 1-88 Table 1-89

Table 1-90

Table 1-100

Table 1-110

Table 1-120

Table 1-123

[0112] Some embodiments of the present disclosure include derivatives of compounds 1-1183, 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 in which at least one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-1183 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 is replaced with silicon. In some embodiments, the derivative is a boron derivative in which at least one carbon atom in Compounds 1-1183 or a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im is replaced with boron, a tautomer thereof, a deuterated derivative of such a compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. In other embodiments, the derivative is a phosphorus derivative in which at least one carbon atom in Compounds 1-1183 or a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im is replaced with phosphorus, a tautomer thereof, a deuterated derivative of such a compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0113] In some embodiments, the derivative is a silicon derivative in which one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-1183 or compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im is replaced with silicon or a silicon derivative (e.g., —Si(CH3)2— or —Si(OH)2—). The carbon replaced with silicon may be a non-aromatic carbon. In other embodiments, fluorine is replaced with a silicon derivative (e.g., —Si(CH3)3). In some embodiments, the silicon derivatives of the present disclosure may contain one or more hydrogen atoms replaced with deuterium. In some embodiments, the silicon derivative, tautomer, deuterated derivative, or pharmaceutically acceptable salt of a compound selected from compounds 1-1183 or compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, can have silicon incorporated within a heterocycle.

[0114] In some embodiments, the derivative is a boron derivative in which one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-1183 or compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with boron or a boron derivative.

[0115] In some embodiments, the derivative is a phosphorus derivative in which one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-1183 or compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with phosphorus or a phosphorus derivative.

[0116] Another aspect of the present disclosure provides pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of the formulas selected from compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, and compounds 1-1183, tautomers thereof, deuterated derivatives of those 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 compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, and compounds 1-1183, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered to a patient in need thereof.

[0117] The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the at least one pharmaceutically acceptable is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0118] It will also be understood that the pharmaceutical compositions of the present disclosure can be employed in combination therapy, i.e., the pharmaceutical compositions described herein can further comprise at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of 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 administered as a separate composition to a subject in need thereof, simultaneously with, before, or after a composition comprising at least one other active therapeutic agent. In some embodiments, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from Compounds 1-1183, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing may be administered as a separate composition simultaneously with, before, or after a composition comprising at least one other active therapeutic agent.

[0119] As mentioned above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, the at least one pharmaceutically acceptable carrier includes any solvent, diluent, other liquid vehicle, dispersion aid, suspension aid, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder, and lubricant suitable for the specific dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988 to 1999, Marcel Dekker, New York, disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), saturated vegetable fatty acids, partial glyceride mixtures of water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxymethylcellulose sodium), and the like. Examples of suitable carriers include, but are not limited to, cellulose acetate, sodium, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants. Compounds and Compositions for Use in Therapy

[0120] 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.

[0121] 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.

[0122] In some embodiments of the present disclosure, the compounds and pharmaceutical compositions described herein are used to treat pancreatic cancer. In some embodiments, the pancreatic cancer is mediated by APOL1.

[0123] In some embodiments, the methods of the present disclosure include administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those 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 1-1183, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the patient in need thereof has an APOL1 gene variant selected from the group consisting of G1;S342G:I384M and G2:N388del:Y389del.

[0124] In another aspect, the present disclosure provides a method for inhibiting APOL1 activity, comprising contacting the APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of 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 for inhibiting APOL1 activity comprises contacting the APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-1183, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. [Example]

[0125] In order that the disclosure set forth herein may be more fully understood, the following examples are set forth, it being understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any manner.

[0126] The compounds of the present invention can be made according to standard chemical practices or as described herein. The following abbreviations are used throughout the following synthetic schemes and in the descriptions for preparing compounds of Formulas I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, compounds 1-1183, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing: Abbreviation AcOH = acetic acid ARP = Assay Ready Plate BocO = di-tert-butyl dicarbonate n-BuLi = n-butyllithium CFL = Compact Fluorescent Lamp 18-Crown-6 = 1,4,7,10,13,16-Hexaoxacyclooctadecane DAST = diethylaminosulfur trifluoride DBDMH = 1,3-dibromo-5,5-dimethylhydantoin DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DCE = 1,2-dichloroethane DCM = dichloromethane Deoxo-fluor = bis(2-methoxyethyl)aminosulfur trifluoride DIBAL-H = diisobutylaluminum hydride DIPEA or DIEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMAP = dimethylaminopyridine DMA = dimethylacetamide DME = dimethoxyethane DMEM = Dulbecco's modified Eagle's medium DMF = dimethylformamide DMPU = N,N'-dimethylpropylene urea DMSO = dimethyl sulfoxide dppf = 1,1'-bis(diphenylphosphino)ferrocene ESI = electrospray ionization EtOAc = ethyl acetate EtOH = ethanol Et2O = diethyl ether Et2NH = diethylamine Et3N = triethylamine FA = formamide FBS = fetal bovine serum GF-AFC = glycyl-phenylalanylaminofluorocoumarin HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium(phosphorus hexafluoride) HDMC = N-[(5-chloro-3-oxido-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-methylmethanaminium hexafluorophosphate HPLC = high-performance liquid chromatography IPA = Isopropyl alcohol (Ir[dF(CF3)ppy]2(dtbpy))PF6 = [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate [Ir{dBMS3ppy}2(bpy)]PF6 = (2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-kN][phenyl-kC]iridium(III) hexafluorophosphate LDA = lithium diisopropylamide LED = Light Emitting Diode MeCN or ACN = acetonitrile MeI = methyl iodide MeMgCl = methylmagnesium chloride MeOH = methanol MsOH = methanesulfonic acid MTBE or TBME = methyl tert-butyl ether n-BuLi = n-butyllithium n-BuOH = 1-butanol NaOtBu = sodium tert-butoxide NBS = N-bromosuccinimide NCS = N-chlorosuccinimide NHPI = N-hydroxyphthalimide NIS = N-iodosuccinimide NMM = N-methylmorpholine NMP = N-methylpyrrolidine PBS = phosphate-buffered saline Pd(dppf)2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride pet = petroleum PP = Polypropylene PPh3 = triphenylphosphine PhMgCl = phenylmagnesium chloride PSCBH = polymer-supported cyanoborohydride PTSA = p-toluenesulfonic acid monohydrate RBF = Round Bottom Flask SFC = Supercritical Fluid Chromatography SPE = solid phase extraction STAB = sodium triacetoxyborohydride T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TBAF = tetra-n-butylammonium fluoride TBS = tert-butyldimethylsilyl TBSCl = tert-butyldimethylsilyl chloride TBTA = Tris((1-benzyl-4-triazolyl)methyl)amine TBuONO = tert-butyl nitrite tBuXPhos Pd G1 = [2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride t-BuOH = tert-butanol TEA = triethylamine tet = tetracycline TFA or TFAA = trifluoroacetic acid TfOH = trifluoromethanesulfonic acid THF = tetrahydrofuran T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide 2-Me-THF = 2-methyltetrahydrofuran THP = tetrahydropyran TLC = thin layer chromatography TMS-OTf = trifluoromethanesulfonic acid trimethylsilyl ester TMSCl = trimethylsilyl chloride TMSCF3 = trifluoromethyltrimethylsilane XPhos Pd G3 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0127] Example 1. Synthesis of Compounds All specific and generic compounds, and intermediates disclosed for making those compounds, are considered to be part of the disclosure disclosed herein.

[0128] Preparation S1 (2'S,4R)-2-Ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S1) [ka] Step 1. Synthesis of (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (C1) To a solution of tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate (10 g, 46.89 mmol) and 2-(5-ethyl-2-thienyl)ethanol (7 g, 42.56 mmol) in dioxane (80 mL) was added a solution of trifluoromethanesulfonic acid (12.4 mL, 140.1 mmol) in dioxane (20 mL) over 15 minutes at 0 °C. The reaction was stirred at the same temperature for 1 hour, then warmed to ambient temperature and stirred for 3.5 hours. The mixture was diluted with water (300 mL) and ethyl acetate (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL × 2). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was dissolved in DCM and filtered through a plug of silica gel (250 g) eluting with DCM followed by 25% MeOH / DCM to give the desired product. The product was dissolved in EtO (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 give the title compound (11.36 g, 67%) as a gray solid (triflate salt). 1 H NMR(400MHz,DMSO-d6)δ 6.46(d,J=1.1Hz,1H),3.96~3.79(m,2H),3.42~3.34(m,1H),3.27~3.00(m,2H),2.8 0~2.63(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] + .

[0129] 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) To a mixture of (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]C1 (triflate salt) (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 stirred at 45 °C for 5 h, then cooled to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (350 mL), brine (150 mL), and 2 M aqueous Na2SO3 (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 material was triturated with Et2O. The resulting colorless solid was filtered and dried to give S1 (55.7 g, 92%). 1 H NMR (300MHz, chloroform-d)δ 6.47(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] + .

[0130] Preparation S2 (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) [ka] Compound S2 was prepared from S1 and 3-azidoazetidine using the same method as described for compound 1.

[0131] compound 1 (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) [ka] 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) 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 reaction was stirred at room temperature for 2 h. The volatiles were then removed, and the crude material was purified by reverse-phase chromatography (C18 column, gradient: MeCN in HO 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 / z 496.14[M+H] + .

[0132] Compounds 2~5 Compounds 2-5 (see Table 2) were prepared from S2 using the appropriate sulfonyl chloride using the same method as described for compound 1. All sulfonyl chlorides were obtained from commercial sources unless otherwise noted. Any modifications to the method are described in Table 2 and the accompanying footnotes. [Table 2-1] [Table 2-2]

[0133] Preparation S3 2-Azido-N-(2-hydroxyethyl)ethane-1-sulfonamide (S3) [ka] 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"). The volatiles were removed to provide the title compound. The crude was used directly without further purification.

[0134] Preparation S4 2-Azido-N-(2-hydroxypropyl)ethane-1-sulfonamide (S4) [ka] Compound S4 was prepared from 2-azidoethanesulfonyl chloride and 1-aminopropan-2-ol using the same method as described for S3. The crude title compound was used directly without further purification.

[0135] compound 6 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) [ka] Preparation of 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) To a solution of 2-azido-N-(2-hydroxyethyl)ethane-1-sulfonamide (67.9 mg, 0.35 mmol) in MeOH (2 mL) and HO (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]SI (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 h. After cooling to room temperature, the mixture was diluted with DCM and HO. 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 was purified by reverse phase chromatography (C18 column; gradient: MeCN in H2O containing 0.1% HCl) to give the title compound (13.9 mg, 17%). 1 H NMR(400MHz,DMSO-d6)δ 8.54(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] + .

[0136] compound 7 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-hydroxypropyl)ethanesulfonamide (7) [ka] Preparation of 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-hydroxypropyl)ethanesulfonamide (7) 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 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)δ 8.53(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] + .

[0137] compound 8 (2'S,4R)-2-ethyl-2'-methyl-1'-(1H-triazol-4-ylmethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (8) [ka] 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) 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 Cul (30 mg, 0.16 mmol). The mixture was stirred at room temperature 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%). 1 H NMR(400MHz,DMSO-d6)δ 8.53(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 333.16[M+H] + .

[0138] Preparation of S5 and S6 (2'R,4R)-2-Ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S5) (2'R,4S)-2-Ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S6) [ka] 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) To a solution of 2-(5-ethyl-2-thienyl)ethanol (1.0 g, 6.4 mmol) and tert-butyl (2R)-2-methyl-4-oxo-piperidine-1-carboxylate (1.5 g, 7.03 mmol) in dioxane (5 mL) was slowly added a solution of trifluoromethanesulfonic acid (1.8 mL, 20.34 mmol) in dioxane (15 mL). The mixture was stirred at room temperature overnight. The mixture was diluted with HO and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc (x2). The combined organic extracts were dried over NaSO, filtered, and concentrated in vacuo. The crude was purified to give the title compounds S5 (2.0 g, 23% purity, 18%) and S6 (2.0 g, 77% purity, 60%) as triflate salts. LCMS m / z 252.11 [M+H] + .

[0139] compound 9 (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) [ka] Step 1. Synthesis of (2R,4R)-2'-ethyl-2-methyl-1-(prop-2-yn-1-yl)-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran (C2) To a solution of (2'R,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] S5 (triflate salt) (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 stirred at 45 °C for 8 h, then cooled to room temperature and stirred overnight. The reaction was diluted with EtOAc (350 mL), brine (150 mL), and 2 M 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 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] + .

[0140] 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) 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, 23% purity) in MeOH (12.75 mL) and HO (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-methylsulfonylethane (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 NaHCO3 solution and HO (1:1, 50 mL). The aqueous washes were back-extracted with EtOAc (25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material 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=6.6Hz,2H),4.13(s,2H),3.91(td,J=6.6 ,5.9,3.3Hz,2H),3.77(t,J=6.6Hz,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). LCMS m / z 440.27[M+H] + .

[0141] compound 10 (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) [ka] Step 1. Synthesis of (2'R,4S)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (C2) To a solution of (2'R,4S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (triflate salt)) 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 prop-2-ynyl 4-methylbenzenesulfonate (500 μL, 2.90 mmol). The reaction mixture was stirred at 30 °C overnight. The reaction mixture was diluted with EtOAc (30 mL), HO (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 NaSO, filtered, and concentrated in vacuo. The crude material was purified using silica gel chromatography (10-35% EtOAc in hexanes) to afford C2 (350 mg, 44%). 1 H NMR (300MHz, chloroform-d)δ 6.41(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] + .

[0142] 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) To a solution of (2'R,4S)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[3a,6,7,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]C2 (350 mg, 1.20 mmol) in MeOH (8 mL) and HO (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 room temperature, and then a solution of 1-azido-2-methylsulfonylethane (200 mg, 1.34 mmol) in MeOH (2 mL) was added dropwise via an addition funnel. The mixture was stirred at room temperature for 2 hours. The reaction 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 give a tan solid. Purification by silica gel chromatography (0-40% EtOAc in hexanes) gave 10 (448 mg, 81%). 1 H NMR (300MHz, chloroform-d)δ 7.66(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] + .

[0143] compound 11 (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) [ka] Preparation 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] (11) 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 material was suspended in EtOAc and heated at 50°C for 10 minutes. The mixture was diluted with EtO, cooled to 0°C, and stirred for 10 minutes. The mixture was filtered, and the cake was washed with EtO and dried to give the title compound (595 mg, 70%). 1 H NMR(400MHz,DMSO-d6)δ 8.08(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] + .

[0144] compound 12 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) [ka] 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) To a solution of 2-amino-N-methyl-ethanesulfonamide (HCl salt) (55 mg, 0.31 mmol) in THF (2.5 mL) and HO (1 mL) was added CuSO (1 mg, 0.0063 mmol) and KCO (30 mg, 0.2171 mmol), followed by N-diazoimidazole-1-sulfonamide(tetrafluoroborate) (120 mg, 0.46 mmol). The reaction was stirred at room temperature overnight. Then, 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 added to the reaction. The resulting mixture was stirred at 55 °C for 30 min. The reaction was cooled to room temperature, and the volatiles were removed. The crude material was then purified by reverse-phase chromatography (C18 column, gradient: MeCN in HO with 0.1% TFA) to give the desired product as the 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 as the free base (53.5 mg, 70%). 1 H NMR(400MHz,chloroform-d)δ 7.54(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=6.4Hz,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] + .

[0145] Preparation S7 Azido(methylsulfonyl)methane (S7) [ka] Preparation of azido(methylsulfonyl)methane (S7) To a solution of bromo(methylsulfonyl)methane (100 mg, 0.58 mmol) in DMF (3 mL) was added sodium azide (150 mg, 2.31 mmol). The resulting mixture was heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo. The crude was dissolved in DCM (5 mL) and filtered again. The filtrate was concentrated in vacuo to give the title compound as a red oil (75 mg, 82%). The crude was 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).

[0146] Preparation S8 1-(azidomethylsulfonyl)ethane (S8) [ka] Preparation of 1-(azidomethylsulfonyl)ethane (S8) Compound S8 was prepared from 1-(bromomethylsulfonyl)ethane using the same method as described for S7. The crude title compound was isolated as a red oil (300 mg, 88%) and used directly without further purification.

[0147] compound 13 (2'S)-2-Ethyl-2'-methyl-1'-[[1-(methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (13) [ka] 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) 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), and HO (2 mL) in MeOH (3 mL) was added CuSO (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 min. After cooling to room temperature, the mixture was concentrated. The crude material was purified by silica gel chromatography (0-10% MeOH in DCM) to give the title compound (59 mg, 85%). 1 H NMR (400MHz, chloroform-d)δ 7.81(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,3 H),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). LCMS m / z 425.52[M+H] + .

[0148] compound 14 (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) [ka] 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) 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 method as described for 13. The crude was purified using silica gel chromatography (0-100% EtOAc in heptane) to give 14 as a clear oil (46 mg, 67%). 1 H NMR (400MHz, chloroform-d)δ 7.81(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),2.78~2.5 2(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] + .

[0149] compound 15 tert-Butyl (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-carboxylate (15) [ka] Preparation of tert-butyl (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-carboxylate (15) To a solution of tert-butyl (R)-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 HO (75 μL) and a solution of NaHCO in HO (75 μL), followed by a solution of trifluazide (0.15 mL, 0.45 mmol) in DCM. After stirring the mixture at room temperature for 1 h, 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 HO (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 material was purified by reverse-phase chromatography (C18 column, gradient: MeCN in HO with 0.1% TFA) to give 15 (5.3 mg, 30%). 1 H NMR (300MHz, methanol-d4)δ 8.01(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] + .

[0150] compound 16 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) [ka] 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) To a solution of 5-aminopyridin-3-ol (18 mg, 0.16 mmol) in MeCN (2 mL) was added dropwise tBuONO (0.28 mL, 0.24 mmol) and TMS azide (0.025 mL, 0.19 mmol). After stirring at room temperature for 2 h, (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 CuSO (1.2 mg, 0.008 mmol) and sodium ascorbate (30 mg, 0.17 mmol) in HO (0.2 mL). The resulting mixture was stirred at 65 °C overnight. After cooling to room temperature, the crude was purified by reverse-phase chromatography (C18 column, gradient: MeCN in HO with 0.1% TFA) to give the desired product as a TFA salt. The product was dissolved in DCM (2 mL) and treated with a saturated aqueous solution of NaHCO (2 mL). The organic layer was isolated and concentrated in vacuo to give the title compound as the free base (15.4 mg, 33%). 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] + .

