2-Methyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] derivatives as inhibitors of APOL1 and methods of using same

Abstract

The disclosure provides at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formula I, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, compositions comprising the same, and methods of using the same, including uses in treating APOL1-mediated diseases, including pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and / or non-diabetic kidney disease (NDKD).

Description

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

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

[0002] This disclosure provides compounds that may inhibit apolipoprotein LI (APOL1) and methods of using those compounds to treat APOL1 -mediated diseases, such as, e.g., pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and / or non-diabetic kidney disease (NDKD). In some embodiments, the FSGS and / or NDKD is associated with at least one of the 2 common APOL1 genetic variants (Gl: S342G:I384M and G2: N388del:Y389del). In some embodiments, the pancreatic cancer is associated with elevated levels of APOL1 (such as, e.g., elevated levels of APOL1 in pancreatic cancer tissues).

[0003] FSGS is a rare kidney disease with an estimated global incidence of 0.2 to 1.1 / 100, 000 / year. FSGS is a disease of the podocyte (glomerular visceral epithelial cells) responsible for proteinuria and progressive decline in kidney function. NDKD is a kidney disease involving damage to the podocyte or glomerular vascular bed that is not attributable to diabetes. NDKD is a disease characterized by hypertension and progressive decline in kidney function. Human genetics support a causal role for the Gl and G1 APOL1 variants in inducing kidney disease. Individuals with 2 APOL1 alleles are at increased risk of developing end-stage kidney disease (ESKD), including primary (idiopathic) FSGS, human immunodeficiency virus (HlV) associated FSGS, NDKD, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. See, P. Dummer et al., Semin Nephrol. 35(3): 222-236 (2015).

[0004] FSGS and NDKD can be divided into different subgroups based on the underlying etiology. One homogeneous subgroup of FSGS is characterized by the presence of independent common sequence variants in the apolipoprotein LI (APOL1) gene termed Gl and G2, which are referred to as the “APOL1 risk alleles.” Gl encodes a correlated pair of non-synonymous amino acid changes (S342G and I384M), G2 encodes a 2 amino acid deletion (N388del:Y389del) near the C terminus of the protein, and GO is the ancestral (low risk) allele. A distinct phenotype of NDKD is found in patients with APOL1 genetic risk variants as well. In both APOL1 -mediated FSGS and NDKD, higher levels of proteinuria and a more accelerated loss of kidney function occur in patients with two risk alleles compared to patients with the same disease who have no or just 1 APOL1 genetic risk variant. Alternatively in AMKD, higher levels of proteinuria and accelerated loss of kidney function can also occur in patients with one risk allele. See, G. Vajgel et al., J. Rheumatol., November 2019, jrheum.190684.

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

[0006] While the ability to lyse T. b. brucei is shared by all 3 APOL1 variants (G0, G1, and G2), APOL1 G1 and G2 variants confer additional protection against parasite species that have evolved a serum resistant associated-protein (SRA) which inhibits APOL1 G0; APOL1 G1 and G2 variants confer additional protection against trypanosoma species that cause sleeping sickness. G1 and G2 variants evade inhibition by SRA; G1 confers additional protection against T. b. gambiense (which causes West African sleeping sickness) while G2 confers additional protection against T. b. rhodesiense (which causes East African sleeping sickness).

[0007] In the kidney, APOL1 is expressed in podocytes, endothelial cells (including glomerular endothelial cells), and some tubular cells. Podocyte-specific expression of APOL1 G1 or G2 (but not G0) in transgenic mice induces structural and functional changes, including albuminuria, decreased kidney function, podocyte abnormalities, and glomerulosclerosis. Consistent with these data, G1 and G2 variants of APOL1 play a causative role in inducing FSGS and accelerating its progression in humans. Individuals with APOL1 risk alleles (i.e., homozygous or compound heterozygous for the APOL1 G1 or APOL1 G2 alleles) have increased risk of developing FSGS and they are at risk for rapid decline in kidney function if they develop FSGS. Thus, inhibition of APOL1 could have a positive impact in individuals who harbor APOL1 risk alleles.

[0008] Although normal plasma concentrations of APOL1 are relatively high and can vary at least 20-fold in humans, circulating APOL1 is not causally associated with kidney disease. However, APOL1 in the kidney is thought to be responsible for the development of kidney diseases, including FSGS and NDKD. Under certain circumstances, APOL1 protein synthesis can be increased by approximately 200-fold by pro-inflammatory cytokines such as interferons or tumor necrosis factor-α. In addition, several studies have shown that APOL1 protein can form pH-gated Na+ / K+pores in the cell membrane, resulting in a net efflux of intracellular K+, ultimately resulting in 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 ancestry as compared to those of European ancestry. In the United States, ESKD is responsible for nearly as many lost years of life in women as from breast cancer and more lost years of life in men than from 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 a higher riskof developing end-stage kidney disease (ESKD) and developing proteinuria-related complications, such as infections or thromboembolic events. There is no standardized treatment regimen nor approved drugs for FSGS or NDKD. Currently, FSGS and NDKD are managed with symptomatic treatment (including blood pressure control using blockers of the renin angiotensin system), and patients with FSGS and heavy proteinuria may be offered high dose steroids. Current therapeutic options for NDKD are anchored on blood pressure control and blockade of the renin angiotensin system.

[0011] Corticosteroids, alone or in combination with other immunosuppressants, induce remission in a minority of patients (e.g., remission of proteinuria in a minority of patients) and are associated with numerous side effects. However, remission is frequently indurable even in patients initially responsive to corticosteroid and / or immunosuppressant treatment. As a result, patients, in particular individuals of recent sub-Saharan African ancestry with 2 APOL1 risk alleles, experience rapid disease progression leading to end-stage renal disease (ESRD). Thus, there is an unmet medical need for treatment for FSGS and NDKD. Illustratively, in view of evidence that APOL1 plays a causative role in inducing and accelerating the progression of kidney disease, inhibition of APOL1 should have a positive impact on patients with APOL1 mediated kidney disease, particularly those who carry two APOL1 risk alleles (i.e., are homozygous or compound heterozygous for the G1 or G2 alleles).

[0012] Additionally, APOL1 is an aberrantly expressed gene in multiple cancers (Lin et al., Cell Death and Disease (2021), 12:760). Recently, APOL1 was found to be abnormally elevated in human pancreatic cancer tissues compared with adjacent tissues and was associated with poor prognosis in pancreatic cancer patients. In in vivo and in vitro experiments, knockdown of APOL1 significantly inhibited cancer cell proliferation and promoted the apoptosis of pancreatic cancer cells.

[0013] One aspect of the disclosure provides at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, tautomers of Formula I, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, which can be employed in the treatment of diseases mediated by APOL1, such as FSGS and NDKD. For example, in some embodiments, the at least one compound is a compound represented by Formula I:a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X1and X2are chosen from -S-, -S(=O)2-, -S(=O)-, and -CR2, wherein: one of X1and X2is chosen from -S-, -S(=O)2-, and -S(=O)-; when X1is -S-, -S(=O)2-, or -S(=O)-, then X2is -CR2; and when X2is -S-, -S(=O)2-, or -S(=O)-, then X1is -CR2; R1is chosen from cyano, halogen, C1-C4alkyl, C1-C4haloalkyl, and C3-C6cycloalkyl groups, wherein: the C1-C4alkyl of R1is optionally substituted with 1 to 3 groups independently chosen from -OH and C1-C4alkoxy groups; R2is chosen from hydrogen, C1-C6alkyl, -C(=O)O(C1-C4alkyl), -C(=O)NRnRo, and halogen groups, wherein: the C1-C6alkyl of R2is optionally substituted with 1 to 3 groups independently chosen from -OH, halogen, and C1-C4alkoxy groups; and Rnand Roare independently chosen from hydrogen, C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, and -(C1-C4alkylene)Rpgroups, wherein Rpis chosen from C3-C6cycloalkyl groups; or R1and R2, together with the carbon atoms to which they are attached, form a C6aryl group; each R3ais independently chosen from -OH, -CN, -NRa1Ra2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -OC(=O)(C1-C4alkyl), 6- to 8-membered aryl, 6- to 8-membered heteroaryl, and halogen groups, wherein: each Ra1and Ra2is independently chosen from hydrogen, C1-C4alkyl, and -C(=O)(C1-C4alkyl) groups; or two R3ataken together form an oxo group; or two R3a, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl group; each R3bis independently chosen from C1-C4alkyl groups, wherein:the C1-C4alkyl of R3bis optionally substituted with 1 to 3 groups independently chosen from -OH, halogen, and C1-C4alkoxy groups; or one R3aand one R3b, together with the carbon atoms to which they are attached, form a C3-C6cycloalkyl group; k is chosen from 0, 1, and 2; m is chosen from 0, 1, and 2; R4a, R4b, R5a, and R5bare each independently chosen from hydrogen and C1-C4alkyl groups; R6is chosen from C1-C6alkyl, -C(=O)O(C1-C4alkyl),groups, wherein: the C1-C6alkyl of R6is optionally substituted with 1 to 5 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, - C(=O)NH2, -C(=O)(C1-C4alkyl), -C(=O)OH, -C(=O)O(C1-C4alkyl), -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, C1-C4alkoxy, C3-C6carbocyclyl, C6aryl, -O-(C6aryl), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein: the C6aryl and -O-(C6aryl) groups are each optionally substituted with 1 to 3 groups independently chosen from halogen and C1-C4haloalkyl groups; Ring B is chosen from C3-C12carbocyclyl, 3- to 12-membered heterocyclyl, C6and C10aryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with 1, 2, 3, 4, or 5 Ragroups; wherein: Ra, for each occurrence, is independently chosen from halogen, cyano, C1-C8alkyl, C1-C6haloalkyl, C2-C8alkenyl, C1-C6haloalkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C12carbocyclyl, C6and C10aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(=O)NRhRi, -C(=O)ORk, - C(=O)(C1-C4alkylene)ORk, -C(=O)Rk, -C(=O)(C1-C4alkylene)S(=O)pRk, -C(=O)(C1-C4alkylene)S(=O)pNRhRi, -C(=O)(C1-C4alkylene)NRiS(=O)pRk, -C(=O)(C1-C4alkylene)NRhC(=O)Rk, -C(=O)C(=O)Rk,-NRhRi, -NH(CH2)qCHRhRi, -NH(CH2)qNRhRi, - NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)(C1-C4alkylene)ORk, -NRhC(=O)O(C1-C4alkylene)Rk, -NRhC(=O)NRiRj, -NRhC(=O)(C1-C4alkylene)NRiS(=O)pRk, -NRhS(=O)pRk,-NRhC(=O)(C1-C4alkylene)S(=O)pRk, -NRhS(=O)p(C1-C4alkylene)C(=O)ORk,-NRhC(=O)[O(CH2)q]rOC(=O)NRhRi(CH2)q[O(CH2)q]r(C1-C6alkyl) (optionally substituted by 1 to 3 Rmgroups), -NRhC(=O)(C1-C6alkylene)[O(CH2)q]rOC(=O)-NRhRi(CH2)q[O(CH2)q]r(C1-C6alkyl) (optionally substituted by 1 to 3 Rmgroups), -ORk, -OC(=O)Rk, -OC(=O)ORk, - OC(=O)NRhRi, -[O(CH2)q]rO(C1-C6alkyl), -S(=O)pRk, and -S(=O)pNRhRigroups, wherein: the C1-C4alkylene in each of -C(=O)(C1-C4alkylene)S(=O)pRk, -C(=O)(C1-C4alkylene)ORk, -C(=O)(C1-C4alkylene)S(=O)pNRhRi, - C(=O)(C1-C4alkylene)-NRiS(=O)pRk, -C(=O)(C1-C4alkylene)- NRhC(=O)Rk, -NRhC(=O)O(C1-C4alkylene)Rk, -NRhC(=O)(C1-C4alkylene)-ORk, NRhS(=O)p(C1-C4alkylene)C(=O)ORk, and - NRhC(=O)(C1-C4alkylene)NRiS(=O)pRkis optionally substituted with 1 to 3 -OH groups, the C1-C8alkyl, the C1-C6haloalkyl, the C1-C6alkoxy, and the C2-C8alkenyl of Raare each optionally substituted with 1 to 3 groups independently chosen from cyano, -C(=O)Rk, -C(=O)ORk, - C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk,- ORk, -[O(CH2)q]rOH, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -SRk, - S(=O)pRk, -S(=O)pNRhRi, -[O(CH2)q]rO(C1-C4alkyl), -O-(C6aryl or 5- to 8- membered heteroaryl) (optionally substituted with 1 to 3 Rmgroups), C3-C6carbocyclyl (optionally substituted with 1 to 3 Rmgroups), C6to C10aryl (optionally substituted with 1 to 3 Rmgroups), 4- to 10- membered heterocyclyl (optionally substituted with 1 to 3 Rmgroups), and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rmgroups) groups; and the C3-C12carbocyclyl, the 3- to 12-membered heterocyclyl, the C6and C10aryl, and the 5- to 10-membered heteroaryl of Raare each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C6alkyl (optionally substituted with 1 to 3 Rmgroups), -C(=O)Rk, -C(=O)ORk, -NRhRi, -ORk, -S(=O)pRk, - S(=O)pNRhRi, and 5- to 10-membered heterocyclyl groups, wherein: Rh, Ri, and Rj, for each occurrence, are each independently chosen from hydrogen, C1-C6alkyl, C6-C10aryl,C3-C8carbocyclyl (optionally substituted with 1 to 3 Rmgroups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rmgroups), and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rmgroups) groups, wherein: the C1-C6alkyl of any one of Rh, Ri, and Rjis optionally substituted with 1 to 4 groups independently chosen from halogen, cyano, -OH, C1-C4alkoxy, - C(=O)NH(C1-C4alkyl), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rmgroups), and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rmgroups) groups; Rk, for each occurrence, is independently chosen from hydrogen, NH2, (optionally substituted with 1 or 2 groups chosen from C1-C3alkyl), C1-C6alkyl, benzyl, C6aryl, C3-C6carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10- membered heteroaryl groups, wherein: the C1-C6alkyl of any one of Rkis optionally substituted with 1 to 5 groups independently chosen from halogen, cyano, -NH2, -OH, C1-C4alkoxy, C3-C6cycloalkyl (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 chosen from C1-C4alkyl and halogen), and 5- to -10-membered heteroaryl (optionally substituted with 1 to 3 -OH groups) groups; and the C3-C6carbocyclyl, benzyl, and C6aryl of any one of Rkare each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, oxo, -OH, -C(=O)NH2, -C(=O)N(CH3)2, C1-C4alkyl (optionally substituted by 1 to 3 -OH groups), C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl (optionally substituted with 1 to 3 halogen groups), C6aryl (optionally substituted with 1 to 3 halogen groups), and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 halogen groups) groups,the 5- to 10-membered heteroaryl and 5- to 10- membered heterocyclyl of any one of Rkare each optionally substituted with 1 to 3 groups independently chosen from halogen, oxo, cyano, -C(=O)CH3, -NH2, - OH, C1-C4alkyl (optionally substituted by 1 to 3 -OH groups), C1-C4haloalkyl, 5- to 10-membered heterocyclyl, and C1-C4alkoxy groups; Rm, for each occurrence, is independently chosen from halogen, cyano, oxo, -NH2, C1-C6alkyl, C1-C6alkoxy, -C(=O)Rk, -S(=O)pRk, -ORk, and 5- to 10-membered heterocyclyl groups, wherein: the C1-C6alkyl, the C1-C6alkoxy, and the 5- to 10-membered heterocyclyl of any one of Rmis optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C4alkoxy groups; p, for each occurrence, is an integer independently chosen from 1 and 2; and q and r, for each occurrence, is an integer independently chosen from 0, 1, 2, and 3.

[0014] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is a compound represented by the structural Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, as follows:wherein R6is as defined above for Formula I.

[0015] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im,R6in the is chosen from:, wherein Ring B is a 5-membered heteroaryl, and Rais as defined for Formula I.

[0016] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R6is chosen from:, wherein Ring B is a 5-membered heteroaryl, and Rais is oxo or is chosen from C1-C8 alkyl, C3-C12carbocyclyl and C6and C10aryl, each of which may be optionally substituted with 1 to 3 groups chosen from halogen and C1-C8alkyl (wherein the C1-C8alkyl may be optionally substituted with 1 to 3 groups chosen from halogen, - OH, SO2CH3, and SO2NH2) .

[0017] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R6is chosen from:

[0018] In one aspect of the disclosure, the compounds of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im are chosen from Compounds 1 to 1183, tautomers thereof, deuterated derivatives of those compounds and tautomers and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the disclosure provides a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae 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, thepharmaceutical composition may comprise at least one compound chosen from Compounds 1 to 1183, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further include at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0019] Another aspect of the disclosure provides methods of treating an APOL1-mediated disease comprising administering to a subject in need thereof, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae Formulae 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 the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the methods comprise administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen 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 disclosure provides methods of treating an APOL1-mediated cancer (such as, e.g., pancreatic cancer) comprising administering to a subject in need thereof, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae 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 the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the methods comprise administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen 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 disclosure provides methods of treating APOL1-mediated kidney disease (such as, 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 chosen from compounds of Formulae 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 the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the methods comprise administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen 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 methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae 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 as separate compositions. In some embodiments, the methods comprise administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1-1183, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing with at least one additional active agent, either in the same pharmaceutical composition or in a separate composition.

[0023] Also provided are methods of inhibiting APOL1, comprising administering to a subject in need thereof, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae 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 the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the methods of inhibiting APOL1 comprise administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen 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 the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.

[0024] All of Compounds 1 to 1183 disclosed herein have demonstrated the ability to inhibit ApoL1 in one or more assays. In some embodiments, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae 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, exclude 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 Definitions

[0025] 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 aberrant APOL1 (e.g., certain APOL1 genetic variants; elevated levels of APOL1). In some embodiments, an APOL1 mediated disease is an APOL1 mediated kidney disease. In some embodiments, an APOL1 mediated disease is associated with patients having two APOL1 risk alleles, e.g., patients who are homozygous or compound heterozygous for the G1 or G2 alleles. In some embodiments, an APOL1 mediated disease is associated with patients having one APOL1 risk allele.

[0027] The term “APOL1 mediated kidney disease” refers to a disease or condition that impairs kidney function and can be attributed to APOL1. In some embodiments, APOL1 mediated kidney disease is associated with patients having two APOL1 risk alleles, e.g., patients who are homozygous or compound heterozygous for the G1 or G2 alleles. In some embodiments, the APOL1 mediated kidney disease is chosen from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1 mediated kidney disease is chronic kidney disease or proteinuria.

[0028] The term “FSGS,” as used herein, means focal segmental glomerulosclerosis, which is a disease of the podocyte (glomerular visceral epithelial cells) responsible for proteinuria and progressive decline in kidney function, and associated with 2 common APOL1 genetic variants (G1: S342G:I384M and G2: N388del:Y389del).

[0029] The term “NDKD,” as used herein, means non-diabetic kidney disease, which is characterized by severe hypertension and progressive decline in kidney function, and associated with 2 common APOL1 genetic variants (G1: S342G:I384M and G2: N388del:Y389del).

[0030] The terms “ESKD” and “ESRD” are used interchangeably herein to refer to end stage kidney disease or end stage renal disease. ESKD / ESRD is the last stage of kidney disease, i.e., kidney failure, and means that the kidneys have stopped working well enough for the patient to survive without dialysis or a kidney transplant. In some embodiments, ESKD / ESRD is associated with two APOL1 risk alleles.

[0031] The term “compound,” when referring to a compound of this disclosure, refers to a collection of molecules having an identical chemical structure unless otherwise indicated as a collection of stereoisomers (for example, a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that there may be isotopicvariation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this disclosure will depend upon a number of factors including the isotopic purity of reagents used to make the compound and the efficiency of incorporation of isotopes in the various synthesis steps used to prepare the compound. However, as set forth above, the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto 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” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an “optionally substituted” group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0033] The term “isotopologue” refers to a species in which the chemical structure differs from a reference compound only in the isotopic composition thereof. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C or14C, are within the scope of this disclosure.

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

[0035] The term “tautomer,” as used herein, refers to one of two or more isomers of compound that exist together in equilibrium, and are readily interchanged by migration of an atom, e.g., a hydrogen atom, or group within the molecule.

[0036] “Stereoisomer,” as used herein, refers to enantiomers and diastereomers.

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

[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] The term “alkyl” or “aliphatic,” as used herein, means a straight-chain (i.e., linear or unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated. Unless otherwise specified, alkyl groups contain 1 to 20 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 10 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1 to 8 aliphatic carbon atoms. In some embodiments, alkyl groups contain 1 to 6 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 4 alkyl carbon atoms, in other embodiments, alkyl groups contain 1 to 3 alkyl carbon atoms, and in yet other embodiments, alkyl groups contain 1 or 2 alkyl carbon atoms. In some embodiments, alkyl groups are linear or straight-chain or unbranched. In some embodiments, alkyl groups are branched.

[0040] The terms “carbocyclyl,” “cycloalkyl” and “cyclic alkyl,” as used herein, refer to a monocyclic C3-8hydrocarbon or a spirocyclic, fused, or bridged bicyclic or tricyclic C8-14hydrocarbon that is completely saturated, wherein any individual ring in said bicyclic ring system has 3 to 7 members. In some embodiments, the cycloalkyl is a C3to C12cycloalkyl. In some embodiments, the cycloalkyl is a C3to C8cycloalkyl. In some embodiments, the cycloalkyl is a C3to C6cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0041] The terms “carbocyclyl” or “cycloaliphatic,” as used herein, encompass the terms “cycloalkyl” or “cyclic alkyl,” and refer to a monocyclic C3-8hydrocarbon or a spirocyclic, fused,or bridged bicyclic or tricyclic C8-14hydrocarbon that is completely saturated, or is partially saturated as in it contains one or more units of unsaturation but is not aromatic, wherein any individual ring in said bicyclic ring system has 3 to 7 members. Bicyclic carbocyclyls include combinations of a monocyclic carbocyclic ring fused to a phenyl. In some embodiments, the carbocyclyl is a C3to C12carbocyclyl. In some embodiments, the carbocyclyl is a C3to C10carbocyclyl. In some embodiments, the carbocyclyl is a C3to C8carbocyclyl.

[0042] The term “heteroalkyl,” or “heteroaliphatic,” as used herein, means an alkyl or aliphatic group as defined above, wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon.

[0043] The term “alkenyl,” as used herein, means a straight-chain (i.e., linear or unbranched) or branched hydrocarbon chain that contains one or more double bonds. In some embodiments, alkenyl groups are straight-chain. In some embodiments, alkenyl groups are branched.

[0044] The terms “heterocycle,” “heterocyclyl,” and “heterocyclic,” are usedherein interchangeably to refer to non-aromatic (i.e., completely saturated or partially saturated as in it contains one or more units of unsaturation but is not aromatic), monocyclic, or spirocyclic, fused, or bridged bicyclic or tricyclic ring systems in which one or more ring members is an independently chosen heteroatom. Bicyclic heterocyclyls include the following combinations of monocyclic rings: a monocyclic heteroaryl fused to a monocyclic heterocyclyl; a monocyclic heterocyclyl fused to another monocyclic heterocyclyl; a monocyclic heterocyclyl fused to phenyl; a monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and a monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl.

[0045] In some embodiments, the heterocycle comprises a ring atom substituted with one or more oxo groups (such as, e.g., a C=O group, a S=O group, or a SO2group).

[0046] In some embodiments, the “heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” or “heterocyclic” group has 3 to 14 ring members in which one or more ring members is a heteroatom independently chosen 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, the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has one heteroatom independently chosen from oxygen, sulfur, nitrogen, silicon, and phosphorus, the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)). In some embodiments, the heterocycle has one heteroatom that is a nitrogen atom. In some embodiments, the heterocycle has one heteroatom that is an oxygen atom. In some embodiments, the heterocycle has two heteroatoms that are each independently chosen from nitrogen and oxygen. In some embodiments, theheterocycle has three heteroatoms that are each independently chosen 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 the state in which not all of the available valence bonds in a compound are satisfied by substituents and thus the compound contains double or triple bonds.

[0048] The term “alkoxy” or “thioalkyl,” as used herein, refers to an alkyl group, as previously defined, wherein one carbon of the alkyl group is replaced by an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom, respectively, provided that the oxygen and sulfur atoms are linked between two carbon atoms. A “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] The terms “haloalkyl,” “haloalkenyl,” and “haloalkoxy,” as used herein, mean a linear or branched alkyl, alkenyl, or alkoxy, respectively, which is substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CF2-, and perhaloalkyls, such as -CF2CF3. Non-limiting examples of haloalkoxy groups include -OCHF2, -OCH2F, -OCF3, and -OCF2.

[0050] The term “halogen” includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.

[0051] The term “aminoalkyl” means an alkyl group which is substituted with or contains an amino group.

[0052] As used herein, an “amino” refers to a group which 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 refer to -C≡N.

[0055] As used herein, a “hydroxy” group refers to -OH.

[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 groups” or “aromatic rings” refer to chemical groups that contain conjugated, planar ring systems with delocalized pi electron orbitals comprised of [4n+2] p orbital electrons, wherein 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 monocyclic or spirocyclic, fused, or bridged bicyclic or tricyclic ring systems having a total of five to fourteen ring members, wherein every ring in the system is an aromatic ring containing only carbon atoms and wherein 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 (C10) rings.

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

[0061] In some embodiments, the heteroaryl comprises a ring atom substituted with one or more oxo groups (such as, e.g., a C=O group, a S=O group, or a SO2group). 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-fluorenylmethyl carbamate (Fmoc) benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods of adding (a process generally referred to as “protecting”) andremoving (process generally referred to as “deprotecting”) such amine protecting groups are well-known in the art and available, for example, in P. J. Kocienski, Protecting Groups, Thieme, 1994, which is hereby incorporated by reference in its entirety and in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999) and 4thEdition (John Wiley & Sons, New Jersey, 2014).

[0063] Non-limiting examples of suitable solvents that may be used in this disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or “methylene chloride” (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2- methyl tetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methyl pyrrolidone (NMP).

[0064] Non-limiting examples of suitable bases that may be used in this disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropyl-ethyl amine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCH3).

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

[0066] The term “pharmaceutically acceptable,” as used herein, 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, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1 to 19.

[0067] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as para-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, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, 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- l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, 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+(C1-4alkyl)4salts. This disclosure also envisions 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 halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. 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 an animal, including a human.

[0070] The terms “effective dose” and “effective amount” are used interchangeably herein and refer to that amount of compound that produces a desired effect for which it is administered (e.g., improvement in a symptom of FSGS and / or NDKD, lessening the severity of FSGS and / NDKD or a symptom of FSGS and / or NDKD, and / or reducing progression of FSGS and / or NDKD or a symptom of FSGS and / or NDKD). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0071] As used herein, the term “treatment” and its cognates refer to slowing or stopping disease progression. “Treatment” and its cognates as used herein, include, but are not limited to, the following: complete or partial remission, lower risk of kidney failure (e.g., ESRD), and disease-related complications (e.g., edema, susceptibility to infections, or thrombo-embolicevents). Improvements in or lessening the severity of any of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed.

[0072] The terms “about” and “approximately,” when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent.

[0073] The at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae 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, may be administered once daily, twice daily, or three times daily, for example, for the treatment of AMKD, including FSGS and / or NDKD. In some embodiments, at least one compound chosen from Compounds 1 to 1183, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing may be administered once daily, twice daily, or three times daily, for example, for the treatment of AMKD, including FSGS and / or NDKD. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae 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 chosed from Compounds 1 to 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 chosen from compounds of Formulae 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 chosed from Compounds 1 to 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 chosen from compounds of Formulae 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 chosed from Compounds 1 to 1183, tautomers thereof, deuterated derivatives of thosecompounds 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 chosen from Formulae 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 administered once daily, twice daily, or three times daily. In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound chosen from Compounds 1 to 1183, tautomera thereof, deuterated derivative of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered once daily, twice daily, or three times daily.

[0075] One of ordinary skill in the art would recognize that, when an amount of compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. The amounts of the compounds, pharmaceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based upon the free base form of the reference compound. For example, “1000 mg of at least one compound or pharmaceutically acceptable salt chosen from compounds of Formula I and pharmaceutically acceptable salts thereof” includes 1000 mg of a compound of Formula I and a concentration of a pharmaceutically acceptable salt of compounds of Formula I equivalent to 1000 mg of a compound of Formula I.

[0076] As used herein, the term “ambient conditions” means room temperature, open air condition, and uncontrolled humidity condition. Compounds and Compositions

[0077] In some embodiments, at least one compound chosen from Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers therof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salt of any of the foregoing may be employed in the treatment of AMKD, including FSGS and NDKD. In some embodiments, the compound of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, maybe chosen from Compounds 1 to 1183, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound chosen from Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers therof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salt of any of the foregoing, may be employed in the treatment of AMKD, including FSGS and NDKD. In some embodiments the pharmaceutical composition comprises at least one compound chosen from Compounds 1 to 1183, tautomers therof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salt of any of the foregoing.

