SPIROPIPERIDINE DERIVATIVES AS INHIBITORS OF APOL1 AND METHODS OF USE THEREOF - Patent application

Abstract

The present disclosure provides at least one compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt selected from compounds of formula I, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharma- ceutically acceptable salts of any of the foregoing, compositions comprising them, and methods of using them, including use in the treatment of APOL1-mediated diseases, including pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and / or non-diabetic kidney disease (NDKD). JPEG2025505645000316.jpg5849

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 307,926, filed February 8, 2022, the entire disclosure of which is incorporated herein by reference.

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

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

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

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

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

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

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

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

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

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

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

[0013] One aspect of the present disclosure provides at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, tautomers of Formula I, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, which can be used to treat diseases mediated by APOL1, such as FSGS and NDKD. For example, in some embodiments, the at least one compound is a compound represented by Formula I: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from a 6-membered aryl group and a 6-membered heteroaryl group, and the 6-membered aryl group or the 6-membered heteroaryl group is selected from 1, 2, 3, or 4 R 1 optionally substituted by a group, X is -CR 1a R 1b -, -C(O)-, -S-, -S(O)2-, -NR 1c -, and -O-; Y is -CR 1a R 1b -, -C(O)-, -S(O)2-, -NR 1c -, and -O-; Z is a bond, -CR 1a R 1b -, -NR 1c -, -C(O)-, -S(O)2-, and -O-, wherein At least one of X and Y is -CR 1a R 1b - and -C(O)-; R1a , R 1b , and R 1c are hydrogen and R for each occurrence, respectively. 1 are independently selected from the group R 1 is, for each occurrence, halogen, —OH, cyano, phenyl, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, —C(═O)OR c , -C(=O)OR c , -C(=O)N(R c )2, and -OS(=O)2R c are independently selected from the group R c is, for each occurrence, independently selected from hydrogen, C-C alkyl, and C-C haloalkyl; R 1 The 4- to 6-membered heterocyclyl contains 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and is optionally substituted with a group selected from oxo and —OH; R 1 and C1-C6 alkyl and C1-C6 alkenyl are selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkoxy, 3- to 5-membered heterocyclyl (R c optionally substituted with 1 to 4 groups independently selected from aryl, aryl, aryl groups ... R 1 wherein the C1-C6 alkoxy is optionally substituted with 1 to 3 groups independently selected from -OH, cyano, and halogen groups; R 1 wherein the C3-C6 carbocyclyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), and -C(=O)N(C1-C4 alkyl)2 groups; R 1wherein the phenyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), C-C alkyl, C-C alkoxy, -C(=O)NH, -C(=O)NH(C-C alkyl), and -C(=O)N(C-C alkyl) groups; R 2 and R 3 are each independently selected from hydrogen and a C1-C4 alkyl group; R 4 is C1-C6 alkyl, -C(=O)O(C1-C4 alkyl), and [ka] is selected from the group R 4 wherein the C1-C6 alkyl is optionally substituted with 1 to 5 groups independently selected from halogen, cyano, —OH, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —C(═O)NH2, —C(═O)(C1-C4 alkyl), —C(═O)OH, —C(═O)O(C1-C4 alkyl), —C(═O)NH(C1-C4 alkyl), —C(═O)N(C1-C4 alkyl)2, C1-C4 alkoxy, C3-C6 carbocyclyl, C6 aryl, —O—(C6 aryl), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups; the C aryl and -O-(C aryl) groups are optionally substituted with 1 to 3 groups independently selected from halogen and C-C haloalkyl groups; Ring B is C3-C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C 10 aryl, and 5- to 10-membered heteroaryl groups, and ring B is selected from 1, 2, 3, 4, or 5 R a optionally substituted with a group, R ais, for each occurrence, selected from halogen, cyano, oxo, C1-C8 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C1-C6 haloalkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Carbocyclyl, C6 and C 10 Aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, -C(=O)NR h R i , -C(=O)OR k , -C(=O)(C1-C4 alkylene) OR k , -C(=O)R k , -C(=O)(C1-C4 alkylene)S(=O) p R k , -C(=O)(C1-C4 alkylene)S(=O) p NR h R i , -C(=O)(C1-C4 alkylene)NR i S(=O) p R k , -C(=O)(C1-C4 alkylene)NR h C(=O)R k , -C(=O)C(=O)R k , -NR h R i , -NH(CH2) q CHR h R i , -NH(CH2) q NR h R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h C(=O)(C1-C4 alkylene) OR k , -NR h C(=O)O(C1-C4 alkylene)R k , -NR h C(=O)NR i R j , -NR h C(=O)(C1-C4 alkylene)NR i S(=O) p R k , -NRh S(=O) p R k 、 -NR h C(=O)(C1-C4 alkylene)S(=O) p R k , -NR h S(=O) p (C1-C4 alkylene)C(=O)OR k 、 -NR h C(=O)[O(CH2) q ] r OC(=O)NR h R i (CH2) q [O(CH2) q ] r (C1-C6 alkyl) (1 to 3 R m optionally substituted with a -NR group, h C(=O)(C1-C6 alkylene)[O(CH2) q ] r OC(=O)NR h R i (CH2) q [O(CH2) q ] r (C1-C6 alkyl) (1 to 3 R m optionally substituted with -OR groups), k , -OC(=O)R k , -OC(=O)OR k , -OC(=O)NR h R i , -[O(CH2) q ] r O(C1-C6 alkyl), -S(=O) p R k , and -S(=O) p NR h R i is independently selected from the group R a -C(=O)(C1-C4 alkylene)S(=O) p R k , -C(=O)(C1-C4 alkylene) OR k , -C(=O)(C1-C4 alkylene)S(=O) p NR h Ri , -C(=O)(C1-C4 alkylene)NR i S(=O) p R k , -C(=O)(C1-C4 alkylene)NR h C(=O)R k , -NR h C(=O)O(C1-C4 alkylene)R k , -NR h C(=O)(C1-C4 alkylene) OR k , -NR h S(=O) p (C1-C4 alkylene)C(=O)OR k , and -NR h C(=O)(C1-C4 alkylene)NR i S(=O) p R k wherein the C1-C4 alkylene in each is optionally substituted with 1 to 3 -OH groups; R a C1-C8 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C2-C8 alkenyl are each cyano, —C(═O)R k , -C(=O)OR k , -C(=O)NR h R i , =NOR k , -NR h R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h C(=O)NR i R j , -NR h S(=O) p R k 、 -OR k , -[O(CH2) q ] r OH, -OC(=O)R k , -OC(=O)OR k , -OC(=O)NR h R i , -SR k, -S(=O) p R k , -S(=O) p NR h R i , -[O(CH2) q ] r O(C1-C4 alkyl), -O-(C6 aryl or 5-8 membered heteroaryl) (1-3 R m C-C carbocyclyl (optionally substituted with 1 to 3 R m optionally substituted with a group), C-C 10 Aryl (1 to 3 R m group), 4- to 10-membered heterocyclyl (1 to 3 R m aryl (optionally substituted with 1 to 3 R m optionally substituted with 1 to 3 groups independently selected from the group R a C3-C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl are each selected from halogen, oxo, cyano, C1-C6 alkyl (1 to 3 R m group), -C(=O)R k , -C(=O)OR k , -NR h R i , -OR k , -S(=O) p R k , -S(=O) p NR h R i and 5- to 10-membered heterocyclyl groups; R h , R i , and R j are, for each occurrence, hydrogen, C1-C6 alkyl, C6-C 10 Aryl, C3-C8 carbocyclyl (1-3 R m aryl (optionally substituted with 1 to 3 R mgroups), and 5- to 10-membered heterocyclyl (1-3 R m and R h , R i , and R j Any one of the C1-C6 alkyl groups is selected from halogen, cyano, -OH, C1-C4 alkoxy, -C(=O)NH(C1-C4 alkyl), C3-C6 carbocyclyl (1 to 3 R m aryl (optionally substituted with 1 to 3 R m groups), and 5- to 10-membered heterocyclyl (1-3 R m optionally substituted with 1 to 3 groups independently selected from the group R k is, for each occurrence, independently selected from hydrogen, C1-C6 alkyl, benzyl, C6 aryl, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups; R k wherein any one of the C1-C6 alkyl groups is optionally substituted with 1 to 5 groups independently selected from halogen, cyano, —NH2, —OH, C1-C4 alkoxy, C3-C6 cycloalkyl (optionally substituted with 1 to 3 halogen groups), 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 —OH groups), and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 —OH groups); R k wherein any one of the C3-C6 carbocyclyl, benzyl, and C6 aryl is each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, oxo, -OH, -C(=O)NH2, -C(=O)N(CH3)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl (optionally substituted with 1 to 3 halogen groups), C6 aryl (optionally substituted with 1 to 3 halogen groups), and 5-10 membered heteroaryl (optionally substituted with 1 to 3 halogen groups), C1-C4 alkyl optionally substituted with 1 to 3 -OH groups; R k wherein any one of the 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl is each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —C(═O)CH3, —NH2, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy groups; C1-C4 alkyl optionally substituted with 1 to 3 -OH groups; R m For each occurrence, halogen, cyano, oxo, -(CH2) n C(=O)NH2, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)R k , -S(=O) p R k , -OR k , C3-C6 cycloalkyl, and 5- to 10-membered heterocyclyl groups; R m wherein any one of C1-C6 alkyl, C1-C6 alkoxy, and 5-10 membered heterocyclyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C4 alkoxy groups; n, for each occurrence, is an integer selected from 0, 1, and 2; p, for each occurrence, is an integer independently selected from 1 and 2; q and r are each an integer independently selected from 0, 1, 2, and 3 for each occurrence. DETAILED DESCRIPTION OF THE INVENTION

[0014] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a compound represented by structural formulas IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, as follows: [ka] [ka] All variables are as defined in Formula I.

[0015] In one aspect of the disclosure, the compound of formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA is selected from compounds 1-299, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0016] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions may comprise at least one compound selected from Compounds 1-299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0017] Another aspect of the present disclosure provides methods for treating an APOL1-mediated disease, comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formulas I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0018] Another aspect of the present disclosure provides a method of treating an APOL1-mediated cancer (e.g., pancreatic cancer), comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formulas I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0019] Another aspect of the present disclosure provides a method of treating an APOL1-mediated kidney disease (e.g., ESKD, FSGS, and / or NDKD), comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formulas I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the methods include administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0020] In some embodiments, the method of treatment comprises administering at least one additional active agent to a subject in need thereof in the same pharmaceutical composition or in a separate composition as at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, together with the at least one additional active agent, either in the same pharmaceutical composition or in a separate composition.

[0021] Also provided is a method of inhibiting APOL1, comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method of inhibiting APOL1 comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. [Mode for Carrying Out the Invention]

[0022] definition The term "APOL1" as used herein means apolipoprotein L1 protein and the term "APOL1" means apolipoprotein L1 gene.

[0023] The term "APOL1-mediated disease" refers to a disease or condition associated with abnormal APOL1 (e.g., a particular APOL1 gene variant, elevated APOL1 levels). In some embodiments, the APOL1-mediated disease is an APOL1-mediated renal disease. In some embodiments, the APOL1-mediated disease is associated with patients with two APOL1 risk alleles, e.g., homozygous or compound heterozygous for the G1 allele or the G2 allele. In some embodiments, the APOL1-mediated disease is associated with patients with one APOL1 risk allele.

[0024] The term "APOL1-mediated renal disease" refers to a disease or condition that impairs kidney function and can be caused by APOL1. In some embodiments, the APOL1-mediated renal disease is associated with a patient who has two APOL1 risk alleles, for example, who is homozygous or compound heterozygous for the G1 allele or the G2 allele. In some embodiments, the APOL1-mediated renal disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arteriosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1-mediated renal disease is chronic kidney disease or proteinuria.

[0025] As used herein, the term "FSGS" means focal segmental glomerulosclerosis, a disease of podocytes (glomerular visceral epithelial cells) that causes proteinuria and progressive decline in kidney function and is associated with two common APOL1 gene variants (G1:S342G:I384M and G2:N388del:Y389del).

[0026] The term "NDKD" as used herein means non-diabetic kidney disease characterized by severe hypertension and progressive decline in kidney function and associated with two common APOL1 gene variants (G1:S342G:I384M and G2:N388del:Y389del).

[0027] The terms "ESKD" and "ESRD" are used interchangeably herein and refer to end-stage renal disease or end-stage renal disease. ESKD / ESRD refers to end-stage renal disease, i.e., kidney failure, in which the kidneys do not function sufficiently and the patient cannot survive without dialysis or a kidney transplant. In some embodiments, ESKD / ESRD is associated with two APOL1 risk alleles.

[0028] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having identical chemical structures, unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic variations may exist among the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom shown also includes lesser amounts of isotopic substitutions having hydrogen atoms at one or more of the designated deuterium positions in the structure. The relative amounts of such isotopic substitutions in the compounds of the present disclosure will depend on several factors, including the isotopic purity of the reagents used to make the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as noted above, the relative amount of such isotopic substitutions overall will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitution overall will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0029] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally," refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0030] The term "isotopically modified" refers to a species whose chemical structure differs from a reference compound only in its isotopic composition. Additionally, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of carbon by C, are within the scope of this disclosure.

[0031] Unless otherwise indicated, structures depicted herein are also intended to include all isomeric forms of the structure, e.g., geometric (or conformational) isomers, such as racemic mixtures, cis / trans isomers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the present compounds are within the scope of this disclosure. Unless otherwise specified, all tautomeric forms of the compounds of this disclosure are within the scope of this disclosure.

[0032] The term "tautomer" as used herein refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by migration of atoms, e.g., hydrogen atoms, or groups, within the molecule.

[0033] "Stereoisomers" as used herein refers to enantiomers and diastereomers.

[0034] As used herein, a "deuterated derivative" has the same chemical structure as a reference compound, but contains a deuterium atom ("D" or " 2"Deuterated derivatives" refers to compounds having one or more hydrogen atoms replaced by deuterium at a level well above its natural isotopic abundance (typically about 0.015%). It will be recognized that some variation in natural isotopic abundance will occur in synthesized compounds depending on the source of the chemicals used in their synthesis. The concentration of naturally occurring stable hydrogen isotopes, despite this variation, is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Thus, unless otherwise specified, when reference is made to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen is replaced with deuterium at a level well above its natural isotopic abundance, which is typically about 0.015%. In some embodiments, deuterated derivatives of the present disclosure have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).

[0035] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0036] As used herein, the term "alkyl" or "aliphatic" refers to a straight-chain (i.e., linear or unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated. Unless otherwise specified, an alkyl group contains 1-20 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-10 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1-8 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1-6 alkyl carbon atoms. In some embodiments, an alkyl group contains 1-4 alkyl carbon atoms, in other embodiments, an alkyl group contains 1-3 alkyl carbon atoms, and in still other embodiments, an alkyl group contains 1 or 2 alkyl carbon atoms. In some embodiments, an alkyl group is linear or straight-chain or unbranched. In some embodiments, an alkyl group is branched.

[0037] As used herein, the terms "cycloalkyl" and "cyclic alkyl" refer to a fully saturated monocyclic C 3-8 hydrocarbon, or spirocyclic, fused, or bridged bicyclic or tricyclic C 8-14 In some embodiments, cycloalkyl refers to a hydrocarbon, and any individual ring within the bicyclic ring system has 3 to 7 members. In some embodiments, cycloalkyl refers to a C3-C 12 In some embodiments, the cycloalkyl is a C-C cycloalkyl. In some embodiments, the cycloalkyl is a C-C cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0038] As used herein, the term "carbocyclyl" or "cycloaliphatic" encompasses the terms "cycloalkyl" or "cyclic alkyl" and refers to a monocyclic C alkyl group that is fully saturated or partially saturated so as to contain one or more saturated units, but is not aromatic. 3-8 hydrocarbon, or spirocyclic, fused, or bridged bicyclic or tricyclic C 8-14

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

[0039] As used herein, the term "heteroalkyl" or "heteroaliphatic" means an alkyl or aliphatic group, as defined above, in which one or two carbon atoms are independently replaced by one or more oxygen, sulfur, nitrogen, phosphorus, or silicon.

[0040] As used herein, the term "alkenyl" means a straight-chain (i.e., linear or unbranched) or branched hydrocarbon chain containing one or more double bonds. In some embodiments, an alkenyl group is straight-chain. In some embodiments, an alkenyl group is branched.

[0041] The terms "heterocycle," "heterocyclyl," and "heterocyclic" are used interchangeably herein and refer to non-aromatic (i.e., fully saturated or partially saturated because it contains one or more units of unsaturation, but not aromatic), monocyclic, or spirocyclic, fused, or bridged bicyclic or tricyclic ring systems in which one or more ring members are independently selected heteroatoms. Bicyclic heterocyclyls include the following combinations of monocyclic rings: monocyclic heteroaryl fused to a monocyclic heterocyclyl; monocyclic heterocyclyl fused to another monocyclic heterocyclyl; monocyclic heterocyclyl fused to a phenyl; monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl.

[0042] In some embodiments, the heterocycle includes ring atoms substituted with one or more oxo groups (eg, C=O, S=O, or SO2 groups).