[0151] Compounds 17~197 Compounds 17-197 (see Table 3) were prepared from S1 using the appropriate amine using general methods B or C. Unless otherwise noted, all amines were obtained from commercial sources. Any modifications to the method are described in Table 2 and the accompanying footnotes. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21 Table 3-22 Table 3-23 Table 3-24 Table 3-25 Table 3-26 Table 3-27 Table 3-28 Table 3-29 Table 3-30 Table 3-31 Table 3-32 Table 3-33 Table 3-34 Table 3-35 Table 3-36 Table 3-37 Table 3-38 Table 3-39 Table 3-40 Table 3-41 Table 3-42 Table 3-43 Table 3-44 Table 3-45 Table 3-46 Table 3-47 Table 3-48 Table 3-49 Table 3-50 Table 3-51 Table 3-52 Table 3-53 Table 3-54 Table 3-55 Table 3-56 Table 3-57 Table 3-58 Table 3-59 Table 3-60 Table 3-61 Table 3-62 Table 3-63 Table 3-64 Table 3-65 Table 3-66

[0152] Compound 198 (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) [ka] Step 1. 2-Chloro-5-(chloromethyl)pyrimidine (C4) A bottom flask was charged with (2-chloropyrimidin-5-yl)methanol (1 g, 6.92 mmol) and thionyl chloride (12.5 mL, 171 mmol). DMF (32.5 μL, 0.42 mmol) was added to the suspension, and the resulting mixture was heated at reflux for 5 h. Upon heating, the mixture dissolved to form a clear, yellow, homogeneous solution. Upon complete conversion, the reaction was cooled to ambient temperature and then concentrated in vacuo. The crude material was azeotroped with dichloroethane (×2) and dried to constant weight under high vacuum to give C4 (1.08 g, 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] + .

[0153] 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) A solution of (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (triflate salt) (2 g, 4.99 mmol), 2-chloro-5-(chloromethyl)pyrimidine (3 g, 6.07 mmol), K2CO3 (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 Na2SO3 (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0-33% EtOAc / hexanes to give 198 (1.34 g, 70%). 1 H NMR (300MHz, chloroform-d)δ 8.62(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] + .

[0154] Compound 199 (2'S,4R)-1'-[(6-chloro-3-pyridyl)methyl]-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (199) [ka] Preparation of (2'S,4R)-1'-[(6-chloro-3-pyridyl)methyl]-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (199) A mixture of (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (triflate salt) S1 (2 g, 4.99 mmol), 2-chloro-5-(chloromethyl)pyridine (900 mg, 5.56 mmol), K2CO3 (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 HO (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 material was purified by silica gel chromatography eluting with 0-33% EtOAc / hexanes 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(td d,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] + .

[0155] compound 200 [(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) [ka] 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) 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), and tBuXPhos Pd G1 (2.41 mg, 0.0037 mmol) in tBuOH (560 μL) was degassed with N, followed by the addition of a 2 M solution of NaOtBu in tBuOH (48 μL). The resulting mixture was heated at 85 °C for 3 h. After cooling to ambient temperature, the reaction was quenched with MeOH. The solvent was removed in vacuo and the crude was purified by reverse phase chromatography (C18 column, gradient: MeCN in H2O with 0.1% TFA) to give 200 (2.2 mg, 8.3%). LCMS m / z 455.58 [M+H] + .

[0156] Compound 201 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) [ka] 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) 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 reaction was heated in a microwave at 230 °C for 6 h. After cooling to room temperature, the reaction was diluted with DCM and washed with HO (×3). The organic layer was separated and concentrated in vacuo. The crude was purified by reverse-phase chromatography (C18 column, gradient: MeCN in HO with 0.1% TFA) to give 201 as the TFA salt (3.6 mg, 9%). 1 H NMR (300MHz, methanol-d4)δ 8.24(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=13.6 Hz, 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] + .

[0157] Compound 202 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) [ka] 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) A mixture of (2'S)-1'-[(6-chloro-3-pyridyl)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), and tBuXPhos Pd G1 (2.50 mg, 0.0038 mmol) in tBuOH (500 μL) was degassed with N, followed by the addition of a 2 M solution of NaOtBu in tBuOH (42 μL). The resulting mixture was heated at 60 °C for 3 h. After cooling to ambient temperature, the reaction was quenched with MeOH. The solvent was removed in vacuo and the crude was purified by reverse phase chromatography (C18 column, gradient: MeCN in H2O with 0.1% TFA) to give 202 (11.9 mg, 49%). 1 H 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).

[0158] Compounds 203~231 Compounds 203-231 (see Table 4) were prepared from 198 or 199 using the appropriate amine using the general method for 200-202. All amines were obtained from commercial sources unless otherwise noted. Any modifications to the method are described in Table 4 and the accompanying footnotes. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7]

[0159] compound 232 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) [ka] 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) To a solution of (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (triflate salt) 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 reaction was heated in a microwave at 150 °C for 6 h. After cooling to ambient temperature, the volatiles were removed in vacuo, and the crude was purified by reverse-phase chromatography (C18 column, gradient: MeCN in HO 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 (300 MHz, chloroform-d) δ 9.16(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),2.4 4~2.24(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: 1H NMR(300MHz,chloroform-d)δ 8.56(s,1H),6.54(d,J=1.0Hz,1H),4.73(t,J=6.3Hz,1H),4.35~4.01(m,3H),3.9 9~3.79(m,2H),3.60(dd,J=9.8,5.9Hz,1H),3.49(d,J=10.3Hz,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] + .

[0160] Compounds 234~263 Compounds 234-263 (see Table 5) were prepared from C1 using the appropriate epoxide using the epoxide ring-opening method described for 232 and 233. All epoxides were obtained from commercial sources unless otherwise noted. Any modifications to the method are described in Table 5 and the accompanying footnotes. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6]

[0161] Preparation S9 (2'S,4S)-2-Ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S9) [ka] Step 1: tert-Butyl (2'S,4S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate (C6) A solution of 2-(5-ethyl-2-thienyl)ethanol (103 mg, 0.622 mmol), tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate (144 mg, 0.675 mmol) in DCM (1 mL) was added at -78°C. ℃ The mixture was cooled to RT. MsOH (0.1 mL, 1.54 mmol) was added dropwise and the resulting solution was stirred for 2 h. Triflic acid (0.1 mL, 1.13 mmol) was added and the reaction was stirred at -78 °C for 1 h. Water (15 mL) and DCM (15 mL) were added and the pH was adjusted to approximately 10 using 2 N NaOH. The aqueous layer was extracted with DCM (3 × 15 mL) and filtered to give a yellow gel. The crude product was dissolved in DCM (1 mL) and EtN (0.2 mL, 1.43 mmol) was added, followed by boc anhydride (0.2 mL, 0.870 mmol). The reaction mixture was stirred at room temperature for 3 h. The solution was diluted with DCM and washed with water (10 mL). The aqueous layer was extracted with DCM (2 × 10 mL), dried over NaSO, and filtered. Purification by silica gel chromatography (gradient: 0-60% EtOAc in heptane) afforded tert-butyl (2'S,4S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate 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). (MeOH peak under 1H).

[0162] Step 2: (2'S,4S)-2-Ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] S9 To a stirred solution of tert-butyl (2'S,4S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate C6 (105 mg, 0.299 mmol) in DCM (1 mL) was added 4 M HCl in dioxane (0.16 mL of 4 M, 0.660 mmol), and the reaction was stirred at room temperature for 4 h. Concentration and purification by preparative HPLC (mobile phase A: 0.1% FA (aqueous), mobile phase B: acetonitrile) gave (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)δ 6.56(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).

[0163] Preparation S10 2-(4-Formylpyrazol-1-yl)-N-methyl-ethanesulfonamide (S10) [ka] Step 1: 2-(4-Formylpyrazol-1-yl)-N-methyl-ethanesulfonamide (S10) A solution of 1H-pyrazole-4-carbaldehyde C8 (250 mg, 2.60 mmol), N-methylethenesulfonamide 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 h, the mixture was cooled to room temperature, and the reaction 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) and then DCM (2 × 20 mL), dried over NaSO, filtered, and concentrated. Purification by silica gel chromatography (gradient: 0–10% methanol in DCM) afforded 2-(4-formylpyrazol-1-yl)-N-methyl-ethanesulfonamide S10 (565 mg, 54%). 1 H NMR(400MHz,DMSO-d6)δδ 9.80(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] + .

[0164] Preparation S11 1-(2-Methylsulfonylethyl)pyrazole-4-carbaldehyde (S11) [ka] Step 1: 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (S11) A solution of 1H-pyrazole-4-carbaldehyde C8 (1 g, 10.4 mmol), 1-methylsulfonylethylene 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 reaction 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) and then DCM (2 × 20 mL), dried over NaSO, filtered, and concentrated. Purification by silica gel chromatography (gradient: 0–10% methanol in DCM) afforded 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde S11 (1.3 g, 58%). 1H NMR (400MHz, chloroform-d)δ 9.90(s,1H),8.10(d,J=0.7Hz,1H),8.06(d,J=0.6Hz,1H),4.75~4.63(m,2H),3.70(tdd,J=6.0,1.4,0.7Hz,2H),2.66(t,J=0.7Hz,3H). LCMS m / z 203.34[M+H] + .

[0165] Preparation S12 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (S12) [ka] Step 1: 2-(Bromomethyl)-2-methyl-propane-1,3-diol (C11) To a solution of (3-methyloxetan-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) oC11 (13.6 g, 74%) was obtained. 1 H NMR (400 MHz, methanol-d₄) δ 3.47 (d, J = 1.1 Hz, 6H), 0.96 (s, 3H).

[0166] Step 2: [2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propoxy]-tert-butyl-dimethyl-silane (C12) To a solution of 2-(bromomethyl)-2-methyl-propane-1,3-diol C11 (10 g, 54.1 mmol) in DCM (200 mL) was added imidazole (7.7 g, 113.1 mmol), followed by TBSCl (17 g, 112.8 mmol). After 5 min, the solid was filtered and washed with DCM. The filtrate was diluted with heptane (25 mL), and the solid was filtered and washed with heptane (10 mL). The filtrate was concentrated to give [2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propoxy]-tert-butyl-dimethyl-silane C12 (22.2 g, 99%). 1 H NMR (400MHz, chloroform-d) δ 3.44(s,4H),3.40(s,2H),0.94(s,3H),0.89(s,18H),0.04(d,J=1.2Hz,12H).

[0167] Step 3: 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (S12) To a solution of 1H-pyrazole-4-carbaldehyde 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-propoxy]-tert-butyl-dimethyl-silane C12 (9.5 g, 23.1 mmol) and stirred at 110 °C for 35 min. The mixture was cooled to room temperature, filtered, rinsed with acetonitrile, and concentrated. Purification by silica gel chromatography (gradient: 30-60% EtOAc in heptane) gave 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde S12 (2.39 mg, 23%). 1 H NMR (400 MHz, chloroform-d) δ 9.85 (s, 1H), 7.98-7.91 (m, 2H), 4.12 (s, 2H), 3.43-3.29 (m, 4H), 0.91 (s, 18H), 0.84 (s, 3H), 0.05 (d, J = 0.6 Hz, 12H). LCMS m / z 427.31 [M+H] + .

[0168] compound 264 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 [ka] 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) 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) afforded 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 H NMR(400MHz,chloroform-d)δ 7.60~7.44(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 / z 453.46 [M+H] + .

[0169] Compounds 265~277 Compounds 265-277 (Table 6) were prepared from an 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 aldehyde was prepared by the method described above or obtained from a commercial source. Any modifications to the method are described in Table 6 and the accompanying footnotes. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6]

[0170] compound 278 (2'S,4R)-2-Ethyl-1'-(2-methoxyethyl)-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] [ka] Step 1: (2'S,4R)-2-Ethyl-1'-(2-methoxyethyl)-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (278) 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 MeCN (8 mL) in DMF (1 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 (Aq), mobile phase B: acetonitrile), and the pure fractions were collected to give (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):δ 6.60(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). LCMS m / z 310.2 [M+H] + .

[0171] compound 279 (2'S,4R)-2-Ethyl-1'-(isoxazol-3-ylmethyl)-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] [ka] 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) 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 overnight at room temperature. 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 gave (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=14.55Hz,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 / z 333.0 [M+H] + .

[0172] Compounds 280~298 Compounds 280-298 were prepared from intermediate C1 and the corresponding commercially available alkyl halides using the method described for compounds 278 and 279. Any modifications to the method are described in Table 7 and the accompanying footnotes. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6]

[0173] Preparation of Compound 299 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]methyl]cyclobutanamine (299) [ka] 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'-piperidine]-1'-yl]methyl]cyclobutyl]carbamate (1039) 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 at 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 1 N NaOH (2 × 100 mL), dried over NaSO, filtered, and evaporated in vacuo. Purification by silica gel chromatography (120 g column, 0-5% MeOH in DCM) gave 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)δ 6.49(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),2.0 0~1.76(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] + .

[0174] Step 3. Synthesis of 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]cyclobutanamine (299) 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 a 4 M solution of HCl in dioxane (10 mL, 40.00 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to give crude 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) (1.7 g, 96%). LCMS m / z 334.68 [M+H] + .

[0175] compound 300 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) [ka] 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]cyclobutanamine (hydrochloride) 299 (20 mg, 0.05979 mmol) and 3,3-difluorocyclobutanecarboxylic acid (8.1 mg, 0.05979 mmol) were dissolved in DMF, to which was added HDMC (32.7 mg, 0.07175 mmol) and 4-methylmorpholine (20 μL, 0.1794 mmol). The reaction was stirred at room temperature for 1 hour. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid. The product N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]cyclobutyl]-3,3-difluoro-cyclobutanecarboxamide (trifluoroacetate) (300) (17 mg, 50%) was obtained. LCMS m / z 453.24 [M+H] + .

[0176] Compound 301 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) [ka] 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) 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) to which was added T3P (38.5 mg, 0.1210 mmol)) and DIPEA (21 μL, 0.1206 mmol). The reaction was allowed to stir overnight at room temperature. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid to give 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] + .

[0177] Compound 302 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) [ka] Synthesis 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) 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 to this was added methyl carbonochloridate (5 μL, 0.06471 mmol) and triethylamine (15 μL, 0.1076 mmol). The reaction was stirred at room temperature for 2 hours, after which the solvent was evaporated in vacuo. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid gave 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] + .

[0178] Compounds 303~384 Compounds 303-384 (see Table 8) were prepared from intermediate 299 using the appropriate reagents and the amide formation method described for compounds 300-302. Coupling partners were obtained from commercial sources. Any modifications to the method are described in Table 8 and the accompanying footnotes. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] Table 8-7 Table 8-8 Table 8-9 Table 8-10 Table 8-11 Table 8-12 Table 8-13 Table 8-14 Table 8-15 Table 8-16 Table 8-17 Table 8-18 Table 8-19 Table 8-20

[0179] Compound 385 6-[2-[2-[2-(6-chlorohexoxy)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) [ka] Preparation of 6-[2-[2-[2-(6-chlorohexoxy)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) 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). To this was added 6-[2-[2-[2-(6-chlorohexoxy)ethoxy]ethoxy]ethoxy]hexanoic acid (25 mg, 0.06529 mmol), DIPEA (50 μL, 0.2871 mmol), and HATU (24 mg, 0.06312 mmol), 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-chlorohexoxy)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) (385) (24 mg, 55%). LCMS m / z 699.24 [M+H] + .

[0180] Compound(386) 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]ethyl N-[2-[2-(6-chlorohexoxy)ethoxy]ethyl]carbamate (386) [ka] Preparation of 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]ethyl N-[2-[2-(6-chlorohexoxy)ethoxy]ethyl]carbamate (386) 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 to this was added 2-[2-[2-[2-[2-(6-chlorohexoxy)ethoxy]ethylcarbamoyloxy]ethoxy]ethoxy]ethyl(4-nitrophenyl)carbonate (59 mg, 0.1044 mmol) and DIPEA (75 μL, 0.4306 mmol), 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 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]ethyl N-[2-[2-(6-chloroethoxy)ethoxy]ethyl]carbamate (formate) (386) (25 mg, 35%). LCMS m / z 760.27 [M+H] + .

[0181] Compound 387 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-trifluoroacetamide (387) [ka] 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) 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 to this was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (9 μL, 0.06475 mmol) and DIPEA (19 μL, 0.1091 mmol). The reaction was stirred at room temperature for 2 hours, after which 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] + .

[0182] Compound 388 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) [ka] 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) 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 to this was added TEA (20 μL, 0.1435 mmol). The reaction was stirred at room temperature for 2 hours, after which the solvent was evaporated and the crude material was redissolved in minimal MeOH. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid 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-hydroxy-ethanesulfonamide (trifluoroacetate) (388) (5.6 mg, 20%). LCMS m / z 443.14 [M+H] +

[0183] Compounds 389~417 Compounds 389-417 (see Table 9) were prepared in a single step from intermediate 299 using the coupling method for 388. The sulfonyl chlorides were obtained from commercial sources. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9]

[0184] Preparation S13 tert-Butyl N-(3-formylcyclobutyl)carbamate (S13) [ka] Preparation of tert-butyl N-(3-formylcyclobutyl)carbamate (S13) tert-Butyl N-[3-(hydroxymethyl)cyclobutyl]carbamate (263 mg, 1.269 mmol) was dissolved in DCM (4 mL) and Dess-Martin perliodate (1.211 g, 2.855 mmol) was added. The reaction was stirred at room temperature for 3 h, after which it was filtered through a SiO2 plug with DCM eluent and evaporated in vacuo. Purification by silica gel chromatography (4 g column, 0-40% EtOAc in heptane) gave the product tert-butyl N-(3-formylcyclobutyl)carbamate (S13) (117 mg, 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] + .

[0185] Preparation of Compound 419 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]methyl]cyclobutanamine (419) [ka] 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'-piperidine]-1'-yl]methyl]cyclobutyl]carbamate (418) 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 g, 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 reaction was filtered, and the filtrate was diluted with DCM (10 mL). The organic phase was washed with 1 M NaOH (10 mL), dried over NaSO, filtered, and evaporated in vacuo. Purification by silica gel chromatography (4 g column, 0-10% MeOH in DCM) gave 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), 2.86–1.59 (m, 17H), 1.46 (s, 9H), 1.28 (t, J = 7.5 Hz, 3H), 1.10 (d, J = 6.2 Hz, 3H). LCMS m / z 435.40 [M+H]+ .

[0186] Step 2. Synthesis of 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]cyclobutanamine (trifluoroacetic acid (2)) (419) 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 by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid gave 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] + .