[0078] In some embodiments of Formula I:the variable X1is chosen from S, S(=O), and S(=O)2and the variable X2is -CR2. In some embodiments of Formula I, the variable X1is S, and the variable X2is -CR2. In some embodiments of Formula I, the variable X2is chosen from S, S(=O), and S(=O)2and the variable X1is -CR2. In some embodiments of Formula I, the variable X2is S, and the variable X1is -CR2.

[0079] In some embodiments (including the embodiments discussed above that define variables X1and X2), R2is chosen from hydrogen, C1-C6alkyl (optionally substituted with 1 to 3 groups independently chosen from -OH, halogen, and C1-C4alkoxy groups), -C(=O)O(C1-C4alkyl), -C(=O)NRnRo, and halogen groups, wherein Rnand Roare independently chosen from hydrogen, C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, and -(C1-C4alkylene)Rpgroups, and wherein Rpis chosen from C3-C6cycloalkyl groups.

[0080] In some embodiments(including the embodiments discussed above that define variables X1and X2), R2is chosen from hydrogen, halogen, -CH2OH, -CH2(OH)CH3, and - C(=O)NRnRo. In some embodiments, R2is hydrogen. In some embodiments (including the embodiments discussed above that define variables X1and X2), R2is halogen. In some embodiments (including the embodiments discussed above that define variables X1and X2), R2is Br. In some embodiments, R2is Cl. In some embodiments (including the embodiments discussed above that define variables X1and X2), R2is CH3. In some embodiments (including the embodiments discussed above that define variables X1and X2), R2is -CH2OH. In some embodiments, R2is CH2(OH)CH3. In some embodiments, R2is -C(=O)OCH3.

[0081] In some embodiments (including the embodiments discussed above that define variables X1and X2), R2is -C(=O)NRnRo, and halogen groups, wherein Rnand Roare independently chosen from hydrogen, C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, and -(C1- C4alkylene)Rpgroups, and wherein Rpis chosen from C3-C6cycloalkyl groups. In some embodiments (including the embodiments discussed above that define variables X1and X2), R2is -C(=O)NRnRo(wherein Rnis hydrogen and Rois CH3). In some embodiments (including the embodiments discussed above that define variables X1and X2), R2is -C(=O)NRnRo(wherein Rnis hydrogen and Rois CH3substitued with a cyclopropyl group). Insome embodiments (including the embodiments discussed above that define variables X1and X2), R2is -C(=O)NH CH2CH2CH3(i.e., wherein Rnis hydrogen and Rois -CH2CH2CH3). In some embodiments (including the embodiments discussed above that define variables X1and X2), R2is -C(=O)NH CH2CF2(i.e., wherein Rnis hydrogen and Rois -CH2CF2).

[0082] In some embodiments of Formula I (including the embodiments set forth above defining variables X1, X2, and R2), the variable R1is chosen from cyano, halogen, -C1-C4alkyl, - C1-C4haloalkyl, and -C3-C6cycloalkyl groups, wherein:the -C1-C4alkyl of R1is optionally substituted with 1 to 3 groups independently chosen from -OH and -C1-C4alkoxy groups.

[0083] In some embodiments of Formula I (including the embodiments set forth above defining variables X1, X2, and R2), the variable R1is chosen from -CN, -Br, -Cl, -C1-C4alkyl, - CH2OH, -CH2CF2, -CF2CF2, -CF2, -CF3, -CH2OCH3, -CH2OCH2CH3, cyclopropyl, and cyclobutyl. In some embodiments of Formula I (including the embodiments set forth above defining variables X1, X2, and R2), the variable R1is chosen -CH3, -CH2OH, -CH2CH3, -CH2CH2CH3, tert-butyl, -Cl, -CH2- CF2, -CF2CF3, and -CF3. In some embodiments of Formula I (including the embodiments set forth above defining variables X1, X2, and R2), the variable R1is deuterated, e.g. -CDOCH2CH3.

[0084] In some embodiments of Formula I (including the embodiments set forth above defining variables X1, X2, and R2), the variable R1is CF3. In some embodiments of Formula I (including the embodiments set forth above defining variables X1, X2, and R2), the variable R1is Cl. In some embodiments of Formula I (including the embodiments set forth above defining variables X1, X2, and R2), the variable R1is -CH2OH. In some embodiments of Formula I (including the embodiments set forth above defining variables X1, X2, and R2), the variable R1is -CH2CF3. In some embodiments of Formula I (including the embodiments set forth above defining variables X1, X2, and R2), the variable R1is -CF2CF3. In some embodiments of Formula I (including the embodiments set forth above defining variables X1, X2, and R2), the variable R1is -CH2(OH)CH3.

[0085] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), variables R1and R2, together with the carbon atoms to which they are attached, form a C6aryl group.

[0086] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is -Cl and the variable R2is -CH2OH. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is Cl and the variable R2is -CH3. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is Cland the variable R2is hydrogen. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is -Cl and the variable R2is -Cl.

[0087] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is -CF3and the variable R2is hydrogen. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is -CF2CF3and the variable R2is hydrogen. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is -CH2CF3and the variable R2is hydrogen. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is -CF2and the variable R2is -CH2OH. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is -CF3and the variable R2is -CH2OH. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is -CF3and the variable R2is -CH2(OH)CH3. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is -CF3and the variable R2is -Cl.

[0088] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is CH3and the variable R2is hydrogen. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is CH2CH3and the variable R2is hydrogen. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2), the variable R1is CH2OH and the variable R2is hydrogen.

[0089] In some embodiments of Formula I, the variables m and k are both zero, resulting in the absence of variables R3aand R3b. In some embodiments of Formula I, the variable m is zero, resulting in the absence of variable R3b, and the variable k is one, resulting in the presence of one R3avariable. In some embodiments of Formula I, the variable m is zero, resulting in the absence of variable R3b, and the variable k is two, resulting in the presence of two R3avariables in Formula I.

[0090] In some embodiments of Formula I, (including the embodiments set forth above defining variables X1and X2, R1, R2), each R3ais independently chosen from -OH, -CN, - NRa1Ra2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -OC(=O)(C1-C4alkyl), 6- to 8-membered aryl, 6- to 8-membered heteroaryl, and halogen groups, wherein: each Ra1and Ra2is independently chosen from hydrogen, C1-C4alkyl, and -C(=O)(C1-C4alkyl) groups; or two R3ataken together form an oxo group; ortwo R3a, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl group.

[0091] In some embodiments of Formula I, (including the embodiments set forth above defining variables X1and X2, R1, R2), each R3ais chosen from -OH, F, F2, CF2, -OCH3, - OCH2CH3, -OCH2(CH3)2, -OC(=O)CH3, NH2, NHC(=O)CH3, CNIn some embodiments of Formula I, the variable k is one, and variable R3ais is chosen from -OH, F, F2, CF2, -OCH3, -OCH2CH3, -O-CH2(CH3)2, -O-C(=O)CH3, NH2, NH-C(=O)CH3, CN,. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2), variable m is zero, variable k is one, and variable R3ais chosen from -OH, F, F2, CF2, -OCH3, -OCH2CH3, -O-CH2(CH3)2, -O-C(=O)CH3, NH2, NH-C(=O)CH3, CN, In someembodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2), variable m is zero, variable k is one, and variable R3ais -OH. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2), variable m is zero, variable k is one, and variable R3ais chosen from -OCH3and -OCH2CH3.

[0092] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2), variable k is two, and the two R3avariables are chosen from (a) -CF2and -OH, (b) -CH3and -OH, and (c) -OH and phenyl. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2), variable m is zero, variable k is two, and the two R3avariables are chosen from (a) -CF2and - OH, (b) -CH3and -OH, and (c) -OH and phenyl.

[0093] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2), variable R3ais deuterated. In some embodiments, the deuterated R3ais -O-CD3.

[0094] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2), two R3aare taken together to form an oxo group.

[0095] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2), two R3aare taken together to form a C3-C6cycloalkyl group.

[0096] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, and R3a), variable R3bis selected from C1-C3alkyl optionally substituted with -OH or halogen. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, and R3a), R3bis CH3. In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, and R3a), R3bis selected from CF2and CF3.

[0097] In some embodiments of Formula I, (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, and R3b), three of variables R4a, R4b, R5a, and R5bare hydrogen and the remaining variable is chosen from C1-C4alkyl groups. In some embodiments of Formula I, three of variables R4a, R4b, R5a, and R5bare hydrogen and the remaining variable is chosen from methyl, ethyl, cyclopropyl, fused cyclopropyl, and fused cyclobutyl. In some embodiments of Formula I, variables R4a, R4b, and R5bare hydrogen and variable R5ais chosen from methyl, ethyl, cyclopropyl, fused cyclopropyl, and fused cyclobutyl. In some embodiments of Formula I, variables R4b, R5a, and R5bare hydrogen and variable R4ais chosen from methyl, ethyl, cyclopropyl, fused cyclopropyl, and fused cyclobutyl. In some embodiments of Formula I, three of variables R4a, R4b, R5a, and R5bare hydrogen and the remaining variable is CH3.

[0098] In the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, and R5b) and embodiments of Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R6is chosen from C1-C6alkyl, -C(=O)O(C1-C4alkyl)groups, wherein: the C1-C6alkyl of R6is optionally substituted with 1 to 5 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -C(=O)NH2, -C(=O)(C1-C4alkyl), -C(=O)OH, -C(=O)O(C1-C4alkyl), -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, C1- C4alkoxy, C3-C6carbocyclyl, C6aryl (optionally substituted with 1 to 3 groups independently chosen from halogen and C1-C4haloalkyl groups), -O-(C6aryl) (optionally substituted with 1 to 3 groups independently chosen from halogen and C1-C4haloalkyl groups), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups; Ring B is chosen from C3-C12carbocyclyl, 3- to 12-membered heterocyclyl, C6and C10aryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with 1, 2, 3, 4, or 5 Ragroups; wherein:Ra, for each occurrence, is independently chosen from halogen, cyano, C1-C8alkyl, C1- C6haloalkyl, C2-C8alkenyl, C1-C6haloalkenyl, C1-C6alkoxy,C1-C6haloalkoxy, C3-C12carbocyclyl, C6and C10aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, - C(=O)NRhRi, -C(=O)ORk, -C(=O)(C1-C4alkylene)ORk, -C(=O)Rk, -C(=O)(C1-C4alkylene)S(=O)pRk, -C(=O)(C1-C4alkylene)S(=O)pNRhRi, -C(=O)(C1-C4alkylene)NRiS(=O)pRk, -C(=O)(C1-C4alkylene)NRhC(=O)Rk, -C(=O)C(=O)Rk,-NRhRi, -NH(CH2)qCHRhRi, -NH(CH2)qNRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)(C1-C4alkylene)ORk, -NRhC(=O)O(C1-C4alkylene)Rk, -NRhC(=O)NRiRj, -NRhC(=O)(C1-C4alkylene)NRiS(=O)pRk, -NRhS(=O)pRk,-NRhC(=O)(C1-C4alkylene)S(=O)pRk, -NRhS(=O)p(C1-C4alkylene)C(=O)ORk,-NRhC(=O)[O(CH2)q]rOC(=O)NRhRi(CH2)q[O(CH2)q]r(C1-C6alkyl) (optionally substituted by 1 to 3 Rmgroups), -NRhC(=O)(C1-C6alkylene)[O(CH2)q]rOC(=O)-NRhRi(CH2)q[O(CH2)q]r(C1-C6alkyl) (optionally substituted by 1 to 3 Rmgroups), -ORk, -OC(=O)Rk, -OC(=O)ORk, - OC(=O)NRhRi, -[O(CH2)q]rO(C1-C6alkyl), -S(=O)pRk, and -S(=O)pNRhRigroups, wherein: the C1-C4alkylene in each of -C(=O)(C1-C4alkylene)S(=O)pRk, -C(=O)(C1-C4alkylene)ORk, -C(=O)(C1-C4alkylene)S(=O)pNRhRi, -C(=O)(C1-C4alkylene)-NRiS(=O)pRk, -C(=O)(C1-C4alkylene)-NRhC(=O)Rk, -NRhC(=O)O(C1-C4alkylene)Rk, -NRhC(=O)(C1-C4alkylene)-ORk, NRhS(=O)p(C1-C4alkylene)C(=O)ORk, and -NRhC(=O)(C1-C4alkylene)NRiS(=O)pRkis optionally substituted with 1 to 3 -OH groups, the C1-C8alkyl, the C1-C6haloalkyl, the C1-C6alkoxy, and the C2-C8alkenyl of Raare each optionally substituted with 1 to 3 groups independently chosen from cyano, -C(=O)Rk, -C(=O)ORk, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk,-ORk, -[O(CH2)q]rOH, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -SRk, -S(=O)pRk, -S(=O)pNRhRi, -[O(CH2)q]rO(C1-C4alkyl), -O-(C6aryl or 5- to 8-membered heteroaryl) (optionally substituted with 1 to 3 Rmgroups), C3-C6carbocyclyl (optionally substituted with 1 to 3 Rmgroups), -C6to C10aryl (optionally substituted with 1 to 3 Rmgroups), 4- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rmgroups), and 5- to 10- membered heteroaryl (optionally substituted with 1 to 3 Rmgroups) groups; and the C3-C12carbocyclyl, the 3- to 12-membered heterocyclyl, the C6and C10aryl, and the 5- to 10-membered heteroaryl of Raare each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C6alkyl (optionally substituted with 1 to 3 Rmgroups), -C(=O)Rk, -C(=O)ORk, -NRhRi, -ORk, -S(=O)pRk, -S(=O)pNRhRi, and 5- to 10- membered heterocyclyl groups, wherein: Rh, Ri, and Rj, for each occurrence, are each independently chosen from hydrogen, C1-C6alkyl (optionally substituted with 1 to 4 Rmgroups), C6-C10aryl, C3-C8carbocyclyl(optionally substituted with 1 to 3 Rmgroups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rmgroups), and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rmgroups) groups, wherein: the C1-C6alkyl of any one of Rh, Ri, and Rjis optionally substituted with 1 to 4 groups independently chosen from halogen, cyano, -OH, C1-C4alkoxy, -C(=O)NH(C1-C4alkyl), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rmgroups), and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rmgroups) groups; Rk, for each occurrence, is independently chosen from hydrogen, NH2, (optionally substituted with 1 or 2 groups chosen from C1-C3alkyl), C1-C6alkyl, benzyl, C6aryl, C3-C6carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein: the C1-C6alkyl of any one of Rkis optionally substituted with 1 to 5 groups independently chosen from halogen, cyano, -NH2, -OH, C1-C6alkoxy, C3-C6cycloalkyl (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 chosen from C1-C4alkyl and halogen), and 5- to -10-membered heteroaryl (optionally substituted with 1 to 3 -OH groups) groups; and the C3-C6carbocyclyl, benzyl, and C6aryl of any one of Rkare each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, oxo, -OH, -C(=O)NH2, -C(=O)N(CH3)2, C1-C4alkyl (optionally substituted by 1 to 3 -OH groups), C1-C6haloalkyl, C1- C6alkoxy, C3-C6cycloalkyl (optionally substituted with 1 to 3 halogen groups), C6aryl (optionally substituted with 1 to 3 halogen groups), and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 halogen groups) groups, the 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl of any one of Rkare each optionally substituted with 1 to 3 groups independently chosen from halogen, oxo, cyano, -C(=O)CH3, -NH2, -OH, C1-C4alkyl (optionally substituted by 1 to 3 -OH groups),, C1-C4haloalkyl, 5- to 10-membered heterocyclyl, and C1-C4alkoxy groups; Rm, for each occurrence, is independently chosen from halogen, cyano, oxo, -NH2, C1-C6alkyl, C1-C6alkoxy, -C(=O)Rk, -S(=O)pRk, -ORk, and 5- to 10-membered heterocyclyl groups, wherein: the C1-C6alkyl, the C1-C6alkoxy, and the 5- to 10-membered heterocyclyl of any one of Rmis optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C4alkoxy groups; p, for each occurrence, is an integer independently chosen from 1 and 2; and q and r, for each occurrence, is an integer independently chosen from 0, 1, 2, and 3.

[0099] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, and R5b) and embodiments of Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, - R6is chosen from C1-C6alkyl optionally substituted with 1 to 5 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -C(=O)NH2, -C(=O)(C1-C4alkyl), -C(=O)OH, -C(=O)O(C1- C4alkyl), -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, C1-C4alkoxy, C3-C6carbocyclyl, C6aryl (which is optionally substituted with 1 to 3 groups independently chosen from halogen and C1-C4haloalkyl groups), -O-(C6aryl) (which is optionally substituted with 1 to 3 groups independently chosen from halogen and C1-C4haloalkyl groups), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups.

[0100] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, and R5b) and embodiments of Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R6is an optionally substituted C1-C6, .

[0101] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, and R5b) and embodiments of Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R6is chosen from -C(=O)O(C1-C4alkyl).

[0102] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, and R5b) and embodiments of Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R6is chosen fromdefined for Formula I above. In some of these embodiments, Ring B is chosen from C3-C12carbocyclyl optionally substituted with 1, 2, 3, 4, or 5 Ragroups as defined for Formula I. In some of these embodiments, Ring B is chosen from 3- to 12-membered heterocyclyl. In some of these embodiments, Ring B is chosen from C6and C10aryl optionally substituted with 1, 2, 3, 4, or 5 Ragroups as defined for Formula I. In some of these embodiments, Ring B is chosen from 5- to 10-membered heteroaryl groups optionally substituted with 1, 2, 3, 4, or 5 Ragroups as defined for Formula I.

[0103] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, and R5b) and embodiments of Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R6is chosen from, and Ring B is chosen from, , , , , ,groups optionally substituted with 1, 2, 3, 4, or 5 Ragroups as defined for Formula I.

[0104] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, and R5b) and embodiments of Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R6is chosen from, and Ring B is chosen from:, , , , , , ,groups optionally substituted with 1, 2, 3, 4, or 5 Ragroups as defined for Formula I.

[0105] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, and R5b) and embodiments ofFormulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R6is chosen from:, wherein Ring B is a 5-membered heteroaryl, and Rais as defined for Formula I.

[0106] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, and R5b) and embodiments of Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R6is chosen from:, wherein Ring B is a 5-membered heteroaryl, and Rais is oxo or is chosen from C1-C8 alkyl, C3-C12carbocyclyl and C6and C10aryl, each of which may be optionally substituted with 1 to 3 groups chosen from halogen and C1-C8alkyl (wherein the C1-C8alkyl may be optionally substituted with 1 to 3 groups chosen from halogen, -OH, SO2CH3, and SO2NH2) . In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, and R5b) and embodiments of Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, R6is chosen from:

[0107] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, R5b, and R6) and embodiments of Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, Rais chosen from C1-C4 alkyl, halogen, -OH, and C1-C4 alkoxy, wherein the C1-C4 alkyl of Rais optionally substituted with 1 to 3 polar groups, e.g. sulfones, sulfonamides, and alcohols.

[0108] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, R5b, and R6) and embodiments of Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, Rais C1- C6alkyl, optionally substituted as defined for Formula I. In some embodiments, the C1- C6 alkyl of Rais optionally substituted with 1 to 3 groups selected from -OH, -SO2CH3, C1-C3alkoxy, C(=O)NHCH3, -SO2NHCH2CH2OH, -SCF3, -S CH2C(CH2)2OH, -SO2phenyl, 4-6 membered heterocycles (optionally substituted with 1 to 3 Rmgroups), 4-6 membered heteroaryls (optionally substituted with 1 to 3 Rmgroups), cyano, NHC(=O)-4-6 membered heteroaryl.

[0109] In some embodiments of Formula I (including the embodiments set forth above defining variables X1and X2, R1, R2, k, m, R3a, R3b, R4a, R4b, R5a, R5b, and R6) and embodiments of Formulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, Rais chosen from 4-6 membered carobcycles, 4-6 membered heterocycles and 4-6 membered heteroaryls, any of which is optionally stubstituted as defined for Formula I.

[0110] In some embodiments, the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is chosen from Compounds 1 to 1183 depicted in Table 1, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. A wavy line in a compound in Table 1depicts a bond between two atoms and indicates a position of mixed stereochemistry for a collection of molecules, such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. An asterisk adjacent to an atomin a compound in Table 1, 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. Compounds 1 to 1183

[0112] Some embodiments of the disclosure include derivatives of Compounds 1 to 1183 or compounds of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the derivatives are silicon derivatives in which at least one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 1183 or compounds of Formulae 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, has been replaced by silicon. In some embodiments, the derivatives are boron derivatives, in which at least one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 1183 or compounds of Formulae 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, has been replaced by boron. In other embodiments, the derivatives are phosphorus derivatives, in which at least one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 1183 or compounds of Formulae 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, has been replaced by phosphorus.

[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 chosen from Compounds 1 to 1183 or compounds of Formulae 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, has been replaced by silicon or a silicon derivative (e.g., -Si(CH3)2- or -Si(OH)2-). The carbon replaced by silicon may be a non-aromatic carbon. In other embodiments, a fluorine has been replaced by silicon derivative (e.g., -Si(CH3)3). In some embodiments, the silicon derivatives of the disclosure may include one or more hydrogen atoms replaced by deuterium. In some embodiments, a silicon derivative of compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 1183 or compounds of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, may have silicon incorporated into a heterocycle ring.

[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 chosen from Compounds 1 to 1183 or compounds of Formulae 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, has been replaced by 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 chosen from Compounds 1 to 1183 or compounds of Formulae 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, has been replaced by phosphorus or a phosphorus derivative.

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

[0117] A pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0118] It will also be appreciated that a pharmaceutical composition of this disclosure can beemployed in combination therapies; that is, the pharmaceutical compositions described herein can further include at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae 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 can be administered as a separate composition concurrently with, prior to, or subsequent to, 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 chosen from Compounds 1 to 1183, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising at least one other active therapeutic agent.

[0119] As described above, pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The at least one pharmaceutically acceptable carrier, as used herein, includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular 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 discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as, e.g., human serum albumin), buffer substances (such as, e.g., phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as, e.g., lactose, glucose, and sucrose), starches (such as, e.g., corn starch and potato starch), cellulose and its derivatives (such as, e.g., sodium carboxymethyl cellulose, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as, e.g., cocoa butter and suppository waxes), oils (such as, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as, e.g., propylene glycol and polyethylene glycol), esters (such as, e.g., ethyl oleate and ethyl laurate), agar, buffering agents (such as, e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as, e.g., sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants. Compounds and Compositions for Use in Treatment

[0120] In some embodiments of the disclosure, the compounds and the 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 disclosure, the compounds and the pharmaceutical compositions described herein are used to treat cancer. In some embodiments, the cancer is mediated by APOL1.

[0122] In some embodiments of the disclosure, the compounds and the 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 disclosure comprise administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae 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 chosen from Compounds 1 to 1183, tautomer thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, said patient in need thereof possesses APOL1 genetic variants, i.e., G1: S342G:I384M and G2: N388del:Y389del.

[0124] Another aspect of the disclosure provides methods of inhibiting APOL1 activity comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae 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 methods of inhibiting APOL1 activity comprise contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen fromCompounds 1 to 1183, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. EXAMPLES

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

[0126] The compounds of the disclosure may be made according to standard chemical practices or as described herein. Throughout the following synthetic schemes and in the descriptions for preparing compounds of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, and Im, Compounds 1 to 1183, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, the following abbreviations are used: Abbreviations AcOH = acetic acid ARP = assay ready plate Boc2O = di-tert-butyl decarbonate 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 = dimethylamino pyridine DMA = dimethyl acetamide DME = dimethoxyethane DMEM = Dulbecco’s modified Eagle’s medium DMF = dimethylformamide DMPU = N,N’-dimethylpropyleneurea DMSO = dimethyl sulfoxide dppf = 1,1′-bis(diphenylphosphino)ferroceneESI = electrospray ionization EtOAc = ethyl acetate EtOH = ethanol Et2O = diethyl ether Et2NH = diethylamine Et3N = triethylamine FA = formamide FBS = fetal bovine serum GF-AFC = glycyl-phenylalanylamino fluorocoumarin HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium (phosphorus hexafluoride ion) HDMC = N-[(5-chloro-3-oxido-1H-benzotriazol-1-yl)-4-morpholinylmethylene]- N- 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{dFCF3ppy}2(bpy)]PF6 = (2,2'-Bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridinyl- kN][phenyl-kC]iridium(III) hexafluorophosphate LDA = lithium diisopropyl amide 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-methyl morpholineNMP = N-methyl pyrrolidine 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 tBuOH = 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 trimethylsilylester TMSCl = trimethylsilyl chloride TMSCF3= trifluoromethyltrimethylsilaneXPhos Pd G3 = (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- amino-1,1′- biphenyl)]palladium(II) methanesulfonate Example 1. Synthesis of Compounds

[0127] All the specific and generic compounds, and the intermediates disclosed for making those compounds, are considered to be part of the disclosure disclosed herein. Preparation S1 (2'S,4R)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]Step 1. Synthesis of (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine(C1)

[0128] 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) at 0 ˚C was added a solution of trifluoromethanesulfonic acid (12.4 mL, 140.1 mmol) in dioxane (20 mL) over 15 min. The reaction was stirred at the same temperature for 1 h, and then warmed to ambient temperature and stirred for 3.5 h. 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 x 2). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude was dissolved in DCM and filtered through a plug of silica gel (250 g) eluting with DCM followed by 25% MeOH / DCM to afford the desired product. The product was dissolved in Et2O (500 mL) and heated at reflux for 15 min. After cooling down to ambient temperature, heptane (500 mL) was added, and the solids were filtered, washed with heptane and dried to furnish the title compound as a grey solid (triflate salt) (11.36 g, 67%).1H NMR (400 MHz, DMSO-d6) δ 6.46 (d, J = 1.1 Hz, 1H), 3.96 - 3.79 (m, 2H), 3.42 - 3.34 (m, 1H), 3.27 - 3.00 (m, 2H), 2.80 - 2.63 (m, 4H), 2.01 - 1.87 (m, 3H), 1.79 (dd, J = 14.5, 12.2 Hz, 1H), 1.24 - 1.16 (m, 6H). LCMS m / z 252.01[M+H]+. 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)

[0129] 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 (900mL) was added propargyl bromide (21 mL, 188.5 mmol, 80 %w / w solution in toluene). The resulting mixture was heated at 45 °C for 5 h, and then cooled down to room temperature and stirred overnight. The reaction was diluted with EtOAc (350 mL), brine (150 mL) and 2M aqueous Na2S2O3solution (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 was triturated with Et2O. The resulting colorless solids were filtered and dried to afford the S1 (55.7 g, 92%).1H NMR (300 MHz, Chloroform-d) δ 6.47 (d, J = 1.1 Hz, 1H), 4.05 - 3.85 (m, 2H), 3.67 (dd, J = 17.3, 2.4 Hz, 1H), 3.44 (dd, J = 17.3, 2.4 Hz, 1H), 3.00 - 2.64 (m, 7H), 2.25 (t, J = 2.4 Hz, 1H), 2.03 - 1.81 (m, 3H), 1.68 (dd, J = 13.8, 11.5 Hz, 1H), 1.28 (t, J = 7.5 Hz, 3H), 1.10 (d, J = 6.3 Hz, 3H). LCMS m / z 290.11 [M+H]+. 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)

[0130] Compound S2 was prepared from S1 and 3-azidoazetidine, employing the same method as described for Compound 1. Compound 1 2-[3-[4-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]triazol-1-yl]azetidin-1-yl]sulfonylethanol (1)Preparation of 2-[3-[4-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran- 4,4'-piperidine]-1'-yl]methyl]triazol-1-yl]azetidin-1-yl]sulfonylethanol (1)

[0131] 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 hours. The volatile was then removed and the crude was purified by reversed phase chromatography (C18 column; Gradient: MeCN in H2O with 0.1 % TFA) to afford 1 (3.1 mg, 24%).1H NMR (300 MHz, Methanol-d4) δ 8.44 (s, 1H), 6.51 (s, 1H), 5.57 (ddd, J = 13.5, 7.8, 5.7 Hz, 1H), 4.80 – 4.37 (m, 6H), 3.97 (t, J = 5.9 Hz, 2H), 3.88 (p, J = 6.0, 5.5 Hz, 2H), 3.57 (d, J = 7.9 Hz, 1H), 3.40 (q, J = 6.4, 5.9 Hz, 4H), 2.88 – 2.56 (m, 4H), 2.28 – 1.85 (m, 4H), 1.58 (d, J = 6.4 Hz, 3H), 1.25 (t, J = 7.5 Hz, 3H). LCMS m / z 496.14 [M+H]+. Compounds 2-5

[0132] Compounds 2-5 (see Table 2) were prepared from S2 using the appropriate sulfonyl chlorides employing the same method as described for Compound 1. All sulfonyl chlorides were obtained from commercial sources, unless noted otherwise. Any modifications to methods are noted in Table 2 and accompanying footnotes. Table 2. Structure and physicochemical data for compounds 2-5Preparation S3 2-azido-N-(2-hydroxyethyl)ethane-1-sulfonamide (S3)