[0043] In some embodiments, a "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" group has 3 to 14 ring members, with one or more ring members being heteroatoms independently selected from oxygen, sulfur, nitrogen, silicon, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, a heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, a heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, a heterocycle is one heteroatom independently selected from oxygen, sulfur, nitrogen, silicon, and phosphorus, a quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (in the case of N-substituted pyrrolidinyl). In some embodiments, the heterocycle has one heteroatom that is a nitrogen atom. In some embodiments, the heterocycle has one heteroatom that is an oxygen atom. In some embodiments, the heterocycle has two heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle has three heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl, tetrahydrothiophenyl 1,1-dioxide, and the like.

[0044] The term "unsaturated," as used herein, means that a moiety has one or more units or degrees of unsaturation. Unsaturation is a situation in which not all of the available valence bonds in a compound are satisfied by substituents, thus causing the compound to contain double or triple bonds.

[0045] The term "alkoxy" or "thioalkyl" as used herein refers to an alkyl group, as previously defined, in which one carbon of the alkyl group is replaced by an oxygen ("alkoxy") or sulfur ("thioalkyl") atom, respectively, provided that the oxygen and sulfur atoms are connected between two carbon atoms. "Cyclic alkoxy" refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group but is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl.

[0046] As used herein, the terms "haloalkyl," "haloalkenyl," and "haloalkoxy" mean straight-chain or branched alkyl, alkenyl, or alkoxy, respectively, substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF, -CHF, -CF, -CF-, and perhaloalkyl, such as -CFCF. Non-limiting examples of haloalkoxy groups include -OCHF, -OCHF, -OCF, and -OCF.

[0047] The term "halogen" includes F, Cl, Br, and I, ie, fluoro, chloro, bromo, and iodo, respectively.

[0048] The term "aminoalkyl" refers to an alkyl group that is substituted with or contains an amino group.

[0049] As used herein, "amino" refers to a group that is a primary, secondary, or tertiary amine.

[0050] As used herein, a "carbonyl" group refers to C=O.

[0051] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0052] As used herein, a "hydroxy" group refers to an --OH group.

[0053] As used herein, a "thiol" group refers to -SH.

[0054] As used herein, "tert" and "t-" each refer to tertiary.

[0055] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system having delocalized pi orbitals consisting of [4n+2]p electrons, where n is an integer ranging from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0056] The term "aryl," used alone or as part of a larger moiety, as in "arylalkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic, or spirocyclic, fused, or bridged bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, in which all rings in the system are aromatic rings containing only carbon atoms, and in which each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C6) and naphthyl (C 10 ) rings.

[0057] The term "heteroaryl," used alone or as part of a larger moiety, such as "heteroarylalkyl" or "heteroarylalkoxy," refers to a monocyclic, spirocyclic, fused, or bridged bicyclic, or tricyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and at least one ring in the system contains one or more heteroatoms, and each ring in the bicyclic and tricyclic ring systems contains 3 to 7 ring members. Bicyclic heteroaryls include the following combinations of monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl. In some embodiments, a heteroaryl group has one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group has one heteroatom. In some embodiments, a heteroaryl group has two heteroatoms. In some embodiments, a heteroaryl group is a monocyclic ring system having five ring members. In some embodiments, a heteroaryl group is a monocyclic ring system having six ring members. In some embodiments, heteroaryl is a 3- to 12-membered heteroaryl. In some embodiments, heteroaryl is a 3- to 10-membered heteroaryl. In some embodiments, heteroaryl is a 3- to 8-membered heteroaryl. In some embodiments, heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, heteroaryl is a 5- to 8-membered heteroaryl. In some embodiments, heteroaryl is a 5- or 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls include pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, and the like.

[0058] Non-limiting examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethylcarbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods for adding (a process commonly referred to as "protecting") and removing (a process commonly referred to as "deprotecting") such amine protecting groups are well known in the art, and are described, for example, in P.J. Kocienski, Protecting Groups, Thieme, 1994, and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999), which are incorporated herein by reference in their entireties. th Edition (John Wiley & Sons, New Jersey, 2014).

[0059] Non-limiting examples of suitable solvents that may be used in the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0060] Non-limiting examples of suitable bases that can be used in the present disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (KCO), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropyl-ethylamine (i-PrEtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH).

[0061] The present disclosure includes pharmaceutically acceptable salts of the disclosed compounds, which are formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0062] As used herein, the term "pharmaceutically acceptable" refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0063] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, and the like. benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0064] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4(Alkyl) 4 salts are also included. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable, non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0065] The terms "patient" and "subject" are used interchangeably herein and refer to animals, including humans.

[0066] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of the compound for which it is administered that produces the desired effect (e.g., amelioration of symptoms of FSGS and / or NDKD, reduction in the severity of FSGS and / or NDKD, or alleviation of symptoms of FSGS and / or NDKD, and / or reduction in the progression of FSGS and / or NDKD, or reduction in the progression of symptoms of FSGS and / or NDKD). The exact amount of the effective dose will depend on the purpose of treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0067] As used herein, the term "treatment" and its cognate terms refer to the slowing or stopping of disease progression.As used herein, "treatment" and its cognate terms include, but are not limited to, complete or partial remission, lower risk of renal failure (e.g., ESRD), and disease-related complications (e.g., edema, susceptibility to infection, or thromboembolic events).The improvement or reduction in severity of any of these symptoms can be easily assessed according to methods and techniques known in the art or subsequently developed.

[0068] The terms "about" and "approximately," when used in reference to a dose, amount, or weight percent of a component of a composition or dosage form, include a particular dose, amount, or weight percent value, or a range of doses, amounts, or weight percent, that would be recognized by one of skill in the art as providing an equivalent pharmacological effect to that obtained from the particular dose, amount, or weight percent.

[0069] At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formulas I and II, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be administered once daily, twice daily, or three times daily, for example, for the treatment of AMKD, including FSGS and / or NDKD. In some embodiments, at least one compound selected from Compounds 1-299, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be administered once daily, twice daily, or three times daily, for example, for the treatment of AMKD, including FSGS and / or NDKD. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered once daily. In some embodiments, at least one compound selected from Compounds 1-299, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered once daily. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily. In some embodiments, at least one compound selected from Compounds 1-299, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily.In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered three times daily. In some embodiments, at least one compound selected from Compounds 1-299, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered three times daily.

[0070] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound selected from Formulas I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once, twice, or three times a day. In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound selected from Compounds 1-299, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once, twice, or three times a day.

[0071] Those skilled in the art will recognize that when the amount of a compound is disclosed, the relative amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. The amounts of compounds, pharmaceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based on the free base form of the reference compound. For example, "1000 mg of at least one compound or pharmaceutically acceptable salt selected from the compound of Formula I and its pharmaceutically acceptable salts" includes 1000 mg of the compound of Formula I and a pharmaceutically acceptable salt of the compound of Formula I at a concentration equivalent to 1000 mg of the compound of Formula I.

[0072] As used herein, the term "ambient conditions" means room temperature, outside air conditions, and uncontrolled humidity conditions.

[0073] Compounds and Compositions In some embodiments, at least one compound selected from I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be used to treat AMKD, including FSGS and NDKD. In some embodiments, the compound I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA can be selected from Compounds 1-299, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound selected from I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be used to treat AMKD, including FSGS and NDKD. In some embodiments, the pharmaceutical composition comprises at least one compound selected from Compounds 1-299, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0074] In some embodiments of Formula I, [ka] Ring A is an unsubstituted phenyl group. In some embodiments, Ring A is a phenyl group having one or two R 1 groups, and each R 1are independently selected from halogen, cyano, -CH, -CHCH, -CHCF, -CFCF, -CF, -CF, -OCH, -OCF, and -OCF. In some embodiments, ring A is selected from one or two R 1 groups, and each R 1 is independently selected from F and Cl.

[0075] In some embodiments of Formula I, X is -C(O)-, -O-, -S-, -CR 1a R 1b -, and -NR 1c In some embodiments of Formula I, X is selected from -CH- and -NH- (i.e., R 1a , R 1b , and R 1c In some embodiments of Formula I, X is -CR 1a R 1b -, wherein R 1a is hydrogen and R 1b is R 1 In some embodiments of Formula I, X is selected from the group -CHOH- (i.e., R 1a is hydrogen and R 1b is R 1 and R 1 is -OH). In some embodiments of Formula I, X is -O-. In some embodiments of Formula I, X is -C(O)-.

[0076] In some embodiments of Formula I, Y is -CR 1a R 1b -, and -NR 1c In some embodiments of Formula I, Y is selected from -CR 1a R 1b where R 1a and R 1b is hydrogen. In some embodiments of Formula I, Y is -CR 1a R 1b where R 1a and R 1b are R 1and R 1 In some embodiments of Formula I, Y is -CR 1a R 1b where R 1a is hydrogen and R 1b is R 1 In some embodiments of Formula I, Y is selected from the group -CR 1a R 1b where R 1a is hydrogen and R 1b is R 1 and R 1 is selected from -OH, -CH, -C(O)NH, C(O)NHCH. In some embodiments of Formula I, Y is -CR 1a R 1b where R 1a and R 1b is R 1 and R 1 is selected from —OH and —CH 3 .

[0077] In some embodiments of Formula I, X is -C(O)- and -CR 1a R 1b -, and Y is selected from -NR 1c - and R 1c is hydrogen. In some embodiments of Formula I, X is selected from the group consisting of -C(O)- and -CR 1a R 1b -, and Y is selected from -NR 1c - and R 1c is R 1 In some embodiments of Formula I, X is selected from the group -C(O)- and -CR 1a R 1b -, and Y is selected from -NR 1c -, wherein R 1c is R 1 and R 1 is selected from C1-C6 alkyl and C1-C6 alkoxy optionally substituted with 1 to 3 halogen groups. In some embodiments of Formula I, X is selected from -C(O)- and -CR 1a R 1b -, and Y is selected from -NR 1c-, wherein R 1c is R 1 and R 1 is selected from -CH3, -CH2CH3, -CH2CH2OH, -CH2CF2, -CH2CF3, and -CH2CH2OCH3. In some embodiments of Formula I, Y is -NR 1c -, wherein R 1c is R 1 and R 1 In some embodiments of Formula I, Y is selected from -NR 1c -, wherein R 1c is R 1 and R 1 teeth, [ka] is.

[0078] In some embodiments of Formula I, Y is -CH(C(O)NH2)-; in some embodiments of Formula I, Y is -CH(C(O)NHCH3)-. In some embodiments of Formula I, Y is -CH(CH3)2-. In some embodiments of Formula I, Y is -CH2-. In some embodiments of Formula I, Y is -CH(OH)-. In some embodiments of Formula I, Y is -NH-. In some embodiments of Formula I, Y is -N(CH3)-. In some embodiments of Formula I, Y is -N(C(O)CH3)-.

[0079] In some embodiments of Formula I, Z is a bond (i.e., Y is directly attached to ring A). In some embodiments of Formula I, Z is -CR 1a R 1b In some embodiments of Formula I, Z is selected from -CR 1a R 1b where R 1a and R 1b is hydrogen. In some embodiments of Formula I, Z is -CR 1a R 1b where R 1a and R 1bis fluorine. In some embodiments of Formula I, Z is -CR 1a R 1b where R 1a is hydrogen and R 1b is -OH.

[0080] In some embodiments of Formula I, R 2 and R 3 is independently selected from hydrogen and CH. In some embodiments of Formula I, R 2 and R 3 are both hydrogen. In some embodiments of Formula I, R 2 and R 3 One of them is hydrogen and the other is CH3.

[0081] In some embodiments of Formula I, including embodiments of each of Formulas IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, R 4 is halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C1-C4 alkoxy, C3-C6 carbocyclyl, C6 aryl (halogen and and C1-C4 haloalkyl), -O-(C6 aryl) (optionally substituted with 1-3 groups independently selected from halogen and C1-C4 haloalkyl), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl. In some embodiments of Formula I, including embodiments of each of Formulas IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, R 4is selected from C1-C6 alkyl substituted with 1-2 groups independently selected from -OH, phenyl, and phenyl further substituted with halogen. In some embodiments of Formula I, R 4 is selected from —OH and C-C alkyl substituted with phenyl. In some embodiments of Formula I, including embodiments of each of Formulas IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, R 4 is selected from C1-C6 alkyl substituted with -OH and phenyl substituted with Cl. In some embodiments of Formula I, R 4 is selected from C1-C6 alkyl substituted with -OH, and phenyl substituted with 2F. In some embodiments of Formula I, R 4 is selected from -C(=O)O(C1-C4 alkyl).

[0082] In some embodiments of Formula I, including embodiments of each of Formulas IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, R 4 teeth, [ka] In some embodiments of Formula I, including embodiments of each of Formulas IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, R 4 teeth, [ka] In some embodiments, ring B is selected from: [ka] is selected from. In some embodiments of Formula I, including embodiments of each of Formulas IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, ring B is unsubstituted. In some embodiments, ring B contains one R a In some embodiments, ring B is substituted with two R a In some embodiments, ring B is substituted with three R a In some embodiments, ring B is substituted with four R a is substituted with a group.

[0083] In some embodiments of Formula I, including embodiments of each of Formulas IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, each R a is halogen, cyano, oxo, C1-C8 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Carbocyclyl, C6 and C 10 Aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, -C(=O)NR h R i , -C(=O)OR k , -NR h R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h S(=O) p R k 、 --S(=O) p R k , and -S(=O) p NR h R i are independently selected from the group R aC1-C8 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C2-C8 alkenyl are each —C(═O)NR h R i , =NOR k , -NR h R i , -NR h C(=O)NR i R j , -NR h S(=O) p R k 、 -OR k , -S(=O) p R k , -S(=O) p NR h R i , C3-C6 carbocyclyl (1 to 3 R m group), 4- to 10-membered heterocyclyl (1 to 3 R m aryl (optionally substituted with 1 to 3 R m optionally substituted with 1 to 3 groups independently selected from the group R a C3-C 12 Carbocyclyl, 3- to 12-membered heterocyclyl, C6 and C 10 Aryl and 5- to 10-membered heteroaryl are each selected from oxo, halogen, cyano, C1-C6 alkyl (1 to 3 R m optionally substituted with -OR groups), k , -S(=O) p R k , -S(=O) p NR h R i and 5- to 10-membered heterocyclyl groups; R h , R i , and R j each occurrence is hydrogen, C1-C6 alkyl, 5-10 membered heteroaryl (1-3 R m groups), and 5- to 10-membered heterocyclyl (1-3 R mand R h , R i , and R j Any one of C1-C6 alkyl is halogen, cyano, -OH, C3-C6 carbocyclyl (1 to 3 R m optionally substituted with 1 to 3 groups independently selected from R k is, for each occurrence, independently selected from hydrogen, C1-C6 alkyl, C3-C6 carbocyclyl, and a 5- to 10-membered heteroaryl group; R k wherein any one of the C1-C6 alkyl groups is optionally substituted with 1 to 5 groups independently selected from halogen, cyano, —NH2, and —OH; R k wherein any one of the 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl is each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, C1-C4 alkyl (optionally substituted with 1 to 3 —OH groups), C1-C4 haloalkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy groups; R m is, for each occurrence, halogen, cyano, oxo, -C(=O)NH2, -NH2, -C1-C6 alkyl, C1-C6 alkoxy, -OR k and C-C cycloalkyl; R m wherein any one of C1-C6 alkyl, C1-C6 alkoxy, and 5-10 membered heterocyclyl is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C1-C4 alkoxy groups; p is an integer independently selected from 1 and 2 for each occurrence.