[0187] Preparation of Compound 421 (2'S,4R)-1'(azetidin-3-ylmethyl)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (421) [ka] 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'-piperidine]-1'-yl]methyl]azetidine-1-carboxylate (420) 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 at 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. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (120 g column, 0-5% MeOH in DCM) gave the product tert-butyl N-[3-[[(2′S,4R)-2-ethyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-yl]methyl]azetidine-1-carboxylate (420) (1.838 g, 67%). 1 H NMR (300 MHz, chloroform-d) δ 6.48(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=12.9,7.8Hz,1H),2. 86~2.70(m,5H),2.70~2.53(m,2H),2.53~2.40(m,2H),1.91~1.77(m,3H),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] + .

[0188] 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) TFA (3.0 mL, 38.94 mmol) was added to tert-butyl N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-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 h. The resulting solution was concentrated in vacuo to give crude (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) (3.657 g, 95%). LCMS m / z 321.22 [M+H] + .

[0189] Compound 422 (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) [ka] 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) (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, after which the solution was diluted with MeOH (500 μL) and filtered. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 5 mM HCl gave 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] + .

[0190] compound 423 [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-pyridyl)methanone (423) [ka] 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-pyridyl)methanone (423) (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 allowed to stir overnight at room temperature. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid gave [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-pyridyl)methanone (2.8 mg, 10%) (423). LCMS m / z 442.16 [M+H] + .

[0191] compound 424 Methyl 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]azetidine-1-carboxylate (424) [ka] Synthesis of methyl N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]azetidine-1-carboxylate (424) (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 methyl carbonochloridate (9.5 μL, 0.1228 mmol). The reaction was stirred at room temperature for 10 minutes, after which it was filtered. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 5 mM HCl gave the product methyl N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]azetidine-1-carboxylate (hydrochloride) (424) (13.4 mg, 86%). LCMS m / z 379.22 [M+H] + .

[0192] Compounds 425~490 Compounds 425-490 (see Table 10) were prepared from intermediate 421 using the appropriate reagents and the amide formation method described for compounds 422-424. Coupling partners were obtained from commercial sources. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8] [Table 10-9] [Table 10-10] [Table 10-11] [Table 10-12] [Table 10-13] [Table 10-14] [Table 10-15] [Table 10-16]

[0193] Compound 491 (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) [ka] (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) (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 (50 mg, 0.05502 mmol) was dissolved in DMF (800 μL) and DIPEA (100 μL, 0.5740 mmol) to which was added ethanesulfonyl chloride (14 μL, 0.1500 mmol). The reaction was stirred at room temperature for 3 hours, after which it was diluted with MeOH (800 μL) and filtered. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 5 mM HCl gave 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] + .

[0194] Compounds 492~496 Compounds 492-496 (see Table 11) were prepared in a single step from intermediate 421 using the coupling method for 491. The sulfonyl chlorides were obtained from commercial sources. [Table 11]

[0195] Compound 497 (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 [ka] 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) 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) C1 in DCM (6 mL) was added BocO (211 μL, 0.9185 mmol) and DIPEA (160 μL, 0.9186 mmol). After 1 h, 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.

[0196] 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) To a mixture of tert-butyl (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate C16 from the previous step in DCM (6 mL) was added mCPBA (200 mg, 0.8692 mmol), and the reaction was stirred at room temperature. The mixture was then split in half, and one half of the mixture was stirred at reflux with mCPBA (300 mg, 1.74 mmol) for 3 hours. At this point, the mixture was cooled to room temperature and diluted with saturated sodium bicarbonate (20 mL) and additional DCM (20 mL). The layers were separated, and the aqueous layer was washed with DCM (10 mL). The combined organic layer was then washed with additional saturated sodium bicarbonate (10 mL), followed by brine (10 mL). 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%). 1H NMR(400MHz,chloroform-d3)δ 6.14(t,J=2.1Hz,1H),4.01(tt,J=11.8,6.5Hz,1H),3.95~3.67(m,3H),3.24(ddd,J=14.0,9.3,5.4Hz,1 H),2.63~2.40(m,4H),1.95~1.74(m,2H),1.70~1.56(m,2H),1.46(d,J=14.0Hz,9H),1.31~1.23(m,6H). LCMS m / z 383.85[M+H] + .

[0197] 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) To 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, 0.12 mmol) was added HCl in dioxane (500 μL of 4 M, 2.000 mmol). The mixture was stirred at room temperature. After 1 hour, the mixture was concentrated in vacuo to give (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] + The crude was used in the next step without further purification.

[0198] Step 4. 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]1,1-dioxide (497) 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 h, 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). Product-containing fractions were pooled, 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'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]1,1-dioxide 497 (12 mg, 23%). 1 H NMR(400MHz,chloroform-d3)δ 7.64(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] + .

[0199] Compound 498 2-Ethyl-2',2'-dimethyl-1'[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] [ka] Step 1. Synthesis of 2-ethyl-2',2'-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (C19) To the vial was added tert-butyl 2,2-dimethyl-4-oxo-piperidine-1-carboxylate (90.9 mg, 0.4 mmol), 2-(5-ethyl-2-thienyl)ethanol (75 mg, 0.48 mmol), and dioxane (2 mL). Trifluoromethanesulfonic acid (100 μL, 1.13 mmol) was then added at 0 °C and stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give 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.

[0200] 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) To the crude material from the previous step in DCM 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 in a microwave reactor at 110° C. for 20 minutes. The reaction mixture was then filtered and concentrated in vacuo. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in HO containing 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] + .

[0201] Preparation S15 2-(4,5-dimethyl-2-thienyl)ethanol (S15) [ka] Preparation of 2-(4,5-dimethyl-2-thienyl)ethanol (S15) To a solution of 2,3-dimethylthiophene (2 g, 17.826 mmol) in EtO (50 mL) was added n-BuLi (8.5564 mL of 2.5 M, 21.391 mmol) over 15 minutes at 0 °C. The mixture was stirred at room temperature for 30 minutes. After cooling to 0 °C, a solution of oxirane (7.1303 mL of 3 M, 21.391 mmol) was added. The reaction 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. Purification by silica gel chromatography (gradient: 20-25% EtOAc in hexanes) gave 2-(4,5-dimethyl-2-thienyl)ethanol S15 (2 g, 67%). 1 H NMR (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 / z 157.1[M+H] + .

[0202] Intermediate S16~S17 Intermediates S16-S17 (see Table 12) were prepared in a single step from the corresponding thiophenes using the method described for S15. Any modifications to the method are described in Table 11 and the accompanying footnotes. [Table 12]

[0203] Preparation S18 (2'R,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S18) [ka] Preparation of (2'R,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S18) A flask was prepared with a solution of 2-(5-ethyl-2-thienyl)ethanol (12.8 g, 85.50 mmol) and tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate (20 g, 93.78 mmol, 1.1 equiv.) in dioxane (158 mL). The flask was cooled in an ice-methanol bath and allowed to equilibrate for 10 minutes, reaching an internal temperature of approximately 0 °C. Trifluoromethanesulfonic acid (17 mL, 192.1 mmol, 2.2 equiv.) was added dropwise via an addition funnel over 30 minutes. After the addition, the mixture was stirred for an additional 30 minutes in the ice bath. The ice bath was removed, and the reaction was allowed to warm to room temperature and stir overnight. The mixture was diluted with a 1:1 mixture of water, saturated aqueous sodium bicarbonate (500 mL), and EtOAc (400 mL). The layers were separated, and the aqueous layer was re-extracted with EtOAc (200 mL). The combined organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The solid was then suspended in EtO (approximately 250 mL) at room temperature and then heated to reflux. The mixture dissolved at reflux and then cooled. Heptane was added, followed by more EtO. A portion of the solvent was removed. The solid was filtered, washed with 1:1 EtO-heptane (3 x 75 mL), and further dried under high vacuum. The solid was suspended in EtO (250 mL), stirred, and heated to reflux for 30 minutes. At this point, the mixture was cooled to 0 °C, stirred for 10 minutes, filtered, and then rinsed with ice-cold EtO to give a colorless solid, which was dried under air for 5 minutes and then under high vacuum overnight. (2'R,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](trifluoromethanesulfonate) S18 (19.3 g, 57%) 1H NMR(300MHz,chloroform-d)δ 7.78(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] + .

[0204] Main intermediates S19~S21 Intermediates S19-S21 (see Table 13) were prepared in a single step using the Pictet-Spengler reaction from tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate and the appropriate thiopheneethanol reagents S15-S17, similar to the preparation of intermediate S18. Any modifications to the method are described in Table 13 and the accompanying footnotes. [Table 13]

[0205] Preparation S21 tert-Butyl (2'S)-2-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate (C21) [ka] Step 1: (2'S)-2'-Methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S20) A solution of 2-(2-thienyl)ethanol (1.028 g, 7.618 mmol) and tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate (1.8 g, 8.440 mmol) in dioxane (15 mL) was cooled in an ice bath. To the solution was added trifluoromethanesulfonic acid (2.5 mL, 28.25 mmol) over 5 minutes. The resulting solution was slowly warmed to room temperature and stirred overnight, after which the reaction was basified to pH 8 with 1N NaOH. The mixture was partitioned with EtOAc, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude amber oil. Purification by HPLC: 10-90% ACN in water (TFA modifier) ​​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)δ 7.13(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] + .

[0206] Step 2: tert-Butyl (2'S)-2'-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate (S21) The resulting material was dissolved in DCM (20 mL) and treated with BocO (1.9 mL, 8.270 mmol) followed by DIPEA (2.7 mL, 15.50 mmol). The resulting solution was stirred at room temperature overnight. The reaction was partitioned between 1 N NaOH and DCM. The organics were collected through a phase separator tube, concentrated in vacuo, and subsequently purified by silica gel chromatography (gradient: 0-50% EtOAc in heptane) to give tert-butyl (2'S)-2'-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate S21 (786.4 mg, 32%). 1 H NMR (300MHz, chloroform-d)δ 7.10(dd,J=5.2,0.7Hz,1H),6.73(d,J=5.2Hz,1H),4.06~3.95(m,1H),3.93~3.88(m,2H),3.81~3.72(m,1H),3.37(ddd,J =14.0,8.8,5.4Hz,1H),2.82(q,J=5.2Hz,2H),2.11~1.93(m,2H),1.86~1.73(m,2H),1.50(s,9H),1.28(d,J=6.6Hz,3H).

[0207] Preparation S22 (2'R,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S22) [ka] 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) A solution of 2-(5-ethyl-2-thienyl)ethanol (107 mg, 0.7524 mmol) and tert-butyl (2R)-2-methyl-4-oxo-piperidine-1-carboxylate (170 mg, 0.7971 mmol) in DCM (1.4 mL) was cooled to −78 °C. To the reaction mixture was added trifluoromethanesulfonic acid (130 μL, 1.469 mmol), and the reaction was stirred at −78 °C for 1.5 h. The reaction was quenched into a biphasic mixture of saturated NaHCO (15 mL) and DCM (15 mL), and the pH of the aqueous layer was adjusted to >10 with 2 N 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) were added to the reaction in that order. The reaction was stirred at room temperature 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: 0-30% EtOAc in heptane) to afford tert-butyl (2'R,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate C20 (138.3 mg, 54%). 1 H NMR (300MHz, methanol-d4)δ 6.42(d,J=1.2Hz,1H),4.35(d,J=7.2Hz,1H),3.99~3.82(m,3H),2.83~2.60(m,2H),2.3 7(s,3H),1.89(d,J=4.3Hz,2H),1.85~1.75(m,2H),1.48(s,9H),1.33(d,J=7.1Hz,3H).

[0208] Step 2. Synthesis of (2'R,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S22) To a stirred solution of tert-butyl (2'R,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate C20 (135 mg, 0.4000 mmol) in DCM (1.3 mL) was added hydrogen chloride in dioxane (500 μL of 4 M, 2.000 mmol), and the reaction was stirred at room temperature for 2.5 h. The reaction was concentrated under a stream of nitrogen. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 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)δ 6.52(s,1H),3.94(t,J=5.4Hz,2H),3.83~3.67(m,1H),3.50(td,J=12.5,3.9Hz,1H),3.19(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] + .

[0209] Preparation S23 (2'S,4S)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S23) [ka] (2'S,4S)-2,2'-Dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] S23 was prepared using the same procedure as for the preparation of S22. 1H NMR(300MHz, methanol d4)δ 6.51(s,1H),3.94(t,J=5.4Hz,2H),3.81~3.69(m,1H),3.50(td,J=12.2,3.6Hz,1H),3.19 (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] + .

[0210] Preparation S24 (2'S)-2-Chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S24) [ka] A solution of tert-butyl (2'S)-2'-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate 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 tert-butyl (2'S)-2-chloro-2'-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate (210 mg, 66%). LCMS m / z 358.22 [M+H]+.

[0211] The product was dissolved in DCM (4 mL) and treated with TFA (210 μL, 2.726 mmol). The resulting solution was stirred at room temperature 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) (180 mg, 46%). LCMS m / z 258.21 [M+H] + .

[0212] Compounds 499 [ENANT-1] and 500 [ENANT-2] 4-[(2'S,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]tetrahydrofuran-3-ol [ka] 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]) (2'R,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 h. The crude reaction mixture was evaporated. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% formic acid. Two products were isolated: 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%) 1H 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=10.8,4.1Hz,1H),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 4-(2'R,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]tetra-hydrofuran-3-ol (500[ENANT-2]) (formic acid) (12 mg, 46%) 1 H NMR(300MHz, methanol-d4)δ 8.38(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),3.28~3.2 0(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] + .

[0213] Compounds 501~507 Compounds 501-507 (see Table 14) were prepared in a single step from intermediates S23 or S24, as were compounds 499 and 500. Epoxides were obtained from commercial sources. Any modifications to the methods are described in Table 14 and the accompanying footnotes. [Table 14-1] [Table 14-2] [Table 14-3]

[0214] Compound 508 (2S)-3-[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]-2-hydroxy-propanamide (508) [ka] Preparation of (2S)-3-(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]-2-hydroxy-propanamide (508) (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 methyl (2S)-oxirane-2-carboxylate (260 μL, 2.970 mmol) were added to a microwave vial, and NH3 (400 μL of 7 M, 2.800 mmol) in MeOH (1.5 mL) was added. DIPEA (260 μL, 1.493 mmol) was added, and the reaction was heated at 120 °C for 3 h. 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 h. The reaction mixture was concentrated in vacuo. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30x150 mm, 5 micron). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid. Further purification was carried out using silica gel chromatography (gradient: 1-16% MeOH in DCM) to give (2S)-3-(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]-2-hydroxy-propanamide (8.5 mg, 7%). 1H NMR (300MHz, chloroform-d)δ 11.37(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=11.8Hz,1H) ,3.29(s,0H),2.92(t,J=11.9Hz,1H),2.76(q,J=5.5Hz,2H),2.37(dd,J=32.2,15.7Hz,2H),2.00(dd,J=14.9,8.1Hz,2H),1.49(d,J=6.4Hz,3H). LCMS m / z 345.21[M+H] + .

[0215] Compound 509 (2S)-3-[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]-2-hydroxy-propanamide [ka] Step 1. Synthesis of methyl (2R)-3-[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]-2-hydroxy-propanoate (C22) Methyl (2R)-3-[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]-2-hydroxy-propanoate C22 was prepared following the epoxide ring-opening method described for 508 starting with S24 and (2R)-oxirane-2-carboxylate.

[0216] 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-propanamide (509) Methyl (2R)-3-[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]-2-hydroxy-propanoate (66 mg, 0.1834 mmol) was added to a microwave vial and NH3 (1.3 mL of 7 M, 9.100 mmol) in MeOH (100 μL) 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 give (2R)-3-[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidin]-1'-yl]-2-hydroxy-propanamide 509 (21.1 mg, 31%). 1 H NMR (300MHz, chloroform-d)δ 7.01(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,3H),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).

[0217] compound 510 (2'S)-2,2'-Dimethyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] [ka] 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) Into a reaction vial was 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 h, then cooled to room temperature 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 give (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)δ 7.81(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] + .

[0218] Compounds 511~514 Compounds 511-514 (see Table 15) were prepared in a single step from the appropriate intermediate piperidine and alkyl halide using the alkylation method for compound 510. The alkyl halides were obtained from commercial sources or as previously described. Any modifications to the method are described in Table 15 and the accompanying footnotes. [Table 15-1] [Table 15-2]

[0219] Compound 515 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 [ka] 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) 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) afforded (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] + .

[0220] 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) 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), and tBuXPhos Pd G1 (15 mg, 0.02303 mmol) in t-BuOH (3.5 mL) was degassed under nitrogen for 10 min, followed by the addition of NaOtBu (388 μL of 2 M, 0.7760 mmol). The resulting mixture was sealed and heated at 60 °C for 45 min. 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] + .

[0221] 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) The crude product from step 2 was dissolved in THF (3 mL) and treated with TBAF (1.8 mL of 1 M in THF, 1.800 mmol). The reaction was stirred at room temperature 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: 10-90% ACN in water (HCl modifier) ​​gave 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 (hydrochloride salt) (6.3 mg, 4%). 1 H NMR (300MHz, methanol-d4)δ 8.43(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] + .

[0222] compound 516 (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) [ka] 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) (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 μL), and acetic acid (40 μL, 0.7034 mmol) was added to the solution, followed by cyanoborohydride, polymer-supported (186 mg of 2 mmol / g, 0.3720 mmol). The solution was heated to 90 °C in a microwave reactor for 95 min. An additional portion of cyanoborohydride, polymer-supported (67 mg, 0.5930 mmol) was added, and the reaction was stirred at room temperature overnight. The suspension was stirred in 1.5 mL of MeOH for 10 minutes, after which the resin was filtered. The solvent was removed, and the residue was dissolved in water (2 mL) and DCM (2 mL). The pH of the aqueous layer was adjusted to pH > 10 with 2 M NaOH. The layers were separated using a phase separator, the aqueous layer was extracted with DCM (2 × 10 mL), and the combined organics were concentrated in vacuo. The crude residue was purified by silica gel chromatography (gradient: 0-20% MeOH in DCM) to give (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] (32.1 mg, 62%). 1 H NMR (300MHz, chloroform-d)δ 7.54(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).

[0223] Compounds 517~518 Compounds 517-518 (see Table 16) were prepared in a single step from intermediates S22 and S24 using a reductive amination step similar to that for compound 516. The aldehydes were described previously. Any modifications to the method are described in Table 16 and the accompanying footnotes. [Table 16]

[0224] Compound 519 (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) [ka] 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) 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-carbaldehyde (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 h. Sodium cyanoborohydride (112.49 mg, 1.7901 mmol) was added to the reaction mixture and stirred at 50 °C for 24 h. The reaction mixture was concentrated in vacuo, washed with water (4 mL), and extracted with EtOAc (3 × 5 mL). The organic layer was dried over sodium sulfate, concentrated in vacuo, and purified by reverse-phase HPLC chromatography. Method: YMC Triart Actus C18 (250 × 20 mm, 5 microns). Gradient: MeCN in HO containing 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%). 1 H NMR(400MHz,DMSO-d6)δ 7.57(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] + .