[0133] 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 volatile was removed to afford the title compound. The crude was used directly without further purification. Preparation S4 2-azido-N-(2-hydroxypropyl)ethane-1-sulfonamide (S4)

[0134] 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. Compound 6 2-[4-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]triazol-1-yl]-N-(2-hydroxyethyl)ethanesulfonamide (6)Preparation of 2-[4-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]triazol-1-yl]-N-(2-hydroxyethyl)ethanesulfonamide (6)

[0135] To a solution of 2-azido-N-(2-hydroxyethyl)ethane-1-sulfonamide (67.9 mg, 0.35 mmol) in MeOH (2 mL) and H2O (0.2 mL) was added (2'S)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] S1 (50 mg, 0.17 mmol), sodium ascorbate (37 mg, 0.21 mmol), and CuSO4(1 mg, 0.006 mmol). The mixture was heated at 50 °C for 1 hour. After cooling down to room temperature, the mixture was diluted with DCM and H2O. The pH of the aqueous layer was adjusted to pH 10. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic extracts were concentrated in vacuo. The crude was purified by reversed phase chromatography (C18 column; Gradient: MeCN in H2O with 0.1 % HCl) to afford the title compound (13.9 mg, 17%).1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.53 (s, 2H), 7.05 (s, 1H), 5.29 (t, J = 7.3 Hz, 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]+. Compound 7 2-[4-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]triazol-1-yl]-N-(2-hydroxypropyl)ethanesulfonamide (7)Preparation of 2-[4-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]triazol-1-yl]-N-(2-hydroxypropyl)ethanesulfonamide (7)

[0136] 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 reversed phase chromatography (C18 column; Gradient: MeCN in H2O with 0.1 % HCl) to afford the title compound (7.1 mg, 8%).1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 3.5 Hz, 1H), 7.71 (t, J = 6.1 Hz, 1H), 7.05 (s, 1H), 5.26 (q, J = 6.9 Hz, 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]+.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)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)

[0137] To a solution of (2'S,4R)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine] (40 mg, 0.14 mmol) in DMF (2 mL) was added sodium azide (30 mg, 0.46 mmol) and CuI (30 mg, 0.16 mmol). The mixture was stirred at rt overnight. The mixture was filtered and the filtrated was concentrated. The crude was purified by reversed phase chromatography (C18 column; Gradient: MeCN in H2O with 0.1 % HCl) to afford the title compound (4.6 mg, 9%).1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 3.5 Hz, 1H), 7.71 (t, J = 6.1 Hz, 1H), 7.05 (s, 1H), 5.26 (q, J = 6.9 Hz, 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]+. Preparation 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)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)

[0138] 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 (15 mL) was added slowly a solution of trifluoromethanesulfonic acid (1.8 mL, 20.34 mmol) in dioxane (5 mL). The mixture was stirred at rt overnight. The mixture was diluted with H2O and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc (x2). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified to afford the title compound 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]+. 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)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)

[0139] 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 heated at 45 °C for 8 hour, and then cooled down to room temperature and stirred overnight. The reaction was diluted with EtOAc (350 mL), brine (150 mL) and 2 M aqueous solution of sodium thiosulfate (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 solids were filtered off, and the filtrate was concentrated in vacuo to afford 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]+. 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)

[0140] 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 H2O (4.25 mL) was added CuSO4(30 mg, 0.19 mmol), TBTA (110 mg, 0.21 mmol), and sodium ascorbate(619 mg, 3.52 mmol). The mixture was stirred at room temperature, and then a solution of 1- azido-2-methylsulfonyl-ethane (600 mg, 4.02 mmol) in MeOH (2 mL) was added drop-wise. After addition, the mixture was stirred for 90 min. The mixture was concentrated in vacuo. The residue was suspended in EtOAc and filtered. The filtrate was washed with a mixture of sat. NaHCO3solution and H2O (1:1, 50 mL). The aqueous wash was back-extracted with EtOAc (25 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by MPLC on silica gel (0-10% MeOH in DCM) to afford the title compound as a colorless glass (40 mg, 48%).1H NMR (300 MHz, Chloroform-d) δ 8.18 (s, 1H), 6.51 (s, 1H), 4.92 (t, J = 6.6 Hz, 2H), 4.13 (s, 2H), 3.91 (td, J = 6.6, 5.9, 3.3 Hz, 2H), 3.77 (t, J = 6.6 Hz, 2H), 3.57 - 3.37 (m, 1H), 3.35 - 3.17 (m, 1H), 2.99 (d, J = 12.0 Hz, 1H), 2.87 (s, 3H), 2.82 - 2.64 (m, 4H), 2.26 (td, J = 15.7, 15.3, 4.8 Hz, 2H), 2.07 - 1.80 (m, 2H), 1.49 (d, J = 6.8 Hz, 3H), 1.26 (t, J = 7.5 Hz, 3H). LCMS m / z 440.27 [M+H]+. 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)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)

[0141] 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, 2.460mmol) 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 mixture was stirred at 30 °C overnight. The reaction was diluted with EtOAc (30 mL), H2O (20 mL) and brine (10 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified using silica gel chromatography (10-35% EtOAc in hexanes) to afford C2 (350 mg, 44%).1H NMR (300 MHz, Chloroform-d) δ 6.41 (d, J = 1.1 Hz, 1H), 3.96 - 3.74 (m, 2H), 3.47 (ddd, J = 71.3, 17.3, 2.4 Hz, 2H), 2.98 - 2.48 (m, 7H), 1.92 - 1.72 (m, 3H), 1.60 (dd, J = 13.8, 11.5 Hz, 1H), 1.21 (t, J = 7.5 Hz, 4H), 1.03 (d, J = 6.3 Hz, 3H). LCMS m / z 290.11 [M+H]+.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)

[0142] To a solution of (2'R,4S)-2-ethyl-2'-methyl-1'-prop-2-ynyl-spiro[3a,6,7,7a- tetrahydrothieno[3,2-c]pyran-4,4'-piperidine] C2 (350 mg, 1.20 mmol) in MeOH (8 mL) and H2O (2 mL) was added CuSO4(5 mg, 0.031 mmol), TBTA (25 mg, 0.047 mmol), and sodium ascorbate (300 mg, 1.70 mmol). The mixture was stirred at rt, and then a solution of 1-azido-2- methylsulfonyl-ethane (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 h. 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) afforded 10 (448 mg, 81%).1H NMR (300 MHz, Chloroform-d) δ 7.66 (s, 1H), 6.40 (d, J = 1.2 Hz, 1H), 4.81 (t, J = 6.4 Hz, 2H), 3.98 (d, J = 14.6 Hz, 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]+. 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)Preparation of (2'S,4R)-2-ethyl-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4- yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (11)

[0143] 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 was suspended in EtOAc and heated at 50 °C for 10 min. The mixture was diluted with Et2O and cooled to 0 °C and stirred for 10 min. The mixture was filtered and the cake was washed with Et2O and dried to afford the title compound (595 mg, 70%).1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 6.58 (d, J = 1.1 Hz, 1H), 4.80 (t, J = 6.9 Hz, 2H), 3.91 - 3.65 (m, 6H), 2.92 (s, 3H), 2.70 (qd, J = 7.5, 0.9 Hz, 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, 11.2 Hz, 1H), 1.19 (t, J = 7.5Hz, 3H), 1.13 (d, J = 6.1 Hz, 3H). LCMS m / z 439.56 [M+H]+. Compound 12 2-[4-[[(2'S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]triazol-1-yl]-N-methyl-ethanesulfonamide (12)Preparation of 2-[4-[[(2'S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]triazol-1-yl]-N-methyl-ethanesulfonamide (12)

[0144] To a solution of 2-amino-N-methyl-ethanesulfonamide (HCl salt) (55 mg, 0.31 mmol) in THF (2.5 mL) and H2O (1 mL) was added CuSO4(1 mg, 0.0063 mmol) and K2CO3(30 mg, 0.2171 mmol) followed by N-diazoimidazole-1-sulfonamide (tetrafluoroborate) (120 mg, 0.46 mmol). The reaction was stirred at room temperature overnight. Subsequently 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 down to room temperature and the volatile was removed. The crude was purified by reversed phase chromatography (C18 column; Gradient: MeCN in H2O with 0.1 % TFA) to give the desired product as a TFA salt. The product was dissolved in DCM and treated with sat. NaHCO3solution. The organic layer was separated and concentrated in vacuo to afford 12 as a free base (53.5 mg, 70%.1H NMR (400 MHz, Chloroform-d) δ 7.54 (s, 1H), 6.38 (s, 1H), 4.74 (t, J = 6.3 Hz, 2H), 4.63 (s, 1H), 3.93 (s, 2H), 3.86 - 3.69 (m, 2H), 3.60 (q, J = 6.4 Hz, 2H), 2.76 - 2.58 (m, 5H), 2.56 (s, 3H), 2.52 - 2.37 (m, 2H), 1.89 - 1.71 (m, 3H), 1.61 (dd, J = 13.8, 11.3 Hz, 1H), 1.24 - 1.10 (m, 6H). LCMS m / z 454.45 [M+H]+. Preparation S7 azido(methylsulfonyl)methane (S7)Preparation of azido(methylsulfonyl)methane (S7)

[0145] 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 down to room temperature, the 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 afford the title compound as a red oil (75 mg, 82%). The crude was used directly without further purification.1H NMR (400 MHz, Chloroform-d) δ 4.20 (s, 2H), 2.98 (t, J = 0.9 Hz, 3H). Preparation S8 1-(azidomethylsulfonyl)ethane (S8)Preparation of 1-(azidomethylsulfonyl)ethane (S8)

[0146] Compounds 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. Compound 13 (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)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)

[0147] To a mixture of azido(methylsulfonyl)methane (75 mg, 0.47 mmol), (2'S,4R)-2-ethyl- 2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (50 mg, 0.16 mmol) in MeOH (3 mL) and H2O (2 mL) was added CuSO4(0.6 mg, 0.004 mmol), TBTA (4 mg, 0.008 mmol) and sodium ascorbate (28 mg, 0.16 mmol). The resulting mixture was heated at 50 °C for 10 min. After cooling down to rt, the mixture was concentrated. The crude was purified using silica gel chromatography (0-10% MeOH in DCM) to afford the title compound (59 mg,85%).1H NMR (400 MHz, Chloroform-d) δ 7.81 (s, 1H), 6.45 (d, J = 1.1 Hz, 1H), 5.61 - 5.47 (m, 2H), 4.08 (d, J = 14.7 Hz, 1H), 3.92 - 3.76 (m, 3H), 2.89 (d, J = 0.9 Hz, 3H), 2.79 - 2.51 (m, 7H), 1.94 - 1.76 (m, 3H), 1.68 (dd, J = 14.0, 11.3 Hz, 1H), 1.25 (t, J = 7.5 Hz, 3H), 1.21 (d, J = 6.2 Hz, 3H). LCMS m / z 425.52 [M+H]+. 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)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)

[0148] 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 afford 14 as a clear oil (46 mg, 67%).1H NMR (400 MHz, Chloroform-d) δ 7.81 (s, 1H), 6.50 - 6.41 (m, 1H), 5.63 - 5.44 (m, 2H), 4.06 (d, J = 14.7 Hz, 1H), 3.94 - 3.74 (m, 3H), 2.96 (q, J = 7.5 Hz, 2H), 2.78 - 2.52 (m, 7H), 1.93 - 1.77 (m, 3H), 1.68 (dd, J = 14.0, 11.3 Hz, 1H), 1.37 (t, J = 7.5 Hz, 3H), 1.25 (t, J = 7.5 Hz, 3H), 1.21 (d, J = 6.2 Hz, 3H). LCMS m / z 439.56 [M+H]+.Compound 15 tert-butyl (3R)-3-[4-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]triazol-1-yl]pyrrolidine-1-carboxylate (15)Preparation of tert-butyl (3R)-3-[4-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]triazol-1-yl]pyrrolidine-1- carboxylate (15)

[0149] 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 CuSO4(0.15 mg, 0.026 mmol) in H2O (75 μL) and a solution of NaHCO3in H2O (75 μL). A solution of triflic azide (0.15 mL, 0.45 mmol) in DCM was then added. After stirring the mixture at rt for 1 hour, a solution of (2'S,4R)-2-ethyl- 2'-methyl-1'-prop-2-ynyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (10 mg, 0.036 mmol) in MeOH (100 μL) was added followed by a solution of sodium ascorbate (7 mg, 0.040 mmol) in H2O (50 μL) and a solution of TBTA (2 mg, 0.004 mmol) in MeOH (100 μL). The resulting mixture was heated at 50 °C overnight. After cooling down to room temperature, the volatile was removed and the crude was purified by reversed phase chromatography (C18 column; Gradient: MeCN in H2O with 0.1 % TFA) to afford 15 (5.3 mg, 30%).1H NMR (300 MHz, Methanol-d4) δ 8.01 (s, 1H), 6.49 (d, J = 1.1 Hz, 1H), 5.26 (tt, J = 6.1, 4.2 Hz, 1H), 4.04 (d, J = 14.5 Hz, 1H), 3.96 – 3.70 (m, 5H), 3.57 (d, J = 7.9 Hz, 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]+.Compound 16 5-[4-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]triazol-1-yl]pyridin-3-ol (16)Preparation of 5-[4-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]triazol-1-yl]pyridin-3-ol (16)

[0150] 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 rt 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 CuSO4(1.2 mg, 0.008 mmol) and sodium ascorbate (30 mg, 0.17 mmol) in H2O (0.2 mL). The resulting mixture was stirred at 65 °C overnight. After cooling down to rt, the crude was purified by reversed phase chromatography (C18 column; Gradient: MeCN in H2O 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 NaHCO3(2 mL). The organic layer was isolated and concentrated in vacuo to afford the title compound as a free base (15.4 mg, 33%).1H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 8.36 (dd, J = 10.0, 2.2 Hz, 2H), 8.10 (s, 1H), 6.40 (d, J = 1.1 Hz, 1H), 4.22 (d, J = 14.5 Hz, 1H), 3.97 - 3.71 (m, 3H), 2.94 - 2.53 (m, 8H), 1.98 - 1.62 (m, 4H), 1.27 (d, J = 6.2 Hz, 3H), 1.19 (t, J = 7.5 Hz, 3H). LCMS m / z 426.17 [M+H]+. Compounds 17-197

[0151] Compounds 17-197 (see Table 3) were prepared from S1 using the appropriate amines employing general method B or C. All amines were obtained from commercial sources, unless noted otherwise. Any modifications to methods are noted in Table 2 and accompanying footnotes.Table 3. Structure and physicochemical data for Compounds 17-197Compound 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)Step 1.2-chloro-5-(chloromethyl)pyrimidine (C4)

[0152] A bottom flask was charged with (2-chloropyrimidin-5-yl)methanol (1 g, 6.92 mmol) and thionyl chloride (12.5 mL, 171 mmol). To the suspension was added DMF (32.5 µL, 0.42 mmol) and the resulting mixture was heated at reflux for 5 h. Upon heating, the mixture dissolved to form a clear yellow homogenous solution. Upon complete conversion, the reaction was cooled to ambient temperature, and then concentrated in vacuo. The crude was azeotroped with dichloroethane (x 2) and dried to constant mass under high vacuum to afford C4 (1.08 g,92%).1H 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]+. 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)

[0153] 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 H2O (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with 2N Na2S2O3(20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography eluting with 0 – 33% EtOAc / Hexanes to afford the 198 (1.34 g, 70%).1H NMR (300 MHz, Chloroform-d) δ 8.62 (s, 2H), 6.48 (d, J= 1.1 Hz, 1H), 4.12 (d, J= 14.2 Hz, 1H), 4.01 - 3.67 (m, 2H), 3.19 (d, J= 14.2 Hz, 1H), 2.89 - 2.61 (m, 5H), 2.57 - 2.30 (m, 2H), 2.00 - 1.53 (m, 4H), 1.29 (t, J= 7.5 Hz, 3H), 1.17 (d, J= 6.2 Hz, 3H). LCMS m / z 378.07 [M+H]+. 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)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)

[0154] 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 H2O (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography eluting with 0 – 33% EtOAc / Hexanes to afford the 199 (2.00 g, 92%).1H NMR (300 MHz, Chloroform-d) 8.30 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.2, 2.4 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.45 (d, J = 1.1 Hz, 1H), 4.06 (d, J = 13.8 Hz, 1H), 3.84 (tdd, J = 11.3, 8.8, 4.9 Hz,2H), 3.11 (d, J = 13.8 Hz, 1H), 2.87 - 2.55 (m, 5H), 2.57 - 2.24 (m, 2H), 1.96 - 1.58 (m, 4H), 1.23 (t, J = 7.5 Hz, 3H), 1.12 (d, J = 6.1 Hz, 3H). LCMS m / z 377.13 [M+H]+. Compound 200 [(1R,4S)-4-[[5-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]pyrimidin-2-yl]amino]cyclopent-2-en-1-yl]methanol (200)Preparation of [(1R,4S)-4-[[5-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2- c]pyran-4,4'-piperidine]-1'-yl]methyl]pyrimidin-2-yl]amino]cyclopent-2-en-1-yl]methanol (200)

[0155] 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), tBuXPhos Pd G1 (2.41 mg, 0.0037 mmol) in tBuOH (560 μL) was degassed with N2, and then a 2M solution of NaOtBu in tBuOH (48 μL) was added. The resulting mixture was heated at 85 °C for 3 h. After cooling down to ambient temperature, the reaction was quenched with MeOH. The solvent was removed in vacuo and the crude was purified by reversed phase chromatography (C18 column; Gradient: MeCN in H2O with 0.1 % TFA) to afford the 200 (2.2 mg, 8.3%). LCMS m / z 455.58 [M+H]+. Compound 201 2-[[5-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-Preparation of 2-[[5-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]pyrimidin-2-yl]amino]-2-methyl-propan-1-ol (201)

[0156] 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 at 230 °C in a microwave for 6 h. After cooling down to rt, the reaction was diluted with DCM, washed with H2O (x3). The organic layer was separated and concentrated in vacuo. The crude was purified by reversed phase chromatography (C18 column; Gradient: MeCN in H2O with 0.1 % TFA) to afford the 201 as a TFA salt (3.6 mg, 9%).1H NMR (300 MHz, Methanol-d4) δ 8.24 (s, 2H), 6.49 (d, J = 1.0 Hz, 1H), 3.97 (d, J = 13.6 Hz, 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, 5.3 Hz, 1H), 1.87 - 1.66 (m, 4H), 1.38 (s, 6H), 1.27 - 1.20 (m, 6H). LCMS m / z 431.49 [M+H]+. Compound 202 5-[[(2'S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]- N- methyl-pyridin-2-amine (202)Preparation of 5-[[(2'S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]-N-methyl-pyridin-2-amine (202)

[0157] 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), tBuXPhos Pd G1 (2.50 mg, 0.0038 mmol) in tBuOH (500 μL) was degassed with N2, and then a 2M solution of NaOtBu in tBuOH (42 μL) was added. The resulting mixture was heated at 60 °C for 3 h. After cooling down to ambient temperature, the reaction was quenched with MeOH. The solvent was removed in vacuo and the crude was purified by reversed phase chromatography (C18 column; Gradient: MeCN in H2O with 0.1 % TFA) to afford 202 (11.9 mg, 49%).1H NMR (300 MHz, Chloroform-d) δ 8.29 (dd, J = 18.9, 9.3 Hz, 1H), 7.99 (s, 1H), 7.03 (d, J = 9.6 Hz, 1H), 6.49 (s, 1H), 6.12 - 6.02 (m,1H), 5.95 (s, 1H), 5.91 - 5.81 (m, 1H), 4.84 - 4.62 (m, 2H), 4.45 (s, 1H), 4.02 - 3.49 (m, 6H), 3.26 - 2.88 (m, 3H), 2.77 (q, J = 7.7 Hz, 4H), 2.58 (dt, J = 14.1, 8.7 Hz, 1H), 2.36 (q, J = 13.4, 12.3 Hz, 2H), 2.12 - 1.91 (m, 2H), 1.83 (dt, J = 14.2, 3.2 Hz, 1H), 1.60 (dd, J = 6.5, 3.6 Hz, 3H), 1.27 (t, J = 7.5 Hz, 3H). Compounds 203-231

[0158] Compounds 203-231 (see Table 4) were prepared from 198 or 199 using the appropriate amines with general methods for 200-202. All amines were obtained from commercial sources, unless noted otherwise. Any modifications to methods are noted in Table 4 and accompanying footnotes. Table 4. Structure and physicochemical data for compounds 203-231Compound 232 4-[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-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'-piperidine]-1'-yl]tetrahydrofuran-3-ol (233)Preparation of 4-[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-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'-piperidine]-1'-yl]tetrahydrofuran-3-ol (233)

[0159] 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 mixture was heated in a microwave at 150 °C for 6 h. After cooling down to ambient temperature, the volatile was removed in vacuo and the crude was purified by reversed phase chromatography (C18 column; Gradient: MeCN in H2O with 0.2 % formic acid) to afford 232 (11.5 mg, 38%) and the corresponding trans diastereomer 233 (10 mg, 33%), Compound 232:1H NMR (300 MHz, Chloroform-d) δ 9.16 (s, 1H), 6.51 (d, J = 1.1 Hz, 1H), 4.91 (t, J = 6.6 Hz, 1H), 4.36 (dd, J = 10.2, 7.2 Hz, 1H), 4.21 (d, J = 11.9 Hz, 1H), 4.12 (d, J = 5.9 Hz, 1H), 4.05 - 3.79 (m, 2H), 3.60(dd, J = 10.2, 5.9 Hz, 1H), 3.51 - 3.31 (m, 1H), 2.92 - 2.72 (m, 4H), 2.59 (s, 4H), 2.44 - 2.24 (m, 1H), 2.21 - 1.99 (m, 2H), 1.46 (d, J = 6.6 Hz, 3H), 1.29 (t, J = 7.5 Hz, 3H). LCMS m / z 338.21 [M+H]+. Compound 233:1H NMR (300 MHz, Chloroform-d) δ 8.56 (s, 1H), 6.54 (d, J = 1.0 Hz, 1H), 4.73 (t, J = 6.3 Hz, 1H), 4.35 - 4.01 (m, 3H), 3.99 - 3.79 (m, 2H), 3.60 (dd, J = 9.8, 5.9 Hz, 1H), 3.49 (d, J = 10.3 Hz, 1H), 3.18 (d, J = 10.9 Hz, 1H), 2.98 (t, J = 12.4 Hz, 1H), 2.86 - 2.71 (m, 5H), 2.40 - 2.20 (m, 1H), 2.13 (d, J = 12.0 Hz, 1H), 1.98 (d, J = 14.4 Hz, 2H), 1.43 (d, J = 6.4 Hz, 3H), 1.28 (t, J = 7.6 Hz, 3H). LCMS m / z 338.21 [M+H]+. Compounds 234-263

[0160] Compounds 234-263 (see Table 5) were prepared from C1 using the appropriate epoxides employing the epoxide opening method described for 232 and 233. All epoxides were obtained from commercial sources, unless noted otherwise. Any modifications to methods are noted in Table 5 and accompanying footnotes. Table 5. Structure and physicochemical data for compounds 234-263Preparation S9Step 1:tert-butyl(2'S,4S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-carboxylate (C6)

[0161] 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 cooled to -78oC. 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 -78oC for 1 h. Water (15 mL) and DCM (15 mL) were added and the pH was adjusted to ~10 using 2 N NaOH. The aqueous layer was extracted with DCM (3 x 15 mL) and filtered to give a yellow gel. The crude product was dissolved in DCM (1 mL) and Et3N (0.2 mL, 1.43 mmol) was added followed by boc anhydride (0.2 mL, 0.870 mmol). The reaction mixture was stirred at rt for 3 h. The solution was diluted with DCM and washed with water (10 mL). The aqueous layer was extracted with DCM (2 x 10 mL), dried over Na2SO4and filtered. Purification by silica gel chromatography (Gradient: 0-60% EtOAc in heptane) gave 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). (1H under MeOH peak). Step 2: (2'S,4S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] S9

[0162] 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 rt for 4 h. Concentrated and purified by Prep-HPLC (Mobile phase A: - 0.1% FA (aq), Mobile phase B: - Acetonitrile) to yield (2'S,4S)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran- 4,4'-piperidine] S9 (65 mg, 72 %).1H NMR (300 MHz, Methanol-d4) δ 6.56 (d, J = 1.6 Hz, 1H), 3.94 (t, J = 5.4 Hz, 2H), 3.81 - 3.70 (m, 1H), 3.50 (td, J = 12.4, 3.6 Hz, 1H), 3.19 (dt, J = 13.0,4.1 Hz, 1H), 2.82 - 2.70 (m, 4H), 2.15 (td, J = 14.7, 14.2, 4.8 Hz, 2H), 2.02 (d, J = 15.2 Hz, 2H), 1.55 (d, J = 7.1 Hz, 3H), 1.25 (t, J = 7.5 Hz, 3H). Preparation S10 2-(4-formylpyrazol-1-yl)-N-methyl-ethanesulfonamide (S10)Step 1: 2-(4-formylpyrazol-1-yl)-N-methyl-ethanesulfonamide (S10)

[0163] 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 x 30 mL) followed by DCM (2 x 20 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (Gradient: 0-10% Methanol in DCM) gave 2-(4-formylpyrazol-1-yl)-N-methyl-ethanesulfonamide S10 (565 mg, 54%).1H NMR (400 MHz, DMSO-d6) δ δ 9.80 (s, 1H), 8.53 (d, J = 0.7 Hz, 1H), 8.03 (d, J = 0.7 Hz, 1H), 7.15 (d, J = 4.3 Hz, 1H), 4.53 (dd, J = 7.4, 6.5 Hz, 2H), 3.60 (dd, J = 7.4, 6.5 Hz, 2H), 2.56 (d, J = 3.5 Hz, 3H). LCMS m / z 218.42 [M+H]+. Preparation S11 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (S11)Step 1: 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (S11)

[0164] 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 x 30 mL) followed by DCM (2 x 20 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (Gradient: 0-10% Methanol inDCM) gave 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde S11 (1.3 g, 58%).1H NMR (400 MHz, Chloroform-d) δ 9.90 (s, 1H), 8.10 (d, J = 0.7 Hz, 1H), 8.06 (d, J = 0.6 Hz, 1H), 4.75 - 4.63 (m, 2H), 3.70 (tdd, J = 6.0, 1.4, 0.7 Hz, 2H), 2.66 (t, J = 0.7 Hz, 3H). LCMS m / z 203.34 [M+H]+. Preparation S12 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl- propyl]pyrazole-4-carbaldehyde (S12)Step 1: 2-(bromomethyl)-2-methyl-propane-1,3-diol (C11)

[0165] To a solution of (3-methyloxetan-3-yl)methanol C10 (10 mL, 100.3 mmol) in THF (70 mL) at 0oC was added hydrogen bromide (14 mL of 48%w / w, 123.7 mmol) and stirred for 24 h. The mixture was concentrated and diluted in dichloromethane / methanol. Excess hydrogen bromide was quenched with saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was dried over Na2SO4, filtered, rinsed with methanol and concentrated to give 2-(bromomethyl)-2-methyl-propane-1,3-diol C11 (13.6 g, 74%).1H NMR (400 MHz, Methanol-d4) δ 3.47 (d, J = 1.1 Hz, 6H), 0.96 (s, 3H). Step 2: [2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propoxy]-tert-butyl- dimethyl-silane (C12)

[0166] 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 thesolid 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 %).1H NMR (400 MHz, Chloroform-d) δ 3.44 (s, 4H), 3.40 (s, 2H), 0.94 (s, 3H), 0.89 (s, 18H), 0.04 (d, J = 1.2 Hz, 12H).Step 3: 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2- methyl-propyl]pyrazole-4-carbaldehyde (S12)

[0167] 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 110oC for 35 min. The mixture was cooled to rt, filtered, rinsed with acetonitrile and concentrated. Purification by silica gel chromatography (Gradient: 30-60% EtOAc in heptane) to give 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2- methyl-propyl]pyrazole-4-carbaldehyde S12 (2.39 g, 23%).1H 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]+. Compound 264 2-[4-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]pyrazol-1-yl]-N-methyl-ethanesulfonamideStep 1: 2-[4-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]pyrazol-1-yl]-N-methyl-ethanesulfonamide (264)

[0168] 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 50oC 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) gave 2-[4-[[(2'S,4R)-2-ethyl-2'- methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]pyrazol-1-yl]-N- methyl-ethanesulfonamide 264 (71 mg, 45 %).1H NMR (400 MHz, Chloroform-d) δ 7.60 - 7.44 (m, 2H), 6.54 - 6.41 (m, 1H), 4.57 (t, J = 6.0 Hz, 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 = 7.5 Hz, 3H), 1.22 (d, J = 6.2 Hz, 3H). LCMS m / zm / z 453.46 [M+H]+.Compounds 265-277