[0084] In some embodiments of Formula I, including embodiments of each of Formulas IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, R a teeth, -halogen; -oxo; -Cyano; -C1 haloalkoxy; -CH3; -CF2; -R k is -CH3, -OR k C1 alkyl substituted with; -R h and R i are both CH3, -C(=O)NR h R i C1 alkyl substituted with; -R h is hydrogen and R i is CH3, -C(=O)NR h R i C1 alkyl substituted with; -R h is hydrogen and R i is a C3-C6 carbocyclyl-substituted CH3, optionally substituted cyano, -C(=O)NR h R i C1 alkyl substituted with; -R h is hydrogen and R i is a 5-membered heteroaryl-substituted CH3, -C(=O)NR h R i C1 alkyl substituted with; -R m is further substituted with R m is a C1 alkyl substituted with cyclopropyl selected from CH3, CH2OH, and CH2C(=O)NH2; -R m is further substituted with R m is C(=O)NH2, [ka] C1 alkyl substituted with; -C1 alkyl substituted with a 5-membered optionally substituted heterocycle; -optionally substituted with oxo and CH3; [ka] C1 alkyl substituted with; -C1 alkyl substituted with a 5-membered optionally substituted heteroaryl; optionally substituted with --OH or C(=O)NH2; [ka] C1 alkyl substituted with; optionally substituted with --C1-C3 alkyl; [ka] C1 alkyl substituted with; optionally substituted with -N(CH3)2, [ka] C1 alkyl substituted with; 1 to 3 R independently selected from —CH, CHOH, and C(═O)NH m optionally substituted with a group, [ka] C1 alkyl substituted with; -C1 alkyl substituted with a 6-membered optionally substituted heteroaryl; -1 to 3 R independently selected from oxo, CH3, and CH2OH m optionally substituted with a group, [ka] C1 alkyl substituted with; 1 to 3 R independently selected from -oxo, CH, -C branched alkyl, cyclopropyl, and NHCH m optionally substituted with a group, [ka] C1 alkyl substituted with; 1 to 3 R independently selected from --OH, oxo, and C1-C3 alkyl m optionally substituted with a group, [ka] C1 alkyl substituted with; -one to two R independently selected from oxo and CH m optionally substituted with a group, [ka] C1 alkyl substituted with; -one to two R independently selected from oxo and CH m optionally substituted with a group, [ka] C1 alkyl substituted with; -1 to 2 R m optionally substituted with a group, [ka] C1 alkyl substituted with; -C1-C3 alkoxy; -C2 alkyl; C2 alkyl substituted with --OH and -C3-C6 carbocyclyl (optionally substituted with --OH); -C2 alkyl substituted with C1 alkoxy; C2 alkyl substituted with --OH; -R h is hydrogen and R i R is selected from -C1-C3 alkyl ma 6-membered heteroaryl optionally substituted with an -NR h R i C2 alkyl substituted with; -R k is -C2 alkyl, =NOR k C2 alkyl substituted with; -R h is hydrogen, p is 2, and R k is cyclopropyl, -NR h S(=O) p R k C2 alkyl substituted with; -R h and R i is hydrogen and R j is -C2 alkyl, -NR h C(=O)NR i R j C2 alkyl substituted with; -p is 2 and R k is CH3, S(=O) p R k C2 alkyl substituted with; -p is 2 and R h and R i are both hydrogen, -S(=O) p NR h R i C2 alkyl substituted with; -R h is hydrogen and R i is CH3, -S(=O) p NR h R i C2 alkyl substituted with; C2 alkyl substituted with --OH and 6-membered heterocycle (optionally further substituted with --OH); -R m is further substituted with R m But, -OR k and R k is —OH, [ka] C2 alkyl substituted with; -OH and optionally substituted -OH further substituted [ka] C2 alkyl substituted with; -C2 alkyl substituted with a 5-membered optionally substituted heteroaryl; 1 to 2 halogen groups optionally substituted with -C1-C3 alkyl, and [ka] C2 alkyl substituted with; -C2 alkyl substituted with a 6-membered optionally substituted heteroaryl; -optionally substituted with oxo, [ka] C2 alkyl substituted with; -C3 alkyl optionally substituted with 1 to 2 -OH groups; C3 haloalkyl substituted with --OH; -C3 carbocycle; -C alkyl substituted with a 5-membered optionally substituted heteroaryl; -optionally substituted with oxo, [ka] C3 alkyl substituted with; -C3 alkyl substituted with a 6-membered heteroaryl optionally substituted with 1 to 2 oxo groups; - [ka] C3 alkyl substituted with; -C4 alkyl substituted with two -OH groups; C4 branched alkyl substituted with --OH; -R h is hydrogen, p is 2, and R k is CH3, -NR hS(=O) p R k C4 branched alkyl substituted with; -R h and R i are both hydrogen, -NR h R i C4 branched alkoxy substituted with; -C5 branched alkyl substituted with two -OH groups; -p is 2 and R h and R i are both hydrogen, -S(=O) p NR h R i C5 branched alkyl substituted with; -C6 aryl optionally substituted with CF3; -R k is CH3, C(=O)OR k ; -R h is hydrogen and R i is CH3, C(=O)NR h R i ; -R h and R i are both hydrogen, C(=O)NR h R i ; -R h and R i are both hydrogen, NR h R i ; -R h is hydrogen and R i is CH3, NR h R i ; -R h is hydrogen and R i is a branched -C4 alkyl substituted with -OH, NR h R i ; -R h is hydrogen and R k is CH3, NR h C(=O)R k ; -R h is hydrogen and R kis a 5-membered heteroaryl substituted with a group selected from Cl and cyclopropyl [ka] NR h C(=O)R k ; -R h is hydrogen and R k is non-substitutive [ka] or substituted with CH3 [ka] NR h C(=O)R k ; -R h is hydrogen, p is 2, and R k is -C2 alkyl, NR h S(=O) p R k ; -R h is hydrogen, p is 2, and R k is cyclopropyl, NR h S(=O) p R k ; -R h is hydrogen, p is 2, and R k is -cyano, NR h S(=O) p R k ; -R k is CH3, S(=O) p R k ; -p is 2 and R h and R i are both hydrogen, S(=O) p NR h R i ; four-membered heterocycles, [ka] Optionally substituted with S(O)2CH3 [ka] Five-membered heterocycle; Optionally substituted with CH3 [ka] Optionally substituted with oxo and CH3 [ka] Six-membered heterocycle; Optionally substituted [ka] optionally substituted with --OH [ka] 5-membered heteroaryl; 6-membered heteroaryl; optionally substituted with -C1-C3 alkyl [ka] optionally substituted with -C1-C3 alkyl [ka] are independently selected from

[0085] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is selected from compounds 1-299 set forth in Table 1, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. [ka] represents a bond between two atoms and indicates the location of mixed stereochemistry for a collection of molecules such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. An asterisk (e.g., [ka] indicates a chiral position in the molecule.

[0086] In some embodiments, the compound of Formula I is selected from the compounds presented in Table 1, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

[0087] Some embodiments of the present disclosure include derivatives of compounds 1-299, or compounds of formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the derivative is a silicon derivative in which at least one carbon atom of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, or compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with silicon. In some embodiments, the derivative is a boron derivative, in which at least one carbon atom of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, or compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with boron. In other embodiments, the derivative is a phosphorus derivative, in which at least one carbon atom of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, or compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with phosphorus.

[0088] In some embodiments, the derivative is a silicon derivative in which one carbon atom of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, or compounds of Formulas I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with silicon or a silicon derivative (e.g., —Si(CH3)2— or —Si(OH)2—). The carbon substituted with silicon may be a non-aromatic carbon. In other embodiments, fluorine is replaced with a silicon derivative (e.g., —Si(CH3)3). In some embodiments, the silicon derivatives of the present invention may contain one or more hydrogen atoms replaced with deuterium. In some embodiments, the derivative is a silicon derivative of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, or compounds of formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein the silicon derivative can be silicon incorporated into a heterocycle.

[0089] In some embodiments, the derivative is a boron derivative, in which one carbon atom of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, or compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with boron or a boron derivative.

[0090] In some embodiments, the derivative is a phosphorus derivative in which one carbon atom of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, or compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is replaced with phosphorus or a phosphorus derivative.

[0091] Another aspect of the present disclosure provides pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of formulas selected from Formulas I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, as well as compounds 1-299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from Formulas I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, and compounds 1-299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, are administered to a patient in need thereof.

[0092] The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the at least one pharmaceutically acceptable is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0093] It will also be understood that the pharmaceutical compositions of the present disclosure can be employed in combination therapy, i.e., the pharmaceutical compositions described herein can further comprise at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing can be administered as a separate composition simultaneously with, before, or after a composition comprising at least one other active therapeutic agent. In some embodiments, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from Compounds 1-299, their tautomers, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing can be administered as a separate composition simultaneously with, before, or after a composition comprising at least one other active therapeutic agent.

[0094] As mentioned above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier.The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles.As used herein, at least one pharmaceutically acceptable carrier includes any solvent, diluent, other liquid vehicle, dispersion aid, suspension aid, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder, and lubricant suitable for the specific dosage form desired.Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J. Swarbrick and JC B. Boylan, 1988 to 1999, Marcel Dekker, New York, disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), saturated vegetable fatty acids, partial glyceride mixtures of water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxymethylcellulose sodium), and the like. Examples of suitable carriers include, but are not limited to, cellulose acetate, sodium, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0095] Uses of the Compounds and Compositions In some embodiments of the present disclosure, the compounds and pharmaceutical compositions described herein are used to treat FSGS and / or NDKD. In some embodiments, FSGS is mediated by APOL1. In some embodiments, NDKD is mediated by APOL1.

[0096] In some embodiments of the present disclosure, the compounds and pharmaceutical compositions described herein are used to treat cancer. In some embodiments, the cancer is mediated by APOL1.

[0097] In some embodiments of the present disclosure, the compounds and pharmaceutical compositions described herein are used to treat pancreatic cancer. In some embodiments, the pancreatic cancer is mediated by APOL1.

[0098] In some embodiments, the methods of the disclosure include administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formula I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is selected from compounds 1-299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the patient in need thereof possesses an APOL1 gene mutation, i.e., G1;S342G:I384M, and G2:N388del:Y389del.

[0099] Another aspect of the present disclosure provides a method for inhibiting APOL1 activity, comprising contacting the APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds of Formulas I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method for inhibiting APOL1 activity comprises contacting the APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from compounds 1-299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. [Example]

[0100] In order that the disclosure set forth herein may be more fully understood, the following examples are set forth, it being understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any manner.

[0101] The compounds of the present invention can be made according to standard chemical practices or as described herein. The following abbreviations are used throughout the following synthetic schemes and in the descriptions for preparing compounds of Formulas I, IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA, compounds 1-299, tautomers thereof, deuterated derivatives of the compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing: Abbreviation AcOH = acetic acid ARP = Assay Ready Plate BF3.OEt2 = boron trifluoride diethyl etherate Boc2O = di-tert-butyl dicarbonate DAST = diethylaminosulfur trifluoride DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DCE = 1,2-dichloroethane DCM = dichloromethane DEE = diethyl ether DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMEM = Dulbecco's Modified Eagle's Medium DMF = dimethylformamide DMPU = N,N'-dimethylpropylene urea DMSO = dimethyl sulfoxide dppb = 1-4-bis[P(Ph)2]-butane ESI-MS = electrospray ionization mass spectrometry EtOAc = ethyl acetate EtOH = ethanol FBS = fetal bovine serum HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphorus hexafluoride ion) IPA = Isopropyl alcohol IP amine = isopropylamine LCMS = Liquid Chromatography Mass Spectrometry LED = Light Emitting Diode mCPBA = meta-chloroperoxybenzoic acid MeCN = acetonitrile MeI = methyl iodide MeMgBr = methylmagnesium bromide MeOH = methanol MTBE or TBME = methyl tert-butyl ether n-BuLi = n-butyllithium NMP = N-methylpyrrolidine NMR=nuclear magnetic resonance Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3) 4= Palladium-tetrakis(triphenylphosphine) PP = Polypropylene PPh3 = triphenylphosphine PTFE = Polytetrafluoroethylene PTSA = p-toluenesulfonic acid monohydrate rf = retention factor rt=room temperature SFC = Supercritical Fluid Chromatography 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 = silyl ether TBSCl = tert-butyldimethylsilyl chloride TBTA = Tris((1-benzyl-4-triazolyl)methyl)amine tBuBrettPhos Pd G3 = [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TEA = triethylamine Tet = tetracycline TFA or TFAA = trifluoroacetic acid TfO = trifluoromethanesulfonic anhydride THF = tetrahydrofuran TLC = thin layer chromatography TMSCN = trimethylsilyl cyanide VT = variable temperature

[0102] Example 1. Synthesis of Compounds All specific and generic compounds, and intermediates disclosed for making those compounds, are considered to be part of the disclosure disclosed herein.

[0103] compound 1 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (1) [ka] Step 1: Preparation of tert-butyl 5-chloro-2-oxo-spiro[indoline-3,4'-piperidine]-1'-carboxylate (C2) N-Chlorosuccinimide (17.8 g, 133.3 mmol) was added to a solution of C1 (20.1 g, 66.58 mmol) in chloroform (300 mL) at room temperature. The resulting mixture was stirred at 56 °C for 24 h. N-Chlorosuccinimide (4.3 g, 32.2 mmol) was added, and the reaction mixture was continued to stir at 56 °C for 12 h. N-Chlorosuccinimide (9 g, 67.4 mmol) was added, and the reaction mixture was continued to stir at 56 °C for 8 h. N-Chlorosuccinimide (17 g, 127.3 mmol) was added, and this time the reaction mixture was refluxed for 4 h. The reaction mixture was then brought to room temperature and washed with a saturated aqueous solution of sodium sulfite (200 mL) and brine (200 mL). The organic layer was concentrated in vacuo, and the product was purified by silica gel chromatography (0–50% EtOAc:hexanes) to give a mixture of starting material and product. The mixture was purified by reverse-phase HPLC (Waters XSelect CSH C18 OBD preparative column; 30 × 150 mm, 5 microns. Gradient: acetonitrile in water with 5 mM hydrochloric acid.) Fractions containing the product were pooled and concentrated to give the title compound (C2) (2.18 g, 9%) as an off-white solid. 1H NMR(500MHz,DMSO-d6)δ10.55(s, 1H), 7.56(d, J=2.2Hz, 1H), 7.24(dd, J=8.3,2.2 Hz, 1H), 6.86(d, J=8.2Hz, 1H), 3.70~3.59(m, 4H), 1.75~1.63(m, 4H), 1.44(s, 9H). LCMS m / z 337.5[M+H] + .

[0104] Step 2: Preparation of 5-chlorospiro[indoline-3,4'-piperidin]-2-one (C3) DCM (5 mL) and a solution of HCl in dioxane (15 mL 4 M, 60.0 mmol) were added to tert-butyl 5-chloro-2-oxo-spiro[indoline-3,4'-piperidine]-1'-carboxylate (C2) (2.25 g, 5.4 mmol), and the resulting mixture was stirred at room temperature for 60 minutes. The reaction mixture was then concentrated in vacuo and dried under high vacuum overnight to give the title compound (C3) dihydrochloride salt (2.1 g, 110%), which was used in the next step without further purification.

[0105] Step 3: Preparation of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (1) To a suspension of 5-chlorospiro[indoline-3,4'-piperidin]-2-one hydrochloride (C3) (199 mg, 0.656 mmol) and 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (C4) (157 mg, 0.668 mmol) in 3 ml of DCE, sodium triacetoxyborohydride (420 mg, 1.99 mmol) was added and the mixture was stirred at room temperature for 20 hours.

[0106] At this point, the mixture was evaporated to remove volatiles. The material was purified by reverse-phase HPLC (Waters XSelect CSH C18 OBD preparative column; 30 × 150 mm, 5 microns. Gradient: acetonitrile in water with 0.1% trifluoroacetic acid). Product-containing fractions were pooled, and the final product was converted to its HCl salt by treatment with HCl (4 M in dioxane). The resulting suspension was filtered and dried to give the title compound 1 dihydrochloride salt (304 mg, 92%). 1 H NMR (300MHz, chloroform-d) δ8.01(d, J=0.7Hz, 1H), 7.74(s, 1H), 7.40~7.16(m, 2H), 7.01~6.81(m, 1H), 4.76~4.64 (m, 2H), 4.37(s, 2H), 3.85~3.66(m, 4H), 3.56~3.44(m, 2H), 2.86(s, 3H), 2.48~2.19(m, 2H), 2.11~1.95(m, 2H). LCMS m / z 423.05[M+H] + LCMS m / z 237.2 [M+H] +

[0107] Table 2. Compounds 2-36 were synthesized by copper-mediated crosslinking, Suzuki coupling, Negishi coupling, S coupling, utilizing the listed intermediates, as well as modified intermediates accessible to those skilled in the art of organic chemistry. N Ar, S N 2 was prepared in a similar manner using chemical transformations such as lithiation, acylation, halogenation, silylation, desilylation, 1,4-addition, and reduction. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11]

[0108] compound 37 5-Chloro-1-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (37) [ka] Step 1: Preparation of tert-butyl 5-chloro-1-methyl-2-oxo-spiro[indoline-3,4'-piperidine]-1'-carboxylate (C28) To a solution of C2 (199 mg, 0.591 mmol) and MeI (100 μL, 1.61 mmol) in 4 mL of THF, NaH (71 mg of 60% w / w, 1.78 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, absorbed onto SiO2, and purified by column chromatography (SiO2, 0–50% EtOAc:heptane). Fractions containing the product were pooled and concentrated to afford the title compound C28 (199 mg, 93%) as a white solid. 1H NMR (300 MHz, chloroform-d): δ 7.43 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 8.3, 2.1 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 3.79 (d, J = 6.0 Hz, 4H), 3.19 (s, 3H), 1.84–1.68 (m, 4H), 1.50 (s, 9H). LCMS m / z 351.03 [M+H] +

[0109] Step 2: Preparation of 5-chloro-1-methyl-spiro[indoline-3,4'-piperidin]-2-one (C29) To a solution of C28 (192 mg, 0.528 mmol) in 3 ml of methanol was added HCl (3 ml, 4 M in dioxane, 12 mmol) and stirred for 40 minutes at 50° C. At this point, the mixture was evaporated to give the title compound C29 hydrochloride salt (156 mg, 101%) as a white solid. 1 H NMR (300MHz, chloroform-d) δ7.45~7.23(m, 2H), 7.03(d, J=8.3Hz, 1H), 3.82(ddd, J=12.8, 11.9, 3.6Hz, 2H ), 3.39(dt, J=13.0, 4.1Hz, 2H), 3.21(s, 3H), 2.17(ddd, J=14.8, 12.0, 4.3Hz, 2H), 2.06~1.90(m, 2H). LCMS m / z 251.05[M+H] +