[0225] Compounds 520~521 Compounds 520-521 (see Table 17) were prepared in a single step from the appropriate piperidine selected from intermediates S20 or S21 using a reductive animation step similar to compound 519. The aldehydes were obtained from commercial sources. Any modifications to the method are described in Table 17 and the accompanying footnotes. [Table 17]

[0226] Preparation S25 tert-Butyl (2'S,4R)-2-bromo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate (S25) [ka] Preparation of tert-butyl (2'S,4R)-2-bromo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate (S25) To a stirred solution of tert-butyl (2'S,4R)-2'-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate 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 room temperature. The reaction mixture was heated to 65 °C and stirred overnight. The reaction mixture was diluted with 1 N NaOH (25 mL) and extracted with EtOAc (2 × 50 mL). The organic layer was washed with saturated aqueous sodium thiosulfate (50 mL), then with brine (50 mL), and dried over NaSO. The organic layer was concentrated in vacuo to give the crude material. The crude compound was purified by silica gel chromatography (gradient: 10-15% EtOAc in petroleum ether) to give tert-butyl (2'S,4R)-2-bromo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate S25 (140 mg, 59%). 1H NMR(400MHz,chloroform-d)δ 6.55(s, 1 H),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=6.4Hz,3H). LCMS m / z 404.24[M+H] + .

[0227] Compound 522 (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) [ka] 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) To a mixture of tert-butyl (2'S,4R)-2-bromo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate 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), to which was added 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (hydrochloride) (45 mg, 0.1730 mmol) and potassium carbonate (50 mg, 0.3618 mmol). The mixture was stirred at 70 °C for 3 hours. The mixture was cooled to room temperature, 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 give (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(400MHz,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=6.3Hz,2H),2.68 ~2.55(m,6H),2.48(s,2H),1.80~1.71(m,3H),1.58(d,J=12.7Hz,1H),1.16(d,J=6.1Hz,3H). LCMS m / z 488.97 [M+H] + .

[0228] Compound 523 (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) [ka] 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) [Ir{dFCFppy}2(bpy)]PF6 (4 mg, 0.003962 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (10 mg, 0.03726 mmol), and dichloronickel, 1,2-dimethoxyethane (10 mg, 0.04551 mmol) were added to a 1-dram vial that was evacuated and refilled with nitrogen three times. Bis(trimethylsilyl)silyl-trimethyl-silane (190 μL, 0.6159 mmol), 2,6-dimethylpyridine (90 μL, 0.7769 mmol), 2-bromo-1,1-difluoroethane (50 μL), and tert-butyl (2'S,4R)-2-bromo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate (150 mg, 0.3728 mmol) were dissolved in 1,2-dimethoxyethane (2 mL) under nitrogen. The reaction was irradiated in a Merck photoreactor at 100% LED power and a 4700 RPM fan for 2 hours. The reaction was diluted with 3 mL of EtOAc and 1 mL of water. The reaction was extracted, the organic layer was dried, and then the volatiles were evaporated. The crude residue was dissolved in HCl (1000 μL of 4 M, 4.000 mmol) and stirred for 1 h before removing volatiles. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid. (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%) was obtained. 1H NMR(400MHz,DMSO-d6)δ 8.91(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] + .

[0229] 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) (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, after which the layers were separated and the aqueous layer was extracted with DCM (×2) on a phase separator. The organic layer was concentrated in vacuo and purified by silica gel chromatography (gradient: 0-20% MeOH in DCM) to give (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)δ 7.71(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 / z 474.02[M+H] + .

[0230] Compound 524 (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] [ka] 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) A solution of tert-butyl (2'S,4R)-2-bromo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate S25 (50 mg, 0.1243 mmol) in THF (1 mL) was cooled to -78 °C. At this point, butyllithium in hexanes (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 an additional 50 minutes, the mixture was allowed to warm slowly to room temperature. The reaction was quenched with saturated ammonium chloride and diluted with 1 mL of water and 5 mL of EtOAc. The layers were mixed, 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 afford tert-butyl (2′S,4R)-2-formyl-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate C26 (29 mg, 65%). 1 H NMR (400MHz, chloroform-d)δ 9.82(s,1H),7.42(s,1H),4.05~3.85(m,3H),3.76(ddd,J=13.8,6.1,4.8Hz,1H),3.37(ddd,J=14.0,8.9,5.4Hz,1H),2.96~2.80(m,2H),2.10 (dddd,J=14.7,8.2,6.0,1.8Hz,1H),1.99(ddd,J=14.2,5.2,1.9Hz,1H),1.83~1.73(m,2H),1.49(s,9H),1.27(d,J=6.6Hz,3H). LCMS m / z 351.93 [M+H] + .

[0231] Step 2. Synthesis of tert-butyl (2'S,4R)-2-(difluoromethyl)-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate (C27) A mixture of tert-butyl (2'S,4R)-2-formyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate C26 (29 mg, 0.08040 mmol) in DCM (500 μL) was stirred at room temperature. N-Ethyl-N-(trifluoro-lambda-4-sulfanyl)ethanamine (30 μL, 0.2271 mmol) was added and the mixture was stirred at reflux. After stirring for 20 h, the mixture was cooled to room temperature, 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 afford tert-butyl (2′S,4R)-2-(difluoromethyl)-2′-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4′-piperidine]-1′-carboxylate C27 (18 mg, 59%). 1 H NMR(400MHz,chloroform-d)δ 6.90(d,J=2.1Hz,1H),6.75(t,J=56.2Hz,1H),4.03~3.83(m,3H),3.74(ddd,J=1 3.9,6.0,4.8Hz,1H),3.33(ddd,J=14.1,8.9,5.4Hz,1H),2.88~2.72(m,2H),2.05 (dddd,J=14.8,9.0,6.1,1.8Hz,1H),1.95(ddd,J=14.2,5.2,1.8Hz,1H),1.80~1.67(m,2H),1.48(s,9H),1.25(d,J=6.5Hz,3H). LCMS m / z 373.99 [M+H] + .

[0232] 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) To a mixture of tert-butyl (2'S,4R)-2-(difluoromethyl)-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate S27 (18 mg, 0.04775 mmol) in DCM (400 μL) was added trifluoroacetic acid (40 μL, 0.5192 mmol) (11:30). After stirring for 60 min, the mixture was dried and redissolved in acetonitrile (1,000 μL). To this was added 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (hydrochloride) (15 mg, 0.05766 mmol) and potassium carbonate (20 mg, 0.1447 mmol), and the mixture was stirred at 60 °C overnight. The mixture was diluted with EtOAc (5 mL) and water (2 mL), and the organic phases were combined 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 give (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)δ 7.57(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] + .

[0233] compound 525 (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] [ka] Step 1. Synthesis of tert-butyl (2'S)-2-iodo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate (C28) tert-Butyl (2'S)-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 overnight at room temperature and then diluted with 1N NaOH / EtOAc. The organic layer was dried, concentrated, and purified by silica gel chromatography (gradient: 0 to 40% EtOAc / heptane) to give tert-butyl (2'S)-2-iodo-2'-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate C28 (222 mg, 80%). LCMS m / z 449.94 [M+H] + .

[0234] 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) tert-Butyl (2'S)-2-iodo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate C28 (215 mg, 0.4785 mmol) was dissolved in DMF (4 mL) and copper bromide, and methylsulfanilmethane (30 mg, 0.1459 mmol) and methyl 2,2-difluoro-2-fluorosulfonyl acetate (150 μL, 1.178 mmol) were added. The reaction mixture was heated to 100°C in a microwave for 40 minutes. Additional methyl 2,2-difluoro-2-fluorosulfonyl acetate (75 μL, 0.5891 mmol) was added, and the reaction mixture was again heated to 100°C in a microwave for 40 minutes. The reaction mixture was diluted with EtOAc / 1N NaOH and filtered through Celite®. The organic layer was dried and concentrated to give an oil, which was purified by silica gel chromatography (gradient: 0 to 25% EtOAc in heptane) to give 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%). H NMR (300 MHz, chloroform-d) δ 7.07 (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).

[0235] Step 3. Synthesis of (2'S,4R)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (525) 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 min, the solvent was removed, 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 h. The reaction mixture was concentrated, dissolved in 1 mL of MeOH, and repurified using a reverse-phase C18 column (gradient: CHCN / HO, TFA modifier). Pure fractions were diluted with EtOAc / 1N NaOH, and the organic layer was dried and concentrated to give (2'S,4R)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 525 (27 mg, 52%). 1H NMR (300MHz, chloroform-d)δ 7.65(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] + .

[0236] Compounds 526 and 527 (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) [ka] Step 1. Synthesis of 3,5-dibromo-2-ethyl-thiophene (C30) To a solution of N-isopropylpropan-2-amine (1.2 mL, 8.562 mmol) in THF (50 mL) was added hexyllithium (4.2 mL of 2.3 M, 9.660 mmol) under nitrogen at 0° C. over 5 minutes, and the reaction was stirred for an additional 30 minutes. The solution was cooled to −78° C. before adding 2,5-dibromothiophene (900 μL, 7.987 mmol). Iodoethane (1.3 mL, 16.25 mmol) was then added and stirred overnight with slow warming to room temperature. The reaction was quenched with saturated ammonium chloride solution, then extracted with DCM (3×100 mL), and the combined organics were washed with saturated bicarbonate solution and saturated brine solution. The combined organic layers were evaporated in vacuo to give 3,5-dibromo-2-ethyl-thiophene (1.1 g, 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).

[0237] Step 2. Synthesis of (2'S)-3-bromo-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (C31) 3,5-Dibromo-2-ethyl-thiophene C30 (500 mg, 1.852 mmol) was dissolved in THF (10 mL) at -78 °C. Hexyllithium (900 μL of 2.3 M, 2.070 mmol) was added and stirred for 30 minutes before adding oxirane (1000 μL of 2.5 M, 2.500 mmol). The reaction mixture was warmed to room temperature and stirred for 2 days. The reaction was quenched with saturated ammonium chloride solution and extracted with DCM (×3). The combined organic layers were concentrated in vacuo and purified by silica gel chromatography (gradient: 0 to 60% EtOAc in heptane) to give 2-(4-bromo-5-ethyl-2-thienyl)ethanol (200 mg, 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).

[0238] The material from step 2 was dissolved in dioxane (5 mL) and tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate (400 mg, 1.876 mmol) was added under nitrogen. Trifluoromethanesulfonic acid (400 μL, 4.520 mmol) was added and stirred overnight. The reaction mixture was quenched with saturated bicarbonate solution, diluted with DCM, and extracted with a phase separator (×3). The solvent was evaporated under positive nitrogen pressure to give (2'S)-3-bromo-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine](trifluoromethanesulfonic acid (1)) C31 (510 mg, 37%). LCMS m / z 330.05 [M+H] + .

[0239] Step 3. Synthesis of (2'R,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) 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 (x3). The combined organic layers were concentrated in vacuo and then purified by silica gel chromatography (gradient: 0-20% MeOH in DCM) to give (2'R,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] + .

[0240] 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) To (2'R,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) in MeOH (2 mL) was added Pd / C (10 mg, 0.09397 mmol) under nitrogen. The reaction was subjected to deuterium gas overnight. The flask was then purged with nitrogen and the Pd / C was filtered to give (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]+ .

[0241] Preparation S26 1-(5-chloro-2-thienyl)propan-2-ol (S26) [ka] Step 1: 1-(5-chloro-2-thienyl)propan-2-ol (S26) 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 2 M solution in THF, 18.9 mmol) at −78° C., and the reaction mixture was stirred for 1 h. 2-Methyloxirane (731 mg, 12.6 mmol) was added, and stirring was continued at −78° C. for 2 h. The reaction was quenched with saturated aqueous NH4Cl (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. Purification was carried out by silica gel chromatography (gradient: 5% EtOAc in heptane) to give 1-(5-chloro-2-thienyl)propan-2-ol S26 (1.3 g, 52%). 1 H NMR(300MHz,DMSO-d6)δ 6.90(d,J=3.6Hz,1H),6.70(d,J=3.9Hz,1H),4.82(d,J=4.8Hz,1H),3.77(m,1H),2.84-2.68(m,2H),1.06(d,J=5.7Hz,3H). LCMS m / z 272.19[M+H] + .

[0242] Intermediate S27-S29 Intermediates S27-S29 (Table 18) were prepared from 2-chlorothiophene and the appropriate epoxide as described in the method for compound S26. [Table 18]

[0243] Preparation S30 (2'S)-2-Chloro-2',6-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S30) [ka] Step 1: Synthesis of (2'S)-2-chloro-2',6-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S30) 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 h. 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 by reverse-phase HPLC. Method Xbridge C18 column (19 × 150 mm, 5 microns). Gradient: MeCN in HO containing 10 mM ammonium bicarbonate gave 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%). 1 H NMR(300MHz,DMSO-d6)δ 6.92(s,1H),3.87(d,J=9.6Hz,1H),2.95-2.78(m,2H),2.71-2.62(m,2H),2.42-2.33(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] + . was obtained.

[0244] Compounds S31~S33 Compounds S31-S33 (Table 19) were prepared from (2S)-2-methylpiperidin-4-one and the appropriate thiophene reagent as described in the method for compound S30. [Table 19]

[0245] Compound 528 (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]) [ka] 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) 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. Upon completion, the solvent was evaporated. Purification by reverse-phase HPLC. Method: XSelect Phenyl hexyl column (19 x 250 mm, 5 microns). Gradient: MeCN in HO with 0.1% formic acid, followed by SFC purification gave two diastereomers: (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%) 1H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.28 (s, 1H), 6.98 (s, 1H), 3.82-3.79 (m, 4H), 3.73 (d, J = 14 Hz, 1H), 3.25 (d, J = 13.6 Hz, 1H), 2.63 (dd, J = 3.2 Hz and 16 Hz, 1H), 2.55-2.45 (m, 2H), 2.39-2.28 (m, 2H), 1.87 (dd, J = 2.4 Hz and 14 Hz, 1H), 1.75-1.69 (m, 1H), 1.57-1.56 (m, 1H), 1.46-1.42 (m, 1H), 1.18 (d, J = 6 Hz, 3H), 1.07 (d, J = 6 Hz, 3H). LCMS m / z 366.1[M+1] + .; and (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%) 1 H NMR(400MHz,DMSO-d6)δ 7.54(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] + .

[0246] Compounds 530~533 Compounds 530-533 (Table 20) were prepared from appropriately selected piperidines and 4-(chloromethyl)-1-methyl-pyrazoles using the methods for compounds 528 and 529. [Table 20]

[0247] Preparation S34 (2'S)-2',7-Dimethyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S34) [ka] Step 1: Synthesis of (2'S)-2',7-dimethyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S34) 2-[5-(trifluoromethyl)-2-thienyl]propan-1-ol (250 mg, 1.18 mmol) and tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate (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 room temperature overnight. The reaction was quenched with NaHCO3 and the solvent was evaporated. DCM and water were added, and the organic layer was collected through a phase separator. Evaporation of the solvent gave (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] + .

[0248] Compounds S35~S41 Compounds S35-S41 (Table 21) were prepared from tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate and the appropriate thiophene using the method for compound S34. [Table 21-1] [Table 21-2]

[0249] Compound 534 (2S,4R)-2,7'-dimethyl-1-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)-2'-(trifluoromethyl)-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] [ka] Step 1: (2S,4R)-2,7′-dimethyl-1-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)-2′-(trifluoromethyl)-6′,7′-dihydrospiro[piperidine-4,4′-thieno[3,2-c]pyran] (534) 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, potassium carbonate (15 mg, 0.111 mmol) was added and the reaction was stirred overnight at 60° C. Water and dichloromethane were added and the organic layer was collected through a phase separator. Purification by silica gel chromatography (gradient: 0-20% MeOH in DCM) gave (2S,4R)-2,7'-dimethyl-1-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)-2'-(trifluoromethyl)-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] 534 (10 mg, 18%). LCMS m / z 493.56 [M+H] + .

[0250] Compounds 535~541 Compounds 535-541 (Table 23) were prepared from the intermediate piperidine and 4-(chloromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazole using the method for compound 534. [Table 23-1] [Table 23-2] [Table 23-3]

[0251] Compound 542 (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 [ka] 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) 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-propanenitrile (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 give the bromide intermediate tert-butyl (2'S,4R)-7-bromo-2'-methyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate. The intermediate was dissolved in THF and treated with saturated NaHCO3 (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 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 (48 mg, 7%). 1 H NMR (300 MHz, chloroform-d) δ 7.09 (s, 1H), 4.74–4.61 (m, 1H), 4.05–3.69 (m, 4H), 3.44–3.24 (m, 1H), 2.39 (t, J = 9.0 Hz, 1H), 2.26–1.73 (m, 3H), 1.50 (s, 9H), 1.28 (d, J = 6.6 Hz, 3H).

[0252] 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) 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 added to dichloromethane (1 mL) and TFA (0.5 mL, 6.490 mmol). The reaction mixture was stirred for 30 min and concentrated to give an oil. The oil was dissolved in dichloromethane (1 mL) and 1-methylpyrazole-4-carbaldehyde (20 mg, 0.181 mmol), AcOH (35 μL, 0.615 mmol), and (trimethylammonio)methyl(cyanoborohydride) resin (180 mg of 2 mmol / g, 0.3600 mmol) were added. The mixture was heated to 110 °C in a microwave for 60 min. The reaction was filtered, and the filtrate was concentrated. Purification by silica gel 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'-piperidin]-7-ol 542 (23 mg, 48%). 1 H NMR(300MHz,chloroform-d)δ 7.40(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 / z 402.04[M+H] + .

[0253] Preparation of S44 (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (S44) [ka] 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) 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 under nitrogen, a solution of hexyllithium in hexane (120 mL of 2.6 M, 312.0 mmol) was added via addition funnel over 20 minutes. After stirring for 70 minutes after the addition of hexyllithium was complete, DMF (100 mL, 1.291 mol) was added over 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 via 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 give 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 (300MHz, chloroform-d)δ 9.83(s,1H),7.42(s,1H),4.01(ddd,J=11.5,6.7,5.3Hz,1H),3.94~3.82(m,2H),3.75(ddd,J=14.0,6.1,4.7Hz,1H),3.35(ddd, J=14.1,8.8,5.4Hz,1H),2.71(td,J=5.5,2.8Hz,2H),2.28~2.06(m,2H),1.90~1.65(m,2H),1.47(s,9H),1.26(d,J=6.6Hz,3H).