[0169] Compounds 265-277 (Table 6) were prepared from intermediate piperidines selected from C1, S5, S6, or S9, and appropriate aldehyde using the appropriate reagents as described in the method for compound 264. Aldehydes were prepared by methods described above or obtained from commercial sources. Any modifications to methods are noted in Table 6 and accompanying footnotes. Table 6. Structure and physicochemical data for compounds 265-277Footnotes: 1) Reductive amination was run with 2 eq of polymer supported cyanoborohydride instead of sodium acetoxyborohydride. After completion of reductive amination product was stirred with aqeous HCl and MeOH for five minutes to deprotect the TBS group. White solid precipitated, was collected and dried to afford final product. Compound 278 (2'S,4R)-2-ethyl-1'-(2-methoxyethyl)-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]Step 1: (2'S,4R)-2-ethyl-1'-(2-methoxyethyl)-2'-methyl-spiro[6,7-dihydrothieno[3,2- c]pyran-4,4'-piperidine] (278)

[0170] 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 60oC for 48 h. The mixture was diluted with MeCN (20 mL) and filtered. The filtrate was concentrated and purified by Prep-HPLC (conditions: mobile phase A: - 0.01 M Ammonium bicarbonate (Aq), mobile phase B: -acetonitrile) and pure fractions 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 (400 MHz, DMSO-d6): δ 6.60 (s, 1H), 3.83-3.79 (q, J = 5.2 Hz, 2H), 3.42-3.39 (t, J = 6.0 Hz, 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 = 7.6 Hz, 3H), 0.98-0.97 (d, J = 6.0 Hz, 3H). LCMS m / z 310.2 [M+H]+. Compound 279 (2'S,4R)-2-ethyl-1'-(isoxazol-3-ylmethyl)-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]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)

[0171] To a solution of (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine] C1 (100 mg, 0.397 mmol) in DMF (2 mL) was added triethylamine (0.16 mL, 1.19 mmol) followed by 3-(chloromethyl)isoxazole C14 (56 mg, 0.477 mmol). The mixture was stirred at room temperature overnight. Diluted with EtOAc (20 mL), 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 Prep-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 (400 MHz, DMSO-d6) 8.85 (s, 1H), 6.60 (s, 1H), 6.52 (s, 1H), 3.91 (d, J = 14.55 Hz, 2H), 3.80-3.76 (m, 2H), 3.63 (d, J = 14.36 Hz, 1H), 2.70 (q, J = 7.44 Hz, 14.92 Hz 2H), 2.62 (bs, , 2H), 2.49- 2.43 (m, 2H), 1.77 – 1.69 (m, 3H), 1.58 (t,J =12.16 Hz 1H), 1.19 (t, J =7.44 Hz, 3H), 1.10 (d, J = 6.08 Hz, 3H). LCMS m / z 333.0 [M+H]+. Compounds 280-298

[0172] Compounds 280-298 were prepared from intermediate C1 and corresponding commercial alkyl halides using methods as described for compounds 278 and 279. Any modifications to methods are noted in Table 7 and accompanying footnotes.Table 7. Structure and physicochemical data for compounds 280-298Footnotes: 1) Epoxide opening was run using NaCN in DMF 2) alcohol was stirred with trifluoromethanesulfonic anhydride at 80oC then added to reaction mixture 3) Compounds 295-298 stereoisomers were separated by chiral SFC purificationPreparation of Compound 299 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]cyclobutanamine (299)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)

[0173] A microwave tube was charged with (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine] trifluoromethanesulfonate (C1) (2.468 g, 6.163 mmol), tert-butyl N-(3-formylcyclobutyl)carbamate (6.54 g, 32.82 mmol), polymer-supported cyanoborohydride (11.4 g of 2 mmol / g, 22.80 mmol), and acetic acid (3 mL, 52.75 mmol) in DCM (45 mL). The reaction was heated to 110 °C for 30 minutes under microwave irradiation. 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 x 100 mL), dried over Na2SO4, filtered, and evaporated in vacuo. Purification by silica gel chromatography (120 g column, 0-5% MeOH in DCM) afforded the product tert-butyl N-[3-[[(2'S,4R)-2-ethyl-2'-methyl- spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]cyclobutyl]carbamate (1042) (2.170 g, 79%).1H NMR (300 MHz, 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), 2.00 - 1.76 (m, 3H), 1.76 - 1.62 (m, 1H), 1.60 - 1.45 (m, 2H), 1.45 (s, 9H), 1.28 (t, J = 7.5 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H).ss LCMS m / z 435.4 [M+H]+. 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)

[0174] 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 (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 allowed to stir 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'-piperidine]-1'- yl]methyl]cyclobutanamine (Hydrochloride salt) (299) (1.7 g, 96%). LCMS m / z 334.68 [M+H]+.Compound 300 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 (300)

[0175] Preparation of 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 (300) 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]cyclobutanamine (Hydrochloride salt) 299 (20 mg, 0.05979 mmol) and 3,3- difluorocyclobutanecarboxylic acid (8.1 mg, 0.05979 mmol) were dissolved in DMF to which HDMC (32.7 mg, 0.07175 mmol) and 4-methylmorpholine (20 µL, 0.1794 mmol) were added. The reaction was stirred at room temperature for 1 hour. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid. afforded 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 (Trifluoroacetic acid salt) (300) (17 mg, 50%). LCMS m / z 453.24 [M+H]+. Compound 301 N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]cyclobutyl]-2-(2,2,2-trifluoroethoxy)acetamide (301)Preparation of N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]cyclobutyl]-2-(2,2,2-trifluoroethoxy)acetamide (301)

[0176] 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]- 1'-yl]methyl]cyclobutanamine (Hydrochloride salt) 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 T3P (38.5 mg, 0.1210 mmol) and ) and DIPEA (21 µL, 0.1206 mmol) were added. The reaction was allowed to stir at room temperature overnight. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid afforded N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2- c]pyran-4,4'-piperidine]-1'-yl]methyl]cyclobutyl]-2-(2,2,2-trifluoroethoxy)acetamide (Trifluoroacetic acid salt) (6.8 mg, 24%) (301). LCMS m / z 475.19 [M+H]+. Compound 302 methyl 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 (302)Preparation 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]cyclobutyl]carbamate (302)

[0177] 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]- 1'-yl]methyl]cyclobutanamine (Hydrochloride salt) 299 (18 mg, 0.03962 mmol) was dissolved in DCM (1 mL), to which methyl carbonochloridate (5 µL, 0.06471 mmol) and triethylamine (15 µL, 0.1076 mmol) were added. The reaction was stirred at room temperature for 2 hours, after which time the solvent was evaporated in vacuo. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid afforded 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]cyclobutyl]carbamate (Trifluoroacetic acid salt) (302) (9.7 mg, 45%). LCMS m / z 393.23 [M+H]+. Compounds 303-384

[0178] Compounds 303-384(see Table 8) were prepared from intermediate 299 using the appropriate reagent and using the amide formation methods as described for compounds 300-302. Coupling partners were obtained from commercial sources. Any modifications to methods are noted in Table 8 and accompanying footnotes. Table 8. Method of preparation, structure and physicochemical data for compounds 303- 384Compound 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'-piperidine]-1'-yl]methyl]cyclobutyl]hexanamide (385)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'-piperidine]-1'- yl]methyl]cyclobutyl]hexanamide (385)

[0179] 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 salt) (299) (30 mg, 0.05333 mmol) was dissolved in DMF (1 mL), to which 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) were added, and the reaction mixture was stirred at room temperature for 1 hour. Purification by reversed-phase chromatography (Column: C18. Gradient: 0-100 % MeCN in water with 0.1 % TFA) afforded 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'-piperidine]-1'- yl]methyl]cyclobutyl]hexanamide (Trifluoroacetic acid salt) (385) (24 mg, 55%). LCMS m / z 699.24 [M+H]+. Compound (386) 2-[2-[2-[[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]- 1'- yl]methyl]cyclobutyl]carbamoyloxy]ethoxy]ethoxy]ethyl N-[2-[2-(6-Preparation of 2-[2-[2-[[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2- c]pyran-4,4'-piperidine]-1'-yl]methyl]cyclobutyl]carbamoyloxy]ethoxy]ethoxy]ethyl N-[2- [2-(6-chlorohexoxy)ethoxy]ethyl]carbamate (386)

[0180] 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 salt) (299) (49 mg, 0.08710 mmol) was dissolved in DMF (1 mL), to which 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) were added, and the reaction was stirred at room temperature for 12 hours. Purification by reversed-phase chromatography (Column: C18. Gradient: 0-100 % MeCN in water with 0.1 % formic acid) afforded the product 2-[2-[2-[[3- [[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]cyclobutyl]carbamoyloxy]ethoxy]ethoxy]ethyl N-[2-[2-(6- chlorohexoxy)ethoxy]ethyl]carbamate (Formic acid salt) (386) (25 mg, 35%). LCMS m / z 760.27 [M+H]+. Compound 387 N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]cyclobutyl]-2,2,2-trifluoro-acetamide (387)Preparation of N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]cyclobutyl]-2,2,2-trifluoro-acetamide (387)

[0181] 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]- 1'-yl]methyl]cyclobutanamine (Hydrochloride salt) (299) (20 mg, 0.05391 mmol) was dissolved in DCM (1 mL), to which (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (9 µL, 0.06475 mmol) and DIPEA (19 µL, 0.1091 mmol) were added. The reaction was stirred at room temperature for 2 hours, after which time the solvent was evaporated. Purification by reversed-phase chromatography (Column: C18. Gradient: 0-100 % MeCN in water with 0.1 % TFA) afforded 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]-2,2,2-trifluoro-acetamide (387) (8.5 mg, 32%). LCMS m / z431.15 [M+H]+. Compound 388 N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]cyclobutyl]-2-hydroxy-ethanesulfonamide (388)Preparation of N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]cyclobutyl]-2-hydroxy-ethanesulfonamide (388)

[0182] 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]- 1'-yl]methyl]cyclobutanamine and 2-hydroxyethanesulfonyl chloride were dissolved in DCM (1 mL), to which TEA (20 µL, 0.1435 mmol) was added. The reaction was stirred at room temperature for 2 hours, after which time the solvent was evaporated, and the crude material was redissolved in minimal MeOH. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid afforded 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]-2-hydroxy-ethanesulfonamide(Trifluoroacetic acid salt) (388) (5.6 mg, 20%). LCMS m / z 443.14 [M+H]+. Compounds 389-417

[0183] Compounds 389-417 (see Table 9) were prepared in a single step from intermediate 299 using coupling method for 388. Sulfonyl chlorides were obtained from commercial sources.Table 9. Structure and physicochemical data for compounds 389-417Preparation S13 tert-butyl N-(3-formylcyclobutyl)carbamate (S13)Preparation of tert-butyl N-(3-formylcyclobutyl)carbamate (S13)

[0184] tert-butyl N-[3-(hydroxymethyl)cyclobutyl]carbamate (263 mg, 1.269 mmol) was dissolved in DCM (4 mL), to which Dess Martin periodate (1.211 g, 2.855 mmol) was added. The reaction was stirred at room temperature for 3 hours, after which time it was filtered through a SiO2plug with DCM eluent, and evaporated in vacuo. Purification by silica gel chromatography (4 g column, 0-40% EtOAc in Heptanes) afforded the product tert-butyl N-(3- formylcyclobutyl)carbamate (S13) (117 mg, 46%).1H 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]+. Preparation of Compound 419 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-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)

[0185] A microwave tube was charged with (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine] trifluoromethanesulfonate (C1) (116 mg, 0.2887 mmol), tert-butyl N-(3-formylcyclobutyl)carbamate (S13) (110 mg, 0.5571 mmol), polymer- supported cyanoborohydride (455 mg of 2 mmol / g, 0.9104 mmol), and acetic acid (100 µL, 1.758 mmol) in DCM (2 mL). The reaction was heated to 110 °C for 30 minutes under microwave irradiation. 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 Na2SO4, filtered, and evaporated in vacuo. Purification by silica gel chromatography (4 g column, 0-10% MeOH in DCM) afforded the product tert-butyl N-[3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]cyclobutyl]carbamate (418) (19 mg, 15%).1H 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]+. 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)

[0186] 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) (16 mg, 0.03706 mmol) was dissolved in DCM (300 µL), to which TFA (100 µL, 1.298 mmol) was added. The reaction was stirred at room temperature for 3 hours, and the reaction mixture was then filtered. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid afforded the product 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) (13 mg, 62%). LCMS m / z 335.21 [M+H]+. 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)Step 1. Synthesis of tert-butyl 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)

[0187] A microwave tube was charged with (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine] trifluoromethanesulfonate (C1) (2.5 g, 6.243 mmol), tert-butyl 3-formylazetidine-1-carboxylate (4.65 g, 25.11 mmol), polymer-supported cyanoborohydride (12.5 g of 2 mmol / g, 25.00 mmol), and acetic acid (2.5 mL, 43.96 mmol) in DCM (50 mL). The reaction was heated to 110 °C for 30 minutes under microwave irradiation. After cooling to room temperature, the reaction was filtered, and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (120 g column, 0-5% MeOH in DCM) afforded the product tert-butyl 3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]azetidine-1-carboxylate (420) (1.838 g, 67%).1H NMR (300 MHz,Chloroform-d) δ 6.48 (s, 1H), 4.05 (td, J = 8.4, 4.3 Hz, 2H), 3.98 - 3.82 (m, 2H), 3.66 (dd, J = 8.6, 5.7 Hz, 1H), 3.59 (dd, J = 8.5, 5.7 Hz, 1H), 3.07 (dd, J = 12.9, 7.8 Hz, 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 = 7.5 Hz, 3H), 1.09 (d, J = 6.2 Hz, 3H). LCMS m / z 421.5 [M+H]+. 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)

[0188] TFA (3.0 mL, 38.94 mmol) was added to a solution of tert-butyl 3-[[(2'S,4R)-2-ethyl- 2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]azetidine-1- carboxylate (420) (1.8 g, 4.205 mmol) in DCM (12 mL), and the reaction was allowed to stir at room temperature for 3 hours. 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]+. 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'-piperidine]-1'-yl]methyl]azetidin-1-yl]methanone (422)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'-piperidine]-1'-yl]methyl]azetidin-1-yl]methanone (422)

[0189] (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 4-amino-1,2,5-oxadiazole-3- carboxylic acid (16 mg, 0.1228 mmol) and HATU (40 mg, 0.1052 mmol) were added. The reaction was stirred at room temperature for 16 hours, after which time the solution was diluted with MeOH (500 µL) and filtered. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 5 mM HCl afforded 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'-piperidine]-1'-yl]methyl]azetidin-1-yl]methanone (Hydrochloridesalt) (422) (7.4 mg, 49%). LCMS m / z 432.19 [M+H]+. Compound 423 [3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]azetidin-1-yl]-(3-hydroxy-2-pyridyl)methanone (423)Preparation of [3-[[(2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]azetidin-1-yl]-(3-hydroxy-2-pyridyl)methanone (423)

[0190] (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 T3P (40 mg, 0.1257 mmol) and 3-hydroxypyridine-2-carboxylic acid (25 mg, 0.1797 mmol) were added. The reaction was allowed to stir at room temperature overnight. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid afforded [3-[[(2'S,4R)-2- ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]methyl]azetidin-1-yl]- (3-hydroxy-2-pyridyl)methanone (2.8 mg, 10%) (423). LCMS m / z 442.16 [M+H]+. 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)Preparation of 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)

[0191] (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 methyl carbonochloridate (9.5 µL, 0.1228 mmol) was added. The reaction was stirred at room temperature for 10 minutes, after which time it was filtered. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 5 mM HCl afforded the product 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 (Hydrochloride salt) (424) (13.4 mg, 86%). LCMS m / z 379.22 [M+H]+. Compounds 425-490

[0192] Compounds 425-490 (see Table 10) were prepared from intermediate 421 using the appropriate reagent and using the amide formation methods as described for compounds 422- 424. Coupling partners were obtained from commercial sources. Table 10. Method of preparation, structure and physicochemical data for compounds 425- 490Preparation of (2'S,4R)-2-ethyl-1'-[(1-ethylsulfonylazetidin-3-yl)methyl]-2'-methyl- spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (491)

[0193] (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 ethanesulfonyl chloride (14 µL, 0.1500 mmol) was added. The reaction was stirred at room temperature for 3 hours, after which time it was diluted with MeOH (800 µL) and filtered. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 5 mM HCl afforded 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 salt) (491) (14.5 mg,63%). LCMS m / z 413.20 [M+H]+. Compounds 492-496

[0194] Compounds 492-496 (see Table 11) were prepared in a single step from intermediate 421 using coupling method for 491. Sulfonyl chlorides were obtained from commercial sources. Table 11. Structure and physicochemical data for compounds 492-496Compound 497 (2'S,4R)-2-ethyl-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-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)

[0195] 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 Boc2O (211 µL, 0.9185 mmol) and DIPEA (160 µL, 0.9186 mmol). After 1 h, the reaction mixture was diluted with sat. aq. ammonium chloride. The layers were separated, and the organic layer was passed over a phase separator and used in the next step without further purification. 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)

[0196] 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 rt. The mixture was then divided in two halves and one half of the mixture was stirred with mCPBA (300 mg, 1.74 mmol) at reflux for 3 h. At this time, the mixture was cooled to rt, diluted with sat. sodium bicarbonate (20 mL) and additional DCM (20 mL). The layers were separated, and the aqueous layer was washed with DCM (10 mL), and then the combined organic layers were washed with additional sat. sodium bicarbonate (10 mL) followed by brine (10 mL). The organic layer was dried with 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 (400 MHz, Chloroform-d3) δ 6.14 (t, J = 2.1 Hz, 1H), 4.01 (tt, J = 11.8, 6.5 Hz, 1H), 3.95 - 3.67 (m, 3H), 3.24 (ddd, J = 14.0, 9.3, 5.4 Hz, 1H), 2.63 - 2.40 (m, 4H), 1.95 - 1.74 (m, 2H), 1.70 - 1.56 (m, 2H), 1.46 (d, J = 14.0 Hz, 9H), 1.31 - 1.23 (m, 6H). LCMS m / z 383.85 [M+H]+. 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)

[0197] 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 (500 µL of 4 M, 2.000 mmol) in dioxane. The mixture was stirred at rt. After 1 h, the mixture was concentrated in vacuo to provide (2'S,4R)-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 1,1-dioxide C18 (Hydrochloride salt) (33 mg, 25%). LCMS m / z 284.03 [M+H]+. It was used in the next step without further purification. Step 4. Synthesis of (2'S,4R)-2-ethyl-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4- yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 1,1-dioxide (497)

[0198] 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 salt) (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 the modifier). The product- containing fractions were pooled, concentrated, and diluted with 6 N NaOH / DCM. The layers were separated, and the aqueous layer was extracted with additional DCM. The organic layer was passed over a phase separator and concentrated to yield (2'S,4R)-2-ethyl-2'-methyl-1'-[[1-(2- methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 1,1-dioxide 497 (12 mg, 23%).1H NMR (400 MHz, Chloroform-d3) δ 7.64 (s, 1H), 6.24 (t, J = 2.2 Hz, 1H), 4.92 - 4.83 (m, 2H), 4.04 (d, J = 14.7 Hz, 1H), 3.88 (d, J = 14.7 Hz, 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]+. Compound 498 2-ethyl-2',2'-dimethyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran- 4,4'- piperidine]Step 1. Synthesis of 2-ethyl-2',2'-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine] (C19)

[0199] To a 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). Then trifluoromethanesulfonic acid (100 µL, 1.13 mmol) was added at 0 °C, and stirred at rt for 4 h. The reaction mixture was concentrated in vacuo to provide 2-ethyl-2',2'-dimethyl-spiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine] C19, which was used in the next step without purification. 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)

[0200] To the crude material from the previous step in DCM were added AcOH (114 µL, 2.0 mmol), 1-methylpyrazole-4-carbaldehyde (88 mg, 0.8 mmol), and cyanoborohydride, polymer supported (500 mg, 1 mmol). The reaction mixture was heated in a microwave reactor at 110 °C for 20 min. The reaction mixture was then filtered, concentrated in vacuo. Purification byreversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid. 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] (trifluoroacetic acid salt) (20.5 mg, 11%). LCMS m / z 360.23 [M+H]+. Preparation S15 2-(4,5-dimethyl-2-thienyl)ethanol (S15) Preparation of 2-(4,5-dimethyl-2-thienyl)ethanol (S15)

[0201] To a solution of 2,3-dimethylthiophene (2 g, 17.826 mmol) in Et2O (50 mL) at 0 °C was added n-BuLi (8.5564 mL of 2.5 M, 21.391 mmol) over 15 min. The mixture was stirred at rt 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 h 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) afforded 2-(4,5-dimethyl-2-thienyl)ethanol S15 (2 g, 67%).1H NMR (400MHz, DMSO-d6) δ 6.51 (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]+. Intermediates S16-S17

[0202] Intermediates S16-S17 (see Table 12) were prepared in a single step the corresponding thiophenes using the method described for S15. Any modifications to methods are noted in Table 11 and accompanying footnotes. Table 12. Structure and physicochemical data for compounds S16-S17Preparation S18 (2'S,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S18)Preparation of (2'S,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S18)

[0203] To a flask was prepared a solution of 2-(5-methyl-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 eq) in dioxane (158 mL). The flask was cooled with an ice-methanol bath allowed to equilibrate for 10 min, reaching an internal temperature of ~0°C. Trifluoromethanesulfonic acid (17 mL, 192.1 mmol, 2.2 eq) was added dropwise via addition funnel over 30 min. After the addition, the mixture was stirred for another 30 min with the ice bath. Then the ice bath was removed, and the reaction was allowed to warm to rt and stirred overnight. The mixture was diluted with a 1:1 mixture of water and saturated sodium bicarbonate aqueous solution (500 mL) and EtOAc (400 mL). The layers were separated the aqueous layer was re-extracted with EtOAc (200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The solids were then suspended in Et2O (~250 mL) at rt and then heated to reflux. The mixture was dissolved while refluxing and then cooled. Heptane was added, followed by more Et2O. Part of the solvent was removed.. Solids were filtered and washed with 1:1 Et2O-heptane (3 x 75mL) and further dried under high vacuum.. Solids were suspended in Et2O (250mL) and was stirred and heated to reflux for 30 min. At this time, the mixture was cooled to 0 °C and stirred for 10 min, filtered, and then rinsed with ice-cold Et2O to yield a colorless solid, which was dried underair for 5 min and then at high vacuum overnight. (2'S,4R)-2,2'-dimethylspiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine] (trifluoromethanesulfonate) S18 (19.3 g, 57%)1H NMR (300 MHz, Chloroform-d) δ 7.78 (bs, 1H), 7.48 (bs, 1H), 6.52 (d, J = 1.3 Hz, 1H), 3.89 (hept, J = 5.8 Hz, 2H), 3.75 - 3.54 (m, 1H), 3.40 (dq, J = 10.9, 4.7, 3.8 Hz, 2H), 2.77 (td, J = 5.2, 2.8 Hz, 2H), 2.43 (d, J = 1.1 Hz, 3H), 2.21 (ddd, J = 15.0, 11.5, 6.4 Hz, 1H), 2.09 - 1.92 (m, 3H), 1.42 (d, J = 6.6 Hz, 3H). LCMS m / z 238.14 [M+H]+. Key Intermediates S19-S21

[0204] Intermediates S19-S21 (see Table 13) were prepared in a single step from tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate and the appropriate thiophene ethanol reagent S15- S17 using Pictet-Spengler reaction as in the preparation of intermediate S18. Any modifications to methods are noted in Table 13 and accompanying footnotes. Table 13. Structure and physicochemical data for compounds S19-S21Footnotes: 1) Tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate (0.9 eq) and trifluoromethanesulfonic acid (2.8 eq) were used.2) Tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate (0.8 eq) and trifluoromethanesulfonic acid (3.0 eq) were used. 3) Tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate (0.9 eq) and trifluoromethanesulfonic acid (2.8 eq) were used. Preparation S21 tert-butyl (2'S)-2'-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate (S21)Step 1: (2'S)-2'-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S20)

[0205] 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 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 rt and stirred overnight, after which time 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 provide an amber colored crude oil. Purification by HPLC: 10-90% ACN in Water (TFA modifier) C18 column followed by lyophilization to afford (2'S)-2'-methylspiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine] (trifluoromethanesulfonate) (1.40 g).1H NMR (300 MHz, Chloroform-d) δ 7.13 (d, J = 5.2 Hz, 1H), 6.87 (d, J = 5.3 Hz, 1H), 3.97 - 3.86 (m, 2H), 3.62 (d, J = 15.1 Hz, 1H), 3.39 (d, J = 8.4 Hz, 2H), 2.84 (td, J = 5.3, 2.0 Hz, 2H), 2.31 - 2.18 (m, 1H), 2.07 - 1.97 (m, 3H), 1.41 (d, J = 6.6 Hz, 3H). LCMS m / z 224.18 [M+H]+. Step 2: tert-butyl (2'S)-2'-methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- carboxylate (S21)

[0206] The material obtained was dissolved in DCM (20 mL) and treated with Boc2O (1.9 mL, 8.270 mmol) followed by DIPEA (2.7 mL, 15.50 mmol). The resulting solution was stirred at rt overnight. The reaction was partitioned between 1N NaOH and DCM. The organics were collected through a phase separator tube, concentrated in vacuo, followed by purification by silica gel chromatography (Gradient: 0-50% EtOAc in heptane) to afford tert-butyl (2'S)-2'- methylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate S21 (786.4 mg, 32%).1H NMR (300 MHz, Chloroform-d) δ 7.10 (dd, J = 5.2, 0.7 Hz, 1H), 6.73 (d, J = 5.2 Hz, 1H), 4.06 - 3.95 (m, 1H), 3.93 - 3.88 (m, 2H), 3.81 - 3.72 (m, 1H), 3.37 (ddd, J = 14.0, 8.8, 5.4 Hz, 1H), 2.82 (q, J = 5.2 Hz, 2H), 2.11 - 1.93 (m, 2H), 1.86 - 1.73 (m, 2H), 1.50 (s, 9H), 1.28 (d, J =6.6 Hz, 3H). Preparation S22 (2'R,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S22)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)

[0207] A solution of 2-(5-methyl-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, trifluoromethanesulfonic acid (130 µL, 1.469 mmol) was added and the reaction was stirred at -78°C for 1.5 h. Reaction was quenched into a biphasic mixture of sat. NaHCO3(15 mL) and DCM (15 mL) and the aqueous layer pH was adjusted to >10 with 2N NaOH. The aqueous layer was then extracted with DCM (3 x 15mL) and filtered through an phase separation cartridge and concentrated. The crude material was dissolved in DCM (1.4 mL) and triethyl amine (250 µL, 1.794 mmol) and di-tert-butyl dicarbonate (250 µL, 1.088 mmol) were added to the reaction in that order. Reaction was stirred at rt for 18 h. The solution was diluted with DCM and washed with water (10 mL). The aqueous layer was extracted with DCM (2 x 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 yield 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%).1H NMR (300 MHz, Methanol-d4) δ 6.42 (d, J = 1.2 Hz, 1H), 4.35 (d, J = 7.2 Hz, 1H), 3.99 - 3.82 (m, 3H), 2.83 - 2.60 (m, 2H), 2.37 (s, 3H), 1.89 (d, J = 4.3 Hz, 2H), 1.85 - 1.75 (m, 2H), 1.48 (s, 9H), 1.33 (d, J = 7.1 Hz, 3H). Step 2. Synthesis of (2'R,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine] (S22)

[0208] 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 dioxanes (500 µL of 4 M, 2.000 mmol) and the reaction was stirred for 2.5 h at rt. The reaction was concentrated under a stream of nitrogen. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % HCl. (2'R,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (Hydrochloride salt) S22 (84.9 mg, 71%).1H NMR (300 MHz, Methanol-d4) δ 6.52 (s, 1H), 3.94 (t, J = 5.4 Hz, 2H), 3.83 - 3.67 (m, 1H), 3.50 (td, J = 12.5, 3.9 Hz, 1H), 3.19 (dt, J = 13.0, 4.1 Hz, 1H), 2.83 - 2.63 (m, 2H), 2.41 (d, J = 1.1 Hz, 3H), 2.24 - 1.96 (m, 4H), 1.55 (d, J = 7.1 Hz, 3H). LCMS m / z 238.0 [M+H]+. Preparation S23 (2'S,4S)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S23)

[0209] (2'S,4S)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] S23 was prepared using the same procedures as in the preparation of S22.1H NMR (300 MHz, Methanol- d4) δ 6.51 (s, 1H), 3.94 (t, J = 5.4 Hz, 2H), 3.81 - 3.69 (m, 1H), 3.50 (td, J = 12.2, 3.6 Hz, 1H), 3.19 (dt, J = 13.0, 4.1 Hz, 1H), 2.74 (td, J = 5.5, 1.7 Hz, 2H), 2.41 (s, 3H), 2.22 - 1.96 (m, 4H), 1.55 (d, J = 7.1 Hz, 3H). LCMS m / z 238.0 [M+H]+. Preparation S24 (2'S)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S24)