[0110] Step 3: Preparation of 5-chloro-1-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (37) To a solution of C29 (16 mg, 0.0546 mmol), C4 (14 mg, 0.0596 mmol), and AcOH (12 μL, 0.2110 mmol) in DCE (1 mL) was added sodium triacetoxyborohydride (36 mg, 0.171 mmol), and the mixture was stirred at room temperature for 6 h. At this point, the mixture was concentrated in vacuo. The material was purified by reverse-phase HPLC (C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO with 0.2% formic acid). Fractions containing the product were pooled and concentrated to give the title compound (37) (16.4 mg, 68%) as a clear oil. 1 H NMR (300MHz, chloroform-d) δ8.51(s, 1H), 7.79(s, 1H), 7.62(s, 1H), 7.29(s, 1H), 6.85~6.70(m, 1H), 4.65(t, J=6.3Hz, 2H), 4.06(s, 2H), 3.66(t, J=6.3 Hz, 2H), 3.50(td, J=12.2, 3.1Hz, 2H), 3.31(d, J=11.7Hz, 2H), 3.19(s, 3H) , 2.67(s, 3H), 2.45(td, J=13.7, 12.6, 4.2Hz, 2H), 1.84(d, J=14.6Hz, 2H). LCMS m / z 437.01[M+H] +

[0111] Compounds 38-40 in Table 3 can be synthesized by a person skilled in the art of organic chemistry. N Prepared in a similar manner using the listed intermediates as well as modified intermediates accessible using Ar. [Table 3]

[0112] compound 41 5-Chloro-1'-[[1-[3-hydroxy-2-(hydroxymethyl)-2-methyl-propyl]triazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (41) [ka] Step 1: Preparation of 5-chloro-1'-prop-2-ynyl-spiro[indoline-3,4'-piperidin]-2-one (C31) To a mixture of C3 hydrochloride (200 mg, 0.732 mmol) and potassium carbonate (200 mg, 1.45 mmol) in acetonitrile (5 mL), 3-bromoprop-1-yne (100 μL of 80% w / w, 0.898 mmol) was added, and the mixture was stirred for 70 minutes. At this point, the mixture was diluted with DCM (20 mL) and water (10 mL). The aqueous layer was extracted with DCM (10 mL), and the organic layers were combined and passed through a phase separator. The mixture was concentrated to dryness, diluted to a minimum with EtOAc, and purified by silica gel column chromatography (100% EtOAc). Product-containing fractions were pooled and concentrated to afford the title compound C31 (171 mg, 83%) as a clear oil. 1 H NMR(400MHz,DMSO-d6)δ10.53(s,1H),7.51(d,J=2.2Hz,1H),7.25(dd,J=8.3,2.1Hz,1H),6.86(d,J=8.3Hz,1H),3.3 9(d, J=2.5Hz, 2H), 3.23(d, J=4.7Hz, 1H), 2.90~2.80(m, 2H), 2.70(d, J=3.7Hz, 2H), 1.85~1.76(m, 2H), 1.71(s, 2H). LCMS m / z 275.02[M+H] +

[0113] Step 2: 5-chloro-1'-[[1-[3-hydroxy-2-(hydroxymethyl)-2-methyl-propyl]triazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (41) To a mixture of 2-(aminomethyl)-2-methyl-propane-1,3-diol (C32) (20 mg, 0.327 mmol) in methanol (3 mL) was added CuSO4 (1 mg, 0.0063 mmol) in water (0.125 mL), followed by sodium bicarbonate (30 mg, 0.357 mmol) in water (0.5 mL) and a solution of triflic azide (0.75 mL of 0.452 M) in DCM. This mixture was stirred for 1 h. At this point, a mixture of C31 (35 mg, 0.127 mmol) in methanol (0.5 mL), ascorbic acid (25 mg, 0.142 mmol) in water (0.25 mL), and TBTA (3.5 mg, 0.0066 mmol) in methanol (0.35 mL) was heated to 55 °C and stirred for 18 h. The material was purified by reverse-phase HPLC (Waters XSelect CSH C18 OBD preparative column; 30 × 150 mm, 5 microns. Gradient: acetonitrile in water with 0.1% trifluoroacetic acid). Fractions containing the product were pooled, concentrated, and then rediluted in DCM (1 mL) and 1 M NaOH (1 mL) to quench residual TFA. The organic layer was passed through a phase separator and concentrated to give the title compound 41 (10.6 mg, 20%) as a clear oil. 1 H NMR (400MHz, chloroform-d) δ7.98(s, 1H), 7.33(d, J=2.1Hz, 1H), 7.21(dd, J=8.3, 2.1Hz, 1H), 6.86(d, J=8.3Hz, 1H), 4.44(s, 2H), 3.90 (s, 2H), 3.46~3.35(m, 4H), 3.04(ddd, J=12.0, 8.3, 3.8Hz, 2H), 2.80(ddd, J=11.4, 6.6, 4.1Hz, 2H), 2.02~1.78(m, 4H), 0.85(s, 3H). LCMS m / z 420.05[M+H] +

[0114] Compounds 42-44 shown in Table 4 were prepared in a similar manner arising from intermediate C29 instead of C3. [Table 4-1] [Table 4-2]

[0115] compound 45 5-Chloro-1-(2-hydroxyethyl)-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (45) [ka] Preparation of 5-chloro-1-(2-hydroxyethyl)-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (45) A suspension of 1 dihydrochloride (36 mg, 0.0713 mmol), CsCO (140 mg, 0.430 mmol), oxirane in THF (1000 μL of 3 M, 3.00 mmol), and CsCO (140 mg, 0.430 mmol) in DMF (2 mL) was stirred at 75 °C for 16 h. At this time, DCM (10 mL) was added, the suspension was filtered, and the filtrate was evaporated to remove volatiles. The crude residue was dissolved in DMSO, and the material was purified by reverse-phase HPLC (C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO with 0.2% formic acid). Fractions containing product were pooled and concentrated to give the title compound 45 (13 mg, 38%) as a white solid. 1 H NMR (300MHz, chloroform-d) δ8.44(s, 1H), 7.85(s, 1H), 7.64(s, 1H), 7.25(d, J=2 .1Hz, 1H), 6.90(d, J=8.3Hz, 1H), 4.66(t, J=6.3Hz, 2H), 4.10(s, 2H), 3.88(t t, J=8.2, 4.1Hz, 4H), 3.67(t, J=6.3Hz, 2H), 3.57(td, J=12.5, 3.1Hz, 2H), 3. 36(d, J=11.7Hz, 2H), 2.71(s, 3H), 2.61~2.40(m, 2H), 1.86(d, J=14.6Hz, 2H). LCMS m / z 467.21[M+H] +

[0116] Compounds 46-51, shown in Table 5, were prepared in a similar manner utilizing alternative electrophiles starting from compound 1. Note that compound 46 was isolated as a by-product from the same reaction to produce 45. [Table 5-1] [Table 5-2] [Table 5-3]

[0117] compound 52 5-Chloro-1'-[[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]methyl]-1-methyl-spiro[indoline-3,4'-piperidin]-2-one (52) [ka] Preparation of 5-chloro-1'-[[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]methyl]-1-methyl-spiro[indoline-3,4'-piperidin]-2-one (52) A suspension of 38 (10 mg, 0.022 mmol), CsCO (43 mg, 0.132 mmol), and 2,2-dimethyloxirane (12 μL, 0.135 mmol) in DMF (1 mL) was stirred at 75 °C for 16 h. At this time, DCM (10 mL) was added, and the mixture was filtered, concentrated in vacuo, and diluted with DMSO (1 mL). The material was purified by reverse-phase HPLC (C18 Waters Sunfire column (30 × 150 mm, 5 microns). Gradient: MeCN in HO with 0.2% formic acid). Fractions containing the product were pooled and concentrated to give the title compound 52 (5.8 mg, 63%) as a white solid. 1H NMR (400MHz, chloroform-d) δ8.48(s, 2H), 7.79(d, J=0.8Hz, 1H), 7.57(d, J=0.7Hz, 1H), 7.34~7.29(m, 1H), 6.79(dd, J=7.9, 0.8Hz, 1H), 4.13(2s, 3H), 3.60(td, J=12.5, 3.1Hz, 2H), 3.41(d, J=12.0Hz, 2H), 3.20(s, 3H), 2.65( s, 1H), 2.52 (td, J=14.0, 4.3Hz, 2H), 1.84 (d, J=14.6Hz, 2H), 1.21 (s, 6H). LCMS m / z 403.17[M+H] +

[0118] Compounds 53-59, shown in Table 6, were prepared in a similar manner starting from compound 38 utilizing alternative epoxides. [Table 6-1] [Table 6-2] [Table 6-3]

[0119] compound 60 N-[3-[(5-chloro-1-methyl-2-oxo-spiro[indoline-3,4'-piperidin]-1'-yl)methyl]cyclobutyl]-3-cyclopropyl-isoxazole-5-carboxamide (60) [ka] Step 1: Preparation of 1'-[(3-aminocyclobutyl)methyl]-5-chloro-1-methyl-spiro[indoline-3,4'-piperidin]-2-one (C46) To a solution of tert-butyl N-(3-formylcyclobutyl)carbamate (C45) (201 mg, 1.01 mmol) and C29 (207 mg, 0.721 mmol) in DCM (5 mL) was added sodium triacetoxyborohydride (460 mg, 2.17 mmol). The mixture was stirred at room temperature for 2 hours. At this time, saturated aqueous sodium bicarbonate (5 mL) was added to the reaction mixture, followed by extraction with DCM (3 × 5 mL). The combined organic fractions were washed with HO (1 × 2 mL), brine (1 × 2 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.

[0120] The crude material was diluted with HCl in dioxane (4 mL of 4 M, 16.00 mmol) and stirred for 1 hour. At this point, the solvent was removed in vacuo and the material was isolated neat. The title compound (C46) trifluoroacetate salt was isolated as a yellow oil. LCMS m / z 334.15 [M+H] +

[0121] Step 2: Preparation of N-[3-[(5-chloro-1-methyl-2-oxo-spiro[indoline-3,4′-piperidine]-1′-yl)methyl]cyclobutyl]-3-cyclopropyl-isoxazole-5-carboxamide (60) To a mixture of C46 (20 mg, 0.057 mmol) and 3-cyclopropylisoxazole-5-carboxylic acid (C47) (8.7 mg, 0.057 mmol) in DMF (1 mL) was added EtN (24 μL, 0.171 mmol) and PyBop (35.6 mg, 0.068 mmol), and the mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo, diluted with DMSO (1 mL), and the material was purified by reverse-phase HPLC (Waters XSelect CSH C18 OBD preparative column; 30 × 150 mm, 5 microns. Gradient: acetonitrile in water with 0.1% trifluoroacetic acid). Fractions containing the product were pooled and concentrated to give the title compound (60) ditrifluoroacetate salt (7.5 mg, 22%) as a clear oil.

[0122] Compounds 61-71 shown in Table 7 were prepared in a similar manner utilizing alternative acids, sulfonyl chlorides, and carbamoyl chlorides derived from compound C46 or the trans-cyclobutyl analog. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0123] compound 72 2-(4-((1-methyl-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)methyl)-1H-pyrazol-1-yl)ethane-1-sulfonamide (72) [ka] Step 1: Preparation of 1-methylspiro[indoline-3,4'-piperidin]-2-one (C55) A stirred solution of NaH (105.3 mg, 57% w / w, 0.0025 mol) in toluene (20 mL) was stirred at 120° C. for 15 minutes. C1 (500 mg, 0.0017 mol) was added to the reaction mixture at 120° C. and stirred at this temperature for 1 hour. A solution of dimethyl sulfate (252 mg, 0.19 mL, 0.0020 mol) in toluene (1 mL) was added to the reaction at 120° C. The reaction was stirred at 120° C. for 16 hours. At this time, the reaction was cooled to 0° C., quenched with water (10 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under vacuum to give a crude residue (600 mg). The crude residue was purified by column chromatography using (SiO2, 20% EtOAc:petroleum ether). Fractions containing the product were pooled and concentrated.

[0124] The residue was dissolved in 1,4-dioxane (5 mL) and HCl in 1,4-dioxane (1.625 mL of 4 M, 0.0065 mol) was added to the solution at 0° C. The reaction mass was allowed to stir for 5 hours. At this point, the reaction was evaporated in vacuo to give a crude residue. The crude residue was washed with diethyl ether (3×5 mL) to give the title compound (C55) hydrochloride salt (150 mg, 89%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ: 8.70 (brs, 1H), 7.37~7.32 (m, 2H), 7.13~7.05 (m, 2H), 3.56 ~3.47(m, 2H), 3.32~3.25(m, 2H), 3.14(s, 3H), 2.11~2.02(m, 2H), 1.91~1.86(m, 2H). LCMS m / z 217.31[M+H] +

[0125] Step 2. 2-(4-((1-methyl-2-oxospiro[indoline-3,4'-piperidine]-1'-yl)methyl)-1H-pyrazol-1-yl)ethane-1-sulfonamide (72) To a stirred solution of C55 hydrochloride (75 mg, 287 μmol) in DMF (5 mL) was added KCO (594 mg, 4.2 mmol), KI (9.5 mg, 56.8 μmol), and 2-[4-(chloromethyl)pyrazol-1-yl]ethanesulfonamide (C56) hydrochloride (200 mg, 384 μmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. At this time, the reaction was filtered and washed with methanol (15 mL). The filtrate was evaporated in vacuo to give the crude compound (200 mg) as a brown gum. The crude compound was purified by preparative HPLC (gradient: 0 to 98% MeCN in 0.1% aqueous TFA) to give the title compound (72) trifluoroacetate (15 mg, 10%) as a light brown gum. VT at 90℃ NMR (400MHz, DMSO-d6)δ:9.74(brs, 1H), 7.88(brs, 1H), 7.57(brs, 1H), 7.30(t, J=8.4Hz, 2H), 7.06(t, J=7.2Hz, 1H), 7.00(d, J=7.6 Hz, 1H), 6.76(s, 2H), 4.52(t, J=7.2Hz, 2H), 4.17(brs, 2H), 3.52(t, J=7.2Hz, 2H), 3.35(brs, 2H), 3.12(s, 5H), 1.91~1.89(brs, 4H). LCMS m / z 404.09[M+H] + .

[0126] Compound 73 was prepared in a similar manner to 72 utilizing 1-iodo-2,2-difluoroethane in step 1 and 4-(chloromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole in step 2. [Table 8]

[0127] compound 74 (2'S,3R)-5-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (74) [ka] Step 1: Preparation of (2S,4S)-4-[(2-bromo-4-chloro-phenyl)carbamoyl]-2-methyl-piperidine-1-carboxylate tert-butyl ester (C59) To a suspension of (2S,4S)-1-tert-butoxycarbonyl-2-methyl-piperidine-4-carboxylic acid (S3) (104 mg, 0.428 mmol), 2-bromo-4-chloro-aniline (96 mg, 0.465 mmol), and pyridine (100 μL, 1.24 mmol) in EtOAc (1.3 mL), a solution of T3P (50 wt% in EtOAc, 500 μL, 0.841 mmol) was added, and the mixture was stirred for 3.5 h. At this time, the mixture was quenched with saturated aqueous sodium bicarbonate (3 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were concentrated in the presence of silica gel and chromatographed (silica gel, 0–50% EtOAc:heptane). Fractions containing the product were pooled and concentrated to afford the title compound (C59) (153 mg, 81%) as a white solid. LCMS m / z 431.0[M+H] +

[0128] Step 2: Preparation of (2S,4S)-4-[(2-bromo-4-chloro-phenyl)-[(4-methoxyphenyl)methyl]carbamoyl]-2-methyl-piperidine-1-carboxylate tert-butyl ester (C60) To a solution of C59 (1.03 g, 2.36 mmol) in THF (12 mL) was added NaH (approximately 284 mg, 7.09 mmol, 60 wt % in mineral oil) at 0 °C.