[0254] 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) To a solution of dibromo(difluoro)methane (33 mL, 361.3 mmol) in THF (600 mL) in a dry ice-acetone cooling bath, N-[bis(dimethylamino)phosphanyl]-N-methyl-methanamine (140 mL, 770.3 mmol) was added via addition funnel over 45 minutes. The dry ice-acetone bath was then replaced with an ice-water bath and stirred for 45 minutes. To the reaction was added a solution of 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, 250.4 mmol) in THF (500 mL) 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% aqueous sodium bisulfite (300 mL) was added. The mixture was stirred for 30 minutes, and the organic layer was isolated. The organic layer was washed with 1 M aqueous HCl (1 L). The organic layer was diluted with MTBE (500 mL), washed with saturated aqueous sodium bicarbonate (1 L), followed by 50% saturated aqueous brine (1 L), dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (gradient: 0-50% EtOAc in heptane) to afford 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 (54 g, 56%) as a viscous, clear, pale yellow oil. 1H NMR (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=28.1Hz),-87.47(d,J=27.9Hz).

[0255] 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) To Pd on carbon (8.2 g, 3.853 mmol, 5% w / w) in a 2 L Parr bottle was added a solution 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 (54 g, 140.1 mmol) in EtOH (700 mL) under nitrogen. The Parr shaker was charged with 50 psi of H2. After 24 h, the reaction mixture was filtered through a pad of Celite, and the filtrate was treated with fresh catalytic Pd on carbon (10 g, 4.698 mmol, 5% w / w) under nitrogen. The Parr shaker was charged with 50 psi of H2, and the reaction was continued for an additional 16 h. The reaction was filtered through a pad of Celite and washed with EtOH (200 mL). 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. 1H 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.

[0256] 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) To a solution 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 (32 g, 82.58 mmol) C23 in dichloromethane (300 mL) at 0 °C (ice-water bath), 2,6-lutidine (18 mL, 155.4 mmol) was added via addition funnel over 12 minutes, followed by trimethylsilyl trifluoromethanesulfonate (15.4 mL, 85.23 mmol). 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 (2 × 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. 1H NMR(300MHz,chloroform-d)δ 6.60(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),1.70(td,J=13.3,4.8Hz,1H),1.39(dd,J=13.6,11.3Hz,2H),1.06(d,J=6.4Hz,3H). 19F NMR (282MHz, chloroform-d) δ -115.07. LCMS m / z 288.1 [M+1] + .

[0257] 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) [ka] 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) 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 point, propargyl bromide (353 μL, 3.961 mmol) in toluene was added, and the mixture was stirred at 50 °C overnight. The reaction was quenched with saturated aqueous sodium bicarbonate and DCM. The layers were separated using a phase separator. The organics were concentrated in vacuo. Purification by silica gel chromatography (gradient: 0 to 10% MeOH-DCM) afforded (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%). 1 H NMR(400MHz, methanol-d4)δ 6.64(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,1H),3.25(d dd,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] + .

[0258] Preparation of 543 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) [ka] Preparation of 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) A solution of 1-aminopropan-2-ol (20.8 mg, 150 μmol) dissolved in DMSO (0.3 mL) was added to aqueous 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 (approximately 0.45 M in MTBE, approximately 250 μmol, prepared according to the protocol in Nature, Vol. 574, 2019, pp. 86-89), and the reaction was 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 reaction. To this mixture was added aqueous CuSO4 (0.085 mL, 0.0085 mmol of a 0.1 M solution), 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, 0.0085 mmol of a 0.1 M solution), and aqueous sodium ascorbate (0.085 mL, 0.017 mmol of a 0.2 M solution). The resulting reaction mixture was opened to air and heated at 50 °C overnight. Additional portions of CuSO4 (0.1 mL, 0.01 mmol of a 0.1 M solution) and sodium ascorbate (0.1 mL, 0.02 mmol of a 0.2 M solution) were added, and the reaction was heated at 50 °C overnight. The reaction was 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 a parallel filter plate and washed with 1 mL of DCM. The organic layer was removed and evaporated. The resulting residue was dissolved in 1 mL of DMSO and purified by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 10 mM ammonium hydroxide to give 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). 1H NMR(300MHz, methanol-d4)δ 7.94(s,1H),6.62(s,1H),5.95 (tt,J=56.6,4.3Hz,1H),4.52~3.67(m,7H),3.24(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] + .

[0259] Preparation of compounds 544-548 Compounds 544-548 (see Table 23) were prepared from intermediate S45 with the appropriate reagents using the azide transfer method and quick chemistry methods described for compound 543. Amines were obtained from commercial sources. [Table 23-4] [Table 23-5]

[0260] Preparation of S46 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 (S46) [ka] 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'-piperidin]-1'-yl]methyl]cyclobutyl]carbamate (C25) 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 triacetoxyboranide (sodium salt) (376 mg, 1.774 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with NaHCO3 (saturated), and the mixture was extracted with DCM (3 x 5 mL). The combined organics were washed with HO and brine, respectively, and 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] + .

[0261] Step 2. Synthesis of 3-[[((2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]methyl]cyclobutanamine (S47) 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 HCl in dioxane (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]cyclobutanamine (189 mg, 83%). LCMS m / z 371.18 [M+H] + .

[0262] Compound 549 1-Cyano-N-((1R,3s)-3-(((2S,4R)-2'-(2,2-difluoroethyl)-2-methyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)methyl)cyclobutyl)methanesulfonamide (549) [ka] Synthesis of 1-cyano-N-((1R,3s)-3-(((2S,4R)-2'-(2,2-difluoroethyl)-2-methyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)methyl)cyclobutyl)methanesulfonamide (549) 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 EtN (22 μL) 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 x 150 mm, 5 microns). Gradient: MeCN in H2O containing 0.1% trifluoroacetic acid gave 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] + .

[0263] Preparation of compounds 550-558 Compounds 550-558 (see Table 24) were prepared from intermediate S47 using the appropriate acyl chloride or sulfonyl chloride reagent using the method described for compound 549. The acyl chloride or sulfonyl chloride was purchased from a commercial source. [Table 24-1] [Table 24-2]

[0264] Compound 559 (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] [ka] 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) (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). To this solution was added triacetoxyboranide (sodium salt) (470 mg, 2.218 mmol), and the reaction was heated to 60 °C and stirred for 4 hours. The reaction mixture was then cooled to room temperature, at which point it was quenched with brine (20 mL) and extracted with EtOAc (20 mL). The organics were 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 give (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%). 1H NMR(400MHz, methanol-d4)δ 8.42(s,1H),7.98(d,J=0.8Hz,1H),7.71(d,J=0.7Hz,1H),6.69(d,J=2.6Hz,1H),5. 97(tt,J=56.6,4.2Hz,1H),4.75~4.65(m,2H),4.46(d,J=14.1Hz,1H),4.23(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] + .

[0265] compound 560 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 [ka] 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) (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-hydroxy-2-methylpropan-2-yl)amino)pyrimidine-2-carbaldehyde (37 mg, 0.19 mmol), acetic acid (52 μL, 0.92 mmol), dichloromethane (1.6 mL), and polymer-supported cyanoborohydride (295 mg, 0.59 mmol) were 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 10 minutes to wash the beads. The solution was filtered and the solvent removed in vacuo. Purification by reverse-phase HPLC. C18 Waters Sunfire column (30x150 mm, 5 micron). Gradient: MeCN in HO containing 10 mM ammonium hydroxide to give 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. 1 H NMR (300 MHz, chloroform-d) δ 8.23(s,2H),6.60(d,J=9.5Hz,2H),5.92(tt,J=56.5,4.4Hz,1H),5.24(s,1 H),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=1 4.2,5.3,2.8Hz,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] + .

[0266] Compound 561 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 [ka] 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) To (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) in a microwave oven 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 µL, 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 min. MeOH was added, and the solution was stirred for 10 min to wash the beads. The reaction was stirred with 4M HCl in dioxane (0.5 mL) for 10 minutes. The solution was filtered and the solvent removed in vacuo. Purification by reverse-phase HPLC: Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns) (basic method) gave 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(300MHz,chloroform-d)δ 7.46(s,1H),7.37(s,1H),6.61(s,1H),5.92(tt,J=56.4,4.5Hz,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=6.2Hz,3H),0.84(s,3H).ESI-MS m / z 470.24.

[0267] Compounds 562~593 Compounds 562-593 were prepared from intermediate S44 and the corresponding aldehyde or ketone via a reductive amination step and, in some cases, a deprotection step using the procedures described for compounds 559-561. Aldehydes and ketones were obtained from commercial sources or synthesized as described above. Any modifications to the methods are described in Table 25 and the accompanying footnotes. [Table 25-1] [Table 25-2] [Table 25-3] [Table 25-4] [Table 25-5] [Table 25-6] [Table 25-7] [Table 25-8] [Table 25-9]

[0268] Compound 594 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) [ka] Preparation of 2-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]-1-phenyl-ethanol (594) 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 by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O with 0.2% formic acid gave 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] + .

[0269] Compounds 595~609 Compounds 595-609 and intermediates S48 and S49 were prepared from intermediate S44 and the related epoxides via the epoxide ring-opening process described for compound 594. Epoxides were obtained from commercial sources. Any modifications to the method are described in Table 26 and the accompanying footnotes. [Table 26-1] [Table 26-2] [Table 26-3] [Table 26-4]

[0270] compound 610 (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-propanamide (610) [ka] 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-propanamide (610) Methyl (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-propanoate S48 (96 mg, 0.2465 mmol) was added to a microwave flask. A solution of NH3 (1.5 mL of 7 M, 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) gave the desired product 610. 1H NMR (300MHz, chloroform-d)δ 6.94(d,J=4.2Hz,1H),6.58(s,1H),6.13~5.61(m,2H),3.93~3.76(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] + .

[0271] compound 611 (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-propanamide (611) [ka] 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-propanamide (611) (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 methyl (2S)-oxirane-2-carboxylate (700 μL, 7.995 mmol) were added to a microwave vial and taken up in NH3 in MeOH (4 mL of 7 M, 28.00 mmol). DIPEA (980 μL, 5.626 mmol) was added, and the reaction was stirred at 120 °C for 6 h. The solvent was removed in vacuo, and the product was rinsed with MeOH and DCM (2x). Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 × 150 mm, 5 micron) followed by silica gel chromatography (gradient: 0-20% MeOH in dichloromethane) gave the product (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-propanamide 611 (17.8 mg, 12%). 1 H NMR (300MHz, chloroform-d)δ 7.29(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). LCMS m / z 375.14[M+1] + .

[0272] compound 612 (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-propanamide (612) [ka] 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-N-methyl-propanamide (612) Methyl (S)-3-((2S,4R)-2'-(2,2-difluoroethyl)-2-methyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)-2-hydroxypropanoate 49 (95 mg, 0.2439 mmol) was taken up 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 by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid to give (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-propanamide (trifluoroacetic acid (2)) 612 (60.1 mg, 39%). 1 H NMR(300MHz,chloroform-d)δ 7.41(d,J=5.8Hz,1H),6.64(d,J=4.2Hz,1H),5.91(tt,J=56.3,4.4Hz,1H),4.81~ 4.46(m,1H),4.02(s,0H),3.89(dp,J=10.6,5.9Hz,2H),3.68(d,J=12.1Hz,1H),3 .53(s,1H),3.27(td,J=16.7,4.4Hz,3H),3.13~2.92(m,1H),2.86(d,J=4.9Hz,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] + .

[0273] compound 613 1-((2S,4R)-2'-(2,2-difluoroethyl)-2-methyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)propan-2-ol (613) [ka] Preparation of 1-((2S,4R)-2'-(2,2-difluoroethyl)-2-methyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)propan-2-ol (613) 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 KCO (32.84 mg, 0.2376 mmol). The reaction was stirred at 110 °C for 72 h, then cooled to room temperature and filtered. The crude reaction mixture was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns) gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give 1-((2S,4R)-2′-(2,2-difluoroethyl)-2-methyl-4′,5′-dihydrospiro[piperidine-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] + .

[0274] Compounds 614~624 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 method are described in Table 27 and the accompanying footnotes. [Table 27-1] [Table 27-2] [Table 27-3]

[0275] compound 625 (2'S,7R)-2-chloro-2'-methyl-1'-prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] [ka] 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) 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), 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 min. The mixture was cooled to room temperature, filtered, and concentrated in vacuo. The crude material was diluted with dichloromethane (10 mL) and 2 M NaOH. The layers were combined, passed through a phase separator, and concentrated. Purification by silica gel chromatography (1-10% MeOH in dichloromethane) gave (2′S,7R)-2-chloro-2′-methyl-1′-prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] 625 (228 g, 57%). 1 H 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, 2.7 Hz, 1H). 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] + .

[0276] compound 626 1-(4-((((2R,4S)-2'-chloro-2-methyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-3-methylbutane-2,3-diol [ka] Preparation of 1-(4-(((2R,4S)-2'-chloro-2-methyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)methyl)-1H-1,2,3-thiazol-1-yl)-3-methylbutane-2,3-diol (626) To a mixture of 1-amino-3-methyl-butane-2,3-diol (40 mg, 0.3357 mmol) in MeOH (3 mL) was added CuSO (0.25 mg, 0.001566 mmol) in water (0.125 mL), followed by sodium bicarbonate (45 mg) in water (0.375 mL) and a solution of trifluazide in dichloromethane (1.25 mL of 0.452 M, 0.5650 mmol) and the solution was stirred for 1 h. To the reaction was 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 h. The reaction was concentrated and purified by reverse-phase HPLC (Method: C18 Waters Purification on a Sunfire column (30 × 150 mm, 5 microns) gradient: MeCN in HO containing 0.1% trifluoroacetic acid gave 1-(4-(((2R,4S)-2′-chloro-2-methyl-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-1H-1,2,3-thiazol-1-yl)-3-methylbutane-2,3-diol (626) (51 mg, 69%). 1H NMR (400MHz, chloroform-d)δ 7.80(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] + .

[0277] Compounds 627~629 Compounds 627-629 (see 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 method are described in Table 28 and the accompanying footnotes. [Table 28]

[0278] Compound 630 #MZ48 (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] [ka] Step 1: Synthesis of (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) 1-Methylpyrazole-4-carbaldehyde (12 mg, 0.109 mmol) and acetic acid (15 mL, 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 cooled to 110°C. o The mixture was stirred at C for 30 min. Purification by preparative HPLC (mobile phase A: 0.1% TFA (aqueous), mobile phase B: acetonitrile) afforded (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)δ 11.80(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 / z 352.12[M+H] + .

[0279] Compounds 631~693 Compounds 631-693 (see Table 29) were prepared from intermediate S50 and the appropriate aldehyde reagent using the method for compound 630. The aldehydes were prepared by the methods described above or obtained from commercial sources. Any modifications to the method are described in Table 29 and the accompanying footnotes. [Table 29-1] [Table 29-2] [Table 29-3] Table 29-4 Table 29-5 Table 29-6 Table 29-7 Table 29-8 Table 29-9 Table 29-10 Table 29-11 Table 29-12 Table 29-13 Table 29-14 Table 29-15 Table 29-16 Table 29-17 Table 29-18 Table 29-19 Table 29-20 [Table 29-21] [Table 29-22]

[0280] Preparation of S50 (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (S50) [ka] Step 1(i): Synthesis of tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate To a mixture of tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate (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 purged five times with vacuum and nitrogen to remove dissolved isobutylene.

[0281] Step 1(ii): Synthesis of (2'S,7R)-2'-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] To the mixture was then added 2-(3-thienyl)ethanol (16.5 g, 128.7 mmol), 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 MgSO4, filtered, and concentrated to give (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] + .

[0282] 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) To a mixture of the products from the first two steps in DCM (500 mL) was added DIPEA (20 mL, 114.8 mmol), followed by BocO (27 mL, 117.5 mmol). The reaction was stirred for 45 min. Imidazole (1 g, 14.69 mmol) was added to quench excess BocO. 2N HCl (100 mL) was then added, and the mixture was stirred for 20 min. 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 give 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] + .

[0283] 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) 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 to 65 °C and stirred overnight. The reaction was diluted with 1 N NaOH / EtOAc, washed with sodium thiosulfate solution, brine, dried over Na2SO4, and concentrated to an oil. Purification by silica gel chromatography (gradient: 0-30% EtOAc in heptane) afforded 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 mg, 83%). LCMS m / z 358.14[M+H] + .

[0284] Step 3: Synthesis of (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (hydrochloride) (C28) A mixture of tert-butyl (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate (9500 mg, 26.37 mmol) in HCl (25 mL of 4 M, 100.0 mmol) in dioxane was stirred overnight at room temperature. After stirring overnight, the mixture solidified into a solid mass. Diethyl ether (200 mL total) was added to the mixture, and the mixture was filtered, rinsed with additional ether, and dried to give (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (hydrochloride) (C28) (7.4757 g, 94%). 1H NMR(400MHz,DMSO-d6)δ 9.25~8.93(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] + .

[0285] Step 4: Synthesis of (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (S50) (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 the mixture was adjusted to pH > 10 by adding saturated sodium bicarbonate followed by NaOH. At this point, the product oiled and was 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 give (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] S50 (2280 mg, 93%). 1 H NMR (400MHz, chloroform-d)δ 6.57(s,1H),3.98~3.81(m,2H),3.18~3.00(m,2H),2.94(ddd,J=12.2,4.8,2.1Hz,1H),2.67~2.51(m ,2H),2.07~1.94(m,2H),1.66(d,J=4.8Hz,1H),1.38(dd,J=13.7,11.4Hz,1H),1.09(d,J=6.4Hz,3H). LCMS m / z 258.09[M+H] + .

[0286] Preparation of S51 (2'S,7S)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (S51) [ka] Step 1(i): Synthesis of (2'S)-2'-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] A solution of 2-(3-thienyl)ethanol (1.275 g, 9.946 mmol) and tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate (2.217 g, 10.40 mmol) in DCM (18 mL) was cooled to −78° C. To the reaction was added trifluoromethanesulfonic acid (1.5 mL, 16.95 mmol), and the reaction was stirred at −78° C. for 1.5 h. The reaction was quenched into a biphasic mixture of saturated NaHCO (75 mL) and DCM (50 mL), and the pH of the aqueous layer was adjusted to >10 with 2 N NaOH. The aqueous layer was then extracted with DCM (3 x 75 mL), filtered through an SPE cartridge and concentrated to give crude (2'S)-2'-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine].