[0210] 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 then purified by silica gel chromatography (Gradient: 10-100% EtOAc in heptane) to afford tert-butyl (2'S)-2-chloro-2'-methyl-spiro[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 rt for 3h, followed by concentration in vacuo and coevaporated with MeOH to afford (2'S)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2- c]pyran-4,4'-piperidine] S24 (Trifluoroacetate salt) (180 mg, 46%). LCMS m / z 258.21 [M+H]+.Compounds 499 [ENANT-1] and 500 [ENANT-2] 4-[(2'S,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]tetrahydrofuran-3-olPreparation of 4-[(2'S,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]tetrahydrofuran-3-ol( 499 [ENANT-1] and 500 [ENANT-2])

[0212] (2'S,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (trifluoromethanesulfonate) S23 (54 mg, 0.1397 mmol), DIPEA (210 µL, 1.206 mmol, 8.6 eq) and 3,6-dioxabicyclo[3.1.0]hexane (43 µL, 0.60 mmol, 4.3 eq) were mixed with n-BuOH (1 ml). And the resulting mixture was heated at 210 °C for 1 h. The crude reaction mixture was evaporated. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % formic acid. Two products were isolated: 4-[(2'S,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-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, 4.1 Hz, 1H), 3.49 (dd, J = 9.6, 5.5 Hz, 1H), 3.30 - 3.21 (m, 1H), 3.09 (td, J = 12.0, 4.2 Hz, 1H), 2.73 (td, J = 5.3, 2.1 Hz, 2H), 2.40 (d, J = 1.0 Hz, 3H), 2.19 - 1.89 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H). LCMS m / z 324.26 [M+H]+; and 4-[(2'S,4R)-2,2'-dimethylspiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]tetra- hydrofuran-3-ol (500 [ENANT-2]) (formic acid) (12 mg, 46%).1H NMR (300 MHz, Methanol- d4) δ 8.38 (s, 1H), 6.53 (q, J = 1.1 Hz, 1H), 4.70 (t, J = 5.3 Hz, 1H), 4.30 - 4.07 (m, 2H), 4.07 - 3.88 (m, 4H), 3.70 - 3.48 (m, 2H), 3.28 - 3.20 (m, 1H), 3.15 (dd, J = 12.2, 2.7 Hz, 1H), 2.73 (t, J = 5.4 Hz, 2H), 2.40 (d, J = 1.0 Hz, 3H), 2.24 - 1.90 (m, 4H), 1.36 (d, J = 6.5 Hz, 3H). LCMS m / z 324.26 [M+H]+. Compounds 501-507

[0213] Compounds 501-507 (see Table 14) were prepared in a single step from intermediate S23 or S24 as in the preparation of compound 499 and 500. Epoxides were obtained from commercial sources. Any modifications to methods are noted in Table 14 and accompanyingfootnotes. Table 14. Structure and physicochemical data for compounds 501-507Footnotes: 1) Oxirane-2-carboxamide (1.6 eq) and DIPEA (5.2 eq) were used. IPA was used instead of n-BuOH. The reaction was heated at 150 °C for 2 h. Purification was completed using silica gel chromatography (Gradient: 0 to 20% MeOH in DCM). 2) The mixture was separated into constituent enantiomers by chiral SFC separation. Column: Daicel Chiralpak ® OJ-H, 10 x 250 mm; Mobile Phase: 30% MeOH (containing 5 mM ammonia), 70 % carbon dioxide. Flow: 15mL / min. 3) 6-Oxabicyclo[3.1.0]hexane (4.2 eq) and DIPEA (8.5 eq) were used. The reaction was heated at 200 °C for 4 h. 4) The corresponding oxirane (3.1 eq) and DIPEA (5.0 eq) were used. MeOH was used instead of n-BuOH. The reaction was heated at 90 °C for 2 h. Purification was completed using silica gel chromatography (Gradient: 0 to 15% MeOH in DCM).Compound 508 (2S)-3-[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]- 2-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)

[0214] (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 added NH3(400 µL of 7 M, 2.800 mmol) in MeOH (1.5 mL). DIPEA (260 µL, 1.493 mmol) was added and reaction was heated at 120 °C for 3 h. An additional 200 μL (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 reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid. Further purification was performed using silica gel chromatography (Gradient: 1-16% MeOH in DCM) to provide (2S)-3- [(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]-2- hydroxy-propanamide (8.5 mg, 7%).1H NMR (300 MHz, 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 = 9.8 Hz, 1H), 4.07 - 3.84 (m, 2H), 3.65 (s, 1H), 3.49 (d, J = 11.8 Hz, 1H), 3.29 (s, 0H), 2.92 (t, J = 11.9 Hz, 1H), 2.76 (q, J = 5.5 Hz, 2H), 2.37 (dd, J = 32.2, 15.7 Hz, 2H), 2.00 (dd, J = 14.9, 8.1 Hz, 2H), 1.49 (d, J = 6.4 Hz, 3H). LCMS m / z 345.21 [M+H]+.Compound 509 (2R)-3-[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]- 2- hydroxy-propanamideStep 1. Synthesis of 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)

[0215] 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 epoxide opening method as describe for 508 starting with S24 and (2R)-oxirane-2-carboxylate. Step 2. Synthesis of (2R)-3-[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2- c]pyran-4,4'-piperidine]-1'-yl]-2-hydroxy-propanamide (509)

[0216] 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 (66 mg, 0.1834 mmol) was added to a microwave vial and added NH3(1.3 mL of 7 M, 9.100 mmol) in MeOH (100 µL). The reaction mixture was stirred at 50 °C overnight. The reaction mixture was concentrated in vacuo and purified via silica gel chromatography (Gradient: 0-12% MeOH in DCM) to provide (2R)-3-[(2'S,4R)-2-chloro-2'- methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-yl]-2-hydroxy-propanamide 509 (21.1 mg, 31%).1H NMR (300 MHz, Chloroform-d) δ 7.01 (d, J = 3.9 Hz, 1H), 6.59 (s, 1H), 5.92 (s, 1H), 4.19 (dd, J = 9.9, 4.9 Hz, 1H), 3.89 (h, J = 6.1 Hz, 2H), 3.15 - 2.86 (m, 3H), 2.80 - 2.59 (m, 3H), 1.84 (dt, J = 14.9, 4.7 Hz, 3H), 1.65 (dd, J = 14.2, 11.4 Hz, 1H), 1.44 (dd, J = 17.0, 7.0 Hz, 1H), 1.10 (d, J = 6.2 Hz, 3H).Compound 510 (2'S)-2,2'-dimethyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7- dihydrothieno[3,2-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)

[0217] In 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 allowed to cool to rt and stirred overnight. The reaction was diluted with DCM, washed with NaHCO3, and extracted with DCM. The combined organic layers were concentrated in vacuo, then purified by silica gel chromatography (Gradient: 0-10% MeOH in DCM) to provide (2'S)-2,2'-dimethyl-1'-[[1-(2- methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 510 (157.4 mg, 57%).1H NMR (300 MHz, Chloroform-d) δ 7.81 (s, 1H), 6.45 (d, J = 1.3 Hz, 1H), 4.87 (t, J = 6.4 Hz, 2H), 4.17 (d, J = 14.7 Hz, 1H), 3.96 (d, J = 14.5 Hz, 1H), 3.89 - 3.78 (m, 2H), 3.73 (t, J = 6.4 Hz, 2H), 2.71 (d, J = 11.4 Hz, 8H), 2.39 (d, J = 1.0 Hz, 3H), 2.00 (s, 1H), 1.85 (d, J = 10.0 Hz, 3H), 1.31 (d, J = 6.3 Hz, 3H). LCMS m / z 425.32 [M+H]+. Compounds 511-514

[0218] Compounds 511-514 (see Table 15) were prepared in a single step from the appropriate intermediate piperidine and alkyl halide using the alkylation method as for compound 510. Alkyl halides were obtained from commercial sources or described previously. Any modifications to methods are noted in Table 15 and accompanying footnotes.Table 15. Structure and physicochemical data for compounds 511-514Footnotes: 1) Purification by silica gel chromatography (Gradient: 10-100% EtOAc in heptane). 2) Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid. Compound 515 2-[[5-[[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'- yl]methyl]pyrimidin-2-yl]amino]-2-methyl-propan-1-olStep 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)

[0219] 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, then partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 10-100% EtOAc in heptane) provided (2'S,4R)-2-chloro-1'-[(2-chloropyrimidin-5-yl)methyl]-2'-methyl-spiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine] C23 (143.7 mg, 59%). LCMS m / z 384.01 [M+H]+. 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'-piperidine]-1'- yl]methyl]pyrimidin-2-amine (C24)

[0220] 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), tBuXPhos Pd G1 (15 mg, 0.02303 mmol), in t-BuOH (3.5 mL) was degassed under nitrogen for 10 min, followedby 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 afford 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'-piperidine]-1'-yl]methyl]pyrimidin-2-amine. LCMS m / z 551.28 [M+H]+. Step 3. Synthesis of 2-[[5-[[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2- c]pyran-4,4'-piperidine]-1'-yl]methyl]pyrimidin-2-yl]amino]-2-methyl-propan-1-ol (515)

[0221] 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 rt for 2 h, 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) to afford 2-[[5-[[(2'S,4R)-2-chloro-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine]-1'-yl]methyl]pyrimidin-2-yl]amino]-2-methyl-propan-1-ol (hydrochloride salt) (6.3 mg, 4%).1H NMR (300 MHz, Methanol-d4) δ 8.43 (s, 2H), 6.81 (s, 1H), 4.56 (s, 1H), 3.96 (h, J = 6.1 Hz, 3H), 3.69 (s, 2H), 3.56 (s, 1H), 3.18 (s, 2H), 2.74 (td, J = 5.3, 1.9 Hz, 2H), 2.09 (dd, J = 23.2, 8.1 Hz, 4H), 1.56 (s, 3H), 1.39 (s, 6H). LCMS m / z 437.11 [M+H]+. 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)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)

[0222] (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 ofcyanoborohydride, polymer supported (67 mg, 0.5930 mmol) was added and the reaction was stirred overnight at rt. The suspension was stirred in 1.5 mL of MeOH for 10 min before filtering off the resin. The solvent was removed, and the residue was dissolved into water (2 mL) and DCM (2 mL). The pH of the aqueous layer was adjusted with 2M NaOH to a pH > 10. The phases were separated through a phase separator and the aqueous layer was extracted with DCM (2 x 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 yield (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%).1H NMR (300 MHz, Chloroform-d) δ 7.54 (s, 1H), 7.49 (s, 1H), 6.46 (d, J = 1.3 Hz, 1H), 4.58 (t, J = 6.8 Hz, 2H), 4.00 - 3.80 (m, 2H), 3.64 (t, J = 6.1 Hz, 2H), 3.55 (s, 2H), 3.06 (q, J = 5.9, 5.3 Hz, 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 = 6.8 Hz, 3H). Compounds 517-518

[0223] Compounds 517-518 (see Table 16) were prepared in a single step from intermediate S22 and S24 using reductive amination step as for compound 516. Aldehydes were described previously. Any modifications to methods are noted in Table 16 and accompanying footnotes.Table 16. Structure and physicochemical data for compounds 517-518Footnotes: 1) Different reagent amounts were used: 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (2.2 eq), acetic acid (7.0 eq), cyanoborohydride, polymer supported (4.7 eq). 2) Different reagent amounts were used: 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (1.5 eq), acetic acid (5.0 eq), cyanoborohydride, polymer supported (2.8 eq). The reaction was performed at 110 °C for 1 h.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)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)

[0224] 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 for 2 h at 50 °C. Sodium cyanoborohydride (112.49 mg, 1.7901 mmol) was added to the reaction mixture and stirred for 24 h at 50 °C. The reaction mixture was concentrated in vacuo and washed with water (4ml) and extracted with EtOAc (3 x 5ml). Organic layer were dried over sodium sulfate and concentrated in vacuo and purified by reverse phase HPLC chromatography. Method: YMC Triart Actus C18 (250 x 20 mm, 5 micron). Gradient: MeCN in H2O with 20 mM ammonium bicarbonate. Product was isolated as (2'S,4R)-2,2',3- trimethyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (56.3 mg, 27%).1H NMR (400MHz, DMSO-d6) δ 7.57 (s, 1H), 7.29 (s, 1H), 3.80 (bs, 3H), 3.77- 3.65 (m, 3H), 3.45 (d, J = 14.52 Hz, 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 = 11.6 Hz, 1H), 1.59 (d, J = 13.8 Hz, 2H), 1.09 (d, J = 5.8 Hz, 3H). LCMS m / z 346.3 [M+H]+. Compounds 520-521

[0225] Compounds 520-521 (see Table 17) were prepared in a single step from the appropriate piperidine chosen from intermediates S20 or S21 using reductive animation step as for compound 519. Aldehydes were obtained from commercial sources. Any modifications to methods are noted in Table 17 and accompanying footnotes.Table 17. Structure and physicochemical data for compounds 520-521Preparation S25 tert-butyl (2'S,4R)-2-bromo-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-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)

[0226] To a stirring 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 rt. Then reaction mixture was heated to 65 °C and stirred for overnight. The reaction mixture was diluted with 1 N NaOH (25 mL), extracted with EtOAc (2 x 50 ml). The organic layer was washed with saturated aqueous sodium thiosulfate solution (50 ml), then washed with brine solution (50ml), dried overNa2SO4. The organic layer was concentrated in vacuo to provide the crude material. The crude compound was purified by silica gel chromatography (Gradient: 10-15 % EtOAc in petroleum ether) to yield 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 (400 MHz, Chloroform-d) δ 6.55 (s ,1 H), 5.30 (s,1 H), 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, 2 H), 1.96-1.91 (m,2H), 1.76-1.64 (m,2H), 1.48 (s, 9H), 1.24 (d, J = 6.4 Hz,3H). LCMS m / z 404.24 [M+H]+. 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)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)

[0227] 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 5 min, the mixture was dried, and redissolved in acetonitrile (2 mL) and to it was added 4-(chloromethyl)-1-(2- methylsulfonylethyl)triazole (Hydrochloride salt) (45 mg, 0.1730 mmol) and potassium carbonate (50 mg, 0.3618 mmol). The mixture was stirred at 70 °C for 3 h. The mixture was cooled to rt, diluted with water (3 mL) and EtOAc (5 mL), the layers were mixed and the aqueous layer was removed. The organic layer was washed with sat. brine, dried with magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (Gradient: 0-10 % MeOH in DCM) to yield (2'S,4R)-2-bromo-2'-methyl-1'-[[1- (2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 522 (33 mg, 58%)1H NMR (400 MHz, Chloroform-d) δ 7.55 (s, 1H), 6.65 (s, 1H), 4.83 - 4.75 (m, 2H), 4.00 - 3.71 (m, 5H), 3.66 (t, J = 6.3 Hz, 2H), 2.68 - 2.55 (m, 6H), 2.48 (s, 2H), 1.80 - 1.71 (m, 3H), 1.58 (d, J = 12.7 Hz, 1H), 1.16 (d, J = 6.1 Hz, 3H). LCMS m / z 488.97 [M+H]+.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)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)

[0228] [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, which 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-difluoro-ethane (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. Reaction was irradiated in a Merck Photoreactor at 100% LED power, 4700 RPM fan for 2 h. Reaction was diluted with 3 mL EtOAc and 1 mL water. Reaction was extracted and the organic layer was dried before evaporating off the volatiles. The crude residue was dissolved in HCl (1000 µL of 4 M, 4.000 mmol) and stirred for 1 h before removing the volatiles. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid. yielded (2'S,4R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine] C25 (Trifluoroacetate salt) (33.2 mg, 22%).1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 6.66 (s, 1H), 6.40 - 6.02 (m, 1H), 3.89 (hept, J = 6.0, 5.5 Hz, 2H), 3.70 - 3.37 (m, 3H), 3.12 (dd, J = 54.9, 12.4 Hz, 2H), 2.74 (t, J = 5.4 Hz, 2H), 2.10 - 1.83 (m, 4H), 1.24 (d, J = 6.4 Hz, 3H). LCMS m / z 288.48 [M+H]+. 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)

[0229] (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 salt) (17 mg, 0.06560 mmol) and K2CO3(100 mg, 0.7236 mmol) were added. Heated to 65 °C overnight under nitrogen. The reaction was thendiluted with water and DCM before separating the layers and extracting the water layer with DCM (x2) on a phase separator. The organic layer was concentrated in vacuo and purified with silica gel chromatography (Gradient: 0-20 % MeOH in DCM) to yield (2'S,4R)-2-(2,2- difluoroethyl)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine] (6.1 mg, 19%).1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.39 (s, 1H), 6.77 (s, 1H), 6.19 (tt, J = 56.2, 4.2 Hz, 1H), 4.51 (t, J = 6.8 Hz, 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 = 6.1 Hz, 3H). LCMS m / z 474.02 [M+H]+. Compound 524 (2'S,4R)-2-(difluoromethyl)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4- yl]methyl]spiro[6,7-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)

[0230] 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 time, butyllithium (50 µL of 2.5 M, 0.1250 mmol) in hexane was added, dropwise. After stirring at this temperature for 60 min, DMF (10 µL, 0.1291 mmol) was added. After another 50 min, the mixture was warmed slowly to rt. The reaction was quenched with sat. ammonium chloride, diluted with 1 mL of water and 5 mL EtOAc. The layers were mixed and separated, and the organic layer was washed with sat. brine. The organic layer was dried with sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (Gradient: 0-50 % EtOAc in heptane) to provide 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%).1H NMR (400 MHz, Chloroform-d) δ 9.82 (s, 1H), 7.42 (s, 1H), 4.05 - 3.85 (m, 3H), 3.76 (ddd, J = 13.8, 6.1, 4.8 Hz, 1H), 3.37 (ddd, J = 14.0, 8.9, 5.4 Hz, 1H), 2.96 - 2.80 (m, 2H), 2.10 (dddd, J = 14.7, 8.2, 6.0, 1.8 Hz, 1H), 1.99 (ddd, J = 14.2, 5.2, 1.9 Hz, 1H), 1.83 - 1.73 (m, 2H), 1.49 (s, 9H), 1.27 (d, J = 6.6 Hz, 3H). LCMS m / z 351.93 [M+H]+. 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)

[0231] 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 rt. N-ethyl-N-(trifluoro-lambda4-sulfanyl)ethanamine (30 µL, 0.2271 mmol) and the mixture was stirred at reflux. After stirring 20 h, the mixture was cooled to rt, diluted with water, and the layers were separated. The organic layer was dried with sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (Gradient: 0-50 % EtOAc in heptane) to provide 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%).1H NMR (400 MHz, Chloroform-d) δ 6.90 (d, J = 2.1 Hz, 1H), 6.75 (t, J = 56.2 Hz, 1H), 4.03 - 3.83 (m, 3H), 3.74 (ddd, J = 13.9, 6.0, 4.8 Hz, 1H), 3.33 (ddd, J = 14.1, 8.9, 5.4 Hz, 1H), 2.88 - 2.72 (m, 2H), 2.05 (dddd, J = 14.8, 9.0, 6.1, 1.8 Hz, 1H), 1.95 (ddd, J = 14.2, 5.2, 1.8 Hz, 1H), 1.80 - 1.67 (m, 2H), 1.48 (s, 9H), 1.25 (d, J = 6.5 Hz, 3H). LCMS m / z 373.99 [M+H]+. 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)

[0232] 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 C27 (18 mg, 0.04775 mmol) in DCM (400 µL) was added trifluoroacetic acid (40 µL, 0.5192 mmol) (11:30). After stirring 60 min, the mixture was dried, and redissolved in acetonitrile (1,000 µL) and to it was added 4- (chloromethyl)-1-(2-methylsulfonylethyl)triazole (Hydrochloride salt) (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 layer was mixed and separated. The organic layer was then washed with brine, dried with magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (Gradient: 0-10 % MeOH in DCM) to provide (2'S,4R)-2-(difluoromethyl)-2'-methyl-1'-[[1-(2- methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 524 (10 mg, 45%).1H NMR (400 MHz, Chloroform-d) δ 7.57 (s, 1H), 6.90 (t, J = 2.1 Hz, 1H), 6.68 (t, J = 56.1 Hz, 1H), 4.86 - 4.74 (m, 2H), 3.97 (d, J = 14.7 Hz, 1H), 3.91 - 3.71 (m, 3H), 3.71 - 3.62 (m, 2H), 2.82 - 2.64 (m, 3H), 2.62 (d, J = 0.7 Hz, 3H), 2.52 (dt, J = 11.5, 5.9 Hz, 2H), 1.86 -1.72 (m, 3H), 1.61 (t, J = 12.6 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H). LCMS m / z 461.1 [M+H]+. Compound 525 (2'S,4R)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]-2- (trifluoromethyl)spiro[6,7-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)

[0233] 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) added. The reaction mixture was stirred at rt overnight and then diluted with 1N NaOH / EtOAc and the organic layer was dried and concentrated, which was purified by silica gel chromatography (Gradient: 0 to 40% EtOAc / heptane) to provide tert-butyl (2'S)-2-iodo-2'- methyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate C28 (222 mg, 80%). LCMS m / z 449.94 [M+H]+. 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)

[0234] 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 bromocopper;methylsulfanylmethane (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 in the microwave to 100 °C for 40 min. Additional methyl 2,2-difluoro-2-fluorosulfonyl-acetate (75 µL, 0.5891 mmol) was added and the reaction mixture again was heated in the microwave to 100 °C for 40 min. The reaction mixture was diluted with EtOAc / 1N NaOH and filtered throughCelite®. The organic layer was dried and concentrated to an oil, which was purified by silica gel chromatography (Gradient: 0 to 25% EtOAc in heptane) to 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%).1H 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). Step 3. Synthesis of (2'S,4R)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]-2- (trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (525)

[0235] 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 and the residue was redissolved in DCE (1 mL) and 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (40 mg, 0.1788 mmol), NaI (3 mg, 0.02001 mmol) and DIPEA (60 µL, 0.3445 mmol) were added. The reaction mixture was heated to 60 °C for 20 h. The reaction mixture was concentrated, dissolved in 1 mL MeOH and repurified using revserse phase C18 column (Gradient: CH3CN / H2O, TFA modifier). The 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]methyl]-2- (trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] 525 (27 mg, 52%) 1H NMR (300 MHz, Chloroform-d) δ 7.65 (s, 1H), 7.14 (s, 1H), 4.88 (t, J = 6.3 Hz, 2H), 4.12 - 3.82 (m, 4H), 3.75 (t, J = 6.3 Hz, 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 = 6.2 Hz, 3H). LCMS m / z 479.11 [M+H]+. Compound 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)Step 1. Synthesis of 3,5-dibromo-2-ethyl-thiophene (C30)

[0236] To a solution of N-isopropylpropan-2-amine (1.2 mL, 8.562 mmol) in THF (50 mL) at 0 °C under nitrogen was added hexyllithium (4.2 mL of 2.3 M, 9.660 mmol) over 5 min and the reaction was stirred for an additional 30 min. The solution was cooled to -78 °C before adding in 2,5-dibromothiophene (900 µL, 7.987 mmol). Then iodoethane (1.3 mL, 16.25 mmol) was added and stirred overnight with slowly warming to rt. The reaction was quenched with saturated ammonium chloride solution then extracted with DCM (3 x 100 mL) and washed the combined organics with saturated bicarbonate solution and saturated brine solution. The combined organic layer was evaporated in vacuo to yield 3,5-dibromo-2-ethyl-thiophene (1.1 g, 52%).1H 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). Step 2. Synthesis of (2'S)-3-bromo-2-ethyl-2'-methyl-spiro[6,7-dihydrothieno[3,2-c]pyran- 4,4'-piperidine] (C31)

[0237] Dissolved 3,5-dibromo-2-ethyl-thiophene C30 (500 mg, 1.852 mmol) in THF (10 mL) at -78 °C. Added hexyllithium (900 µL of 2.3 M, 2.070 mmol) and stirred for 30 min before adding oxirane (1000 µL of 2.5 M, 2.500 mmol). The reaction mixture was allowed to warm to rt and stir for 2 days. The reaction was quenched with saturated ammonium chloride solution and extracted with DCM (x3). The combined organic layer was concentrated in vacuo and purified by silica gel chromatography (Gradient: 0 to 60% EtOAc in heptane) to yield 2-(4-bromo-5- ethyl-2-thienyl)ethanol (200 mg, 46%).1H 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 added tert-butyl (2S)-2- methyl-4-oxo-piperidine-1-carboxylate (400 mg, 1.876 mmol) under nitrogen. Addedtrifluoromethanesulfonic acid (400 µL, 4.520 mmol) and stirred overnight. The reaction mixture was quenched with saturated bicarbonate solution, diluted with DCM and extracted on a phase separator (x3). The solvent was evaporated under positive nitrogen pressure to yield (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]+. Step 3. Synthesis of (2'S,4R)-3-bromo-2-ethyl-2'-methyl-1'-[[1-(2- methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine] (526)

[0239] 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 with K2CO3(88 mg, 0.6367 mmol) and 4-(chloromethyl)-1-(2- methylsulfonylethyl)triazole (Hydrochloride salt) (42 mg, 0.1615 mmol). Reaction was stirred at 60 °C overnight. The reaction mixture was quenched with water and extracted with DCM (x3). The combined organic layer was concentrated in vacuo and then purified by silica gel chromatography (Gradient: 0-20% MeOH in DCM) to yield (2'S,4R)-3-bromo-2-ethyl-2'-methyl- 1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine] 526 (60 mg, 71%). LCMS m / z 517.1 [M+H]+. 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)

[0240] (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 (10mg) in MeOH (2 mL) and added Pd / C (10 mg, 0.09397 mmol) under nitrogen. The reaction was subjected under deuterium gas overnight. Then the flask was purged with nitrogen and filtered off Pd / C to yield (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]+. Preparation S26 1-(5-chloro-2-thienyl)propan-2-ol (S26)Step 1: 1-(5-chloro-2-thienyl)propan-2-ol (S26)

[0241] To a stirred solution of 2-chlorothiophene (1.5 g, 12.6 mmol) in THF (20 mL) was added LDA (9.45 mL of 2 M solution in THF, 18.9 mmol) at -78oC and the reaction mixture wasstirred for 1 h.2-methyloxirane (731 mg, 12.6 mmol) was added, and stirring was continued at - 78oC for 2 hours. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (Gradient: 5% EtOAc in heptane) gave 1-(5-chloro-2-thienyl)propan-2-ol S26 (1.3 g, 52 %).1H NMR (300 MHz, DMSO-d6) δ 6.90 (d, J = 3.6 Hz, 1H), 6.70 (d, J = 3.9 Hz, 1H), 4.82 (d, J = 4.8 Hz, 1H), 3.77 (m, 1H), 2.84-2.68 (m, 2H), 1.06 (d, J = 5.7 Hz, 3H). LCMS m / z 272.19 [M+H]+. Intermediates S27-S29

[0242] Intermediates S27-S29 (Table 18) were prepared from 2-chlorothiophene and the appropriate epoxide as described in the method for compound S26. Table 18. Structure and LCMS data of thiophene cores S27-S29Preparation S30 (2'S)-2-chloro-2',6-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] (S30)Step 1: Synthesis of (2'S)-2-chloro-2',6-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'- piperidine] (S30)

[0243] 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 Methane sulfonic 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 Na2CO3and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (50 mL) dried over anhydrous Na2SO4, filtered, and concentrated. Purification by reversed-phase HPLC. Method Xbridge C18 column (19 x 150 mm, 5 micron). Gradient: MeCN in H2O with 10mM Ammoninum bicarbonate yielded the product. The collected fractions were lyophilize to afford (2'S)-2-chloro-2',6-dimethyl-spiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine] S30 (370 mg, 20%)1H NMR (300 MHz, DMSO-d6) δ 6.92 (s, 1H), 3.87 (d, J = 9.6 Hz, 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 = 6.3 Hz, 3H), 1.15-1.07 (m, 1H), 0.94-0.91 (m, 3H). LCMS m / z 272.11 [M+1]+. Compounds S31-S33

[0244] 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. Structure and LCMS data of spiropiperidine cores S31-S33Footnotes: 1) Trifluoro methane sulfonic acid (1 eq.) was used as an acid. 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'-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)

[0245] 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 h. Upon completion, the solvent was evaporated. Purification by reversed-phase HPLC. Method: XSelect Phenyl hexyl column (19 x 250 mm, 5 micron). Gradient: MeCN in H2O 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%)1H NMR (400 MHz, 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 = 2.8 Hz and 16 Hz, 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 = 6 Hz, 3H), 1.09 (d, J = 6 Hz, 3H). LCMS m / z 366.1 [M+1]+. Compounds 530-533

[0246] Compounds 530-533 (Table 20) were prepared from the appropriately chosen piperidine and 4-(chloromethyl)-1-methyl-pyrazole using the method for compound 528 and 529. Table 20. Structure and physicochemical data for compounds 530-533Preparation S34 (2'S)-2',7-dimethyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]Step 1: Synthesis of (2'S)-2',7-dimethyl-2-(trifluoromethyl)spiro[6,7-dihydrothieno[3,2- c]pyran-4,4'-piperidine] (S34)