[0129] After stirring for 10 min, PMB-Br (600 μL, 4.12 mmol) was added, and after stirring for an additional 10 min, the reaction was warmed to room temperature and stirred for 18 h. At this point, the reaction was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was absorbed onto SiO and purified by loading onto a silica gel column (0–50% EtOAc in heptane). Fractions containing the product were pooled and concentrated before further purification to afford the title compound (C60) (797 mg, 60%) as a white solid. 1 H NMR (300MHz, CDCl3) δ7.70 (d, J=2.3Hz, 1H), 7.20~7.12 (m, 1H), 7.06 (dd, J=8.7, 2.1Hz, 2H), 6.78 (dd, J=8.7, 2.1Hz, 2H), 6.60(dd, J=12.4, 8.4Hz, 1H), 5.55(dd, J=14.2, 7.6Hz, 1H), 3.87(dd, J=14 .2, 3.4Hz, 1H), 3.78(d, J=0.9Hz, 3H), 3.63(d, J=29.6Hz, 2H), 3.23~2.93(m, 1H), 2.22~1.86(m, 1 H), 1.85~1.70(m, 1H), 1.60(t, J=7.7Hz, 2H), 1.38(d, J=5.1Hz, 9H), 1.14(dd, J=10.0, 6.3Hz, 3H). LCMS m / z 550.93[M+H] +

[0130] Step 3: Preparation of tert-butyl (2'S)-5-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-2-oxo-spiro[indoline-3,4'-piperidine]-1'-carboxylate (C61) A mixture of C60 (200 mg, 0.36 mmol), racemic BINAP Pd G3 (36 mg, 0.0363 mmol), and sodium t-butoxide (104 mg, 1.08 mmol) was purged with N2 for 15 minutes, at which point dioxane (3.6 mL) was added and the mixture was heated to 100 °C and stirred for 16 hours. At this time, the mixture was quenched with saturated NaHCO3 (5 mL) and the solution was extracted with EtOAc (4 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography (0-30% EtOAc in heptane) to afford the product as a 1.8:1 dr. The title compound (C61) (153 mg, 88%) was isolated as a clear oil. LCMS m / z 471.18 [M+H] +

[0131] Step 4: Preparation of (2'S,3R)-5-chloro-2'-methylspiro[indoline-3,4'-piperidin]-2-one (C62) To a solution of C61 (37 mg, 0.076 mmol) in toluene (300 μL) was added TFA (120 μL, 1.56 mmol). The reaction became an orange solution. The reaction was stirred at room temperature for 1 h and then heated at 80 °C for 1 h. At this time, triflic acid (34 μL, 0.384 mmol) was added, and the mixture was stirred for 18 h. At this time, the reaction was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (2 mL), and extracted with DCM (4 × 2 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was purified by silica gel column chromatography (0–20% MeOH:DCM), and the product-containing fractions were pooled and purified again as described above. The title compound (C62) (4.5 mg, 21%) was isolated as a clear oil. 1H NMR (300MHz, CDCl3) δ7.37(s, 1H), 7.29(d, J=2.1Hz, 1H), 6.95~6.82(m, 1H), 3.71(ddd, J=12.4, 10.3, 3.0Hz, 2H), 3.14(ddd, J=12.4, 4 .7, 2.1Hz, 1H), 2.01(td, J=13.2, 12.7, 4.6Hz, 2H), 1.87(dp, J=13.7, 2.1Hz, 2H), 1.65(dd, J=13.7, 11.4Hz, 1H), 1.22(d, J=6.3Hz, 3H). LCMS m / z 251.11[M+H] +

[0132] Step 5: Preparation of (2'S,3R)-5-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (74) To a solution of C62 (4.5 mg, 0.017 mmol), C4 (5.1 mg, 0.025 mmol) in THF (200 μL) was added sodium triacetoxyborohydride (8.9 mg, 0.042 mmol), and the mixture was heated to 50 °C and stirred for 90 min. At this point, the mixture was quenched with saturated aqueous sodium bicarbonate (1 mL) and extracted with DCM (8 × 1 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography (0-100% 3:1 EtOAc / EtOH:heptane). Fractions containing the product were pooled, concentrated, and the purification was repeated once more. The title compound (74) (7.1 mg, 87%) was isolated as a clear oil. LCMS m / z 437.19 [M+H] +

[0133] Compounds 75-76 were prepared by the S-catalysis of intermediate C65 using commercially available aldehydes and modified intermediates available to those skilled in the art of organic chemistry. N 2 was prepared in a similar manner using chemical transformations such as silylation and desilylation. [Table 9]

[0134] compound 77 5-Chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one trifluoroacetic acid (77) [ka] Step 1: Preparation of tert-butyl 4-[(2-bromo-4-chloro-phenyl)carbamoyl]-2-methyl-piperidine-1-carboxylate (C63) To 1-tert-butoxycarbonyl-2-methyl-piperidine-4-carboxylic acid (S4) (2 g, 8.22 mmol) in DCM (10 ml) was added oxalyl chloride (8.8 mL of 2 M, 17.60 mmol). At this time, one drop of DMF was added, and the mixture was stirred at room temperature for 2 hours. At this time, the reaction mixture was concentrated to dryness and redissolved in pyridine (5 mL) and DCM (10 mL). The solution was cooled to 0 °C, and 2-bromo-4-chloro-aniline (C58) (1.88 g, 9.11 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 18 hours. At this time, EtOAc (300 mL) was added, and the organic layer was washed with brine (300 mL), cold 1 M HCl (2 × 300 mL), NaHCO (300 mL), and brine (300 mL). The organic layer was dried over Na2SO4, concentrated onto silica gel, and purified by loading onto a silica gel column (0-50% EtOAc:heptane) to give the title compound (C63) (1.47 g, 41%) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 8.31 (d, J = 8.9 Hz, 1H), 7.68 (s, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 8.9, 2.4 Hz, 1H), 4.13 (q, J = 6.8 Hz, 1H), 3.98-3.79 (m, 1H), 3.28-3.04 (m, 1H), 2.61 (dtd, J = 9.1, 7.3, 4.4 Hz, 1H), 2.21-1.90 (m, 3H), 1.90-1.65 (m, 1H), 1.49 (s, 9H), 1.19 (d, J = 6.5 Hz, 3H). LCMS m / z 431.08 [M+H] +

[0135] Step 2: Preparation of tert-butyl 5-chloro-2'-methyl-2-oxo-spiro[indoline-3,4'-piperidine]-1'-carboxylate (C64) To a suspension of C63 (107 mg, 0.245 mmol), Pd2dba3 (21 mg, 0.0365 mmol), and racemic BINAP (46 mg, 0.074 mmol) in dioxane (3 mL), sodium tert-butoxide (71 mg, 0.74 mmol) was added, and the reaction was heated to 170 °C for 2 h. At this point, the crude mixture was adsorbed onto silica gel, loaded onto a silica gel column (0–50% EtOAc:heptane), and purified. Fractions containing the product were pooled and concentrated to afford the title compound (C64) (31 mg, 8%) as a clear oil and a 1:1 mixture of diastereomers. 1 H NMR (300 MHz, chloroform-d): δ 9.05 (d, J = 3.1 Hz, 1H), 7.20 (ddd, J = 8.3, 4.2, 1.8 Hz, 1H), 7.17–6.97 (m, 1H), 6.98–6.74 (m, 1H), 4.31–3.93 (m, 1H), 3.57–3.22 (m, 1H), 2.19–1.65 (m, 5H), 1.62–1.50 (m, 9H), 1.31–1.23 (m, 5H). LCMS m / z 351.11 [M+H] +

[0136] Step 3: Preparation of 5-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (77) To a mixture of C64 in MeOH (2 mL) was added HCl in dioxane (1 mL, 4 M, 4.00 mmol), and the solution was heated to 50° C. for 1 h. At this point, the mixture was evaporated. To the crude solid was added C4 (48 mg, 0.204 mmol), DCE (4 mL), AcOH (35 μL, 0.616 mmol), and sodium triacetoxyborohydride (64 mg, 0.303 mmol), and the reaction was stirred at room temperature for 12 h. At this point, additional sodium triacetoxyborohydride (32 mg, 0.150 mmol) was added, and the mixture was heated to 60° C. for 3 h. At this point, the mixture was concentrated to dryness, diluted with DMSO (1 mL), and the material was purified by reverse-phase HPLC (Waters XSelect CSH C18 OBD preparative column; 30 × 150 mm, 5 micron. Gradient: acetonitrile in water with 0.1% trifluoroacetic acid). Fractions containing the product were pooled and concentrated to give the title compound (77) trifluoroacetate salt (2 mg, 7%) as a clear oil. 1 H NMR (300MHz, chloroform-d) δ8.32(s,1H),7.91(d,J=13.0Hz,1H),7.73(s,1H),6.97~6.89(m,1H),6.79(s,1H),4.81(s,1H),4.68(s,1H),4.48(s,1H),4 .23(d,J=28.6Hz,1H),3.80~3.58(m,2H),3.49(d,J=37.9Hz,1H),3.23(t, J=13.0Hz,1H),2.86(s,2H),1.74(d,J=14.2Hz,1H),1.65(d,J=6.1Hz,3H). LCMS m / z 437.08[M+H] +

[0137] Compounds 78 and 79 were prepared in a similar manner to compound 77, using an alternative aniline during step 1. [Table 10]

[0138] compound 80 (2'S,3R)-5-Chloro-1,2'-dimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one trifluoroacetic acid (80) [ka] Step 1: Preparation of tert-butyl 4-[(2-bromo-4-chloro-phenyl)carbamoyl]-2-methyl-piperidine-1-carboxylate (C63) See the procedure above for preparing intermediate C63 in the preparation of compound 77.

[0139] Step 2: Preparation of tert-butyl 4-[(2-bromo-4-chloro-phenyl)-methyl-carbamoyl]-2-methyl-piperidine-1-carboxylate (C67) To a solution of C63 (310 mg, 0.711 mmol) and MeI (135 μL, 2.17 mmol) in 4 mL of THF, NaH (90 mg of 60% w / w, 2.25 mmol) was added, and the mixture was stirred at room temperature overnight. At this point, the mixture was adsorbed onto silica gel and purified by silica gel column chromatography (0-50% EtOAc:heptane). Fractions containing the product were pooled and concentrated to afford the title compound (C67) (294 mg, 89%) as a yellow oil. LCMS m / z 445.08 [M+H] +

[0140] Step 3: Preparation of (2'S,3R)-5-chloro-1,2'-dimethyl-spiro[indoline-3,4'-piperidin]-2-one (C68) To a suspension of C67 (285 mg, 0.615 mmol), Pd2dba3 (53 mg, 0.092 mmol), and racemic BINAP (115 mg, 0.185 mmol) in dioxane (8 mL) was added sodium tert-butoxide (120 mg, 1.25 mmol). The reaction was heated to 160 °C for 2.5 h. At this point, the reaction was concentrated and diluted with 3 mL of MeOH and HCl (3 mL of 4 M, 12.00 mmol) in dioxane, and the reaction was heated to 50 °C for 40 min. The mixture was concentrated, diluted with DMSO (1 mL), loaded onto a C18 column, and subjected to reverse-phase purification (10–100% MeCN:water, 0.1% TFA modifier). Fractions containing the product were concentrated and diluted with HCl in dioxane to obtain the HCl salt. Title compound (C68) hydrochloride (49.9 mg, 25%) 1 H NMR (300MHz, chloroform-d) δ7.41~7.25(m,2H),7.01(dd,J=8.2,0.5Hz,1H),4.13(h,J=6.8Hz,1H),3.96~3.80(m,1H),3.39(ddd, J=12.7,4.6,2.0Hz,1H),3.31(p,J=1.7Hz,3H),2.17(ddd,J=14.9,13.6,4.6Hz,1H),2.06~1.89(m,3H),1.34(d,J=6.6Hz,3H). LCMS m / z 265.01[M+H] + Retention time: 0.61 min. Final purity was determined by reversed-phase UPLC using a Waters Acquity UPLC Acquity CSH C18 (2.1 x 50 mm, 1.7 μm particle size) and a dual gradient run of 5 to 95% mobile phase B over 0.6 min. Mobile phase A = HO (0.1% CF3CO2H). Mobile phase B = CH3CN (0.1% CF3CO2H). Flow rate = 0.6 mL / min, injection volume = 2.0 μL.

[0141] Step 4: Preparation of (2'S,3R)-5-chloro-1,2'-dimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (80) C68 (12 mg, 0.037 mmol) in 2 ml of DCE was converted to C4 (20 mg, 0.085 mmol). After 5 min, sodium triacetoxyborohydride (28 mg, 0.133 mmol) was added, and the mixture was stirred at room temperature for 14 h. At this point, the mixture was evaporated, diluted with DMSO (1 mL), and the material was purified by reverse-phase HPLC (Waters XSelect CSH C18 OBD preparative column; 30 × 150 mm, 5 microns. Gradient: acetonitrile in water with 0.1% trifluoroacetic acid). Fractions containing the product were pooled and concentrated to give the title compound (80) trifluoroacetate salt (4.9 mg, 22%). LCMS m / z 451.09 [M+H] +

[0142] Compounds 81-87 were prepared in a similar manner to compound 80, utilizing an alternative aniline in step 1 as well as an alternative piperidine. [Table 11-1] [Table 11-2] [Table 11-3]

[0143] Compound S1 (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine] (S1) [ka] Step 1. Synthesis of (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-6-ol (C85) A solution of (2S)-tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate C83 (9.21 g, 38.00 mmol) in DCM (125 mL) was cooled to approximately 6 °C in an ice bath. Methanesulfonic acid (10.8 mL, 166.4 mmol) was added in four portions over 5 minutes. After the addition was complete, the reaction was warmed in a 35 °C water bath, then the bath was removed and the reaction was stirred at room temperature for 15 minutes. House vacuum was applied for 2 minutes to remove residual isobutylene. To this solution was added 2-chloro-5-(2-hydroxyethyl)phenol C84 (7 g, 40.55 mmol), and the reaction mixture was allowed to warm to 36 °C using a heating mantle. The reaction was stirred at this temperature for 15 hours under a reflux condenser. The reaction was allowed to warm to ambient temperature, poured into a 1 L Erlenmeyer flask, and cooled in a brine / ice bath with stirring. 6 M NaOH was added slowly until the pH was adjusted to 9. A colorless white precipitate formed. Stirring was continued with cooling for 30 minutes. The solid was filtered, air-dried, and then evaporated to dryness in vacuo to give (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-6-ol C85 (10.5 g, 98%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ7.09(s, 1H), 6.75(s, 1H), 3.81(td, J=5.8, 2.6Hz, 2H), 3.44~2.87(m, 4H) ), 2.65 (t, J=5.6Hz, 2H), 2.18 (dt, J=13.5, 7.2Hz, 1H), 2.10~1.83 (m, 3H), 1.26 (d, J=6.5Hz, 3H). LCMS m / z 267.97[M+H] + .

[0144] Step 2. Synthesis of tert-butyl (1R,2'S)-7-chloro-6-hydroxy-2'-methyl-spiro[isochroman-1,4'-piperidine]-1'-carboxylate (C86) To a solution of (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-6-ol C85 (3.6 g, 12.77 mmol) in DCM (45 mL) was added BocO (2.9 g, 13.29 mmol), followed by sodium bicarbonate (33 mL of 1.8 M, 59.40 mmol) and stirred at room temperature for 16 h. The aqueous layer was extracted with DCM (50 mL) through a phase separator and then back-extracted three times, each time with DCM (50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product (1R,2'S)-7-chloro-6-hydroxy-2'-methyl-spiro[isochroman-1,4'-piperidine]-1'-carboxylate C86 (4.8 g, 97%). LCMS m / z 268.03[M-100+H] + .

[0145] Step 2. Synthesis of tert-butyl (1R,2'S)-7-chloro-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochroman-1,4'-piperidine]-1'-carboxylate (C87) To a suspension of tert-butyl (1R,2'S)-7-chloro-6-hydroxy-2'-methyl-spiro[isochroman-1,4'-piperidine]-1'-carboxylate C86 (5.7 mg, 15.49 mmol) in DCM (126 mL) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (17 g, 47.59 mmol), tetrabutylammonium hydrogen sulfate (9 g, 26.51 mmol), and NaOH (72 mL of 2.0 M, 144.0 mmol). The flask was equipped with an air condenser, and the reaction was vigorously stirred at 30 °C for 16 h. The aqueous layer was extracted with DCM (3 × 50 mL). 50 mL of DCM was added to the aqueous layer, and the pH was adjusted to 8-9 using 2 M HCl. Extraction was performed using DCM (3 × 50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude material as a gummy solid. The crude material was purified by silica gel chromatography using 0 to 50% ethyl acetate in heptane to give tert-butyl (1R,2'S)-7-chloro-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochroman-1,4'-piperidine]-1'-carboxylate C87 (7.9 g, 97%). 1 H NMR (400MHz, chloroform-d) δ7.44~7.27(m,2H),7.21(s,1H),7.08(s,1H),4.03(ddd,J=11.7,6.8,5.4Hz,1H),3.94~3.74(m,3H),3.38(ddd,J=14.3,9.4 ,5.3Hz,1H),2.89~2.67(m,2H),2.15(dddd,J=15.6,9.4,6.2,1.7Hz,1H), 2.08~1.98(m,1H),1.89~1.69(m,3H),1.51(s,9H),1.28(d,J=6.5Hz,4H). LCMS m / z 400.05[M-Boc+H] + .

[0146] Step 4. Synthesis of tert-butyl (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine]-1'-carboxylate (C88) To a suspension of tert-butyl (1R,2'S)-7-chloro-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochroman-1,4'-piperidine]-1'-carboxylate C87 (375 mg, 0.7501 mmol) in DMF (7 mL) was added Pd(dppf)Cl2 (63 mg, 0.07715 mmol), triethylamine (360 μL, 2.583 mmol), followed by formic acid (72 μL, 1.909 mmol). The resulting red solution was purged with nitrogen and heated at 60 °C under nitrogen for 3 h. The reaction was cooled to room temperature, diluted with MTBE (25 mL), and quenched with brine (25 mL). The aqueous layer was extracted with MTBE (3 × 25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0-30% EtOAc in heptane to afford (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine]-1'-carboxylate tert-butyl C88 (270 mg, 97%). 1 H NMR (400MHz, chloroform-d) δ7.13(dd,J=8.1,2.1Hz,1H),7.07~6.99(m,2H),4.02( ddd,J=11.7,6.7,5.4Hz,1H),3.92~3.74(m,3H),3.39(ddd,J=14.3,9.4,5.3Hz ,1H),2.87~2.66(m,2H),2.14(dddd,J=15.5,9.4,6.1,1.7Hz,1H),2.02(ddd,J =14.2,5.2,1.7Hz,1H),1.93~1.74(m,2H),1.52(s,9H),1.28(d,J=6.5Hz,3H). LCMS m / z 252.06 [M-Boc+H] + .