[0287] 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) The crude material from the previous step was dissolved in DCM (20 mL) and triethylamine (3.1 mL, 22.24 mmol) was added, followed by tert-butoxycarbonyl tert-butyl carbonate (3.1 mL, 13.49 mmol). The reaction was stirred at room temperature for 18 h. The solution was diluted with DCM and washed with water (50 mL). The aqueous layer was extracted with DCM (2 × 50 mL), dried over NaSO, filtered through an SPE filter, and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0–30% EtOAc in heptane) afforded tert-butyl (2′S,7S)-2′-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate C29 (2.95 g, 92%). 1 H NMR (300MHz, methanol-d4)δ 7.21(d,J=5.1Hz,1H),6.77(d,J=5.1Hz,1H),4.37(p,J=7.0Hz,1H),4.03~3.84(m,3H),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).

[0288] 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) To a solution of tert-butyl (2'S,7S)-2'-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate C29 (239 mg, 0.7389 mmol) in MeCN (3 mL) was added NCS (138 mg, 1.033 mmol) followed by DMAP (5 mg, 0.04093 mmol) at room temperature. The reaction mixture was heated to 55 °C for 24 h. The reaction was cooled to room temperature and stirred overnight, then quenched with 15% aqueous sodium bisulfite (10 mL). Stirred for 15 min, then partitioned between brine (20 mL) and DCM (20 mL). The aqueous layer was separated and extracted with DCM (2 × 20 mL), and the pooled organic layers were dried over NaSO, filtered through a phase separator, and concentrated. Purification by silica gel chromatography (0-30% EtOAc in heptane) gave a crude mixture with some remaining starting material.

[0289] The crude material was resubmitted to the reaction conditions by dissolving in MeCN (2.5 mL), and N-chlorosuccinimide (50 mg, 0.3744 mmol) and DMAP (5 mg, 0.04093 mmol) were added. The reaction was heated to 60° C. for 6 h, then cooled to room temperature and quenched with 15% aqueous sodium bisulfite (10 mL). Stirred for 15 min, then partitioned between brine and DCM (20 mL each). The aqueous layer was separated and extracted with DCM (2×20 mL), and the pooled organic layers were dried over NaSO, filtered through a phase separator, and concentrated. Purification by silica gel chromatography (0–30% EtOAc in heptane) afforded tert-butyl (2′S,7S)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-carboxylate C30 (170 mg, 63%). 1H NMR (300MHz, methanol-d4)δ 6.66(s,1H),4.35(q,J=6.9Hz,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=14.5,6.6Hz,1H),1.68(ddd,J=13.7,12.9,4.7Hz,1H),1.47(s,9H),1.32(d,J=7.1Hz,3H).

[0290] Step 3: Synthesis of (2'S,7S)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (S51) To a stirred solution of tert-butyl (2'S,7S)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate C30 (170 mg, 0.4750 mmol) in dioxane (2 mL), HCl in dioxane (600 μL of 4 M, 2.400 mmol) was added and the reaction was stirred at room temperature for 20 hours. The reaction was concentrated. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in H2O containing 5 mM HCl and lyophilization gave 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%). 1 H NMR (300MHz, methanol-d4)δ 6.77(s,1H),3.98(t,J=5.8Hz,2H),3.72(h,J=6.3Hz,1H),3.53(ddd,J=13.8,9.7,4.0H z,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] + .

[0291] Preparation of C31 1-Methylprop-2-yl 4-methylbenzenesulfonate (C31) [ka] Synthesis of 1-methylprop-2-yl 4-methylbenzenesulfonate (C31) To a stirred solution of but-3-yn-2-ol (1.5 g, 0.0214 mol) in DCM (15 mL) at 0 °C, DMAP (1 g, 0.0082 mol), TEA (726.00 mg, 1 mL, 0.0072 mol), and 4-methylbenzenesulfonyl chloride (0.45 g, 0.0024 mol) were added. The reaction mixture was stirred at 0 °C for 30 minutes and at room temperature for 1 hour. The reaction mixture was then filtered. The filtrate was washed with saturated CuSO solution (200 mL), saturated NaHCO solution (200 mL), and brine (200 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. Purification by silica gel chromatography (gradient: 10–30% EtOAc in pet ether) afforded 1-methylprop-2-yl 4-methylbenzenesulfonate C31 (1.2 g, 25%). 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).

[0292] compound 694 (2'S,7R)-2-chloro-2'-methyl-1'-(1-methylprop-2-ynyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (694) [ka] 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) 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 K2CO3 (415 mg, 0.0030 mol) and 1-methylprop-2-yl 4-methylbenzenesulfonate (C31) (403 mg, 0.0018 mol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The reaction was cooled to room temperature, quenched with water (50 ml), and extracted with EtOAc (2 x 100 ml). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-30% EtOAc in hexanes) followed by reverse-phase chromatography (Column: -xselect Phenyl Hexyl (250*19) mm, 5 u, 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)δ ppm 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] + .

[0293] compound 695 (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) [ka] 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) (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 in a sealed tube at 60° C. 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 by reverse-phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid gave (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) (trifluoroacetate salt) (32 mg, 41%). 1 H NMR(300MHz,chloroform-d)δ 8.26(s,1H),6.60(s,1H),4.94(t,J=6.8Hz,2H),4.41(d,J=19.1Hz,2H),3.93(t,J=5.1Hz,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=7.1Hz,3H). LCMS m / z 445.31[M+H] + .

[0294] compound 696 (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) [ka] 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) (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 continued for 24 h. The reaction mixture was concentrated. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid to give (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%). 1H NMR(300MHz,chloroform-d)δ 8.28(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),3.97~3.65(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] + .

[0295] compound 697 (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) [ka] 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) i. To a solution of tert-butyl (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate (65 mg, 0.1780 mmol) in DCM (1 mL) was added TFA (200 μL, 2.596 mmol), and the mixture was refluxed for 5 min. At this point, UPLC indicated complete conversion, and the mixture was concentrated to dryness, diluted with DCM, and concentrated again.

[0296] ii. The oil from the first step was diluted with acetonitrile (1.5 mL) and K2CO3 (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 reaction mixture was cooled to room temperature and diluted with water (10 mL) and EtOAc (15 mL). The layers were separated and the organic layer was washed with water (2 × 10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (0-20% MeOH in DCM) gave (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) (41.6 g, 51%). 1 H NMR (400MHz, chloroform-d)δ 7.51(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] + .

[0297] compound 698 (2'S,7R)-2-chloro-2'-methyl-1'-(1H-pyrazol-4-ylmethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (698) [ka] 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) 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), and cyanoboranide (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% EtOAc 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 (400MHz, chloroform-d) δ7.56(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=6.3Hz,3H). LCMS m / z 337.88[M+H] + .

[0298] compound 699 (2S,7R)-2'-chloro-1-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)methyl)-2-methyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] (699) [ka] Preparation of (2S,7R)-2'-chloro-1-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)methyl)-2-methyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] (699) 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-methoxyethane (16 mL). The reaction was stirred at room temperature for 80 minutes, then heated to 60 °C and stirred for 5 hours. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO with 5 mM HCl gave the product (HCl salt) EA#6 (18.8 mg, 73.3%). 1 H NMR (400 MHz, DMSO-d6) δ 10.94(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,2 H),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] + .

[0299] Compounds 700~707 Compounds 700-707 (see Table 30) were prepared in a single step from the alkylation of 698 and the related alkyl halides as described for compound 699. The alkyl halides were obtained from commercial sources. Any modifications to the method are described in Table 30 and the accompanying footnotes. [Table 30-1] [Table 30-2] [Table 30-3]

[0300] Compound 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-propanamide [ka] 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-propanamide (708) (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 methyl (2S)-oxirane-2-carboxylate (100 μL, 1.142 mmol) were added to a microwave vial and taken up in NH3 (3.5 mL of 7 M, 24.50 mmol) and MeOH (99 μL). DIPEA (340 μL, 1.952 mmol) was added and the reaction was stirred at 120 °C for 4 h. An additional 70 μL of oxirane and 800 μL of NH3 / MeOH were added and the reaction was heated at 120 °C for 2 h. An additional 50 μL of oxirane and 500 μL of NH3 / MeOH were added and the reaction was heated at 120 °C for an additional 2 h. The reaction mixture was concentrated via rotovap, then diluted with water / DCM, and the organics were extracted (3×DCM, 3×EtOAc) and concentrated via rotovap. The material was purified by normal phase chromatography (12 g HP silica gel, 90:10 MeOH / DCM in DCM 0-100%) 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-propanamide (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),1.77(dd d,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] + .

[0301] Compound 709 (2R)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2-hydroxy-propanamide [ka] 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-propanamide (709) (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 methyl (2R)-oxirane-2-carboxylate (360 μL, 4.112 mmol) were added to a microwave vial and taken up in NH3 (4.7 mL of 7 M, 32.90 mmol) in MeOH (4.7 mL). DIPEA (750 μL, 4.306 mmol) was added and the reaction was stirred at 120 °C for 5 h. An additional 200 μL of oxirane and 500 μL of NH3 were added and the reaction was stirred at 120 °C for an additional 4 h. The material was concentrated via rotovap and rinsed with MeOH / DCM (2×). The remaining solid was insoluble in DCM for column loading, so citric acid was added to acidify it, and the organics were extracted with EtOAc (3x). The organic phase was dried via rotovap, and the material was purified by normal phase chromatography (40 g silica gel, MeOH / DCM 0-20%) to give the product (2R)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2-hydroxy-propanamide (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] + .

[0302] compound 710 (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-propanamide [ka] Step 1: Synthesis of methyl (2R)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]-2-hydroxy-propanoate (C32) (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 taken up in MeOH (3.5 mL) and added to a microwave vial. Methyl (2S)-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 h. The reaction mixture was concentrated via rotovap and purified via normal phase chromatography (24 g silica gel EtOAC / heptane 0-80%) to afford methyl (2R)-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 (147.5 mg, 57%). LCMS m / z 360.02 [M+1] + .

[0303] Step 2: Synthesis of (2S)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]-2-hydroxy-N-methyl-propanamidomethyl (710) (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 taken in 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 h. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron) to give the product (2S)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]-2-hydroxy-N-methyl-propanamide 710 (22.4 mg, 62%). 1H NMR (300 MHz, chloroform-d) δ 10.65(s,1H),7.46(s,1H),6.61(s,1H),4.70(dd,J=9.7,3.1Hz,1H),4.04(d, J=13.7Hz,1H),3.89(p,J=5.8Hz,3H),3.66(d,J=12.0Hz,1H),3.53(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] + .

[0304] Compound 711 (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-propanamide [ka] Step 1: Synthesis 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-propanoic acid (C33) A solution of methyl (2R)-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 (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 room temperature for 2 hours. The reaction mixture was concentrated via rotovap, 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-propanoic acid (lithium salt) C33 (147 mg, 98%) LCMS m / z 344 [M+1] + .

[0305] 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-propanamide (711) (2S)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]-2-hydroxy-propanoic acid C33 (lithium salt) (147 mg, 0.2917 mmol), N-methylmethanamine (500 μL of 2 M, 1.000 mmol), and HATU (379.5 mg, 0.9981 mmol) were taken up in DMF (2 mL). DIPEA (200 μL, 1.148 mmol) was added and the reaction was stirred for 2 h. An additional 500 μL of DMF was added to rinse the sides of the flask. An additional 332 mg of HATU and 300 μL of dimethylamine in 500 μL of DMF were added and the reaction was stirred overnight. The reaction mixture was concentrated via rotovap. Excess water was added, and the organics were extracted with DCM and concentrated via rotovap. 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-propanamide 711 (7.6 mg, 6%). 1 H NMR (300MHz, chloroform-d)δ 6.60(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] + .

[0306] Preparation S53 (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]methanol (S53) [ka] Step 1. Synthesis of tert-butyl (2'S,7R)-2-chloro-3-formyl-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate (S52) - Preparation of LDA solution: A solution of diisopropylamine (3 mL, 21.41 mmol) in EtO (3 mL) in an oven-dried flask was purged with nitrogen and cooled to −20° C. At this point, sec-butyllithium (15 mL of 1.333 M, 19.99 mmol) was added dropwise. The reaction mixture was stirred at this temperature for 30 min.

[0307] A solution of tert-butyl (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate C27 (6.3 g, 17.49 mmol) in THF (100 mL) in an oven-dried flask was purged with nitrogen and cooled to -78 °C. At this point, the LDA mixture from the previous step was transferred over 2 min. The mixture was stirred at this temperature for 5 min. At this point, DMF (5 mL, 64.57 mmol) was added. After 5 min, saturated aqueous ammonium chloride (25 mL) was added to the mixture, and the mixture was allowed to warm to room temperature. The mixture was then diluted with EtO (200 mL) followed by water (200 mL). The organic layer was washed with additional water (2 x 200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The mixture was purified by silica gel chromatography (gradient: 0-25% EtOAc in heptane) to give tert-butyl (2'S,7R)-2-chloro-3-formyl-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate (5.0 g, 73%). 1H NMR (400 MHz, chloroform-d) δ 10.09(s,1H),4.01(tt,J=11.6,6.5Hz,1H),3.95~3.80(m,2H),3.74(dt,J=14.0 ,5.5Hz,1H),3.36(ddd,J=13.9,8.6,5.3Hz,1H),2.99~2.84(m,2H),2.21(dddd,J =14.6,8.3,5.9,1.9Hz,1H),2.12(ddd,J=14.1,5.1,2.0Hz,1H),1.76(dt,J=14. 5,5.2Hz,1H),1.67(dd,J=14.2,10.9Hz,1H),1.50(s,9H),1.29(d,J=6.5Hz,3H). LCMS m / z 385.96[M+H] + .

[0308] Step 2. Synthesis of (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-3-carbaldehyde (C34) A mixture of tert-butyl (2'S,7R)-2-chloro-3-formyl-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate S52 (3.0 mg, 7.649 mmol) in a 4 M solution of HCl in dioxane (7.5 mL, 30.00 mmol) was stirred at room temperature overnight. After 5 min, EtO (15 mL) was added, and the suspension was allowed to stir at room temperature. After 30 min, the mixture was filtered, rinsed with EtO, and concentrated to give (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-3-carbaldehyde (hydrochloride salt) (2.369 g, 96%). LCMS m / z 286.05[M+H] + .

[0309] Step 3. Synthesis of [(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]methanol (S53) To (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-3-carbaldehyde (hydrochloride salt) C34 (2.369 g, 7.35 mmol) dissolved in water (40 mL) was added NaBH4 (100 mg, 2.643 mmol). Then, aqueous HCl (7.5 mL of 1 M, 7.500 mmol) was added until the pH reached 1. After stirring for 5 minutes, the mixture pH was adjusted to approximately pH = 12 with NaOH (2.5 mL of 6 M, 15.00 mmol). The mixture was extracted with DCM (2 × 25 mL), dried over sodium sulfate, filtered, and concentrated to give [(2′S,7R)-2-chloro-2′-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidin]-3-yl]methanol (1.88 g, 82%) as a white amorphous solid. 1 H NMR(400MHz,DMSO-d6)δ 5.03(t,J=5.4Hz,1H),4.31(d,J=5.2Hz,2H),3.86(td,J=5.7,3.0Hz,2H),2.95~2.78(m,2H),2.78~2.68(m,1H),2.59( t,J=5.5Hz,2H),1.93~1.80(m,2H),1.49(td,J=13.0,4.8Hz,1H),1.18(dd,J=13.4,11.2Hz,1H),0.94(d,J=6.4Hz,3H). LCMS m / z 288.08[M+H] + .

[0310] Compound 712 2-chloro-6-[[(2'S,7R)-2-chloro-3-(hydroxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]methyl]phenol (712) [ka] Standard Method #A: Reductive Amination with Polymer-Supported Cyanoborohydride To a 1-dram vial was added cyanoborohydride, polymer-supported (75 mg of 2 mmol / g, 0.15 mmol), followed by a solution of 3-chloro-2-hydroxy-benzaldehyde (15.7 mg, 0.1 mmol) in DMF (400 μL) and a solution of [(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]methanol S53 (16 mg, 0.056 mmol) in DMF (400 μL). The vial was sealed and heated at 85 °C overnight. The vial was then cooled to room temperature. The resulting suspension was filtered through a polypropylene filter plate. 400 μL of 0.1 wt% TFA in water was added to the reaction vial, which was stirred for several minutes to rinse the beads. DMSO (200 uL) was added to the resulting filtrate. Purification by reverse phase HPLC. Method: C18 Waters Sunfire column (30x150 mm, 5 microns). Gradient: MeCN in H2O containing 0.1% trifluoroacetic acid to give 2-chloro-6-[[(2'S,7R)-2-chloro-3-(hydroxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-1'-yl]methyl]phenol (trifluoroacetate) (2.8 mg, 9.2%). LCMS m / z 428.29 [M+H] + .

[0311] Compound 713 (2'S,7R)-2-chloro-1'[(2-fluorophenyl)methyl]-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (713) [ka] Standard Method #B: Reductive Amination Using Polymer-Supported Cyanoborohydride and Acetic Acid A stock solution of [(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]methanol S53 (20 mg, 0.068 mmol) and AcOH (2 μL) in DMF (0.7 mL) was added to a mixture of 2-fluorobenzaldehyde (25 μL, 0.237 mmol) in DMF (0.7 mL). To this mixture was added polymer-supported cyanoborohydride (75 mg, 0.15 mmol at 2 mmol / g), and the mixture was heated to 85 °C. After stirring overnight, the mixture was cooled to room temperature, filtered, and the polymer was rinsed with additional DMF. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid. (2'S,7R)-2-chloro-1'[(2-fluorophenyl)methyl]-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine](trifluoroacetate) (19.3 mg, 56%). 1 H NMR (400 MHz, chloroform-d) δ 7.74~7.65(m,1H),7.48(q,J=6.3Hz,1H),7.31(s,1H),7.21~7.14(m,1H),4.6 3(d,J=13.4Hz,1H),4.57(s,2H),4.13(d,J=13.2Hz,1H),3.91(dq,J=21.8,5.9 Hz,2H),3.52(s,1H),3.22(d,J=12.1Hz,1H),3.05(t,J=12.6Hz,1H),2.71(q,J =5.5,5.1Hz,2H),2.53~2.37(m,2H),2.22~2.03(m,2H),1.68(d,J=6.5Hz,3H). LCMS m / z 396.32[M+H] + .