[0247] 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 rt overnight. The reaction was quenched with NaHCO3and solvent was evaporated. DCM and water were added and the organic layer was collected through phase separator. The solvent was evaporated to give (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]+.Compounds S35-S41

[0248] 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 22. Structure and physicochemical data for compounds S35-S41Footnotes: 1) (2'S)-2-ethyl-2',7-dimethyl-spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine] was separated into constituent diastereomers (cis and trans) by chiral SFC separation. Column: Phenomenex Lux® Cellulose-2, 20 x 250 mm. Mobile phase: 40% MeOH (containing 5 mM Ammonia), 60% CO2 Compound 534 (2S,4R)-2,7'-dimethyl-1-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-2'-Step 1: (2S,4R)-2,7'-dimethyl-1-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)- 2'-(trifluoromethyl)-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] (534)

[0249] To a stirred solution of (2S,4R)-2,7'-dimethyl-2'-(trifluoromethyl)-6',7'- dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] S34 (71 mg, 0.111 mmol) and 4- (chloromethyl)-1-(2-methylsulfonylethyl)triazole (25 mg, 0.111 mmol) in DMF was added potassium carbonate (15 mg, 0.111 mmol) and reaction was stirred at 60oC overnight. Water and dichloromethane were added and the organic layer was collected through phase separator. Purification by silica gel chromatography (Gradient: 0-20% Methanol in DCM) gave (2S,4R)- 2,7'-dimethyl-1-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-2'-(trifluoromethyl)- 6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] 534 (10 mg, 18%). LCMS m / z 493.56 [M+H]+. Compounds 535-541

[0250] Compounds 535-541 (Table 23) were prepared from intermediate piperidines and 4- (chloromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazole using the method for compound 534 Table 23. Structure and physicochemical data for compounds 535-541Compound 542 (2'S,4R)-2'-methyl-1'-[(1-methylpyrazol-4-yl)methyl]-2-(trifluoromethyl)spiro[6,7- dihydrothieno[3,2-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)

[0251] 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 h. Sodium thiosulfate was added and the reaction mixture was diluted with water and ethyl acetate. The organic layer was concentrated and purification by silica gel chromatography (Gradient: 0-30% EtOAc in heptane) gave 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. 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 dried and concentrated. Purification by silica gel chromatography (Gradient: 0-50% EtOAc in heptane) 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%)1H 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). 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'-piperidine]-7-ol (542)

[0252] Tert-butyl (2'S,4R)-7-hydroxy-2'-methyl-2-(trifluoromethyl)spiro[6,7- dihydrothieno[3,2-c]pyran-4,4'-piperidine]-1'-carboxylate (48 mg, 0.117 mmol) was dissolved in dichloromethane (1 mL) and TFA (0.5 mL, 6.490 mmol) was added. The reaction mixture was stirred for 30 min then concentrated to 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) (180 mg of 2 mmol / g, 0.3600 mmol) resin were added. The reaction mixture was heated to 110 °C in microwave for 60 mins, The reaction was filtered and the filtrate concentrated. Purification by silica chromatography (Gradient: 0-20% Methanol in DCM) gave (2'S,4R)-2'-methyl-1'-[(1-methylpyrazol-4-yl)methyl]-2- (trifluoromethyl)spiro[6,7-dihydrothieno[3,2-c]pyran-4,4'-piperidine]-7-ol 542 (23 mg, 48%)1H NMR (300 MHz, 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]+. Preparation of S44 (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (S44)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)

[0253] 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 was added a solution of hexyllithium in hexane (120 mL of 2.6 M, 312.0 mmol) via an addition funnel over the course of 20 min. After stirring for 70 min following completion of addition of the hexyllithium, DMF (100 mL, 1.291 mol) was added over the course of 5 min. The solution was stirred at -78 °C for 30 min, then the reaction warmed to 0°C and stirred for 45 min. The reaction was then quenched via addition of saturated aqueous ammonium chloride (600 mL). Mixture was partitioned between EtOAc (1 L) and water (500 mL). Organic layer was separated,washed with a saturated aqueous ammonium chloride solution, water, and brine (600 mL each). The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield tert-butyl (2'S,7R)-2-formyl-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate C22 (88 g, 99%) as a viscous amber oil which was used without further purification.1H NMR (300 MHz, Chloroform-d) δ 9.83 (s, 1H), 7.42 (s, 1H), 4.01 (ddd, J = 11.5, 6.7, 5.3 Hz, 1H), 3.94 - 3.82 (m, 2H), 3.75 (ddd, J = 14.0, 6.1, 4.7 Hz, 1H), 3.35 (ddd, J = 14.1, 8.8, 5.4 Hz, 1H), 2.71 (td, J = 5.5, 2.8 Hz, 2H), 2.28 - 2.06 (m, 2H), 1.90 - 1.65 (m, 2H), 1.47 (s, 9H), 1.26 (d, J = 6.6 Hz, 3H). 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)

[0254] To a solution of dibromo(difluoro)methane (33 mL, 361.3 mmol) in THF (600 mL) in a dry ice-acetone cooling bath was added N-[bis(dimethylamino)phosphanyl]-N-methyl- methanamine (140 mL, 770.3 mmol) over the course of 45 min via addition funnel. The dry-ice acetone bath was then replaced with an ice-water bath and stirred for 45 min. 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 the course of 30 min at which point the ice-water bath was removed. After 2 hours, the reaction was cooled in an ice-water bath then quenched via addition of water (300 mL) added over 5 min. An aqueous solution of 10% sodium bisulfite (300 mL) was added. The mixture was stirred for 30 min, then 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 heptanes 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 = 28.1 Hz), -87.47 (d, J = 27.9 Hz). 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)

[0255] To Pd on carbon (8.2 g of 5 %w / w, 3.853 mmol) in a 2 L Parr bottle under nitrogen 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). The Parr shaker was charged with 50 psi of H2. After 24 hours, the reaction mixture wasfiltered through a Celite pad and the filtrate was treated with fresh catalyst Pd on carbon (10 g of 5 %w / w, 4.698 mmol) under nitrogen. The Parr shaker was charged with 50 psi H2and the reaction continued for an additional 16 hours. The reaction was then filtered through a Celite pad washing with EtOH (200 mL). The filtrate was concentrated to a yellow oil which was purified by silica gel chromatography (Gradient: 0-50% EtOAc in heptanes), to afford 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. 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)

[0256] 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) was added 2,6-lutidine (18 mL, 155.4 mmol) followed by trimethylsilyl trifluoromethanesulfonate (15.4 mL, 85.23 mmol) via addition funnel over the course of 12 min. After stirring for 50 min, the reaction was quenched with 1 M aqueous sodium hydroxide (150 mL) and stirred for 10 min. The layers were then separated. The organic layer was washed with 1 M aqueous sodium hydroxide (2 x 200 mL), dried over magnesium sulfate, filtered, and concentrated to afford (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 pale amber oil.1H NMR (300 MHz, Chloroform-d) δ 6.60 (s, 1H), 5.90 (tt, J = 56.5, 4.5 Hz, 1H), 3.91 (td, J = 5.6, 2.9 Hz, 2H), 3.26 (td, J = 16.7, 4.5 Hz, 2H), 3.17 - 2.99 (m, 2H), 2.92 (ddd, J = 12.1, 4.8, 2.0 Hz, 1H), 2.63 (td, J = 5.5, 2.9 Hz, 2H), 2.01 (dt, J = 13.9, 2.2 Hz, 2H), 1.70 (td, J = 13.3, 4.8 Hz, 1H), 1.39 (dd, J = 13.6, 11.3 Hz, 2H), 1.06 (d, J = 6.4 Hz, 3H).19F NMR (282 MHz, Chloroform-d) δ -115.07. LCMS m / z 288.1 [M+1]+.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)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)

[0257] A mixture of (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3- c]pyran-7,4'-piperidine] S44 (700 mg, 2.436 mmol) and potassium carbonate (440 mg, 3.184 mmol) in tetrahydrofuran (14 mL) was heated to 50 °C and stirred. At this time, 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 through a phase separator. The organics were concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0 - 10% MeOH-DCM), yielded (2'S)-2-(2,2- difluoroethyl)-2'-methyl-1'-prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (S45)(537 mg, 67%) 1H NMR (400 MHz, Methanol-d4) δ 6.64 (s, 1H), 5.96 (tt, J = 56.6, 4.3 Hz, 1H), 3.91 (td, J = 5.6, 2.2 Hz, 2H), 3.64 (dd, J = 17.4, 2.4 Hz, 1H), 3.41 (dd, J = 17.3, 2.4 Hz, 1H), 3.25 (ddd, J = 17.2, 4.3, 0.9 Hz, 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, 11.6 Hz, 1H), 1.07 (d, J = 6.4 Hz, 3H). LCMS m / z 326.04 [M+1]+.Preparation of 543 1-[4-[[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine]- 1'-yl]methyl]triazol-1-yl]propan-2-ol (543)Preparation of 1-[4-[[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3- c]pyran-7,4'-piperidine]-1'-yl]methyl]triazol-1-yl]propan-2-ol (543)

[0258] To containing solution of 1-aminopropan-2-ol (20.8 mg, 150 µmol) dissolved in DMSO (0.3 mL) was added aqueous hydrogen carbonate (Sodium salt) (0.25 mL of a 1M solution, 0.25 mmol). To this mixture was added 0.550 mL of fluorosulfonyl azide solution (~0.45M in MTBE, ~250 µmol, prepared according the protocol in Nature, 574, 2019, 86-89) and the reaction was stirred at room temperature for 20 minutes. A solution of the 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 a solution of aqueous CuSO4(0.085 mL of a 0.1 M solution, 0.0085 mmol), a solution of 4-[bis[4-hydroxy-1-(1H-triazol-4-yl)butyl]amino]-4-(1H-triazol-4-yl)butan-1-ol in DMSO (0.085 mL of a 0.1 M solution, 0.0085 mmol), and an aqueous solution of sodium ascorbate (0.085 mL of a 0.2 M solution, 0.017 mmol). The resulting reaction mixture was heated at 50 °C open to the air overnight. An additional portion of CuSO4(0.1 mL of a 0.1 M aq. solution, 0.01 mmol) and sodium ascorbate (0.1 mL of a 0.2 M aq. solution, 0.02 mmol) were added, and the reaction was heated at 50 °C overnight. The reaction was cooled to room temperature, diluted with 2 mL water and 1 mL DCM, and stirred for several minutes. The mixture was passed through a parallel filtration plate and washed with 1mL DCM. The organic layer was taken and evaporated. The resulting residue was dissolved in 1mL DMSO and purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 10 mM Ammonium Hydroxide to yield 1-[4-[[(2'S,7R)-2- (2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'- yl]methyl]triazol-1-yl]propan-2-ol (543)1H NMR (300 MHz, Methanol-d4) δ 7.94 (s, 1H), 6.62(s, 1H), 5.95 (tt, J = 56.6, 4.3 Hz, 1H), 4.52 - 3.67 (m, 7H), 3.24 (dd, J = 17.1, 4.3 Hz, 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]+. Preparation of Compounds 544-548

[0259] Compounds 544-548 (see Table 23) were prepared from intermediate S45 using the appropriate reagents, using the azide transfer and click chemistry methods as described for compound 543. Amines were purchased from commercial sources. Table 23. Method of preparation, structure and physicochemical data for compounds 544- 548Preparation of S46 3-[[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine]-1'-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'-piperidine]-1'-yl]methyl]cyclobutyl]carbamate (C25)

[0260] 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 triacetoxyboranuide (Sodium salt) (376 mg, 1.774 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with NaHCO3(sat.), and the mixture was extracted with DCM (3x5mL). The combined organics were washed with H2O and brine respectfully and then dried over Na2SO4. The solvent was removed in vacuo to afford tert-butyl N-[3-[[(2'S,7R)-2-(2,2- difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'- yl]methyl]cyclobutyl]carbamate C25 (270 mg, 87%) LCMS m / z 471.68 [M+H]+. 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)

[0261] tert-butyl N-[3-[[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]methyl]cyclobutyl]carbamate C25 was treated with HCl (3 mL of 4 M, 12.00 mmol) in dioxane. The reaction mixture was stirred at room temperature for 1hour. The solvent was removed to afford 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 (189 mg, 83%) LCMS m / z 371.18 [M+H]+. 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)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)

[0262] 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 (20 mg) and cyanomethanesulfonyl chloride (7.2 mg, 0.052 mmol) were mixed in DCM (1 mL), to which, Et3N (22 uL) was added. The mixture was stirred at room temperature for 2 hours. The solvent was removed. The resulting residue wasre-dissolved in MeOH, and purified by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid to afford 3-[[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine]-1'-yl]methyl]-N-oxo-cyclobutanamine (4.7 mg) LCMS m / z 474.02 [M+H]+Preparation of Compounds 550-558

[0263] Compounds 550-558 (see Table 24) were prepared from intermediate S47 using the appropriate using the appropriate acyl chloride or sulfonyl chloride reagents with the method as described for compound 549. Acyl chlorides or sulfonyl chlorides were purchased from commercial sources. Table 24. Method of preparation, structure and physicochemical data for compounds 550- 558Compound 559Preparation 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)

[0264] (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 triacetoxyboranuide (Sodium salt) (470 mg, 2.218 mmol) and the reaction was heated to 60 ºCand stirred for 4 hours. The reaction was then cooled to room temperature at which point the reaction 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 via reverse phase column chromatography (Isco 150 g gold C-18 gradient 5-95% ACN / water 0.2% FA modifer) to yield (2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-1'-[[1-(2- methylsulfonylethyl) pyrazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] 559 (142.9 mg, 31%)1H NMR (400 MHz, Methanol-d4) δ 8.42 (s, 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.71 (d, J = 0.7 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 5.97 (tt, J = 56.6, 4.2 Hz, 1H), 4.75 - 4.65 (m, 2H), 4.46 (d, J = 14.1 Hz, 1H), 4.23 (d, J = 14.1 Hz, 1H), 3.89 (dt, J = 6.2, 5.3 Hz, 2H), 3.76 - 3.66 (m, 3H), 2.85 (d, J = 0.7 Hz, 3H), 2.63 (td, J = 5.4, 1.5 Hz, 2H), 2.36 - 2.13 (m, 3H), 2.13 - 1.89 (m, 2H), 1.50 (d, J = 6.5 Hz, 3H). LCMS m / z 474.38 [M+H]+. Compound 560Preparation of 2-[[4-[[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]methyl]pyrazol-1-yl]methyl]-2-methyl- propane-1,3-diol (560)

[0265] (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 put in a microwave vial 5-((1-hydroxy-2-methylpropan- 2-yl)amino)pyrimidine-2-carbaldehyde (37 mg, 0.19 mmol), acetic acid (52 uL, 0.92 mmol), dichloromethane (1.6 mL) were added, and polymer supported cyanoborohydride (295 mg, 0.59 mmol)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 ten minutes to wash the beads. The solutions were filtered, and the solvent removed in vacuo. Purification by reversed-phase HPLC. C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 10 mM Ammonium Hydroxide yielded product 2-[[4-[[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl- spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]methyl]pyrazol-1-yl]methyl]-2- methyl-propane-1,3-diol1H NMR (300 MHz, Chloroform-d) δ 8.23 (s, 2H), 6.60 (d, J = 9.5 Hz,2H), 5.92 (tt, J = 56.5, 4.4 Hz, 1H), 5.24 (s, 1H), 4.05 - 3.59 (m, 6H), 3.28 (td, J = 16.7, 4.5 Hz, 2H), 3.06 (d, J = 13.6 Hz, 1H), 2.64 (hept, J = 4.4 Hz, 4H), 2.39 (td, J = 12.2, 11.7, 2.6 Hz, 1H), 2.01 (ddt, J = 14.2, 5.3, 2.8 Hz, 2H), 1.91 - 1.68 (m, 2H), 1.38 (s, 7H), 1.21 (d, J = 6.1 Hz, 4H). LCMS m / z 467.18[M+H]+. Compound 561Preparation of 2-[[4-[[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]methyl]pyrazol-1-yl]methyl]-2-methyl- propane-1,3-diol (561)

[0266] 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 via was added l 1-[3-[tert- butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4- carbaldehyde (82 mg, 0.19 mmol), acetic acid (52 uL, 0.92 mmol), dichloromethane (1.6 mL), and polymer supported cyanoborohydride (295 mg, 0.59 mmol). The solution was capped and heated to 95 °C in a microwave reactor for 120 minutes. MeOH was added and the solution was stirred for ten minutes to wash the beads. Reaction was stirred with HCl 4M (0.5 mL) in Dioxane for 10 minutes The solutions were filtered and the solvent removed in vacou. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron) (Basic method) yielded product (2'S,7R)-2-(2,2-difluoroethyl)-1'-ethyl-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine] 1H NMR (300 MHz, Chloroform-d) δ 7.46 (s, 1H), 7.37 (s, 1H), 6.61 (s, 1H), 5.92 (tt, J = 56.4, 4.5 Hz, 1H), 4.26 (s, 2H), 4.00 - 3.74 (m, 3H), 3.74 - 3.06 (m, 9H), 2.86 - 2.41 (m, 5H), 2.16 - 1.64 (m, 5H), 1.21 (d, J = 6.2 Hz, 3H), 0.84 (s, 3H). ESI-MS m / z 470.24. Compounds 562-593

[0267] Compounds 562-593 were prepared from the reductive amination steps and in some cases deprotection steps using procedures as described for compounds 559-561 from intermediate S44 and the relevant aldehydes or ketones. Aldehydes or ketones were obtained from commercial sources or synthesized as described above. Any modifications to methods are noted in Table 25 and accompanying footnotes.Table 25. Preparation method, structure and physicochemical data for compounds 562-593.Footnotes: 1. DCM was used in place of THF as the solvent and the reaction was run at room temperature for 2 hours. 2. DCM was used in place of THF as the solvent and Et3N (1 equiv.) was used in addition to the standard reagents. The reaction was stirred at 50C for 30 min. prior to the addition of the sodium triacetoxytborhydride which was added to the reaction after cooling to room temperature and stirred overnight before the reaction was quenched. Additionally, the compound was purified via silica gel (Redi-Sep cartridge, 4 g), eluting with 0-10% DCM in MeOH (with 7N NH3) to afford product.3. DCM was used in place of THF as the solvent and DIPEA (1 equiv.) was used in addition to the standard reagents. The reaction was stirred at reflux for 30 min. prior to the addition of the sodium triacetoxytborhydride which was added to the reaction after cooling to room temperature and stirred overnight before the reaction was quenched. Additionally, the compound was purified via silica gel (Redi-Sep cartridge, 4 g), eluting with 0-10% DCM in MeOH (with 7N NH3) to afford product. 4. TBS deprotection with HCl was not used. Compound 594 2-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine]-1'-yl]-1-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)

[0268] 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 salt) (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. Reaction was run in the microwave for 15 minutes at 100 ºC. Solvent was evaporated. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.2 % formic acid afforded 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 (6.5 mg, 55%) LCMS m / z 408.16 [M+1]+. Compounds 595-609

[0269] Compounds 595-609 and intermediates S48 and S49 were prepared from an epoxide opening step as described for compound 594 from intermediate S44 and the relevant epoxides. Epoxides were obtained from commercial sources. Any modifications to methods are noted in Table 26 and accompanying footnotes.Table 26. Method of preparation, structure and physicochemical data for compounds 595- 609 and intermediates S48 and S49Footnotes: 1. IPA (1 mL) was used as the solvent, 2. Additional 3 eq. epoxide was added after heating at 150ºC for two hours. 3. Reaction was heated for 150ºC for eight hours in the microwave 4. Product was repurified by silica gel chromatography (Gradient: 0-20% MeOH in DCM) 5. Product was submitted as a formic acid salt 6. Two diastereomers were separated during purification 7. Reaction was heated for 90ºC for 1.5 hours in the microwave 8. After reaction had gone to completion solvent was removed in vacuo, rinsed with MeOH and DCM and the crude reaction was telescoped to the next reaction.Compound 610 (2R)-3-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-Preparation of (2R)-3-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]-2-hydroxy-propanamide (610)

[0270] Methyl (2R)-3-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3- c]pyran-7,4'-piperidine]-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. Solvent was removed in vacuo. Purification by Silica Gel Chromotagrphy (Gradient: 0-10% MeOH in DCM) provided the desired product 610..1H NMR (300 MHz, Chloroform-d) δ 6.94 (d, J = 4.2 Hz, 1H), 6.58 (s, 1H), 6.13 - 5.61 (m, 2H), 3.93 - 3.76 (m, 2H), 3.24 (td, J = 16.8, 4.4 Hz, 2H), 2.91 (dd, J = 12.9, 9.9 Hz, 1H), 2.80 (ddq, J = 11.5, 7.0, 2.5 Hz, 2H), 2.62 (tdd, J = 13.1, 10.3, 3.7 Hz, 4H), 1.99 - 1.86 (m, 2H), 1.86 - 1.69 (m, 1H), 1.56 (dd, J = 14.0, 11.4 Hz, 1H), 1.03 (d, J = 6.2 Hz, 3H). LCMS m / z 375.14 [M+1]+. Compound 611 (2S)-3-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine]-1'- yl]-2-hydroxy-propanamide (611)Preparation of (2S)-3-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]-2-hydroxy-propanamide (611)

[0271] (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 brought up in NH3(4 mL of 7 M, 28.00 mmol) inMeOH. DIPEA (980 µL, 5.626 mmol) was added and reaction stirred at 120°C for 6 hours. Solvent was removed in vacuo and product was rinsed with MeOH and DCM (2x). Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron) followed by Silica gel chromatography (Gradient: 0-20% MeOH in dichloromethane) yielded the product (2S)-3-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran- 7,4'-piperidine]-1'-yl]-2-hydroxy-propanamide 611 (17.8 mg, 12%).1H NMR (300 MHz, 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 = 5.9 Hz, 2H), 3.61 (s, 1H), 3.26 (td, J = 16.7, 4.4 Hz, 4H), 3.11 (s, 1H), 2.77 (dd, J = 13.5, 8.2 Hz, 1H), 2.63 (q, J = 5.2 Hz, 2H), 1.29 (d, J = 6.4 Hz, 3H). LCMS m / z 375.14 [M+1]+. Compound 612 (2S)-3-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine]-1'-Preparation of (2S)-3-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]-2-hydroxy-N-methyl-propanamide (612)

[0272] 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 brought up in dioxane (1.9 mL) and added to a microwave flask. Methyl amine (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. Solvent was removed in vacuo. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid yielded (2S)-3-[(2'S,7R)-2-(2,2-difluoroethyl)-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]-2-hydroxy-N-methyl-propanamide (Trifluoroacetic Acid (2)) 612 (60.1 mg, 39%).1H NMR (300 MHz, Chloroform-d) δ 7.41 (d, J = 5.8 Hz, 1H), 6.64 (d, J = 4.2 Hz, 1H), 5.91 (tt, J = 56.3, 4.4 Hz, 1H), 4.81 - 4.46 (m, 1H), 4.02 (s, 0H), 3.89 (dp, J = 10.6, 5.9 Hz, 2H), 3.68 (d, J = 12.1 Hz, 1H), 3.53 (s, 1H), 3.27 (td, J = 16.7, 4.4 Hz, 3H), 3.13 - 2.92 (m, 1H), 2.86 (d, J = 4.9 Hz, 2H), 2.71 - 2.60 (m, 2H), 2.46 - 2.26 (m, 1H), 2.26 - 2.07 (m, 2H), 1.48 (d, J = 6.4 Hz, 2H). LCMS m / z 389.28 [M+1]+.Compound 613 1-((2S,4R)-2'-(2,2-difluoroethyl)-2-methyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3- c]pyran]-1-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)

[0273] 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 salt) (27 mg, 0.07921 mmol) in DMF (2 mL) was added K2CO3(32.84 mg, 0.2376 mmol). The reaction was stirred at 110 °C for 72 hours, then cooled to room temperature and filtered. The crude reaction mixture was purified by reverse phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid) to afford 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]+. Compounds 614-624

[0274] 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 methods are noted in Table 27 and accompanying footnotes.Table 27. Structure and physicochemical data for compounds 614-624Footnotes: 1Reaction was stirred at 90 °C for 18 hours. Compound 625 (2'S,7R)-2-chloro-2'-methyl-1'-prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine]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)

[0275] A mixture of (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine] (Trifluoroacetate salt) S50 (500 mg, 1.345 mmol) and propargyl bromide (267 mg, 1.796 mmol), and potassium carbonate (250 mg, 1.809 mmol) in acetonitrile (10 mL) was heated to 70 °C for 2 minutes. The mixture was cooled to room temperature, filtered, and concentrated. The crude material was diluted in dichloromethane (10 mL) and 2 M NaOH. The layers were mixed, passed over a phase separator, and concentrated. Purification by silica gel chromatography (1-10% MeOH in dichloromethane) afforded (2'S,7R)-2-chloro-2'-methyl-1'- prop-2-ynyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] 625 (228 mg, 57%).1H NMR (400 MHz, Chloroform-d) δ 6.54 (s, 1H), 3.96 - 3.82 (m, 2H), 3.61 (dd, J= 17.4, 2.4 Hz, 1H), 3.38 (dd, J= 17.4, 2.4 Hz, 1H), 2.87 (ddd, J= 12.8, 11.5, 2.7 Hz, 1H), 2.78 (dqd, J= 12.5, 6.3, 2.6 Hz, 1H), 2.63 (ddd, J= 11.4, 4.7, 2.4 Hz, 1H), 2.60 - 2.49 (m, 2H), 2.22 (t, J= 2.4 Hz, 1H), 2.10 - 2.01 (m, 1H), 1.98 (dt, J= 13.8, 2.8 Hz, 1H), 1.84 (ddd, J= 13.9, 12.8, 4.6 Hz, 1H), 1.55 (dd, J= 13.8, 11.5 Hz, 1H), 1.05 (d, J= 6.3 Hz, 3H). LCMS m / z 296.36 [M+H]+.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-diolPreparation 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-triazol-1-yl)-3-methylbutane-2,3-diol (626)

[0276] To a mixture of 1-amino-3-methyl-butane-2,3-diol (40 mg, 0.3357 mmol) in MeOH (3 mL) was added CuSO4(0.25 mg, 0.001566 mmol) in water (0.125 mL) followed by sodium bicarbonate (45 mg) in water (0.375 mL) and a solution of triflic azide (1.25 mL of 0.452 M, 0.5650 mmol) in dichloromethane and the solution was stirred for 1 hour. 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 hours. The reactions were concentrated and purification by reverse phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1% trifluoroacetic acid) to afford 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 (626) (51 mg, 69%).1H NMR (400 MHz, 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, 9.4 Hz, 1H), 3.95 - 3.78 (m, 4H), 2.75 (d, J = 78.1 Hz, 4H), 2.65 - 2.54 (m, 2H), 2.22 (d, J = 10.7 Hz, 1H), 2.04 (d, J = 7.0 Hz, 3H), 1.79 (s, 2H), 1.47 - 1.27 (m, 9H). LCMS m / z 441.11 [M+H]+. Compounds 627-629

[0277] Compounds 627-629 (Table 28) were prepared from intermediate S50 and the appropriate amine reagent using the method for compound 626. Amines were obtained from commercial sources. Any modifications to methods are noted in Table 28 and accompanying footnotes.Table 28. Structure and physicochemical data for compounds 627-629Compound 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]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)

[0278] 1-methylpyrazole-4-carbaldehyde (12 mg, 0.109 mmol) and acetic acid (15 L, 0.266 mmol) were added to a solution of (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3- c]pyran-7,4'-piperidine] S50 (14 mg, 0.0290 mmol) in DMF (2 mL). NaBH3CN (81 mg, 0.162 mmol) was added and the reaction mixture was stirred at 110oC for 30 min. Purification by Prep- HPLC (Mobile phase A: - 0.1% TFA (aq), Mobile phase B: - Acetonitrile) gave (2R,4S)-2'- chloro-2-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-4',5'-dihydrospiro[piperidine-4,7'- thieno[2,3-c]pyran] 630 (13 mg, 67%).1H NMR (300 MHz, Chloroform-d) δ 11.80 (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 6.58 (s, 1H), 4.51 (d, J = 14.2 Hz, 1H), 3.95 (s, 4H), 3.89 - 3.75 (m, 2H), 3.31 (d, J = 13.0 Hz, 2H), 3.02 (d, J = 9.6 Hz, 1H), 2.63 - 2.48 (m, 2H), 2.39 - 2.23 (m, 2H), 2.23 - 2.06 (m, 2H), 1.56 (d, J = 6.5 Hz, 3H). LCMS m / z 352.12 [M+H]+. Compounds 631-693