[0147] Step 5. Synthesis of (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine] (S1) To tert-butyl (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine]-1'-carboxylate C88 (4 g, 10.80 mmol), hydrochloric acid (45 mL of 4 M, 180.0 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with MTBE (100 mL), and the solid was filtered. The solid was washed with MTBE and evaporated to dryness in vacuo to give the white HCl salt (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine] S1 (3.0452 g, 97%). 1 H NMR(400MHz,DMSO-d6)δ9.01(s,2H),7.27(dd,J=8.1,2.1Hz,1H),7.23~7.16(m,2 H),3.84(hept,J=5.8Hz,2H),3.66~3.49(m,4H),3.43~3.27(m,1H),3.20(dd,J=12 .6,3.8Hz,1H),3.14~2.99(m,1H),2.75(t,J=5.6Hz,2H),2.26(td,J=14.0,4.7Hz, 1H),2.11(dd,J=14.3,12.1Hz,1H),1.98(t,J=12.6Hz,2H),1.27(d,J=6.4Hz,3H). LCMS m / z 252.00[M+H] + .

[0148] Preparation S2 (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-4-ol (S2) [ka] Steps 1 and 2. Synthesis of (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-4-ol (S2) To a solution of (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine] (HCl salt) S1 (50 mg, 0.1735 mmol) in acetonitrile (430 μL) and water (1.3 mL), ammonium hydrogen sulfate (80 mg, 0.3506 mmol) and Mn(OAc)2 (13.7 mg, 0.07918 mmol) were added. The reaction was stirred at 70 °C for 16 h. It was cooled to room temperature and concentrated in vacuo. The crude product was carried forward without further purification as a mixture of ketone C89 and alcohol S2. Methanol (2.7 mL), NaBH4 (7.9 mg, 0.2088 mmol) and the crude mixture was stirred at 23 °C for 2 h with the needle outlet open to air. The reaction was concentrated and purified by reverse phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30 x 150 mm, 5 micron. Gradient: acetonitrile in water with 0.2 formic acid) to give the formate salt S1 (20.70 mg, 89%). LCMS m / z 268.23 [M+H] + .

[0149] Preparation S3 (1R,2'S)-7-chloro-4,4-difluoro-2'-methyl-spiro[isochroman-1,4'-piperidine] (S3) [ka] Step 1. Synthesis of 1-[(1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone (C90) To a solution of (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine] 1 (332 mg, 1.319 mmol) in DCM (5.6 mL) was added DIPEA (600 μL, 3.445 mmol) and trifluoromethanesulfonic anhydride (400 μL, 2.878 mmol). The reaction was stirred at 23 °C for 16 h. The crude reaction was diluted with DCM (3 ml) and quenched with 3 ml of saturated ammonium chloride. The mixture was extracted with DCM (3 × 10 ml) using a phase separator. The organic layer was washed with 1.5 ml of 1 M HCl, followed by 1 ml of water and 1.5 ml of brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel chromatography eluting with 0-10% ethyl acetate in heptane to give the clear adhesive 1-[(1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone C90 (362 mg, 77%). LCMS m / z 348.15 [M+H] + .

[0150] Step 2. Synthesis of 1-[(1R,2'S)-7-chloro-4-hydroxy-2'-methyl-spiro[isochroman-1,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone (C91) To a solution of 1-[(1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone C90 (1.77 g, 5.090 mmol) in water (31.5 mL) and acetonitrile (11 mL) was added ammonium hydrogen sulfate (5.8 g, 25.42 mmol) and copper(II) acetate (470 mg, 2.588 mmol). The mixture was heated at 70 °C for 16 hours. The reaction was cooled to ambient temperature, diluted with DCM (25 ml), quenched with saturated sodium bicarbonate, and separated using a phase separator (3 x 25 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel chromatography eluting with 0-10% ethyl acetate in heptane to give C91 (1R,2'S)-7-chloro-2'-methyl-1'-(2,2,2-trifluoroacetyl)spiro[isochroman-1,4'-piperidin]-4-one (1.58 g, 85%) as a pale yellow solid. LCMS m / z 362.05 [M+H] + .

[0151] Step 3. Synthesis of 1-[(1R,2'S)-7-chloro-4,4-difluoro-2'-methyl-spiro[isochroman-1,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone (C92) To (1R,2'S)-7-chloro-2'-methyl-1'-(2,2,2-trifluoroacetyl)spiro[isochroman-1,4'-piperidin]-4-one C91 (30.2 mg, 0.08348 mmol) was added DAST (200 μL, 1.514 mmol) over three consecutive days and stirring was continued at 40 °C for three days. The reaction was cooled to room temperature and slowly quenched with saturated sodium bicarbonate. The organic layer was extracted with DCM (3 × 15 ml) using a phase separator. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 1-[(1R,2'S)-7-chloro-4,4-difluoro-2'-methyl-spiro[isochroman-1,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone C92 without further purification.

[0152] Step 4. Synthesis of (1R,2'S)-7-chloro-4,4-difluoro-2'-methyl-spiro[isochroman-1,4'-piperidine] (S3) To a solution of 1-[(1R,2'S)-7-chloro-4,4-difluoro-2'-methyl-spiro[isochroman-1,4'-piperidine]-1'-yl]-2,2,2-trifluoro-ethanone C92 in methanol (1 ml) was slowly added NaOH (600 μL of 2 M, 1.200 mmol) at 0° C. The reaction was allowed to warm to ambient temperature over 3 hours and then stirred at 40° C. for 16 hours. The reaction was concentrated under reduced pressure and purified by reverse-phase HPLC (Method: Waters XBridge Prep C8 column; 30 × 150 mm, 5 micron. Gradient: acetonitrile in water with 10 mM ammonium hydroxide) to give a white solid (1R,2'S)-7-chloro-4,4-difluoro-2'-methyl-spiro[isochroman-1,4'-piperidine] S3 (10.2 mg, 41%). 1 H NMR (300MHz, chloroform-d) δ7.66(d,J=8.4Hz,1H),7.51~7.29(m,2H),4.11(t,J =10.6Hz,2H),3.26~2.92(m,3H),2.10~1.79(m,3H),1.68~1.55(m,1H),1.24 -1.06(m,3H). LCMS m / z 288.09[M+H] + .

[0153] Compound S4 (1R,2'S,4S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-4-ol (S4) [ka] Steps 1 and 2: Synthesis of (1R,2'S,4S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-4-ol (S4). To a solution of N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-4-methyl-benzenesulfonamide (6.9 mg, 0.01883 mmol) and dichloro(pentamethylcyclopentadienyl)rhodium(II) dimer (3.1 mg, 0.004935 mmol) in acetonitrile (688 μL) was added a 5:2 mixture of triethylamine:formic acid (240 μL, 0.5716 mmol). The solution turned bright red, and some slight effervescence was observed. After 10 min, the mixture was cooled to 0 °C and treated with (1R,2'S)-7-chloro-2'-methyl-1'-(2,2,2-trifluoroacetyl)spiro[isochroman-1,4'-piperidin]-4-one C90 (144 mg, 0.3801 mmol) in acetonitrile (6.9 mL). The reaction was stirred at 0°C for 1 hour and then allowed to warm to room temperature over 1 hour. The reaction was concentrated to give C93 without further purification. To a solution of 1-[(1R,2'S,4S)-7-chloro-4-hydroxy-2'-methyl-spiro[isochroman-1,4'-piperidin]-1'-yl]-2,2,2-trifluoro-ethanone C93 in methanol (6.9 ml) was added NaOH (950 µL of 2 M, 1.900 mmol) and stirred at 23°C for 2 hours. The crude was concentrated and purified by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30 × 150 mm, 5 microns. Gradient: acetonitrile in water with 0.2% formic acid) to give the formate salt (1R,2′S,4S)-7-chloro-2′-methyl-spiro[isochroman-1,4′-piperidin]-4-ol S4 (78 mg, 65%, >99:1 dr) 1R,2′S,4S)-7-chloro-2′-methyl-spiro[isochroman-1,4′-piperidin]-4-ol (formate (1)) (78 mg, 65 mg) as a white solid. 1H NMR (300MHz, chloroform-d) δ8.51(s,1H),7.47(d,J=8.3Hz,1H),7.39~7.28(m,1H),7.24(s,1H),4.64~4.45(m,1H),3.98(dd,J=12.1,3.5Hz,1H) ,3.81(dd,J=12.1,4.7Hz,1H),3.73~3.56(m,1H),3.49~3.35(m,2H),2.20(dd,J=23.3,14.6Hz,2H),2.08~1.85(m,2H),1.35(d,J=6.5Hz,3H). LCMS m / z 268.23[M+H] + . Note that the stereochemistry of alcohol S4 was assigned based on literature understanding of reductions using this catalyst and complex system. (See: New Chiral Rhodium and Iridium Complexes with Chiral Diamine Ligands for Asymmetric Transfer Hydrogenation of Aromatic Ketones. Kunihiko Murata, Takao Ikariya, and Ryoji Noyori. The Journal of Organic Chemistry 1999 64(7), 2186-2187.)

[0154] Preparation S5 (1R,2'S)-7-chloro-2'-methyl-1'-prop-2-ynyl-spiro[isochroman-1,4'-piperidine] (S5) [ka] To a solution of (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine] S1 (263 mg, 0.5223 mmol) in acetonitrile (2.6 mL) was added propargyl bromide (270 μL, 3.030 mmol, 80% v / v in toluene) and potassium carbonate (182 mg, 1.317 mmol). The reaction was stirred at 70 °C for 17 min. The reaction was cooled to room temperature and quenched with water (5 mL). The aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel chromatography eluting with 0-10% methanol in DCM to give (1R,2'S)-7-chloro-2'-methyl-1'-prop-2-ynyl-spiro[isochroman-1,4'-piperidine] S5 (137.8 mg, 86%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.20 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.2, 2.1 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 4.03–3.83 (m, 2H), 3.69 (dd, J = 17.3, 2.4 Hz, 1H), 3.45 (dd, J = 17.3, 2.5Hz,1H),2.96(td,J=11.2,4.6Hz,1H),2.89~2.64(m,4H),2.27(s,1H),2.08~1. 96(m,2H),1.96~1.87(m,1H),1.72(dd,J=13.8,11.4Hz,1H),1.12(d,J=6.3Hz,3H). LCMS m / z 290.24[M+H] + .

[0155] Preparation S6 5-Methylspiro[isochroman-1,4'-piperidine] (S6) [ka] Step 1. Synthesis of 5-methylspiro[isochroman-1,4'-piperidine] To a solution of 2-(o-tolyl)ethanol C94 (410 mg, 2.4084 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate C95 (576 mg, 2.8331 mmol) in DCM (2.5 mL) was added TFA (2.5 mL). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. The crude material was dissolved in dioxane (10 mL), cooled to 0° C., and triflic acid (678.16 mg, 0.4 mL, 4.4284 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with 1 M NaOH (150 ml), and the aqueous layer was extracted with ethyl acetate (250×2 ml). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give 5-methylspiro[isochroman-1,4'-piperidine] S6 as a yellow adhesive (350 mg, 16%). LCMS m / z 218.21 [M+H] + .

[0156] Preparation S7 7-Chlorospiro[isochroman-1,4'-piperidine]S7 [ka] Step 1. Synthesis of 2-(2-bromo-4-chloro-phenyl)ethoxy-tert-butyl-dimethyl-silane C97 To a solution of 2-(2-bromo-4-chloro-phenyl)ethanol C96 (1860 mg, 7.898 mmol) in DCM (16 mL) was added TBSCl (1.80 g, 11.94 mmol) and imidazole (1.08 g, 15.86 mmol). The resulting white slurry was stirred at room temperature for 2.5 h. The reaction was diluted with DCM and quenched with 1 M HCl. The organic layer was extracted with DCM (3 × 50 mL) and washed with brine (50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel chromatography eluting with 0–50% ethyl acetate in heptane to afford a colorless oil, 2-(2-bromo-4-chloro-phenyl)ethoxy-tert-butyl-dimethyl-silane C97 (2738 mg, 99%). 1H NMR (300MHz, chloroform-d) δ7.54(d, J=1.6Hz, 1H), 7.20(d, J=1.8Hz, 2H), 3.80(t, J=6.7Hz, 2H), 2.93(t, J=6.7Hz, 2H), 0.86(s, 9H), -0.03(s, 6H).

[0157] Step 2. Synthesis of tert-butyl 4-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-phenyl]-4-hydroxy-piperidine-1-carboxylate C98 To a solution of 2-(2-bromo-4-chloro-phenyl)ethoxy-tert-butyl-dimethyl-silane C97 (10 g, 28.591 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (5.6967 g, 28.591 mmol) in THF (100 mL) was added n-BuLi (18.646 mL of 2.3 M, 42.886 mmol) dropwise at −78° C. and stirred for 4 hours. The reaction mixture was diluted with saturated NH4Cl solution (200 mL) and allowed to warm to room temperature. The reaction mixture was extracted with ethyl acetate (3×250 ml). The organic layer was washed with water (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 0-40% ethyl acetate in heptane to give tert-butyl 4-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-phenyl]-4-hydroxy-piperidine-1-carboxylate C98 (4 g, 30%). LCMS m / z 470.00 [M+H] + .

[0158] Step 3. Synthesis of tert-butyl 4-[5-chloro-2-(2-hydroxyethyl)phenyl]-4-hydroxy-piperidine-1-carboxylate C99 To a solution of tert-butyl 4-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-phenyl]-4-hydroxy-piperidine-1-carboxylate C98 (4 g, 8.5085 mmol) in THF (10 mL) was added TBAF (12.763 mL of 1 M, 12.763 mmol) at room temperature, and the reaction was allowed to stir for 2 hours. The reaction mixture was extracted with ethyl acetate (2 × 100 ml). The combined organic layers were washed with water (80 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0–17% ethyl acetate in heptane to give tert-butyl 4-[5-chloro-2-(2-hydroxyethyl)phenyl]-4-hydroxy-piperidine-1-carboxylate C9 (2.9 g, 96%). 1 H NMR(400MHz,DMSO-d6)δ7.39(d,J=2.0Hz,1H),7.28%E2%80%93 7.18(m,2H),5.19(s,1H),4.76(t,J=5.1Hz,1H),3.85(d,J=12.7Hz,2H),3.59(td,J=7.2,4.9Hz ,2H),3.06(t,J=7.2Hz,2H),1.86(dt,J=12.5,6.6Hz,2H),1.75(d,J=13.1Hz,2H),1.41(s,9H). LCMS m / z 356.20[M+H] + .

[0159] Step 4. Synthesis of tert-butyl 7-chlorospiro[isochroman-1,4'-piperidine]-1'-carboxylate C100 To a solution of tert-butyl 4-[5-chloro-2-(2-hydroxyethyl)phenyl]-4-hydroxy-piperidine-1-carboxylate C99 (1.2 g, 3.3722 mmol) in DCM (30 mL) was added triethylamine (853.08 mg, 1.1750 mL, 8.4305 mmol) and methanesulfonyl chloride (579.44 mg, 0.3915 mL, 5.0583 mmol). The reaction was then stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 2). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude tert-butyl 7-chlorospiro[isochroman-1,4'-piperidine]-1'-carboxylate C100 (650 mg, 57%). LCMS m / z 338.00[M+H] + .

[0160] Step 5. Synthesis of 7-chlorospiro[isochroman-1,4'-piperidine] S7 To a solution of tert-butyl 7-chlorospiro[isochroman-1,4'-piperidine]-1'-carboxylate C100 (1 g, 2.960 mmol) in dioxane (23 ml) was added HCl (7.4 mL of 4 M, 29.60 mmol). The reaction was stirred at room temperature for 16 hours. The solid was filtered and dried under vacuum to give a white solid 7-chlorospiro[isochroman-1,4'-piperidine] S7 (700 mg, 70%). LCMS m / z 238.44 [M+H] + .

[0161] Preparation S8 Chlorospiro[isochroman-1,4'-piperidine] (S6) [ka] Synthesis of spiro[isochroman-1,4'-piperidine]S8 The compound was prepared from commercially available C101 according to the method described for compound S7. The reaction was evaporated to give spiro[isochroman-1,4'-piperidine] S8 (985 mg, 89%) as a white HCl salt. 1H NMR(400MHz,DMSO)δ9.02(s,1H),7.25(t,J=7.3Hz,1H),7.19(t,J=6.8Hz,1H),7.17~7.12(m,2H),3.86(t,J=5.5Hz,2H),3.19(d d,J=12.2,3.3Hz,2H),3.06(td,J=12.8,2.2Hz,2H),2.77(t,J=5.4Hz,2H),2.27(td,J=14.0,4.6Hz,2H),1.93(d,J=14.2Hz,2H). LCMS m / z 204.30[M+H] + .

[0162] Preparation S9 6-Methoxyspiro[isochroman-1,4'-piperidine] (S9) [ka] Synthesis of 6-methoxyspiro[isochroman-1,4'-piperidine] (S9) The compound was prepared from commercially available C106 according to the method described for compound S7. The reaction mixture was concentrated under reduced pressure. Saturated Na2CO3 solution was added to maintain pH 10, diluted with cold (50 mL), and extracted with DCM (50 mL x 2). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 6-methoxyspiro[isochroman-1,4'-piperidine] S9 (120 mg, 65%). LCMS m / z 234.17 [M+H] + .

[0163] Preparation S10 7-(Trifluoromethyl)spiro[isochroman-1,4'-piperidine] (S10) [ka] Synthesis of 7-(trifluoromethyl)spiro[isochroman-1,4'-piperidine] S10 Compound S8 was prepared from compound C29 according to the method described for compound S7. The reaction mixture was concentrated under reduced pressure to give 7-(trifluoromethyl)spiro[isochroman-1,4'-piperidine] S10 (110 mg, 41%) as the trifluoroacetic acid salt. LCMS m / z 272.00 [M+H] + .