[0312] Compounds 714~758 Compounds 714-758 (see Table 31) were prepared in a single step from intermediate S53 using the same method as for the preparation of compound 712 or 713. The aldehydes were commercially available or previously described. Any modifications to the method are described in Table 31 and the accompanying footnotes. [Table 31-1] [Table 31-2] [Table 31-3] [Table 31-4] [Table 31-5] [Table 31-6] [Table 31-7] [Table 31-8] [Table 31-9] [Table 31-10] [Table 31-11] [Table 31-12]

[0313] Compound 759 [(2'S,7R)-2-chloro-1'-[(1-isobutylpyrazol-4-yl)methyl]-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]methanol (759) [ka] Step 1. Synthesis of [(2'S,7R)-2-chloro-2'-methyl-1'-(1H-pyrazol-4-ylmethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]methanol (S54) [(2'S,7R)-2-chloro-2'-methyl-1'-(1H-pyrazol-4-ylmethyl)spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]methanol S54 was prepared according to standard procedure A with the following modifications: cyanoborohydride, polymer-supported (2.0 equiv.) was used, and DCM was used as the solvent. Purification was carried out by silica gel chromatography (gradient: 0-20% MeOH in DCM) to give the title compound. 1 H NMR(400MHz,DMSO-d6)δ 12.68(s,1H),7.49(d,J=73.3Hz,2H),5.02(t,J=5.4Hz,1H),4.31(t,J=5.7Hz,2H),3.81(q,J=5.6Hz,2H),3.72(s,1H),3.50(s ,1H),3.17(d,J=5.2Hz,1H),2.56(t,J=5.5Hz,3H),2.38(s,1H),1.92(d,J=6.4Hz,2H),1.63(s,1H),1.42(s,1H),1.12(s,3H). LCMS m / z 368.05[M+H] + .

[0314] Step 2. Synthesis of [(2'S,7R)-2-chloro-1'-[(1-isobutylpyrazol-4-yl)methyl]-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]methanol (759) - Standard Method #C: Pyrazole N-Alkylation 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'-piperidin]-3-yl]methanol S54 (20 mg, 0.05320 mmol) in DMF (1000 μL) was added NaH (3.5 mg, 0.08751 mmol of a 60% dispersion in mineral oil), followed by 1-bromo-2-methyl-propane (20 μL, 0.1839 mmol). After stirring overnight, the mixture was purified on a C18 column (gradient: 10-100% MeCN in water, 0.1% TFA modifier). Product-containing fractions were pooled, concentrated, and rediluted in saturated aqueous sodium bicarbonate / DCM to remove TFA. The organic layer was passed through a phase separator and concentrated to give [(2'S,7R)-2-chloro-1'-[(1-isobutylpyrazol-4-yl)methyl]-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidin]-3-yl]methanol (11 mg, 48%). 1 H NMR (400MHz, chloroform-d)δ 7.39(d,J=0.8Hz,1H),7.31~7.26(m,1H),4.52(s,2H),3.86(d,J=7.3Hz,5H),3.53(d,J=14. 2Hz,1H),2.66(dtd,J=10.4,5.3,3.3Hz,3H),2.54(ddt,J=11.2,6.1,2.9Hz,1H),2.47(td,J= 12.0,11.5,2.5Hz,1H),2.18(hept,J=6.8Hz,1H),1.95(d,J=13.7Hz,3H),1.78(td,J=13.4,4 .4Hz,1H),1.60(dd,J=13.8,11.4Hz,1H),1.18(d,J=6.2Hz,3H),0.89(dd,J=6.7,0.9Hz,6H). LCMS m / z 424.23[M+H] + .

[0315] Compounds 760~761 Compounds 760-761 (see Table 32) were prepared in a single step from intermediate S54 using the method described for the preparation of compound 759. The alkyl halides were obtained from commercial sources. Any modifications to the method are described in Table 32 and the accompanying footnotes. [Table 32]

[0316] compound 762 (2'S,7R)-2-chloro-3-(methoxymethyl)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (762) [ka] Step 1. Synthesis of tert-butyl (2'S,7R)-2-chloro-3-(hydroxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate (C35) To a mixture of tert-butyl (2'S,7R)-2-chloro-3-formyl-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate S52 (400 mg, 1.023 mmol) in tetrahydrofuran (8 mL), NaBH4 (13 μL, 0.3247 mmol) was added, followed by MeOH (160 μL), and the reaction was heated to 50 °C. After 10 min, the mixture was quenched with saturated aqueous sodium bicarbonate and EtOAc. The organic layer was separated and rinsed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give tert-butyl (2'S,7R)-2-chloro-3-(hydroxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate. LCMS m / z 387.9 [M+H] + This material was used in the next step without further purification.

[0317] Step 2. Synthesis of tert-butyl (2'S,7R)-2-chloro-3-(methoxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate (C36) tert-Butyl (2'S,7R)-2-chloro-3-(hydroxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate C35 (400 mg, 1.031 mmol) was dissolved in THF (11 mL), and MeI (192 μL, 3.084 mmol) and NaH (74 mg, 3.084 mmol) were added. The mixture was stirred at room temperature for 48 hours. The reaction was then quenched by the addition of saturated aqueous NH4Cl solution, and the solution was extracted with DCM, dried over sodium sulfate, and filtered to give the crude product. Purification by silica gel chromatography (gradient: 0-20% EtOAc in heptane) afforded tert-butyl (2'S,7R)-2-chloro-3-(methoxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate (340 mg, 82%). LCMS m / z 402.04 [M+H] + .

[0318] Step 3. (2'S,7R)-2-chloro-3-(methoxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (S55) Tert-butyl tert-butyl (2'S,7R)-2-chloro-3-(methoxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate C36 (113 mg, 0.2811 mmol) was dissolved in HCl (703 μL of 4 M, 2.812 mmol). After 20 min, the solvent was removed to give (2'S,7R)-2-chloro-3-(methoxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]. LCMS m / z 302.22 [M+H] + This material was used in the next step without further purification.

[0319] Step 4. Synthesis of (2'S,7R)-2-chloro-3-(methoxymethyl)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (762) (2'S,7R)-2-chloro-3-(methoxymethyl)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] S55 (70 mg, 0.17 mmol) and 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (57 mg, 0.2819 mmol) were dissolved in DCM (3 mL). Acetic acid (50.7 mg, 0.8443 mmol) was added to the solution. The solution was transferred to a microwave tube, and polymer-supported cyanoborohydride (253 mg of 2 mmol / g, 0.5060 mmol) was added. The tube was capped and heated to 110 °C in a microwave reactor for 45 min. The borohydride resin was filtered and the solvent removed in vacuo. Purification by reverse-phase HPLC. Method: C18 Waters Sunfire column (30x150 mm, 5 micron). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid to give (2'S,7R)-2-chloro-3-(methoxymethyl)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (trifluoroacetate) (38.2 mg, 37%). 1 H NMR (300MHz, chloroform-d)δ 7.84(s,1H),7.64(s,1H),4.81~4.51(m,3H),4.34(s,2H),4.10~3.60(m,5H),3.35 (s,3H),2.99(s,4H),2.86~2.61(m,5H),2.45~2.05(m,4H),1.58(d,J=6.5Hz,3H). LCMS m / z 488.21[M+H] + .

[0320] compound 763 (2'S,7R)-2-(difluoromethyl)-3-(methoxymethyl)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (763) [ka] Step 1. Synthesis of tert-butyl (2'S,7R)-2-formyl-3-(methoxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate (C37) A mixture of tert-butyl (2'S,7R)-2-chloro-3-(methoxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate S55 (226 mg, 0.5615 mmol) in THF (5 mL) in an oven-dried vial was cooled to -70 °C. At this point, sec-butyllithium in cyclohexane (570 μL of 1.25 M, 0.7125 mmol) was added dropwise and stirred at this temperature. After 20 minutes, N,N-dimethylformamide (222 μL, 2.867 mmol) was added. The mixture was allowed to warm to room temperature. The reaction mixture was stirred at this temperature overnight. To this mixture was added saturated aqueous ammonium chloride (6 mL), and the mixture was allowed to warm to room temperature. At this point, the mixture was diluted with EtO, followed by water. The organic layer was washed with brine. The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The mixture was purified by silica gel chromatography (gradient: 0-25% EtOAc in heptane) to give tert-butyl (2'S,7R)-2-formyl-3-(methoxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate (75 mg, 34%). 1H NMR(300MHz, methanol-d4)δ 10.13(s,1H),4.68(s,2H),4.11~3.73(m,4H),3.41(s,3H),2.65(t,J=5.6Hz,2 H),2.43~2.01(m,2H),1.99~1.60(m,2H),1.48(s,10H),1.22(d,J=6.5Hz,3H). LCMS m / z 396.05[M+H] + .

[0321] Step 2. Synthesis of (2'S,7R)-2-(difluoromethyl)-3-(methoxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (C38) To a solution of tert-butyl (2'S,7R)-2-formyl-3-(methoxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate C37 (70 mg, 0.1763 mmol) in DCM (700 μL) was added DAST (116 μL, 0.8780 mmol), and the reaction was heated to 40 °C. After 4 h, additional DAST (116 μL, 0.8780 mmol) was added. After stirring overnight, the solution was diluted with DCM, washed with saturated NaHCO solution, extracted with DCM (2x), and washed with brine. The solvent was removed to give the crude product. This crude material was redissolved in dioxane (2 mL), and HCl (1.3 mL of 4 M, 5.200 mmol) was added. After 30 minutes, the solvent was removed and the residue was purified by reverse-phase HPLC. Method: C18 Waters Sunfire column (30x150 mm, 5 microns). Gradient: MeCN in HO containing 0.1% trifluoroacetic acid. The pro...

Claims

1. The following structural formula: 【Chemistry 290】 or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X １ and X ２ is -S-, -S(=O) ２ -, -S(=O)-, and -CR ２ is selected from: X １ and X ２ One of them is -S-, -S(=O) ２ -, and -S(=O)-; X １ -S-, -S(=O) ２ - or -S(=O)-, X ２ Ha-CR ２ and X ２ -S-, -S(=O) ２ - or -S(=O)-, X １ Ha-CR ２ and R １ is cyano, halogen, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, and C ３ -C ６ cycloalkyl groups, wherein R １ The above C １ -C ４ Alkyl is —OH and C １ -C ４ optionally substituted with 1 to 3 groups independently selected from alkoxy groups; R ２ is hydrogen, C １ -C ６ Alkyl, —C(═O)O(C １ -C ４ alkyl), —C(═O)NR ｎ R ｏ and a halogen group, R ２ The above C １ -C ６ Alkyl is substituted with —OH, halogen, and C １ -C ４ optionally substituted with 1 to 3 groups independently selected from alkoxy groups; and R ｎ and R ｏ is hydrogen, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C ６ cycloalkyl, and -(C １ -C ４ alkylene)-R ｐ groups, wherein R ｐ is C ３ -C ６ cycloalkyl groups, or R １ and R ２ together with the carbon atoms to which they are attached, C ６ forming an aryl group, k is selected from 0, 1, and 2; m is selected from 0, 1, and 2; Each R ３ａ is -OH, -CN, -NR ａ１ R ａ２ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, —OC(═O)(C １ -C ４ alkyl), 6- to 8-membered aryl, 6- to 8-membered heteroaryl, and halogen groups, wherein Each R ａ１ and R ａ２ is hydrogen, C １ -C ４ Alkyl, and -C(=O)(C １ -C ４ alkyl) groups, or Two R's ３ａ together form an oxo group, or Two R's ３ａ together with the carbon atoms to which they are attached, C ３ -C ６ forming a cycloalkyl group, Each R ３ｂ is C １ -C ４ alkyl groups, wherein R ３ｂ The above C １ -C ４ Alkyl is substituted with —OH, halogen, and C １ -C ４ optionally substituted with 1 to 3 groups independently selected from alkoxy groups; One R ３ａ and one R ３ｂ together with the carbon atoms to which they are attached, C ３ -C ６ forming a cycloalkyl group, R ４ａ , R ４ｂ , R ５ａ , and R ５ｂ At least one of them is C １ -C ４ alkyl groups, the others being hydrogen; R ６ is C １ -C ６ Alkyl, —C(═O)O(C １ -C ４ alkyl), and 【Chemistry 291】 is selected from the group R ６ The above C １ -C ６ Alkyl is a halogen, cyano, —OH, —NH ２ , —NH(C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , —C(═O)NH ２ , -C(=O)(C １ -C ４ alkyl), -C(=O)OH, -C(=O)O(C １ -C ４ alkyl), -C(=O)NH(C １ -C ４ alkyl), -C(=O)N(C １ -C ４ alkyl) ２ , C １ -C ４ Alkoxy, C ３ -C ６ Carbocyclyl, C ６ Aryl, —O—(C ６ aryl), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein Said C ６ Aryl and —O—(C ６ aryl) groups are each selected from halogen and C １ -C ４ optionally substituted with 1 to 3 groups independently selected from haloalkyl groups; Ring B is C ３ -C １２ Carbocyclyl, 3- to 12-membered heterocyclyl, C ６ and C １０ aryl, and 5- to 10-membered heteroaryl groups, wherein ring B is selected from 1, 2, 3, 4, or 5 R ａ and optionally substituted with a group, wherein R ａ For each occurrence halogen, Cyano, C １ -C ８ Alkyl, C １ -C ６ haloalkyl, C ２ -C ８ alkenyl, C １ -C ６ haloalkenyl, C １ -C ６ Alkoxy, C １ -C ６ haloalkoxy, C ３ -C １２ carbocyclyl, C ６ and C １０ aryl, 3- to 12-membered heterocyclyl, 5-10 membered heteroaryl, -C(=O)NR ｈ R ｉ 、 -C(=O)OR ｋ 、 -C(=O)(C １ -C ４ alkylene) OR ｋ , -C(=O)R ｋ 、 -C(=O)(C １ -C ４ alkylene)S(=O) ｐ R ｋ , -C(=O)(C １ -C ４ alkylene)S(=O) ｐ NR ｈ R ｉ , -C(=O)(C １ -C ４ alkylene)NR ｉ S (= O) ｐ R ｋ , -C(=O)(C １ -C ４ alkylene)NR ｈ C(=O)R ｋ , -C(=O)C(=O)R ｋ 、 -NR ｈ R ｉ 、 -NH(CH ２ ) ｑ CHR ｈ R ｉ 、 -NH(CH ２ ) ｑ NR ｈ R ｉ 、 -NR ｈ C(=O)R ｋ 、 -NR ｈ C(=O)OR ｋ 、 -NR ｈ C(=O)(C １ -C ４ alkylene) OR ｋ , -NR ｈ C(=O)O(C １ -C ４ alkylene) R ｋ , -NR ｈ C(=O)NR ｉ R ｊ 、 -NR ｈ C(=O)(C １ -C ４ alkylene)NR ｉ S (= O) ｐ R ｋ , -NR ｈ S(=O) ｐ R ｋ 、 -NR ｈ C(=O)(C １ -C ４ alkylene)S(=O) ｐ R ｋ , -NR ｈ S (= O) ｐ (C １ -C ４ alkylene)C(=O)OR ｋ 、 -NR ｈ C(=O)[O(CH ２ ) ｑ ] ｒ OC(=O)NR ｈ R ｉ (CH ２ ) ｑ [O(CH ２ ) ｑ ] ｒ (C １ -C ６ alkyl) (1 to 3 R ｍ optionally substituted with a group), -NR ｈ C(=O)(C １ -C ６ alkylene) [O(CH ２ ) ｑ ] ｒ OC(=O)NR ｈ R ｉ (CH ２ ) ｑ [O(CH ２ ) ｑ ] ｒ (C １ -C ６ alkyl) (1 to 3 R ｍ optionally substituted with a group), -OR ｋ 、 -OC(=O)R ｋ 、 -OC(=O)OR ｋ 、 -OC(=O)NR ｈ R ｉ , -[O(CH ２ ) ｑ ] ｒ O (C １ -C ６ alkyl), -S(=O) ｐ R ｋ , and -S(=O) ｐ NR ｈ R ｉ are independently selected from the group During the ceremony, -C(=O)(C １ -C ４ alkylene)S(=O) ｐ R ｋ , -C(=O)(C １ -C ４ alkylene) OR ｋ , -C(=O)(C １ -C ４ alkylene)S(=O) ｐ NR ｈ R ｉ , -C(=O)(C １ -C ４ alkylene)NR ｉ S (= O) ｐ R ｋ , -C(=O)(C １ -C ４ alkylene)NR ｈ C(=O)R ｋ , -NR ｈ C(=O)O(C １ -C ４ alkylene) R ｋ , -NR ｈ C(=O)(C １ -C ４ alkylene) OR ｋ , － NR ｈ S (= O) ｐ (C １ -C ４ alkylene)C(=O)OR ｋ , and -NR ｈ C(=O)(C １ -C ４ alkylene)NR ｉ S (= O) ｐ R ｋ The C in each of １ -C ４ The alkylene is optionally substituted with 1 to 3 groups independently selected from —OH; R ａ The above C １ -C ８ alkyl, the C １ -C ６ haloalkyl, the C １ -C ６ Alkoxy, and the C ２ -C ８ Alkenyl is 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(CH ２ ) 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(CH ２ ) ｑ ] ｒ O (C １ -C ４ alkyl), —O—(C ６ aryl or 5- to 8-membered heteroaryl) (1 to 3 R ｍ optionally substituted with a group), C ３ -C ６ Carbocyclyl (1 to 3 R ｍ optionally substituted with a group), C ６ -C １０ Aryl (1 to 3 R ｍ group), 4-10 membered heterocyclyl (1-3 R ｍ and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 R ｍ optionally substituted with 1 to 3 groups independently selected from the group R ａ The above C ３ -C １２ carbocyclyl, the 3- to 12-membered heterocyclyl, the C ６ and C １０ The aryl and the 5- to 10-membered heteroaryl are each selected from halogen, cyano, C １ -C ６ Alkyl (1 to 3 R ｍ optionally substituted with a —C(═O)R group, ｋ , -C(=O)OR ｋ , -NR ｈ R ｉ , -OR ｋ , -S(=O) ｐ R ｋ , -S(=O) ｐ NR ｈ R ｉ and 5- to 10-membered heterocyclyl groups, R ｈ , R ｉ , and R ｊ are hydrogen, C, １ -C ６ Alkyl (1 to 4 R ｍ optionally substituted with a group), C ６ -C １０ Aryl, C ３ -C ８ Carbocyclyl (1 to 3 R ｍ aryl (optionally substituted with 1 to 3 R ｍ and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 R ｍ and optionally substituted with a group, wherein R ｈ , R ｉ , and R ｊ Any one of the C １ -C ６ Alkyl is a group containing halogen, cyano, —OH, C １ -C ４ Alkoxy, —C(═O)NH(C １ -C ４ alkyl), 5- to 10-membered heteroaryl (1 to 3 R ｍ and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 R ｍ optionally substituted with 1 to 3 groups independently selected from the group R ｋ For each occurrence, hydrogen, -NH2 (C １ -C ３ alkyl), C １ -C ６ Alkyl, benzyl, C ６ Aryl, C ３ -C ６ independently selected from carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein R ｋ Any one of the C １ -C ６ Alkyl is a halogen, cyano, -NH ２ , -OH, C １ -C ４ Alkoxy, C ３ -C ６ 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 (C １ -C ４ optionally substituted with 1 to 5 groups independently selected from alkyl and halogen; and 5-10 membered heteroaryl (optionally substituted with 1 to 3 —OH groups); and R ｋ Any one of the C ３ -C ６ Carbocyclyl, benzyl, and C ６ Aryl is halogen, cyano, oxo, —OH, —C(═O)NH ２ , -C(=O)N(CH ３ ) ２ , C １ -C ６ alkyl (optionally substituted with 1 to 3 —OH groups), C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C ３ -C ６ cycloalkyl (optionally substituted with 1 to 3 halogen groups), C ６ optionally substituted with 1 to 3 groups independently selected from aryl (optionally substituted with 1 to 3 halogen groups), and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 halogen groups); and R ｋ wherein each of the 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl is halogen, oxo, cyano, —C(═O)CH ３ , -NH ２ , -OH, C １ -C ４ alkyl (optionally substituted with 1 to 3 —OH groups), C １ -C ４ haloalkyl, 5- to 10-membered heterocyclyl, and C １ -C ４ optionally substituted with 1 to 3 groups independently selected from alkoxy groups; R ｍ is, for each occurrence, a halogen, cyano, oxo, -NH ２ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, —C(═O)R ｋ , -S(=O) ｐ R ｋ , -OR ｋ and a 5- to 10-membered heterocyclyl group, R ｍ Any one of the C １ -C ６ alkyl, the C １ -C ６ Alkoxy, and the 5- to 10-membered heterocyclyl are substituted with halogen, cyano, —OH, and C １ -C ４ optionally substituted with 1 to 3 groups independently selected from alkoxy groups; p, for each occurrence, is an integer independently selected from 1 and 2; and and q and r, for each occurrence, are integers independently selected from 0, 1, 2, and 3; a compound, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