[0279] Compounds 631-693 (Table 29) were prepared from intermediate S50 and the appropriate aldehyde reagent using the method for compound 630. Aldehydes were prepared by methods described above or obtained from commercial sources. Any modifications to methods are noted in Table 29 and accompanying footnotes.Table 29. Structure and physicochemical data for compounds 631-693Footnotes 1. Second Step: Deprotection of TBS group using HCl in methanol 2. Second step: SnAr using cyclopropanamine(2.5 eq), potassium carbonate (4eq) in DMF (0.5mL) at 90oC overnight. Reaction was diluted in DCM and water and aqueous layer was collected through a phase separator. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 5mM HCl followed by Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 10 mM Ammonium Hydroxide yielded the product. Preparation of S50 (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (S50)Step1(i): Synthesis of tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate

[0280] 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 min. The mixture was vacuum-nitrogen purged five times to remove dissolved isobutylene. Step 1(ii): Synthesis of (2'S,7R)-2'-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine]

[0281] To the mixture was then added 2-(3-thienyl)ethanol (16.5 g, 128.7 mmol) and the reaction stirred overnight. The mixture was concentrated to about 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 x 200 mL), pH 14 brine (200 mL), dried with MgSO4, filtered, and concentrated to yield (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]+. Step1(iii): Synthesis of tert-butyl (2'S,7R)-2'-methylspiro[4,5-dihydrothieno[2,3-c]pyran- 7,4'-piperidine]-1'-carboxylate (C26)

[0282] To a mixture of the product from the first two steps in DCM (500 mL) was added DIPEA (20 mL, 114.8 mmol) followed by Boc2O (27 mL, 117.5 mmol). The reaction stirred for 45 min. Imidazole (1 g, 14.69 mmol) was added to quench excess Boc2O. Then 2 N HCl (100 mL) was added and the mixture was stirred for 20 min. The layers were separated, and the organic layer was washed with 1 N HCl (100 mL). The organic layer was passed over a phase separator and concentrated to yield 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]+. 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)

[0283] 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 as heated at 65 °C and stirred overnight. The reaction was diluted with 1N NaOH / EtOAc washed with sodium thiosulfate solution, brine and dried over Na2SO4and concentrated to an oil. Purification by silica gel chromatography (Gradient: 0-30 % EtOAc in heptane) yielded the product. tert-butyl (2'S,7R)-2-chloro-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate (15.4 g, 83%). LCMS m / z 358.14 [M+H]+.Step 3: Synthesis of (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine] (Hydrochloride salt) (C28)

[0284] 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 a solution of HCl (25 mL of 4 M, 100.0 mmol) in dioxane was stirred at room temperature overnight. After stirring overnight, the mixture had congealed into a solid mass. To the mixture was added diethyl ether (200 mL total), the mixture was filtered and rinsed with additional ether and dried to yield (2'S,7R)-2- chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (Hydrochloride salt) (C28) (7.4757 g, 94%).1H NMR (400 MHz, 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 = 12.2 Hz, 1H), 2.58 (t, J = 5.5 Hz, 2H), 2.13 (t, J = 15.0 Hz, 2H), 2.01 (td, J = 14.1, 13.7, 4.6 Hz, 1H), 1.84 (dd, J = 14.3, 12.1 Hz, 1H), 1.25 (d, J = 6.5 Hz, 3H). LCMS m / z 258.09 [M+H]+. Step 4:Synthesis of (2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine] (S50)

[0285] (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 to the mixture was added sat. sodium bicarbonate, followed by NaOH to adjust to pH >10. At this time, the product had oiled out 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 yield (2'S,7R)-2-chloro-2'- methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] S50 (2280 mg, 93%).1H NMR (400 MHz, Chloroform-d) δ 6.57 (s, 1H), 3.98 - 3.81 (m, 2H), 3.18 - 3.00 (m, 2H), 2.94 (ddd, J = 12.2, 4.8, 2.1 Hz, 1H), 2.67 - 2.51 (m, 2H), 2.07 - 1.94 (m, 2H), 1.66 (d, J = 4.8 Hz, 1H), 1.38 (dd, J = 13.7, 11.4 Hz, 1H), 1.09 (d, J = 6.4 Hz, 3H). LCMS m / z 258.09 [M+H]+. Preparation of S51 Preparation of (2'S,7S)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (S51)Step 1(i): Synthesis of (2'S)-2'-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]

[0286] 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 trifluoromethanesulfonic acid (1.5 mL, 16.95 mmol) was added and the reaction was stirred at -78°C for 1.5 hours. The reaction was quenched into a biphasic mixture of sat. NaHCO3 (75 mL) and DCM (50 mL) and the aqueous layer pH was adjusted to >10 with 2N NaOH. The aqueous layer was then extracted with DCM (3 x 75mL) and filtered through an SPE cartridge and concentrated to give crude(2'S)-2'-methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine]. 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)

[0287] Dissolved the crude from previous step in DCM (20 mL) and added triethylamine (3.1 mL, 22.24 mmol) followed by tert-butoxycarbonyl tert-butyl carbonate (3.1 mL, 13.49 mmol). The reaction was stirred at room temperature for 18 hours. The solution was diluted with DCM and washed with water (50 mL). The aqueous layer was extracted with DCM (2 x 50 mL), dried over Na2SO4, filtered through an SPE filter, and concentrated under vacuum. Purification by silica gel chromatography (0 to 30 % EtOAc in heptane) yielded tert-butyl (2'S,7S)-2'- methylspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate C29 (2.95 g, 92%).1H NMR (300 MHz, Methanol-d4) δ 7.21 (d, J = 5.1 Hz, 1H), 6.77 (d, J = 5.1 Hz, 1H), 4.37 (p, J = 7.0 Hz, 1H), 4.03 - 3.84 (m, 3H), 3.39 - 3.21 (m, 1H), 2.68 (td, J = 5.5, 2.6 Hz, 2H), 2.16 - 1.65 (m, 4H), 1.48 (s, 9H), 1.34 (d, J = 7.2 Hz, 3H). 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)

[0288] 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) at room temperature was added NCS (138 mg, 1.033 mmol) followed by DMAP (5 mg, 0.04093 mmol). The reaction was heated to 55 °C for 24 hours. The reaction was cooled to rt and stirred overnight, then reaction was quenched with 15% aq sodium bisulfite (10 mL). Stirred for 15 min, then partitioned between brine (20 mL) and DCM (20 mL). Aqueous layer was separated and extracted with DCM (2x20 mL), the pooled organic layers were dried over Na2SO4, filtered through a phase separator, and concentrated. Purification by silica gel chromatography (0 to 30% EtOAc in heptane) afforded a crude mixture with some starting material remaining.

[0289] The crude material was resubjected 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 hours, then cooled to room temperature and quenched with 15% aq sodium bisulfite (10 mL). Stirred for 15 min, then partitioned betweenbrine and DCM (20 mL each). Aqueous layer was separated and extracted with DCM (2x20 mL), the pooled organic layers were dried over Na2SO4, filtered through a phase separator, and concentrated. Purification by silica gel chromatography (0 to 30 % EtOAc in heptane) to afford 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 (300 MHz, Methanol-d4) δ 6.66 (s, 1H), 4.35 (q, J = 6.9 Hz, 1H), 4.03 - 3.85 (m, 3H), 3.27 (s, 1H), 2.69 - 2.50 (m, 2H), 2.14 - 1.94 (m, 2H), 1.80 (dd, J = 14.5, 6.6 Hz, 1H), 1.68 (ddd, J = 13.7, 12.9, 4.7 Hz, 1H), 1.47 (s, 9H), 1.32 (d, J = 7.1 Hz, 3H). Step 3: Synthesis of of (2'S,7S)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran- 7,4'-piperidine] (S51)

[0290] 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) was added HCl (600 µL of 4 M, 2.400 mmol) in dioxane and the reaction was stirred for 20 hours at room temperature. The reaction was concentrated. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 5 mM HCl and lyopholization afforded the product (2'S,7S)-2-chloro-2'- methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] S51 (Hydrochloride salt) (108.2 mg, 75%).1H NMR (300 MHz, Methanol-d4) δ 6.77 (s, 1H), 3.98 (t, J = 5.8 Hz, 2H), 3.72 (h, J = 6.3 Hz, 1H), 3.53 (ddd, J = 13.8, 9.7, 4.0 Hz, 1H), 3.29 - 3.16 (m, 1H), 2.70 - 2.60 (m, 2H), 2.25 - 2.05 (m, 4H), 1.52 (d, J = 7.0 Hz, 3H). LCMS m / z 258.0 [M+H]+. Preparation of C31Synthesis of 1-methylprop-2-ynyl 4-methylbenzenesulfonate (C31)

[0291] 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 for 30 min at 0 °C and 1 hour at room temperature. Then the reaction mixture was filtered. The filtrate was washed with saturated CuSO4solution (200 mL), saturated NaHCO3solution (200 mL) and brine (200 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. Purification by silica gel chromatography (gradient: 10-30 % EtOAc in petether) afforded 1-methylprop-2-ynyl 4-methylbenzenesulfonate C31 (1.2 g, 25%).1H 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). 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)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)

[0292] 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), K2CO3(415 mg, 0.0030 mol) and 1-methylprop-2-ynyl 4-methylbenzenesulfonate (C31) (403 mg, 0.0018 mol) were added at room temperature. The reaction mixture was stirred for 16 h at 80 °C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The reaction mixture was cooled to room temperature and 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 purification by reversed-phase chromatography (Column: - xselectPhenyl hexyle (250*19)mm,5u,. Gradient: 0-20 % MeCN in water with 0.1 % formic acid) afforded (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%).1H NMR (400 MHz, 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 =6.8 Hz, 3H), 0.98 (d, J =6.4Hz, 3H). LCMS m / z 310.0 [M+H]+.Compound 695 (2'S,7S)-2-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[4,5-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)

[0293] (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 overnight at 60 °C. The reaction mixture was concentrated. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid afford (2'S,7S)-2-chloro-2'-methyl-1'-[[1-(2- methylsulfonylethyl)triazol-4-yl]methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] (695). (Trifluoroacetate salt) (32 mg, 41%).1H NMR (300 MHz, Chloroform-d) δ 8.26 (s, 1H), 6.60 (s, 1H), 4.94 (t, J = 6.8 Hz, 2H), 4.41 (d, J = 19.1 Hz, 2H), 3.93 (t, J = 5.1 Hz, 2H), 3.81 - 3.65 (m, 3H), 3.56 - 3.37 (m, 2H), 2.95 (s, 3H), 2.69 - 2.58 (m, 2H), 2.38 - 2.09 (m, 4H), 1.70 (d, J = 7.1 Hz, 3H). LCMS m / z 445.31 [M+H]+. Compound 696Synthesis 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)

[0294] (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 overnight in a sealed tube. Additional 4- (chloromethyl)-1-(2-methylsulfonylethyl)triazole (15 mg, 0.06706 mmol) added and heating continued for 24 hrs. The reaction mixture was concentrated. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid afforded (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 salt) (696) (46 mg, 43%).1H NMR (300 MHz, Chloroform-d) δ 8.28 (s, 1H), 6.61 (s, 1H), 4.97 (td, J = 6.6, 4.0 Hz, 2H), 4.78 (d, J = 14.0 Hz, 1H), 4.26 (d, J = 14.0 Hz, 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 = 6.5 Hz, 3H). LCMS m / z 445.21 [M+H]+. 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)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)

[0295] 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 minutes. At this time, UPLC indicated complete conversion and the mixture was concentrated to dryness, diluted in 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 salt) (90 mg, 0.3473 mmol). The mixture was stirred at 70 °C. The mixture was stirred overnight. The mixture was cooled to room temperature and diluted with water (10 mL)and EtOAc (15 mL). The phases were separated, and the organic layer was washed with water (2 x 10 mL) and brine (10 mL), and the organic layer was dried with MgSO4, filtered, and concentrated. Purification by silica gel chromatography (0-20% MeOH in DCM). afforded (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 mg, 51%).1H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 0.7 Hz, 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, 2.9 Hz, 2H), 1.82 (td, J = 13.3, 4.6 Hz, 1H), 1.62 (dd, J = 13.8, 11.4 Hz, 1H), 1.20 (d, J = 6.2 Hz, 3H). LCMS m / z 444.04 [M+H]+. 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)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)

[0297] 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), cyanoboranuide (Sodium salt) (1000 mg of 2 mmol / g, 2.000 mmol), in DCM (10 mL) was stirred at 110 °C. The mixture was cooled to room temperature, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-20% MeOH in DCM) to afford 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%).1H NMR (400 MHz, Chloroform-d) δ 7.56 (s, 2H), 6.50 (s, 1H), 4.05 (s, 1H), 3.88 - 3.71 (m, 3H), 3.70 - 3.57 (m, 1H), 2.82 (s, 2H), 2.66 - 2.47 (m, 4H), 2.01 - 1.91 (m, 3H), 1.28 (d, J = 6.3 Hz, 3H). LCMS m / z 337.88 [M+H]+.Compound 699 (2S,7R)-2'-chloro-1-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)methyl)-2-methyl-4',5'-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)

[0298] To a mixture of (2'S,7R)-2-chloro-2'-methyl-1'-(1H-pyrazol-4-ylmethyl)spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine] 698 (20 mg) in DMF (1 mL) was added NaH (3 mg, 60 %w / w) followed by 1-bromo-2-methoxy-ethane (16 mL). The reaction stirred at room temperature for 80 min and was then heated to 60 °C and stirred for 5 hours. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 5 mM HCl afforded the product (HCl salt) EA#6 (18.8 mg, 73.3 %).1H 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 = 14.3 Hz, 1H), 4.28 (t, J = 5.3 Hz, 2H), 4.18 (dd, J = 14.0, 5.3 Hz, 1H), 3.82 (hept, J = 6.0 Hz, 2H), 3.68 (t, J = 5.2 Hz, 2H), 3.21 (s, 5H), 3.16 (d, J = 14.3 Hz, 1H), 2.98 (d, J = 15.3 Hz, 1H), 2.56 (s, 1H), 2.18 (q, J = 14.1, 13.1 Hz, 4H), 1.45 (d, J = 6.3 Hz, 3H). LCMS m / z 396.14 [M+H]+. Compounds 700-707

[0299] Compounds 700-707 (see Table 30) were prepared in a single step from an alkylation of 698 and the relevant alkyl halide as described for compound 699. Alkyl halides were obtained from commercial sources. Any modifications to methods are noted in Table 30 and accompanying footnotes.Table 30: Preparation method, structure and physiochemical data for compounds 700-707Footnotes: 1. The reaction stirred at room temperature for 10 min. 2. Purified with formic acid modifier. Isolated the product as formic acid salt Compound 708 (2S)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]- 2-hydroxy-propanamidePreparation 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-propanamide(708)

[0300] (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 brought 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 reaction stirred at 120°C for 4 h. An additional 70μL oxirane and 800μL NH3 / MeOH were added and the reaction was heated for 2 h at 120°C. An additional 50μL oxirane and 500μL NH3 / MeOH were added and the reaction was heated for an additional 2 h at 120°C. Reaction mixture was concentrated down via rotovap, then diluted in water / DCM and the organics were extracted (3x DCM, 3x EtOAc) and concentrated down via rotovap. Material was purified via normal phase chromatography (12g HP silica gel, 0- 100% 90:10 MeOH / DCM in DCM) to afford desired product 708 (2S)-3-[(2'S,7R)-2-chloro-2'- methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-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= 2.3 Hz, 1H), 1.97 (q, J= 2.8 Hz, 1H), 1.77 (ddd, J= 13.8, 10.5, 6.7 Hz, 1H), 1.52 (dd, J= 14.0, 11.4 Hz, 1H), 1.10 (d, J= 6.3 Hz, 3H). LCMS m / z 345.08 [M+1]+. Compound 709 (2R)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]- 2-hydroxy-propanamidePreparation of (2R)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran- 7,4'-piperidine]-1'-yl]-2-hydroxy-propanamide(709)

[0301] (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 brought 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 reaction stirred at 120°C for 5 h. An additional 200 μL oxirane and 500 μL NH3 were added and the reaction was stirred an additional 4 h at 120 °C. Material was concentrated down via rotovap and rinsed with MeOH / DCM (2x). Remaining solid was insoluble in DCM to load onto column, so citric acid was added to acidify and the organics were extracted with EtOAc (3x). Organic layer was dried down via rotovap and material was purified via normal phase chromatography (40 g silica gel 0-20% MeOH / DCM) afforded product (2R)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]-2-hydroxy-propanamide (36.9 mg, 22%).1H NMR (300 MHz, Chloroform-d) δ 6.93 (d, J= 4.4 Hz, 1H), 6.56 (s, 1H), 5.88 (s, 1H), 4.07 (d, J= 7.1 Hz, 3H), 3.95 - 3.77 (m, 2H), 2.92 (dd, J= 12.9, 9.9 Hz, 1H), 2.85 - 2.75 (m, 2H), 2.70 - 2.42 (m, 4H), 1.98 (p, J= 2.7 Hz, 1H), 1.73 (td, J= 13.4, 4.6 Hz, 1H), 1.51 (dd, J= 14.0, 11.3 Hz, 1H), 1.04 (d, J= 6.2 Hz, 3H). LCMS m / z 345.03 [M+1]+. Compound 710 (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-propanamideStep 1: Synthesis of methyl (2S)-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)

[0302] (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 brought 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. Reaction mixture was concentrated via rotovap, and purified via normal phase chromatography (24g silica gel 0-80% EtOAC / Heptanes) to afford methyl (2S)-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 (147.5 mg, 57%). LCMS m / z 360.02 [M+1]+. 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-propanamidemethyl (710)

[0303] (2S)-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 (35.7 mg, 0.09920 mmol) was brought up in dioxane (700 µL) in a microwave flask. Methyl amine (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 reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). afforded 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, 3.1 Hz, 1H), 4.04 (d, J= 13.7 Hz, 1H), 3.89 (p, J= 5.8 Hz, 3H), 3.66 (d, J= 12.0 Hz, 1H), 3.53 (s, 1H), 3.32 (q, J= 11.6, 10.9 Hz, 1H), 2.87 (d, J= 4.9 Hz, 3H), 2.63 (q, J= 5.2 Hz, 3H), 2.32 (q, J= 13.7, 12.7 Hz, 1H), 2.17 (d, J= 15.6 Hz, 2H), 1.49 (dd, J= 6.5, 2.2 Hz, 4H). LCMS m / z 359.42 [M+1]+. Compound 711 (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,N-dimethyl-propanamideStep 1: 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-propanoic acid (C33)

[0304] A solution of methyl (2S)-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 (107 mg, 0.2973 mmol) and LiOH (31.6 mg, 1.320 mmol) in MeOH (1.1 mL) and THF (1 mL), and stirred at rt for 2 h. Reaction mixture was concentrated down via rotovap and 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'-piperidine]-1'-yl]-2-hydroxy-propanoic acid (Lithium salt) C33 (147 mg, 98%) LCMS m / z 344 [M+1]+. 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,N-dimethyl-propanamide(711)

[0305] (2S)-3-[(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine]-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 brought up in DMF (2 mL). DIPEA (200 µL, 1.148 mmol) was added and the reaction was allowed to stir 2 h. An additional 500μL DMF was added to rinse down sides of flask. An additional 332mg HATU in 500μL DMF and 300μL dimethylamine were added and reaction was stirred overnight. Reaction mixture was concentrated via rotovap. An excess of water was added,and 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) afforded (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,N-dimethyl-propanamide 711 (7.6 mg, 6%).1H NMR (300 MHz, Chloroform-d) δ 6.60 (s, 1H), 4.69 (dd, J = 7.4, 4.0 Hz, 1H), 4.14 (q, J = 7.1 Hz, 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, 11.6 Hz, 1H), 1.33 – 1.07 (m, 4H). LCMS m / z 373.12 [M+1]+. Preparation S53 [(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-3-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:

[0306] A solution of diisopropylamine (3 mL, 21.41 mmol) in Et2O (3 mL) in an oven dried flask was purged with nitrogen and cooled to -20 °C. At this time, 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 time, the mixture of LDA from the previous step was transferred over the course of 2 min. The mixture was stirred at this temperature for 5 min. At this time, DMF (5 mL, 64.57 mmol) was added. After 5 min, to this mixture was added sat. aqueous ammonium chloride (25 mL), and the mixture was warmed to room temperature. The mixture was then diluted with Et2O (200 mL), followed by water (200mL). The organic layer was washed with additional water (2 x 200 mL) and brine (200 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The mixture was purified by silica gel chromatography (Gradient: 0-25 % EtOAc in heptane) to yield 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, 6.5 Hz, 1H), 3.95 - 3.80 (m, 2H), 3.74 (dt, J = 14.0, 5.5 Hz, 1H), 3.36 (ddd, J = 13.9, 8.6, 5.3 Hz, 1H), 2.99 - 2.84 (m, 2H), 2.21 (dddd, J = 14.6, 8.3, 5.9, 1.9 Hz, 1H), 2.12 (ddd, J = 14.1, 5.1, 2.0 Hz, 1H), 1.76 (dt, J = 14.5, 5.2 Hz, 1H), 1.67 (dd, J = 14.2, 10.9 Hz, 1H), 1.50 (s, 9H), 1.29 (d, J = 6.5 Hz, 3H). LCMS m / z 385.96 [M+H]+. 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)

[0308] 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 g, 7.649 mmol) in a dioxane solution of HCl (7.5 mL of 4 M, 30.00 mmol) was stirred at room temperature. After 5 min, Et2O (15 mL) was added and the suspension was stirred at room temperature. After 30 min, the mixture was filtered, rinsed with Et2O and concentrated to yield (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]+. Step 3. Synthesis of [(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'- piperidine]-3-yl]methanol (S53)

[0309] 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). Aqueous HCl (7.5 mL of 1 M, 7.500 mmol) was then added till pH = 1. After stirring for 5 min, the mixture pH was then adjusted with NaOH (2.5 mL of 6 M, 15.00 mmol) to about pH=12. The mixture was extracted with DCM (2 x 25 mL), dried with sodium sulfate, filtered and concentrated to provide [(2'S,7R)-2-chloro-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine]-3-yl]methanol (1.88 g, 82 %) as a white amorphous solid.1H NMR (400 MHz, DMSO-d6) δ 5.03 (t, J = 5.4 Hz, 1H), 4.31 (d, J = 5.2 Hz, 2H), 3.86 (td, J = 5.7, 3.0 Hz, 2H), 2.95 - 2.78 (m, 2H), 2.78 - 2.68 (m, 1H), 2.59 (t, J = 5.5 Hz, 2H), 1.93 - 1.80 (m, 2H), 1.49 (td, J = 13.0, 4.8 Hz, 1H), 1.18 (dd, J = 13.4, 11.2 Hz, 1H), 0.94 (d, J = 6.4 Hz, 3H). LCMS m / z 288.08 [M+H]+.Compound 712 2-chloro-6-[[(2'S,7R)-2-chloro-3-(hydroxymethyl)-2'-methyl-spiro[4,5-dihydrothieno[2,3- c]pyran- 7,4'-piperidine]-1'-yl]methyl]phenol (712)Standard Method #A: Reductive Amination with Polymer Supported Cyanoborohydride

[0310] To a 1-dram vial was added cyanoborohydride, polymer supported (75 mg of 2 mmol / g, 0.15 mmol), followed by a solution 3-chloro-2-hydroxy-benzaldehyde (15.7 mg, 0.1 mmol) in DMF (400 uL) and a solution of [(2'S,7R)-2-chloro-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine]-3-yl]methanol S53 (16 mg, 0.056 mmol) in DMF (400 uL). The vial was sealed and heated at 85 °C overnight. Then the vial was cooled to room temperature. The resulting suspension was filtered through a polypropylene filter plate.0.1 wt % TFA (400 uL) in water was added to the reaction vial, which was stirred for several min to rinse the beads. DMSO (200 uL) was added to the resulting filtrate. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid.2-chloro-6-[[(2'S,7R)-2-chloro-3-(hydroxymethyl)-2'-methyl- spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl]methyl]phenol (trifluoroacetic acid salt) (2.8 mg, 9.2 %). LCMS m / z 428.29 [M+H]+.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)Standard Method #B: Reductive Amination with Polymer Supported Cyanoborohydride and Acetic Acid

[0311] A stock solution of [(2'S,7R)-2-chloro-2'-methyl-spiro[4,5-dihydrothieno[2,3-c]pyran- 7,4'-piperidine]-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 cyanoborohydride, polymer supported (75 mg of 2 mmol / g, 0.15 mmol), and the mixture was heated to 85 °C. After stirring overnight, the mixtures were cooled to room temperature, filtered and the polymer was rinsed with additional DMF. Purification by reversed- phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 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] (trifluoroacetic acid salt) (19.3 mg, 56 %).1H NMR (400 MHz, Chloroform-d) δ 7.74 - 7.65 (m, 1H), 7.48 (q, J = 6.3 Hz, 1H), 7.31 (s, 1H), 7.21 - 7.14 (m, 1H), 4.63 (d, J = 13.4 Hz, 1H), 4.57 (s, 2H), 4.13 (d, J = 13.2 Hz, 1H), 3.91 (dq, J = 21.8, 5.9 Hz, 2H), 3.52 (s, 1H), 3.22 (d, J = 12.1 Hz, 1H), 3.05 (t, J = 12.6 Hz, 1H), 2.71 (q, J = 5.5, 5.1 Hz, 2H), 2.53 - 2.37 (m, 2H), 2.22 - 2.03 (m, 2H), 1.68 (d, J = 6.5 Hz, 3H). LCMS m / z 396.32 [M+H]+. Compounds 714-758

[0312] Compounds 714-758 (see Table 31) were prepared in a single step from intermediate S53 using method as for preparation of 712 or preparation of 713. Aldehydes were commercially available or described previously. Any modifications to methods are noted in Table 31 and accompanying footnotes.Table 31. Structure and physicochemical data for compounds 714-758Footnotes: 1) NaBH3CN was used instead of polymer supported cyanoborohydride. The reaction was heated at 95 °C in DCM. Purification was completed using silica gel chromatography (Gradient: 0 to 20 % MeOH in DCM). Compounds 759 [(2'S,7R)-2-chloro-1'-[(1-isobutylpyrazol-4-yl)methyl]-2'-methyl-spiro[4,5-dihydrothieno[2,3-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'-piperidine]-3-yl]methanol (S54)

[0313] [(2'S,7R)-2-chloro-2'-methyl-1'-(1H-pyrazol-4-ylmethyl)spiro[4,5-dihydrothieno[2,3- c]pyran-7,4'-piperidine]-3-yl]methanol S54 was prepared according to standard method A, with the modifications as following: cyanoborohydride, polymer supported (2.0 eq) was used and DCM was used as the solvent. Purification was performed by silica gel chromatography (Gradient: 0 -20 % MeOH in DCM) to yield the title compound.1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 7.49 (d, J = 73.3 Hz, 2H), 5.02 (t, J = 5.4 Hz, 1H), 4.31 (t, J = 5.7 Hz, 2H), 3.81 (q, J = 5.6 Hz, 2H), 3.72 (s, 1H), 3.50 (s, 1H), 3.17 (d, J = 5.2 Hz, 1H), 2.56 (t, J = 5.5 Hz, 3H), 2.38 (s, 1H), 1.92 (d, J = 6.4 Hz, 2H), 1.63 (s, 1H), 1.42 (s, 1H), 1.12 (s, 3H). LCMS m / z 368.05 [M+H]+.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'-piperidine]-3-yl]methanol (759) - Standard Method #C: Pyrazole N-Alkylation

[0314] 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]-3-yl]methanol S54 (20 mg, 0.05320 mmol) in DMF (1000 µL) was added NaH (3.5 mg of 60 % dispersion in mineral oil, 0.08751 mmol), followed by 1-bromo-2-methyl-propane (20 µL, 0.1839 mmol). After stirring overnight, the mixture was purified with a C18 column (Gradient: 10-100 % MeCN in water, 0.1 % TFA modifier). The product-containing fractions were pooled and concentrated, rediluted in sat. aq. sodium bicarbonate / DCM to remove TFA. The organic layer was passed over a phase separator and concentrated to yield [(2'S,7R)-2-chloro-1'-[(1-isobutylpyrazol-4-yl)methyl]-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine]-3-yl]methanol (11 mg, 48 %).1H NMR (400 MHz, Chloroform-d) δ 7.39 (d, J = 0.8 Hz, 1H), 7.31 - 7.26 (m, 1H), 4.52 (s, 2H), 3.86 (d, J = 7.3 Hz, 5H), 3.53 (d, J = 14.2 Hz, 1H), 2.66 (dtd, J = 10.4, 5.3, 3.3 Hz, 3H), 2.54 (ddt, J = 11.2, 6.1, 2.9 Hz, 1H), 2.47 (td, J = 12.0, 11.5, 2.5 Hz, 1H), 2.18 (hept, J = 6.8 Hz, 1H), 1.95 (d, J = 13.7 Hz, 3H), 1.78 (td, J = 13.4, 4.4 Hz, 1H), 1.60 (dd, J = 13.8, 11.4 Hz, 1H), 1.18 (d, J = 6.2 Hz, 3H), 0.89 (dd, J = 6.7, 0.9 Hz, 6H). LCMS m / z 424.23 [M+H]+. Compounds 760-761

[0315] Compounds 760-761 (see Table 32) were prepared in a single step from intermediate S54 using method as in the preparation of compound 759. Alkyl halides were obtained from commercial sources. Any modifications to methods are noted in Table 32 and accompanying footnotes. Table 32. Structure and physicochemical data for compounds 760-761Compound 762 (2'S,7R)-2-chloro-3-(methoxymethyl)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-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)

[0316] 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) was added NaBH4(13 µL, 0.3247 mmol) followed by MeOH (160 µL) and the reaction was heated to 50 °C. After 10 min, the mixture was quenched with sat. aq.sodium bicarbonate and EtOAc. The organic layer was separated, rinsed with water and brine. The organic layer was dried with sodium sulfate, filtered and concentrated to provide 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]+. The material was used in the next step without further purification. 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)

[0317] 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. Then saturated NH4Cl aqueous solution was added to quench the reaction and the solution was extracted with DCM, dried with sodium sulfate and filtered to give crude product. Purification by silica gel chromatography (Gradient: 0-20 % EtOAc in heptane) yielded 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]+. Step 3. Synthesis of (2'S,7R)-2-chloro-3-(methoxymethyl)-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine] (S55)

[0318] 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 provide (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]+. The material was used in the next step without further purification. 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)

[0319] (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 cyanoborohydride, polymer supported (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 off and the solvent was removed in vacuo. Purification by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acidafforded (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 salt) (38.2 mg, 37 %).1H NMR (300 MHz, 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 = 6.5 Hz, 3H). LCMS m / z 488.21 [M+H]+. Compound 763 (2'S,7R)-2-(difluoromethyl)-3-(methoxymethyl)-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol- 4-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)

[0320] 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 time, sec-butyllithium (570 µL of 1.25 M, 0.7125 mmol) in cyclohexane was added dropwise, and stirred at this temperature. After 20 min, 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 sat. aq. ammonium chloride (6 mL), and the mixture was warmed to room temperature. At this time, the mixture was diluted with Et2O, followed by water. The organic layer was washed with brine. The organic layer was dried with MgSO4, 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 (300 MHz, 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 = 5.6 Hz, 2H), 2.43 - 2.01 (m, 2H), 1.99 - 1.60 (m, 2H), 1.48 (s, 10H), 1.22 (d, J = 6.5 Hz, 3H). LCMS m / z 396.05 [M+H]+. 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)

[0321] 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 and washed with saturated NaHCO3solution, extracted with DCM (2x) and washed with brine. The solvent was removed to give the crude product. The crude material was redissolved in dioxane (2 mL) and HCl (1.3 mL of 4 M, 5.200 mmol) was added. After 30 min, the solvent was removed and purified by reversed-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.1 % trifluoroacetic acid. Product was isolated as (2'S,7R)-2-(difluoromethyl)-3-(methoxymethyl)-2'-methyl-spiro[4,5- dihydrothieno[2,3-c]pyran-7,4'-piperidine] (Trifluoroacetate salt) (43 mg, 55 %).1H NMR (300 MHz, Chloroform-d) δ 9.48 (s, 1H), 8.80 (s, 1H), 7.04 (t, J = 55.5 Hz, 1H), 4.43 (d, J = 1.3 Hz, 2...