[0164] Preparation S11 7-Chlorospiro[isochroman-1,4'-piperidin]-4-ol (S11) [ka] Step 1. Synthesis of tert-butyl 4-(2-bromo-5-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (C118) To a solution of 1-bromo-4-chloro-2-iodo-benzene C116 (6.8 g, 21.43 mmol) in water (10 mL) and 1,4-dioxane (30 mL), Pd(dppf)Cl2 (1.2 g, 1.640 mmol), K2CO3 (6.7 g, 48.48 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate C117 (5000 mg, 16.17 mmol) were added. Nitrogen gas was bubbled through the stirred reaction mixture for 15 minutes. The reaction mixture was then stirred at 80 °C for 16 hours. The reaction was warmed to room temperature, quenched with water (25 ml), extracted with ethyl acetate (3 × 25 ml), and washed with brine (75 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0 to 15% ethyl acetate in heptane to afford tert-butyl 4-(2-bromo-5-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate C118 (4.42 g, 71%) as a yellow oil. 1H NMR (300MHz, chloroform-d) δ7.49(d, J=8.5Hz, 1H), 7.18(d, J=2.6Hz, 1H), 7.12(dd, J=8.4, 2.6H z, 1H), 5.66(s, 1H), 4.06(d, J=3.6Hz, 2H), 3.64(t, J=5.5Hz, 2H), 2.42(s, 2H), 1.52(s, 9H). LCMS m / z 372.05[M+H] + .

[0165] Step 2. Synthesis of tert-butyl 4-(2-bromo-5-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylate (C119) To a solution of tert-butyl 4-(2-bromo-5-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate C118 (500 mg, 1.342 mmol) in THF (10 mL) under oxygen, Co(acac)2 (38 mg, 0.2147 mmol) was added, followed by PhSiH3 (250 μL, 2.028 mmol) and stirred for 1 day. The mixture was quenched with 1 M sodium thiosulfate solution and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel chromatography using 0 to 35% ethyl acetate in heptane to give tert-butyl 4-(2-bromo-5-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylate C119 (280 mg, 53%). 1 H NMR(300MHz,DMSO-d6)δ7.84(d,J=2.7Hz,1H),7.62(d,J=8.4Hz,1H),7.28(dd,J=8.4,2.7 Hz, 1H), 5.52 (s, 1H), 3.86 (d, J=12.8Hz, 2H), 3.11 (s, 2H), 2.74~2.54 (m, 4H), 1.42 (s, 9H).

[0166] Step 3. Synthesis of tert-butyl 4-(5-chloro-2-vinyl-phenyl)-4-hydroxy-piperidine-1-carboxylate (C120) To a solution of tert-butyl 4-(2-bromo-5-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylate C119 (2000 mg, 5.119 mmol) in toluene (30 mL) under nitrogen, tributyl(vinyl)stannane (2.5 mL, 8.554 mmol) and Pd(PPh3)4 (180 mg, 0.1558 mmol) were added. The mixture was sparged with nitrogen for 15 minutes and capped. The reaction was stirred at 120 °C for 1 hour. It was warmed to room temperature and washed with 1 M NaOH. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel chromatography eluting with 0–25% ethyl acetate in heptane to give tert-butyl 4-(5-chloro-2-vinyl-phenyl)-4-hydroxy-piperidine-1-carboxylate C120 (1.2403 g, 72%). 1 H NMR (400MHz, chloroform-d) δ7.58(dd,J=17.4,10.9Hz,1H),7.45~7.35(m,2H),7.29~7.24(m,1H),5.52(dd,J= 17.3,1.4Hz,1H),5.35~5.27(m,1H),4.09(d,J=35.8Hz,2H),3.28(s,2H),2.09~1.91(m,4H),1.50(s,9H).

[0167] Step 4. Synthesis of tert-butyl 7-chloro-4-hydroxy-spiro[isochroman-1,4'-piperidine]-1'-carboxylate (C121) To a solution of tert-butyl 4-(5-chloro-2-vinyl-phenyl)-4-hydroxy-piperidine-1-carboxylate (315 mg, 0.9324 mmol) in DCM (5 mL) was added mCPBA (270 mg, 1.173 mmol). The reaction was stirred for 16 h. It was quenched with 1 M NaOH, extracted with DCM (2 × 10 mL) on a PTFE frit, and loaded directly onto a silica gel column. Elution with 0–60% ethyl acetate in heptane afforded tert-butyl 7-chloro-4-hydroxy-spiro[isochroman-1,4′-piperidine]-1′-carboxylate C121 (200 mg, 61%). 1H NMR (400MHz, chloroform-d) δ7.25~7.18(m,1H),7.07(dt,J=8.0,0.7Hz,1H),7.00(d,J=1.8Hz,1H),5.19(ddd,J=5.5,3.5,1.0Hz,1H),4.05(q,J=7.1Hz, 2H),3.85(dd,J=11.7,3.5Hz,1H),3.69(dd,J=11.7,5.4Hz,1H),3.11(s,2 H),1.86(td,J=13.2,5.0Hz,1H),1.65(q,J=11.1,9.2Hz,3H),1.42(s,9H). LCMS m / z 353.73[M+H] + .

[0168] Step 5. Synthesis of 7-chlorospiro[isochroman-1,4'-piperidin]-4-ol S11 To a solution of tert-butyl 7-chloro-4-hydroxy-spiro[isochroman-1,4'-piperidine]-1'-carboxylate (25 mg, 0.07065 mmol) in dioxane (1 mL) was added HCl (250 μL of 4 M, 1.000 mmol) and stirred for 3 h. The crude reaction was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns), Gradient: MeCN in HO with 0.1% trifluoroacetic acid) to give 7-chlorospiro[isochroman-1,4'-piperidin]-4-ol (17 mg, 62%) as the trifluoroacetate salt S11. 1 H NMR(400MHz,DMSO-d6)δ9.01(s,2H),7.44~7.31(m,2H),7.21(d,J=1.8Hz,1H),5.16(t,J=4.5Hz,1H),4.92(s,1H),3.71 ~3.59(m,2H),3.39~3.25(m,2H),3.11(dq,J=23.0,11.7Hz,2H),2.18(dtd,J=27.6,13.6,4.6Hz,2H),1.90~1.72(m,2H). LCMS m / z 254.08[M+H] + .

[0169] Compound S12 (2'S)-7-Chloro-2'-methyl-spiro[isochroman-1,4'-piperidine] (S12) [ka] Step 1. Synthesis of 2-(4-chloro-3-nitro-phenyl)acetic acid C123 To a solution of 2-(4-chlorophenyl)acetic acid C122 (10 g, 0.0586 mol) in H2SO4 (50 mL) was added potassium nitrate (6.6 g, 0.0646 mol) portionwise at 0 °C and stirred for 2 h. The progress of the reaction was monitored by TLC with 50% ethyl acetate in hexane (0.4 rf). After completion, the reaction mass was poured into ice-cold water (500 mL) and the solid was filtered, washed with water, and dried under reduced pressure to give an off-white solid 2-(4-chloro-3-nitro-phenyl)acetic acid C123 (10 g, 71%). 1 H NMR (400MHz, CDCl3) δ7.82 (s, 1H), 7.52 (d, J=8.0Hz, 1H), 7.46~7.43 (m, 1H), 3.72 (s, 2H).

[0170] Step 2. Synthesis of 2-(4-chloro-3-nitro-phenyl)ethanol C124 To a solution of 2-(4-chloro-3-nitro-phenyl)acetic acid C123 (8 g, 0.0371 mol) in THF (80.000 mL) was slowly added BH3 (solution in THF) (55.700 mL of 1 M, 0.0557 mol) at 0 °C. The reaction was heated at 60 °C for 16 h. The reaction was cooled to ambient temperature, quenched with 1 M HCl (50 ml), water (250 ml) was added, and extracted with ethyl acetate (2 × 300 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using silica gel chromatography using 0–20% ethyl acetate in petroleum ether to give a yellow oil, 2-(4-chloro-3-nitro-phenyl)ethanol C124 (7 g, 92%). (400MHz, CDCl3), δppm7.77(d, J=1.6Hz, 1H), 7.48~7.46(m, 1H), 7.42~7.39(m, 1H), 3.905(t, J=6.4Hz, 2H), 2.91(t, J=6.4Hz, 2H).

[0171] Step 3. Synthesis of 2-(3-amino-4-chloro-phenyl)ethanol C125 To a solution of 2-(4-chloro-3-nitro-phenyl)ethanol C124 (420 mg, 0.0015 mol) in acetic acid (5.0 mL) was added Fe (503 mg, 0.0090 mol) at room temperature, and the reaction mixture was stirred at 80 °C for 1 hour. The progress of the reaction was monitored by TLC with 50% ethyl acetate in hexane (0.3 rf). After completion, the reaction mass was filtered and washed with ethyl acetate (100 mL). The filtrate was washed with sodium bicarbonate solution (100 mL), and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography eluting with 40% ethyl acetate in hexane to give 2-(3-amino-4-chloro-phenyl)ethanol C125 (200 mg, 76%). 1 H NMR (400MHz, CDCl3) δ7.17(d, J=8.0Hz, 1H), 6.44(s, 1H), 6.55(dd, J=8.4, 2.0Hz, 1H), 3.821(t, J=6.4Hz, 2H), 2.751(t, J=6.4Hz, 2H). LCMS m / z 172.13[M+H] + .

[0172] Step 4. Synthesis of (2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine]-6-amine C126 To a solution of 2-(3-amino-4-chloro-phenyl)ethanol C125 (100 mg, 582.67 μmol) in toluene (1.5 mL) was added tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate C1 (149.12 mg, 699.20 μmol), followed by BF3.OEt2 (411.59 mg, 0.3642 mL, 0.0029 mol) at ambient temperature. The reaction was stirred at 120° C. for 16 hours. The reaction was concentrated under reduced pressure, basified with saturated sodium bicarbonate solution (10 ml), and extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine]-6-amine C126 (150 mg, 49%). LCMS m / z 267.00 [M+H] + .

[0173] Step 6. Synthesis of (2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine] S12 To a solution of (2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine]-6-amine C126 (50 mg, 129.33 μmol) in HCl (3.0000 mL of 2 M, 0.0060 mol) was added NaNO2 (11.896 mg, 129.33 μmol) at ambient temperature and then cooled to 0 °C. Fluoroboric acid (0.0341 mL of 50% w / v, 194.00 μmol) was added slowly at 0 °C, and the reaction was allowed to warm to ambient temperature and stirred for 16 h. The reaction was quenched with water (10 ml), basified with saturated sodium bicarbonate solution (5 ml), and extracted with ethyl acetate (2 × 50 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine] 3 (25 mg, 28%). LCMS m / z 252.00 [M+H] + .

[0174] Preparation S13 7-Chloro-3'-methylspiro[isochroman-1,4'-piperidine] (S13) [ka] Step 2. Synthesis of tert-butyl 4-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-phenyl]-4-hydroxy-3-methyl-piperidine-1-carboxylate C128 To a solution of 2-(2-bromo-4-chloro-phenyl)ethoxy-tert-butyl-dimethyl-silane C97 (1 g, 0.0029 mol) in THF (15.000 mL) was added t-BuLi (2.0588 mL of 1.7 M, 0.0035 mol) slowly over 10 minutes at −100° C. The reaction was stirred at −100° C. for 30 minutes, and then tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate C127 (746.46 mg, 0.0035 mol) in 1 ml of THF was added slowly over 15 minutes at −100° C. The reaction was stirred at the same temperature for 30 minutes, then slowly warmed to ambient temperature and stirred for 1 hour. The reaction was quenched with saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 4-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-phenyl]-4-hydroxy-3-methyl-piperidine-1-carboxylate C128 (1.5 g, 31%). LCMS m / z 484.00 [M+H] + .

[0175] Step 3. Synthesis of 7-chloro-3'-methyl-spiro[isochroman-1,4'-piperidine] S13 To a solution of tert-butyl 4-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-phenyl]-4-hydroxy-3-methyl-piperidine-1-carboxylate C128 (100 mg, 206.55 μmol) in toluene (1.5 mL) was added BF 3.OEt2 (298.05 mg, 0.2638 mL, 0.0021 mol) was added at room temperature, and the reaction was then stirred at ambient temperature for 16 hours, monitored by TLC until completion. The reaction was concentrated under reduced pressure, basified with saturated sodium bicarbonate solution (20 ml), and extracted with ethyl acetate (2 x 100 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 7-chloro-3'-methyl-spiro[isochroman-1,4'-piperidine] S13 (40 mg, 42%). LCMS m / z 252.00 [M+H] + .

[0176] Compound S14 (2'S)-2'-Methylspiro[isochroman-1,4'-piperidine] (S14) [ka] Compound S14 was prepared from compound C13 according to the method described for compound S1. The crude reaction was purified by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD Prep Column; 30 × 150 mm, 5 microns. Gradient: acetonitrile in water with 5 mM hydrochloric acid) to give 2'S)-2'-methylspiro[isochroman-1,4'-piperidine] S14 (26 mg, 47%) as the HCl salt. 1 H NMR (300MHz, chloroform-d) δ7.33~7.08(m,3H),3.93(t,J=5.6Hz,2H),3.62(s,1H),3.42(d d,J=12.6,3.8Hz,1H),2.83(t,J=5.6Hz,2H),2.31~1.87(m,4H),1.36(d,J=6.6Hz,3H). LCMS m / z 218.24[M+H] + .

[0177] Preparation of C136 and C137 (1R,2'S)-tert-butyl 2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochroman-1,4'-piperidine]-1'-carboxylate (C136) and tert-butyl (1S,2'S)-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochroman-1,4'-piperidine]-1'-carboxylate (C137) [ka] Synthesis of (1R,2'S)-tert-butyl 2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochroman-1,4'-piperidine]-1'-carboxylate (C136) and tert-butyl (1S,2'S)-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochroman-1,4'-piperidine]-1'-carboxylate (C137). To a solution of tert-butyl (2'S)-6-hydroxy-2'-methyl-spiro[isochroman-1,4'-piperidine]-1'-carboxylate C132 (766.1 mg, 2.298 mmol) in DCM (18 mL) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (2.1 g, 5.878 mmol), tetrabutylammonium hydrogen sulfate (1.1 g, 3.240 mmol), and then NaOH (8.5 mL of 2 M, 17.00 mmol). The mixture was stirred at room temperature for 16 h. The organic layer was separated using a phase separator and DCM (3 × 25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel chromatography using 0–10% ethyl acetate in hexane to give two diastereomers. The absolute stereochemistry was confirmed by H NMR analysis. (1R,2'S)-2'-Methyl-6-(trifluoromethylsulfonyloxy)spiro[isochroman-1,4'-piperidine]-1'-carboxylate tert-butyl C136 (425.6 mg, 79%) LCMS m / z 366.01 [M-Boc+H] +and (1S,2'S)-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochroman-1,4'-piperidine]-1'-carboxylate tert-butyl C137 (240.8 mg, 42%) LCMS m / z 366.01 [M-Boc+H] +

[0178] Compound S15 (1R,2'S)-6-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine] (S15) [ka] Steps 1 and 2. Synthesis of (1R,2'S)-6-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine] (S15) To tert-butyl (2'S)-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochroman-1,4'-piperidine]-1'-carboxylate (307 mg, 0.6595 mmol) was added tBuBrettPhos Pd G3 (59.34 mg, 0.06945 mmol), KCl (127 mg, 1.704 mmol), and KF (25.42 mg, 0.4375 mmol) and purged with nitrogen three times. Dioxane (3.4 mL) was added and the mixture was heated to 130°C for 24 hours. The reaction was cooled to 23°C, and HCl (4.397 mL of 6 M, 26.38 mmol) was added and stirred for 16 hours. The crude reaction material was concentrated. The crude reaction was purified using reverse-phase HPLC (Method: Waters XBridge preparative C8 column, 30 × 150 mm, 5 micron. Gradient: acetonitrile in water with 10 mM ammonium hydroxide) to give (1R,2′S)-6-chloro-2′-methyl-spiro[isochroman-1,4′-piperidine] S15 (27 mg, 16%). 1 H NMR (300MHz, chloroform-d) δ7.28~6.96(m,3H),3.94~3.81(m,2H),3.48~3.35(m,2H),2.96~2.64(m,3H),2.11~1.75(m,4H),1.43(d,J=7.0Hz,3H). LCMS m / z 252.20[M+H] + .

[0179] Preparation C140 (2'S)-2',7-Dimethylspiro[isochroman-1,4'-piperidine](C140) [ka] Compound C140 was prepared from C83 and C139 according to the method described for compound S6. The reaction was basified with 1M NaOH (20 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the product (2'S)-2',7-dimethylspiro[isochroman-1,4'-piperidine] C140 (180 mg, 36%). LCMS m / z 232.00 [M+H] + .