2. A compound having the following structural formula: 【Chemical 401】 or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 and X 2 are selected from —S—, —S(═O) 2 —, —S(═O)—, and —CR 2 , wherein: one of X 1 and X 2 is selected from —S—, —S(═O) 2 —, and —S(═O)—; When X 1 is —S—, —S(═O) 2 —, or —S(═O)—, X 2 is —CR 2 , and When X 2 is —S—, —S(═O) 2 —, or —S(═O)—, X 1 is —CR 2 ; R 1 is selected from cyano, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl groups; said C 1 -C 4 alkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from —OH and C 1 -C 4 alkoxy groups; R 2 is selected from hydrogen, C 1 -C 6 alkyl, —C(═O)O(C 1 -C 4 alkyl), —C(═O)NR n R o , and a halogen group, wherein: said C 1 -C 6 alkyl of R 2 is optionally substituted with 1 to 3 groups independently selected from —OH, halogen, and C 1 -C 4 alkoxy groups; and R n and R o are independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, and -(C 1 -C 4 alkylene)R p groups, where R p is selected from C 3 -C 6 cycloalkyl groups; or R 1 and R 2 together with the carbon atom to which they are attached form a C 6 aryl group; k is selected from 0, 1, and 2; m is selected from 0, 1, and 2; each R 3a is independently selected from —OH, —CN, —NR a1 R a2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —OC(═O)(C 1 -C 4 alkyl), 6- to 8-membered heteroaryl, and a halogen group; each R a1 and R a2 is independently selected from hydrogen, C 1 -C 4 alkyl, and —C(═O)(C 1 -C 4 alkyl) groups; or two R 3a together form an oxo group; or two R 3a together with the carbon atoms to which they are attached form a C 3 -C 6 cycloalkyl group; Each R 3b is independently selected from a C 1 -C 4 alkyl group, wherein: said C 1 -C 4 alkyl of R 3b is optionally substituted with 1 to 3 groups independently selected from —OH, halogen, and C 1 -C 4 alkoxy groups; or one R 3a and one R 3b together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl group; R 4a , R 4b , R 5a , and R 5b are each hydrogen; R 6 is 【Chemical 402】 wherein: Ring B is selected from C 3 -C 12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6 and C 10 aryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is substituted with 1, 2, 3, 4, or 5 R a groups; R a is for each occurrence halogen, Cyano, C 1 -C 8 alkyl, C 1 -C 6 haloalkyl, C2-C8 alkenyl, C 1 -C 6 haloalkenyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -C(=O)NR h R i , -C(=O)OR k, -C(=O)(C 1 -C 4 alkylene)OR k , -C(=O)Rk, -C(=O)(C 1 -C 4 alkylene)S(=O) p R k , -C(=O)(C 1 -C 4 alkylene)S(=O) p NR h R i , -C(=O)(C 1 -C 4 alkylene)NR i S(=O) p R k , -C(=O)(C1-C4 alkylene)NRhC(=O)Rk, -C(=O)C(=O)R k , -NR h R i , -NH(CH 2 ) q CHR h R i , -NH(CH 2 ) q NR h R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NRhC(=O)(C1-C4 alkylene)ORk, -NRhC(=O)O(C1-C4 alkylene)Rk, -NR h C(=O)NR i R j , -NRhC(=O)(C1-C4 alkylene)NRiS(=O)pRk, -NR h S(=O) p R k , -NRhC(=O)(C1-C4 alkylene)S(=O)pRk, -NRhS(=O)p(C1-C4 alkylene)C(=O)ORk, -NRhC(=O)[O(CH2)q]rOC(=O)NRhRi(CH2)q[O(CH2)q]r(C1-C6 alkyl) (optionally substituted with 1 to 3 Rm groups); -NRhC(=O)(C1-C6 alkylene)[O(CH2)q]rOC(=O)NRhRi(CH2)q[O(CH2)q]r(C1-C6 alkyl)(optionally substituted with 1 to 3 Rm groups); -OR k , -OC(=O)R k , -OC(=O)ORk, -OC(=O)NRhRi, -[O(CH2)q]rO(C1-C6 alkyl), -S(=O) p R k , and independently selected from -S(=O) p NR h R i groups; During the ceremony, -C(=O)(C 1 -C 4 alkylene)S(=O) p R k , -C(=O)(C 1 -C 4 alkylene)OR k , -C(=O)(C 1 -C 4 alkylene)S(=O) p NR h R i , -C(=O)(C 1 -C 4 alkylene)NR i S(=O) p R k , -C(=O)(C 1 -C 4 alkylene)NR h C(=O)R k , -NR h C(=O)O(C 1 -C 4 alkylene)R k , -NR h C(=O)(C 1 -C 4 alkylene)OR k , - NR h S(=O) p (C 1 said C 1 -C 4 alkylene in each of —C 4 alkylene)C(═O)OR k and —NR h C(═O)(C 1 -C 4 alkylene)NR i S(═O) p R k is optionally substituted with 1 to 3 groups independently selected from —OH; The C 1 -C 8 alkyl, the C 1 -C 6 haloalkyl, the C 1 -C 6 alkoxy, and the C 2 -C 8 alkenyl of R a are each 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(CH 2 ) q ] r OH, —OC(═O)R k , —OC(═O)OR k , —OC(═O)NR hR i , -SR k , -S(═O) pR k , -S(═O) p NR h R i , -[O(CH 2 ) q ] r O(C 1 -C 4 alkyl), -O-(C 6 aryl or 5-8 membered heteroaryl) (optionally substituted with 1-3 R m groups), C 3 -C 6 carbocyclyl (optionally substituted with 1-3 R m groups), C 6 -C 10 aryl (optionally substituted with 1-3 R m groups), 4-10 membered heterocyclyl (optionally substituted with 1-3 R m groups), and 5-10 membered heteroaryl (optionally substituted with 1-3 R m groups); each of said C 3 -C 12 carbocyclyl, said 3- to 12-membered heterocyclyl, said C 6 and C 10 aryl, and said 5- to 10-membered heteroaryl of R a is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, C 1 -C 6 alkyl (optionally substituted with 1 to 3 R m groups), —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 heterocyclyl group; R h , R i , and R j are each, for each occurrence, independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1 to 4 R m groups), C 6 -C 10 aryl, C 3 -C 8 carbocyclyl (optionally substituted with 1 to 3 R m groups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 R m groups), and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 R m groups), the C 1 -C 6 alkyl of any one of R h , R i , and R j is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, C 1 -C 4 alkoxy, —C(═O)NH(C 1 -C 4 alkyl), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 R m groups), and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 R m groups); R k for each occurrence is independently selected from hydrogen, —NH 2 (optionally substituted with 1 or 2 groups selected from C 1 -C 3 alkyl), C 1 -C 6 alkyl, benzyl, C 6 aryl, C 3 -C 6 carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; said C 1 -C 6 alkyl of any one of R k is optionally substituted with 1 to 5 groups independently selected from halogen, cyano, —NH 2 , —OH, C 1 -C 4 alkoxy, C 3 -C 6 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 C 1 -C 4 alkyl and halogen), and 5 to 10 membered heteroaryl (optionally substituted with 1 to 3 —OH groups); and each of said C 3 -C 6 carbocyclyl, benzyl, and C 6 aryl of any one of R k is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, oxo, —OH, —C(═O)NH 2 , —C(═O)N(CH 3 ) 2 , C 1 -C 6 alkyl (optionally substituted with 1 to 3 —OH groups), C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl (optionally substituted with 1 to 3 halogen groups), C 6 aryl (optionally substituted with 1 to 3 halogen groups), and a 5-10 membered heteroaryl group (optionally substituted with 1 to 3 halogen groups); and each of said 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl of any one of R k is optionally substituted with 1 to 3 groups independently selected from halogen, oxo, cyano, —C(═O)CH 3 , —NH 2 , —OH, C 1 -C 4 alkyl (optionally substituted with 1 to 3 —OH groups), C 1 -C 4 haloalkyl, 5- to 10-membered heterocyclyl, and C 1 -C 4 alkoxy; R m for each occurrence is independently selected from halogen, cyano, oxo, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —C(═O)R k , —S(═O) p R k , —OR k , and a 5- to 10-membered heterocyclyl group; any one of R m 's C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and 5- to 10-membered heterocyclyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C 1 -C 4 alkoxy groups; p, for each occurrence, is an integer independently selected from 1 and 2; and and q and r, for each occurrence, are integers independently selected from 0, 1, 2, and 3; a compound, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. (a) The compound has the following structural formula: 【Chemistry 292】 or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; (b) the compound has the following structural formula: 【Chemistry 293】 or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; (c) the compound has the following structural formula: 【Chemistry 294】 or a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; (d) the compound has the following structural formula: 【Chemistry 295】 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, represented by one of the following:

4. X １ and one of X 2 is S and the other is —CR ２ and R ２ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein is hydrogen.

5. R ２ is hydrogen, halogen, -CH ３ , -CH ２ OH, -CH ２ (OH)CH ３ and —C(═O)NR ｎ R ｏ is selected from R ｎ and R ｏ is hydrogen, -C １ -C ４ Alkyl, —C １ -C ４ Haloalkyl, —C ３ -C ６ cycloalkyl, and -(C １ -C ４ alkylene) R ｐ are independently selected from the group R ｐ is -C ３ -C ６ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein the compound is selected from the group consisting of cycloalkyl groups.

6. R １ But cyano, halogen, C １ -C ４ Alkyl (-OH and C １ -C ４ optionally substituted with 1 to 3 groups independently selected from alkoxy groups), C １ -C ４ Haloalkyl, and C ３ -C ６ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein the compound is selected from the group consisting of cycloalkyl groups.

7. (a) R １ is -CN, -Br, -Cl, CH3, CH ２ OH, -CH ２ CH ３ , -CH ２ CH ２ CH3, tert-butyl, -CH ２ CF ２ , -CF ２ , -CF ３ , -CF ２ CF ２ , -CH ２ OCH ３ , -CH ２ OCH ２ CH ３ , cyclopropyl, and cyclobutyl; (b) R 1 is CF 3 ; (c) R 1 is Cl; (d) R 1 is —CH 2 OH; (e) R 1 is —CH 2 CF 3 ; (f) R 1 is —CF 2 CF 3 ; (g) R 1 is —CH 2 (OH)CH 3 ; or (h) The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 6, wherein R 1 is CHD-OCH 2 CH 3 .

8. R １ is —Cl, and R ２ is hydrogen, —CH 3 , Cl, and —CH ２ 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein:

9. R １ is Cl, and R ２ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein is hydrogen.

10. (a) R １ But, -CF ３ and R ２ is selected from hydrogen, Cl, —CH 2 OH, and —CH 2 (OH)CH 3 ; (b) R 1 is —CHF 2 and R 2 is —CH 2 OH; or (c) The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein R 1 is selected from CH 3 , CH 2 CH 3 , —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , and —CH 2 OH, and R 2 is hydrogen. (a) m is zero and k is selected from zero, 1, and 2; or (b) The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein m is selected from 1 and 2 and k is zero.

12. m is zero, k is 1 or 2, and each R3a is -OH, -F, or -CHF ２ , -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -OC(=O)CH ３ , -NH ２ , -NHC(=O)CH ３ , C.N., 【Chemistry 296】 or when k is 2, two R 3a together form =0. (a) three of the variables R 4a , R 4b , R 5a , and R 5b are hydrogen, and the remaining variables are selected from C 1 -C 4 alkyl groups; or (b) Variable R ４ａ , R ４ｂ , R ５ａ , and R ５ｂ Three of the variables are hydrogen, and the remaining variable is -CH ３ 2. The compound of claim 1, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein:

14. R ６ but, 【Chemistry 299】 Substituted C selected from １ -C ６ 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein: R is alkyl.

15. R ６ but, 【Chemical 300】 2. The compound of claim 1, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein:

16. Ring B is a ring having 1, 2, 3, 4, or 5 R ａ optionally substituted with a group 【Chemical 301】 16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 15 selected from the group:

17. (a) R ａ But C １ -C ４ Alkyl, halogen, —OH, and C １ -C ４ alkoxy; R ａ The above C １ -C ４ The alkyl is optionally substituted with 1 to 3 polar groups; (b) R a is C 1 -C 6 alkyl optionally substituted with 1 to 3 groups selected from —OH, —SO 2 CH 3 , C 1 -C 3 alkoxy, C(═O)NHCH 3 , —SO 2 NHCH 2 CH 2 OH, —SCF 3, —SCH 2 C(CH 2 ) 2 OH, —SO 2 -phenyl, 4- to 6-membered heterocycle (optionally substituted with 1 to 3 R m groups), 4- to 6-membered heteroaryl (optionally substituted with 1 to 3 R m groups), cyano, and —NHC(═O)-4- to 6-membered heteroaryl; or (c) The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 15, wherein R a is selected from optionally substituted 4-6 membered carbocycle, 4-6 membered heterocycle, and 4-6 membered heteroaryl. 【Request Item 18】 【Chemistry 403】 【Chemical 404】 【Chemical 405】 【Chemical 406】 【Chemical 407】 【Chemical 408】 【Chemical 409】 【Chemical 410】 【Chemical 411】 【Chemical 412】 【Chemical 413】 【Chemical 414】 【Chemical 415】 【Chemical 416】 【Chemical 417】 【Chemical 418】 【Chemical 419】 【Chemical 420】 【Chemistry 421】 【Chemistry 422】 【Chemistry 423】 【Chemistry 424】 【Chemical 425】 【Chemistry 426】 【Chemistry 427】 【Chemical 428】 【Chemistry 429】 【Chemistry 430】 【Chemistry 431】 【Chemistry 432】 【Chemistry 433】 【Chemistry 434】 【Chemical 435】 【Chemistry 436】 【Chemistry 437】 【Chemistry 438】 【Chemistry 439】 【Chemical 440】 【Chemistry 441】 【Chemistry 442】 【Chemistry 443】 【Chemistry 444】 【Chemistry 445】 【Chemistry 446】 【Chemistry 447】 【Chemistry 448】 【Chemistry 449】 [Chemical 450] 【Chemistry 451】 【Chemistry 452】 【Chemistry 453】 【Chemical 454】 【Chemistry 455】 【Chemistry 456】 【Chemistry 457】 【Chemistry 458】 【Chemistry 459】 【Chemical 460】 【Chemistry 461】 【Chemistry 462】 【Chemical Formula 463】 【Chemical 464】 【Chemical Formula 465】 【Chemical Formula 466】 【Chemistry 467】 【Chemical 468】 【Chemistry 469】 【Chemical 470】 【Chemistry 471】 【Chemistry 472】 【Chemistry 473】 【Chemistry 474】 【Chemistry 475】 【Chemistry 476】 【Chemistry 477】 【Chemistry 478】 【Chemistry 479】 【Chemical 480】 【Chemistry 481】 【Chemistry 482】 【Chemistry 483】 【Chem.484】 【Chemistry 485】 【Chemical 486】 【Chemistry 487】 【Chemical 488】 【Chemistry 489】 【Chemistry 490】 【Chemistry 491】 【Chemistry 492】 【Chemistry 493】 【Chem.494】 【Chemical 495】 【Chemistry 496】 【Chemistry 497】 【Chem.498】 【Chem.499】 [500] 【Chemical 501】 【Chemical 502】 【Chemical 503】 【Chemical 504】 【Chemical 505】 【Chemical 506】 【Chemical 507】 【Chemical 508】 【Chemical 509】 【Chemical 510】 【Chemical 511】 【Chemical 512】 【Chemical 513】 【Chemical Formula 514】 【Chemical 515】 【Chemical 516】 【Chemical 517】 【Chemical Formula 518】 【Chemical 519】 【Chemical 520】 【Chem.521】 【Chemical 522】 【Chemical 523】 【Chemical 524】 【Chemical 525】 【Chemical 526】 【Chemical 527】 【Chemical 528】 【Chemical 529】 【Chemical 530】 【Chemistry 531】 【Chemical 532】 【Chemical Formula 533】 【Chemistry 534】 and tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Compounds, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein said 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. 【Request Item 19】 【Chemistry 535】 A compound selected from:

20. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 19.

21. 20. Use of a compound according to any one of claims 1 to 19 in the manufacture of a medicament for treating an ApoL1 mediated disease.

22. Use of a compound described in any one of claims 1 to 19 in the manufacture of a pharmaceutical for treating focal segmental glomerulosclerosis (FSGS) and / or non-diabetic kidney disease (NDKD).

23. A composition for use in the treatment of an ApoL1 mediated disease, comprising a compound according to any one of claims 1 to 19.

24. A composition for use in the treatment of focal segmental glomerulosclerosis (FSGS) and / or non-diabetic kidney disease (NDKD), comprising a compound described in any one of claims 1 to 19.

Images