Claims

CLAIMS:

1. A compound represented by the following structural formula: ^a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X1and X2are chosen from -S-, -S(=O)2-, -S(=O)-, and -CR2, wherein: one of X1and X2is chosen from -S-, -S(=O)2-, and -S(=O)-; when X1is -S-, -S(=O)2-, or -S(=O)-, then X2is -CR2; and when X2is -S-, -S(=O)2-, or -S(=O)-, then X1is -CR2; R1is chosen from cyano, halogen, C1-C4alkyl , C1-C4haloalkyl, and C3-C6cycloalkyl groups, wherein: the C1-C4alkyl of R1is optionally substituted with 1 to 3 groups independently chosen from -OH and C1-C4alkoxy groups; R2is chosen from hydrogen, C1-C6alkyl, -C(=O)O(C1-C4alkyl), -C(=O)NRnRo, and halogen groups, wherein: the C1-C6alkyl of R2is optionally substituted with 1 to 3 groups independently chosen from -OH, halogen, and C1-C4alkoxy groups; and Rnand Roare independently chosen from hydrogen, C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, and -(C1-C4alkylene)Rpgroups, wherein Rpis chosen from C3-C6cycloalkyl groups; or R1and R2, together with the carbon atoms to which they are attached, form a C6aryl group; k is chosen from 0, 1, and 2; m is chosen from 0, 1, and 2; each R3ais independently chosen from -OH, -CN, -NRa1Ra2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -OC(=O)(C1-C4alkyl), 6- to 8-membered aryl, 6- to 8-membered heteroaryl, and halogen groups, wherein: each Ra1and Ra2is independently chosen from hydrogen, C1-C4alkyl, and -C(=O)(C1-C4alkyl) groups; or two R3ataken together form an oxo group; ortwo R3a, together with the carbon atom to which they are attached, form a C3-C6cycloalkyl group; each R3bis independently chosen from C1-C4alkyl groups, wherein: the C1-C4alkyl of R3bis optionally substituted with 1 to 3 groups independently chosen from -OH, halogen, and C1-C4alkoxy groups; or one R3aand one R3b, together with the carbon atoms to which they are attached, form a C3- C6cycloalkyl group; R4a, R4b, R5a, and R5bare each independently chosen from hydrogen and C1-C4alkyl groups; R6is chosen from C1-C6alkyl, -C(=O)O(C1-C4alkyl)groups, wherein: the C1-C6alkyl of R6is optionally substituted with 1 to 5 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, - C(=O)NH2, -C(=O)(C1-C4alkyl), -C(=O)OH, -C(=O)O(C1-C4alkyl), -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, C1-C4alkoxy, C3-C6carbocyclyl, C6aryl, -O-(C6aryl), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein: the C6aryl and -O-(C6aryl) groups are each optionally substituted with 1 to 3 groups independently chosen from halogen and C1-C4haloalkyl groups; Ring B is chosen from C3-C12carbocyclyl, 3- to 12-membered heterocyclyl, C6and C10aryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with 1, 2, 3, 4, or 5 Ragroups; wherein: Ra, for each occurrence, is independently chosen from halogen, cyano, C1-C8alkyl, C1-C6haloalkyl, C2-C8alkenyl, C1-C6haloalkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C12carbocyclyl,C6and C10aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(=O)NRhRi, -C(=O)ORk, -C(=O)(C1-C4alkylene)ORk, -C(=O)Rk, -C(=O)(C1-C4alkylene)S(=O)pRk, -C(=O)(C1-C4alkylene)S(=O)pNRhRi, -C(=O)(C1-C4alkylene)NRiS(=O)pRk, -C(=O)(C1-C4alkylene)NRhC(=O)Rk,-NH(CH2)qCHRhRi, -NH(CH2)qNRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)(C1-C4alkylene)ORk, -NRhC(=O)O(C1-C4alkylene)Rk, -NRhC(=O)NRiRj, -NRhC(=O)(C1-C4alkylene)NRiS(=O)pRk, -NRhS(=O)pRk, -NRhC(=O)(C1-C4alkylene)S(=O)pRk, -NRhS(=O)p(C1-C4alkylene)C(=O)ORk,-NRhC(=O)[O(CH2)q]rOC(=O)NRhRi(CH2)q[O(CH2)q]r(C1-C6alkyl) (optionally substituted by 1 to 3 Rmgroups), -NRhC(=O)(C1-C6alkylene)[O(CH2)q]rOC(=O)NRhRi(CH2)q[O(CH2)q]r(C1-C6alkyl) (optionally substituted by 1 to 3 Rmgroups), -ORk, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -[O(CH2)q]rO(C1-C6alkyl), -S(=O)pRk, and -S(=O)pNRhRigroups, wherein:the C1-C4alkylene in each of -C(=O)(C1-C4alkylene)S(=O)pRk, -C(=O)(C1-C4alkylene)ORk, -C(=O)(C1-C4alkylene)S(=O)pNRhRi, -C(=O)(C1-C4alkylene)NRiS(=O)pRk, -C(=O)(C1-C4alkylene)NRhC(=O)Rk, -NRhC(=O)O(C1-C4alkylene)Rk, -NRhC(=O)(C1-C4alkylene)ORk, -NRhS(=O)p(C1-C4alkylene)C(=O)ORk, and -NRhC(=O)(C1-C4alkylene)NRiS(=O)pRkis optionally substituted with 1 to 3 groups independently chosen from - OH, the C1-C8alkyl, the C1-C6haloalkyl, the C1-C6alkoxy, and the C2-C8alkenyl of Raare each optionally substituted with 1 to 3 groups independently chosen from cyano, -C(=O)Rk, -C(=O)ORk, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk,-ORk, -[O(CH2)q]rOH, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -SRk, -S(=O)pRk, -S(=O)pNRhRi, -[O(CH2)q]rO(C1-C4alkyl), -O-(C6aryl or 5- to 8-membered heteroaryl) (optionally substituted with 1 to 3 Rmgroups), C3-C6carbocyclyl (optionally substituted with 1 to 3 Rmgroups), C6to C10aryl (optionally substituted with 1 to 3 Rmgroups), 4- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rmgroups), and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rmgroups) groups; the C3-C12carbocyclyl, the 3- to 12-membered heterocyclyl, the C6and C10aryl, and the 5- to 10-membered heteroaryl of Raare each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C6alkyl (optionally substituted with 1 to 3 Rmgroups), -C(=O)Rk, -C(=O)ORk, -NRhRi, -ORk, -S(=O)pRk, - S(=O)pNRhRi, and 5- to 10-membered heterocyclyl groups, wherein: Rh, Ri, and Rj, for each occurrence, are each independently chosen from hydrogen, C1-C6alkyl (optionally substituted with 1 to 4 Rmgroups), C6-C10aryl, C3-C8carbocyclyl (optionally substituted with 1 to 3 Rmgroups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rmgroups), and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rmgroups) groups, wherein: the C1-C6alkyl of any one of Rh, Ri, and Rjis optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, C1-C4alkoxy, -C(=O)NH(C1-C4alkyl), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rmgroups), and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rmgroups) groups; Rk, for each occurrence, is independently chosen from hydrogen, NH2, (optionally substituted with 1 or 2 groups chosen from C1-C3alkyl), C1-C6alkyl, benzyl, C6aryl, C3-C6carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein: the C1-C6alkyl of any one of Rkis optionally substituted with 1 to 5 groups independently chosen from halogen, cyano, -NH2, -OH, C1-C4alkoxy, C3- C6cycloalkyl (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 C1-C4alkyl and halogen), and 5- to -10-membered heteroaryl (optionally substituted with 1 to 3 -OH groups) groups; and the C3-C6carbocyclyl, benzyl, and C6aryl of any one of Rkare each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, oxo, -OH, -C(=O)NH2, -C(=O)N(CH3)2, C1-C6alkyl (optionally substituted by 1 to 3 -OH groups), C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl (optionally substituted with 1 to 3 halogen groups), C6aryl (optionally substituted with 1 to 3 halogen groups), and 5- to 10-membered heteroaryl groups (optionally substituted with 1 to 3 halogen groups); and the 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl of any one of Rkare each optionally substituted with 1 to 3 groups independently chosen from halogen, oxo, cyano, - C(=O)CH3, -NH2, -OH, C1-C4alkyl (optionallysubstituted by 1 to 3 -OH groups),, C1-C4haloalkyl, 5- to 10-membered heterocyclyl, and C1-C4alkoxy groups; Rm, for each occurrence, is independently chosen from halogen, cyano, oxo, -NH2, C1-C6alkyl, C1-C6alkoxy, - C(=O)Rk, -S(=O)pRk, -ORk, and 5- to 10-membered heterocyclyl groups, wherein: the C1-C6alkyl, the C1-C6alkoxy, and the 5- to 10-membered heterocyclyl of any one of Rmis optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C4alkoxy groups; p, for each occurrence, is an integer independently chosen from 1 and 2; and q and r, for each occurrence, is an integer independently chosen from 0, 1, 2, and 3.

2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein the compound is represented by one of the following structural formulae:a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6is as defined in claim 1.

3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein the compound is represented by one of the following structural formulae:a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6is as defined in claim 1.

4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein the compound is represented by one of the following structural formulae:a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6is as defined in claim 1.

5. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein the compound is represented by one of the following structural formulae: ^a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6is as defined in claim 1.

6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein the variable X1is chosen from S, S(=O), and S(=O)2and the variable X2is -CR2.

7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein the variable X2is chosen from S, S(=O), and S(=O)2and the variable X1is -CR2.

8. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6 and 7, wherein the variable R2is hydrogen.

9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein the variable X1is S, the variable X2is -CR2, and the variable R2is hydrogen.

9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein the variable X1is -CR2, the variable X2is S, and the variable R2is hydrogen.

10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7, wherein R2is chosen from hydrogen, halogen, -CH3, - CH2OH, -CH2(OH)CH3, and -C(=O)NRnRo, wherein Rnand Roare independently chosen from hydrogen, -C1-C4alkyl, -C1-C4haloalkyl, -C3- C6cycloalkyl, and -(C1-C4alkylene)Rpgroups, and wherein Rpis chosen from -C3-C6cycloalkyl groups.

11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 10, wherein R2is chosen from halogen.

12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 11, wherein R2is chosen from Br and Cl.

13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 10, wherein the variable R2is chosen from -CH3, -CH2OH, and CH(OH)CH3.

14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 10, wherein R2is -C(=O)NRnRo, and wherein Rnis hydrogen and Rois CH3.

15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 10, wherein R2is -C(=O)NRnRo, and wherein Rnis hydrogen and Rois CH3substituted with a cyclopropyl group.

16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 10, wherein R2is -C(=O)NRnRo, and wherein Rnis hydrogen and Rois - CH2CH2CH3.

17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 10, wherein R2is -C(=O)NRnRo, and wherein Rnis hydrogen and Rois - CH2CF2.

18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 and 6-17, wherein R1is chosen from cyano, halogen, C1-C4alkyl (optionally substituted with 1 to 3 groups independently chosen from -OH and C1-C4alkoxy groups), C1-C4haloalkyl, and C3-C6cycloalkyl groups.

19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 18, wherein the variable R1is chosen from -CN, -Br, -Cl, CH3, CH2OH, - CH2CH3, -CH2CH2CH3, tert-butyl, -CH2CF2, -CF2, -CF3, -CF2CF2, -CH2OCH3, -CH2OCH2CH3, cyclopropyl, and cyclobutyl.

20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 18, wherein the variable R1is CF3.

21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 18, wherein the variable R1is Cl.

22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 18, wherein the variable R1is -CH2OH.

23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 18, wherein the variable R1is -CH2CF3.

24. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 18, wherein the variable R1is -CF2CF3.

25. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 18, wherein the variable R1is -CH2(OH)CH3.

26. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 18, wherein the variable R1comprises deuterium.

27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 26, wherein the variable R1is CD-OCH2CH3.

28. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variables R1and R2, together with the carbon atoms to which they are attached, form a C6aryl group.

29. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variable R1is -Cl and the variable R2is - CH2OH.

30. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variable R1is Cl and the variable R2is - CH3.

31. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variable R1is Cl and the variable R2is hydrogen.

32. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variable R1is -Cl and the variable R2is - Cl.

33. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variable R1is -CF3and the variable R2is hydrogen.

34. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein 35. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein -CF2CF3and the variable R2is hydrogen.

36. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein -CH2CF3and the variable R2is hydrogen.

37. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variable R1is -CF2and the variable R2is - CH2OH.

38. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variable R1is -CF3and the variable R2is - CH2OH.

39. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variable R1is -CF3and the variable R2is - CH2(OH)CH3.

40. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variable R1is -CF3and the variable R2is - Cl.

41. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variable R1is CH3and the variable R2is hydrogen.

42. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variable R1is CH2CH3and the variable R2is hydrogen.

43. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 6, and 7 wherein the variable R1is CH2OH and the variable R2is hydrogen.

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

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

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

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

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

49. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, and 6-43, wherein the variable m is zero, the variable k is one or two, and each R3avariable is independently chosen from -OH, F, F2, CF2, -OCH3, -OCH2CH3,50. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, and 6-43, wherein the variable m is zero, the variable k is one, and the variable R3ais independently chosen from - OCH2(CH3)2, -OC(=O)CH3, NH2, NHC(=O)CH3, C50. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, and 6-43, wherein the variable m is zero, the variable k is one, and the variable R3ais -OH.

51. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, and 6-43, wherein the variable m is zero, the variable k is one, and the variable R3ais chosen from -OCH3and -OCH2CH3.

52. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, and 6-43, wherein the variable m is zero, the variable k is two, and two R3avariables taken together to form =O.

53. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein two R3avariables are present and are chosen from: -CF2and -OH; -CF2and -CH3; -OH and -CH3; and -OH and phenyl.

54. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 and 6 to 53, wherein three of variables R4a, R4b, R5a, and R5bare hydrogen and the remaining variable is chosen from C1-C4 alkyl groups.

55. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 and 6 to 53, wherein three of variables R4a, R4b, R5a, and R5bare hydrogen and the remaining variable is CH3.

56. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 6 to 55 wherein R6is chosen from C1-C6alkyl, -C(=O)O(C1-C4alkyl)groups, wherein: the C1-C6alkyl of R6is optionally substituted with 1 to 5 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(C1-C4alkyl), -N(C1-C4alkyl)2, -C(=O)NH2, -C(=O)(C1-C4alkyl), -C(=O)OH, -C(=O)O(C1-C4alkyl), -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, C1-C4alkoxy, C3-C6carbocyclyl, C6aryl, -O-(C6aryl), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein: the C6aryl and -O-(C6aryl) groups are each optionally substituted with 1 to 3 groups independently chosen from halogen and C1-C4haloalkyl groups; Ring B is chosen from C3-C12carbocyclyl, 3- to 12-membered heterocyclyl, C6and C10aryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with 1, 2, 3, 4, or 5 Ragroups; wherein: Ra, for each occurrence, is independently chosen from halogen, cyano, C1-C8alkyl, C1-C6haloalkyl, C2-C8alkenyl, C1-C6haloalkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C12carbocyclyl, C6and C10aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(=O)NRhRi, -C(=O)ORk, -C(=O)(C1-C4alkylene)ORk, -C(=O)Rk, -C(=O)(C1-C4alkylene)S(=O)pRk, -C(=O)(C1-C4alkylene)S(=O)pNRhRi, -C(=O)(C1-C4alkylene)NRiS(=O)pRk, -C(=O)(C1-C4alkylene)NRhC(=O)Rk,-NH(CH2)qCHRhRi, -NH(CH2)qNRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)(C1-C4alkylene)ORk, -NRhC(=O)O(C1-C4alkylene)Rk,-NRhC(=O)NRiRj, -NRhC(=O)(C1-C4alkylene)NRiS(=O)pRk, -NRhS(=O)pRk, -NRhC(=O)(C1-C4alkylene)S(=O)pRk, -NRhS(=O)p(C1-C4alkylene)C(=O)ORk,-NRhC(=O)[O(CH2)q]rOC(=O)NRhRi(CH2)q[O(CH2)q]r(C1-C6alkyl) (optionally substituted by 1 to 3 Rmgroups), -NRhC(=O)(C1-C6alkylene)[O(CH2)q]rOC(=O)NRhRi(CH2)q[O(CH2)q]r(C1-C6alkyl) (optionally substituted by 1 to 3 Rmgroups), -ORk, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -[O(CH2)q]rO(C1-C6alkyl), -S(=O)pRk, and -S(=O)pNRhRigroups, wherein: the C1-C4alkylene in each of -C(=O)(C1-C4alkylene)S(=O)pRk, -C(=O)(C1-C4alkylene)ORk, -C(=O)(C1-C4alkylene)S(=O)pNRhRi, -C(=O)(C1-C4alkylene)NRiS(=O)pRk, -C(=O)(C1-C4alkylene)NRhC(=O)Rk, -NRhC(=O)O(C1-C4alkylene)Rk, -NRhC(=O)(C1-C4alkylene)ORk, -NRhS(=O)p(C1-C4alkylene)C(=O)ORk, and -NRhC(=O)(C1-C4alkylene)NRiS(=O)pRkis optionally substituted with 1 to 3 groups independently chosen from -OH, the C1-C8alkyl, the C1-C6haloalkyl, the C1-C6alkoxy, and the C2-C8alkenyl of Raare each optionally substituted with 1 to 3 groups independently chosen from cyano, -C(=O)Rk, -C(=O)ORk, -C(=O)NRhRi, -NRhRi, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)pRk,-ORk, -[O(CH2)q]rOH, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -SRk, -S(=O)pRk, -S(=O)pNRhRi, -[O(CH2)q]rO(C1-C4alkyl), -O-(C6aryl or 5- to 8-membered heteroaryl) (optionally substituted with 1 to 3 Rmgroups), C3-C6carbocyclyl (optionally substituted with 1 to 3 Rmgroups), C6to C10aryl (optionally substituted with 1 to 3 Rmgroups), 4- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rmgroups), and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rmgroups) groups;the C3-C12carbocyclyl, the 3- to 12-membered heterocyclyl, the C6and C10aryl, and the 5- to 10-membered heteroaryl of Raare each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C6alkyl (optionally substituted with 1 to 3 Rmgroups), -C(=O)Rk, -C(=O)ORk, -NRhRi, -ORk, -S(=O)pRk, -S(=O)pNRhRi, and 5- to 10-membered heterocyclyl groups, wherein: Rh, Ri, and Rj, for each occurrence, are each independently chosen from hydrogen, C1-C6alkyl (optionally substituted with 1 to 4 Rmgroups), C6-C10aryl, C3-C8carbocyclyl (optionally substituted with 1 to 3 Rmgroups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rmgroups), and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rmgroups) groups, wherein: the C1-C6alkyl of any one of Rh, Ri, and Rjis optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, C1- C4alkoxy, -C(=O)NH(C1-C4alkyl), 5- to 10- membered heteroaryl (optionally substituted with 1 to 3 Rmgroups), and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 Rmgroups) groups; Rk, for each occurrence, is independently chosen from hydrogen, , NH2, (optionally substituted with 1 or 2 groups chosen from C1-C3alkyl), C1-C6alkyl, benzyl, C6aryl, C3-C6carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein: the C1-C6alkyl of any one of Rkis optionally substituted with 1 to 5 groups independently chosen from halogen, cyano, -NH2, -OH, C1-C4alkoxy, C3- C6cycloalkyl (optionally substituted with 1 to 3 halogen groups), 5- 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 C1-C4alkyl and halogen), and 5- to -10-membered heteroaryl (optionally substituted with 1 to 3 -OH groups) groups; andthe C3-C6carbocyclyl, benzyl, and C6aryl of any one of Rkare each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, oxo, -OH, -C(=O)NH2, -C(=O)N(CH3)2, C1-C4alkyl (optionally substituted by 1 to 3 -OH groups), C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl (optionally substituted with 1 to 3 halogen groups), C6aryl (optionally substituted with 1 to 3 halogen groups), and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 halogen groups) groups; and the 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl of any one of Rkare each optionally substituted with 1 to 3 groups independently chosen from halogen, oxo, cyano, - C(=O)CH3, -NH2, -OH, C1-C4alkyl (optionally substituted by 1 to 3 -OH groups),, C1-C4haloalkyl, 5- to 10-membered heterocyclyl, and C1-C4alkoxy groups; Rm, for each occurrence, is independently chosen from halogen, cyano, oxo, -NH2, C1-C6alkyl, C1-C6alkoxy, -C(=O)Rk, -S(=O)pRk, -ORk, and 5- to 10-membered heterocyclyl groups, wherein: the C1-C6alkyl, the C1-C6alkoxy, and the 5- to 10-membered heterocyclyl of any one of Rmis optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C4alkoxy groups; p, for each occurrence, is an integer independently chosen from 1 and 2; and q and r, for each occurrence, is an integer independently chosen from 0, 1, 2, and 3.

57. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 56 wherein R6is chosen from C1-C6alkyl optionally substituted with 1 to 5 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(C1- C4alkyl), -N(C1-C4alkyl)2, -C(=O)NH2, -C(=O)(C1-C4alkyl), -C(=O)OH, -C(=O)O(C1-C4alkyl), -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, C1-C4alkoxy, C3-C6carbocyclyl, C6aryl (which is optionally substituted with 1 to 3 groups independently chosen from halogen and C1-C4haloalkyl groups), -O-(C6aryl) (which is optionally substituted with 1 to 3 groups independently chosen from halogen and C1-C4haloalkyl groups), 5- to 10-membered heterocyclyl, and 5- to 10- membered heteroaryl groups.

58. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 57, wherein , R6is a substituted C1-C6alkyl chosen from ,, .

58. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 56, wherein R6is chosen from -C(=O)O(C1-C4alkyl).

59. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 56, wherein R6is chosen from R6is chosen fromdefined in claim 56.

60. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 59, wherein Ring B is chosen from C3-C12carbocyclyl optionally substituted with 1, 2, 3, 4, or 5 Ragroups as defined in claim 56.

61. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 59, wherein Ring B is chosen from 3- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 Ragroups as defined in claim 56.

62. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 59, wherein Ring B is chosen from C6and C10aryl optionally substituted with 1, 2, 3, 4, or 5 Ragroups as defined in claim 56.

63. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 59, wherein Ring B is chosen from 5- to 10-membered heteroaryl groups optionally substituted with 1, 2, 3, 4, or 5 Ragroups as defined in claim 56.

64. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 59, wherein Ring B is chosen from: , ,optionally substituted with 1, 2, 3, 4, or 5 Ragroups as defined in claim 56.

65. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 64, wherein Ring B is chosen from:groups optionally substituted with 1, 2, 3, 4, or 5 Ragroups as defined in claim 56.

66. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 56, wherein R6in the is chosen from:, wherein Ring B is a 5-membered heteroaryl, and Rais as defined for Formula I.

67. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 56, wherein R6is chosen from:, wherein Ring B is a 5-membered heteroaryl, and Rais is oxo or is chosen from C1-C8 alkyl, C3-C12carbocyclyl and C6and C10aryl, each of which may be optionally substituted with 1 to 3 groups chosen from halogen and C1-C8 alkyl (wherein the C1-C8 alkyl may be optionally substituted with 1 to 3 groups chosen from halogen, -OH, SO2CH3, and SO2NH2) .

68. The compound, tautomer, deuterated derivative, or pharmaceutically acceptablesalt according to claim 56, wherein R6is chosen from:

69. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 59, wherein Rais chosen from C1-C4alkyl, halogen, -OH, and C1- C4 alkoxy, wherein the C1-C4 alkyl of Rais optionally substituted with 1 to 3 polar groups, e.g. sulfones, sulfonamides, and alcohols.

70. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 59, wherein Rais C1-C6 alkyl, optionally substituted as defined for Formula I. In some embodiments, the C1-C6 alkyl of Rais optionally substituted with 1 to 3 groups selected from -OH, -SO2CH3, C1-C3alkoxy, C(=O)NHCH3, -SO2NHCH2CH2OH, -SCF3,-SCH2C(CH2)2OH, -SO2phenyl, 4-6 membered heterocycles (optionally substituted with 1 to 3 Rmgroups), 4-6 membered heteroaryls (optionally substituted with 1 to 3 Rmgroups), cyano, NHC(=O)-4-6 membered heteroaryl.

71. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 59, wherein Rais chosen from optionally substituted 4-6 membered carobcycles, 4-6 membered heterocycles and 4-6 membered heteroaryls.

72. A compound selected from Compounds 1 to 1183, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein the compound is not Compound 285, Compound 489, Compound 539, Compound 691, Compound 692, Compound 741, Compound 747, Compound 749, Compound 751, Compound 752, Compound 753, Compound 795, Compound 814, or Compound 868.

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

74. A method of treating a disease mediated by ApoL1, comprising administering a compound according to any one of claims 1 to 72 or a pharmaceutical composition according toclaim 73.

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

76. The method of treating non-diabetic kidney disease (NDKD), comprising administering a compound according to any one of claims 1 to 72 or a pharmaceutical composition according to claim 73.

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

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

79. The method of treating according to any one of claims 74 to 78, wherein the patient to be treated possesses an APOL1 genetic variants 80. The method of treating according to claim 79, wherein the genetic variant is chosen from G1: S342G:I384M and G2: N388del:Y389del.

81. A method of inhibiting APOL1 activity comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 72, or a pharmaceutical composition according to claim 73.

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

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

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

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

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

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

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

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

90. A compound according to any one of claims 1 to 72, or a pharmaceutical composition according to claim 73, for use in treating FSGS.

91. A compound according to any one of claims 1 to 72, or a pharmaceutical composition according to claim 73, for use in treating NDKD.

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

93. A compound according to any one of claims 1 to 72, or a pharmaceutical composition according to claim 73, for use in treating pancreatic cancer mediated by ApoL1.