[0180] Preparation of compound S16 2',7-Dimethylspiro[isochroman-1,4'-piperidine] (S16) [ka] Step 1. Synthesis of 5-(2-hydroxyethyl)-2-methyl-phenol (C142) To a solution of 2-(3-hydroxy-4-methyl-phenyl)acetic acid C141 (890 mg, 5.356 mmol) in THF (11 mL) at 0 °C was slowly added BH3-THF (10.7 mL of 1 M, 10.70 mmol). The reaction was warmed to room temperature and stirred overnight for 16 hours. The reaction was cooled to 0 °C and slowly quenched with methanol (12 ml) until effervescence disappeared. The reaction was concentrated in vacuo. The crude material was purified using silica gel chromatography eluting with 0-100% ethyl acetate in heptane to give 5-(2-hydroxyethyl)-2-methyl-phenol C142 (800 mg, 98%). 1H NMR (300MHz, chloroform-d) δ7.06(d,J=7.5Hz,1H),6.71(dd,J=7.6,1.7Hz,1H),6.66(d,J= 1.7Hz, 1H), 4.83 (s, 1H), 3.84 (s, 2H), 2.79 (t, J=6.5Hz, 2H), 2.22 (s, 3H), 1.43 (s, 1H). LCMS m / z 135.00[M-OH+H] + .

[0181] Step 2. Synthesis of 1'-benzyl-2',7-dimethyl-spiro[isochroman-1,4'-piperidin]-6-ol (C144) To a solution of 1-benzyl-2-methyl-piperidin-4-one C142 (150 mg, 0.7379 mmol) and 1-benzylpiperid-4-one C143 (124 mg, 0.8148 mmol) in dioxane (2.3 mL) was added triflic acid (221 mg, 1.473 mmol) slowly at 0 °C. The reaction was warmed to room temperature and stirred for 2.5 hours. The reaction was quenched with saturated NaHCO3 and extracted with DCM (15 ml × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. This material was carried forward as a mixture of diastereomers. 1'-benzyl-2',7-dimethyl-spiro[isochroman-1,4'-piperidin]-6-ol C61 (310 mg, 125%) LCMS m / z 338.00 [M+H] + .

[0182] Step 3. Synthesis of (1'-benzyl-2',7-dimethyl-spiro[isochroman-1,4'-piperidin]-6-yl)trifluoromethanesulfonate (C145) To a solution of 1'-benzyl-2',7-dimethyl-spiro[isochroman-1,4'-piperidin]-6-ol C144 (249 mg, 0.7379 mmol) in DCM (3.7 mL) was added pyridine (134 μL, 1.2587 mmol) at 0 °C, followed by trifluoromethanesulfonic anhydride (149 μL, 0.8856 mmol). The resulting yellow solution was warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated NaHCO and extracted with DCM (8 mL × c) using a phase separator. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (1'-benzyl-2',7-dimethyl-spiro[isochroman-1,4'-piperidin]-6-yl)trifluoromethanesulfonate C145 (346 mg, >99%). LCMS m / z 470.00[M+H] + .

[0183] Step 4. Synthesis of (cis) 1'-benzyl-2',7-dimethyl-spiro[isochroman-1,4'-piperidine] C146 and (trans) 1'-benzyl-2',7-dimethyl-spiro[isochroman-1,4'-piperidine] C147 To (1'-benzyl-2',7-dimethyl-spiro[isochroman-1,4'-piperidin]-6-yl)trifluoromethanesulfonate C145 (346 mg, 0.7369 mmol) was added Pd(dppf)Cl2 (60 mg, 0.07347 mmol). The mixture was purged with nitrogen three times. Under nitrogen, DMF (3.7 mL), triethylamine (308 μL, 2.210 mmol), and formic acid (56 μL, 1.484 mmol) were added. The resulting solution was stirred at 60 °C for 16 hours. The reaction was concentrated in vacuo. The crude was diluted with DCM (5 mL) and quenched with saturated sodium bicarbonate. The organic layer was extracted with DCM (5 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. 20 mg of the crude material was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns), Gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give a mixture of cis and trans diastereomers C146 and C147 1′-benzyl-2′,7-dimethyl-spiro[isochroman-1,4′-piperidine](trifluoroacetate) (11.8 mg, 3%). 1 H NMR (300 MHz, chloroform-d) δ 7.52 (dd, J = 6.9, 3.7 Hz, 5H), 7.01 (s, 2H), 6.92 (s, 1H), 4.85 (d, J = 13.1 Hz, 1H), 4.13 (d, J = 13.1 Hz, 1H), 3.96–3.81 (m, 2H), 3.74 (dt, J = 11.7, 6.1 Hz,1H),3.25~3.35(m,1H),3.18(dt,J=12.4,3.5Hz,1H),2.77(q,J=5.3Hz,2H),2.2 9(s,3H),2.18(d,J=9.9Hz,2H),2.09(dd,J=11.5,4.1Hz,2H),1.61(d,J=6.5Hz,3H). LCMS m / z 322.31[M+H] +The remaining material was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns), Gradient: MeCN in HO containing 0.1% trifluoroacetic acid) to give the cis and trans diastereomers as trifluoroacetate (cis) 1'-benzyl-2',7-dimethyl-spiro[isochroman-1,4'-piperidine] (trifluoroacetate) C146 (11.8 mg, 3%). 1 H NMR (300 MHz, chloroform-d) δ 7.52 (dd, J = 6.9, 3.7 Hz, 5H), 7.01 (s, 2H), 6.92 (s, 1H), 4.85 (d, J = 13.1 Hz, 1H), 4.13 (d, J = 13.1 Hz, 1H), 3.96–3.81 (m, 2H), 3.74 (dt, J = 11.7, 6.1 Hz, 1H), 3.25~3.35(m, 1H), 3.18(dt, J=12.4, 3.5Hz, 1H), 2.77(q, J=5.3Hz, 2H), 2.2 9(s, 3H), 2.18(d, J=9.9Hz, 2H), 2.09(dd, J=11.5, 4.1Hz, 2H), 1.61(d, J=6.5Hz, 3H). LCMS m / z 322.31[M+H] + and (trans)1'-benzyl-2',7-dimethyl-spiro[isochroman-1,4'-piperidine](trifluoroacetate) C147 (4.1 mg, 1%) 1 H NMR (300MHz, chloroform-d) δ7.61(dd,J=6.6,2.9Hz,2H),7.52(q,J=3.4,2.8Hz,3H),7.0 2(d,J=10.4Hz,2H),6.91(s,1H),4.44~4.28(m,2H),3.92(dd,J=6.5,4.6Hz,2H),3.7 9(q,J=7.0Hz,1H),3.70~3.55(m,1H),3.30~3.15(m,1H),2.79(dt,J=9.9,5.5Hz,2H) ,2.44~2.32(m,2H),2.25(d,J=13.3Hz,4H),2.14~2.00(m,1H),1.68(d,J=7.2Hz,3H). LCMS m / z 322.00[M+H] + .

[0184] Step 5. Synthesis of 2',7-dimethylspiro[isochroman-1,4'-piperidine] (S16) To a solution of (trans)1'-benzyl-2',7-dimethyl-spiro[isochroman-1,4'-piperidine] (trifluoroacetate) C147 (160 mg, 0.4977 mmol) in MeOH (3.3 mL) was added Pd(OH)2 (35 mg, 0.04985 mmol). The resulting slurry was bubbled with H2 for 1 minute and then stirred under a hydrogen atmosphere using a balloon for 4 hours. The reaction was filtered through Celite, washed with MeOH, and concentrated in vacuo to give a white solid. 14 mg of the crude material was purified by reverse-phase HPLC (Method: C18 Waters Sunfire column (30 × 150 mm, 5 microns), Gradient: MeCN in HO with 0.1% trifluoroacetic acid) to give 4:1 trans:cis 2',7-dimethylspiro[isochroman-1,4'-piperidine] S16 (12.6 mg, 7%) as the triflate salt. LCMS m / z 232.00 [M+H] + .

[0185] Preparation S17 4-Methylspiro[isochroman-1,4'-piperidine] (S17) [ka] Compound S17 was prepared from compound C148 according to the method described for compound S7. The crude reaction was quenched with saturated sodium bicarbonate to achieve pH 10, diluted with cold water (50 mL), and extracted with DCM (50 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude 4-methylspiro[isochroman-1,4'-piperidine] S17 (170 mg, 87%). LCMS m / z 218.2 (M+H) + .

[0186] Preparation S18 1-(2-Methylsulfonylethyl)triazole-4-carbaldehyde (S18) [ka] Synthesis of 1-(2-methylsulfonylethyl)triazole-4-carbaldehyde (S18) To a solution of 1-azido-2-methylsulfonyl-ethane C154 (2 g, 0.0134 mol) in MeOH (80.000 mL) and HO (10.000 mL) was added 3,3-diethoxyprop-1-yne C153 (1.6662 g, 0.0130 mol), sodium (+)-L-ascorbate (2.6348 g, 0.0133 mol), and CuSO4 (49.191 mg, 308.20 μmol). The reaction was stirred at 65 °C for 4 hours and cooled to ambient temperature. The reaction was diluted with ethyl acetate (150 mL), water (100 mL), and stirred for 20 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. This material was suspended in 1 M HCl (80 mL) and stirred at ambient temperature for 24 h. The reaction mixture was concentrated in vacuo to give 1-(2-methylsulfonylethyl)triazole-4-carbaldehyde S18 (1.2 g, 33%). 1 H NMR (300MHz, DMSO-d6) δ=8.27(s,1H),5.65(s,1H),5.07~4.97(t,J=6.6Hz,2H),3.07~3.03(t,J=6.6Hz,2H),2.97(s,3H). LCMS m / z 203.90[M+H] + .

[0187] compound 88 (1R,2'S)-7-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isochroman-1,4'-piperidine] (88) [ka] Reductive amination: Standard method A Synthesis of (1R,2'S)-7-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isochroman-1,4'-piperidine] (88) To a solution of (1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine] 1 (24.4 mg, 0.084 mmol) in 1,2-dichloroethane (1.7 mL) was added 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde S12 (23.7 mg), NaBH(OAc)3 (53 mg), and stirred for 16 h at 80° C. The reaction was cooled to room temperature, filtered through a silica gel plug, and concentrated. The crude material was purified by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30 × 150 mm, 5 micron. Gradient: acetonitrile in water with 0.1% trifluoroacetic acid) to give (1R,2'S)-7-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isochroman-1,4'-piperidine] 88 (28.2 mg, 59%) as the trifluoroacetate salt. 1 H NMR (300MHz, chloroform-d) δ8.01(s,1H),7.75(d,J=0.8Hz,1H),7.28~7.10(m,3H),4.76~4.66(m,2H),4.55(d,J=14.1Hz,1H),4.31(d,J=14.1Hz,1H),3 .97~3.81(m,3H),3.73(dd,J=6.8,5.5Hz,2H),3.59~3.43(m,1H),2.87(d, J=0.7Hz,3H),2.85~2.73(m,3H),2.28~1.95(m,4H),1.54(d,J=6.4Hz,3H). LCMS m / z 438.31[M+H] + 。

[0188] Preparation of Compound 89 4-Methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isochroman-1,4'-piperidine] (89) [ka] Synthesis of 4-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isochroman-1,4'-piperidine] (89) Reductive amination: Standard method B To a solution of 4-methylspiro[isochroman-1,4'-piperidine] S17 (300 mg, 1.3805 mmol) in methanol (3 mL) was added 1-methylpyrazole-3-carbaldehyde C74 (152.01 mg, 1.3805 mmol) and a catalytic amount of acetic acid. After 1 h, sodium cyanoborohydride (260.26 mg, 4.1415 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with cold water (50 mL), and extracted with DCM (50 mL × 2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC (Waters automated purification system: YMC Triart Actus C18 (250 × 20 mm, 5μ), operated at ambient temperature and a flow rate of 16 mL / min. Mobile phase: A = 20 mM ammonium bicarbonate in water, B = acetonitrile, gradient profile: initial mobile phase composition 80% A and 20% B, then 70% A and 30% B at 3 min, then 45% A and 55% B at 20 min, then 5% A and 95% B at 21 min, held at this composition up to 23 min for column wash, then returned to the initial composition at 24 min and held until 26 min) to give 4-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isochroman-1,4'-piperidine] 89. (150mg,34%)H NMR(400MHz,DMSO-d6)δ7.56(s,1H),7.30(s,1H),7.16(s,4H),3.82~3.80(m,1H),3.82(s,3H),3.51(dd,J=11.4,4.3Hz,1H),3.36(s,2H) ,2.77~2.76(m,1H),2.63~2.60(m,2H),2.29~2.19(m,2H),1.97~1.94(m,1H),1.81~1.79(m,2H),1.71~1.67(m,1H),1.20(d,J=7.0Hz,3H). LCMS m / z 312.00[M+H] + 。

[0189] Preparation of Compound 90 (1R,2'S)-7-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[isochroman-1,4'-piperidine] (90) [ka] Representative Procedure for Reductive Amination 3 A solution of (2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidine](trifluoromethanesulfonic acid) (15 mg, 0.03733 mmol) in DCM (1 mL) was washed with saturated bicarbonate solution on a phase separator (3 x 2 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was dissolved in DCM (1 mL) and, under nitrogen, 1-(2-methylsulfonylethyl)triazole-4-carbaldehyde S13 (23 mg, 0.1132 mmol) and (trimethylammonio)methylcyanoborohydride (100 mg of 1.2 mmol / g, 0.1200 mmol) were added. The mixture was capped and irradiated at 110 °C for 30 min. The resin was filtered and concentrated in vacuo. The crude material was purified by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30 x 150 mm, 5 microns. Gradient: acetonitrile in water with 0.1% trifluoroacetic acid) to give (1R,2'S)-7-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[isochroman-1,4'-piperidine] 90 as the trifluoroacetate salt (10.3 mg, 63%). LCMS m / z 439.22 [M+H] + 。

[0190] Compounds 91-139 were prepared in a single step using the reductive amination method described for compounds 88-90, using the appropriate intermediates and reagents. The aldehydes were prepared by the methods described above or obtained from commercial sources. Any modifications to the method are described in Table 12 and the accompanying footnotes. [Table 12-1]

Table 12-2

Table 12-3

Table 12-4

Table 12-5

Table 12-6

Table 12-7

Table 12-8

Table 12-9

Table 12-10

Table 12-11

Table 12-12

Table 12-13

Table 12-14

Table 12-15

Table 12-16

[0191] Compound 140 7-Chloro-3'-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isochroman-1,4'-piperidine] (140) [ka] Synthesis of 7-chloro-3'-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isochroman-1,4'-piperidine] (140) To a stirred solution of 7-chloro-3'-methyl-spiro[isochroman-1,4'-piperidine] S13 (110 mg, 419.46 μmol) in DMF (1.1000 mL) was added 4-(chloromethyl)-1-methyl-pyrazole C155 (32.863 mg, 251.68 μmol), KI (41.780 mg, 251.68 μmol), and K2CO3 (179.67 mg, 0.0013 mol) at room temperature. The reaction was heated to 80 °C for 16 hours. The reaction was cooled to room temperature, quenched with water (20 ml), and extracted with ethyl acetate (2 × 50 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified using reverse HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30 × 150 mm, 5 microns. Gradient: acetonitrile in water with 0.1% trifluoroacetic acid) to give 7-chloro-3′-methyl-1′-[(1-methylpyrazol-4-yl)methyl]spiro[isochroman-1,4′-piperidine] 140 (18 mg, 9%) as the trifluoroacetate salt. (400MHz,DMSO d6),δppm 7.88(s,1H),7.59(s,1H),7.29~7.27(m,1H),7.23~7.20(m,1H),7.05( s,1H),4.26(s,2H),3.98~3.94(m,1H),3.87(s,3H),3.71(t,J=9.2Hz, 1H),3.28~3.23(m,2H),3.09~3.03(m,1H),2.92~2.78(m,2H),2.63~2. 51(m,1H),2.33~2.29(m,2H),2.02~1.98(m,1H),0.55(d,J=6.8Hz,3H). [LCMS m / z 346.48[M+H] + 。

[0192] Preparation S19 N-Diazo-1,1,1-trifluoro-methanesulfonamide (S19) [ka] Synthesis of N-diazo-1,1,1-trifluoro-methanesulfonamide (S19) To a mixture of sodium azide C157 (300 mg, 4.615 mmol) in water (1 mL) was added DCM (2 mL) and the biphasic mixture was cooled to 0 °C. To this mixture was added TfO C156 (380 μL, 2.259 mmol) and stirred for 2 h. At this point, the layers were separated and the aqueous layer was extracted with an additional layer of DCM (2 mL). The combined organic layers were washed with saturated sodium bicarbonate (1 mL). The organic layer was added to a volumetric flask and diluted up to 5 mL with additional DCM to produce a stock solution (0.452 M) that was used the same day and the reaction was not further characterized.

[0193] compound 141 2-[4-[[(1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-1'-yl]methyl]triazol-1-yl]ethanol (141) [ka] Synthesis of 2-[4-[[(1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-1'-yl]methyl]triazol-1-yl]ethanol (141) Representative procedure for azide-transfer click. Method A The substrate, 2-aminoethanol C158 (8.348 mg, 0.1367 mmol), CuSO4 (0.2755 mg, 0.07646 μL, 0.001726 mmol), and NaHCO3 (6.175 mg, 0.07351 mmol) were suspended in water (380 μL) at a volume equal to the volume of TfN3 solution used. TfN3 (370 μL of 0.452 M, 0.1672 mmol) solution was then added, followed by methanol (700 μL) until the solution became homogeneous. The reaction was stirred at room temperature for 1 hour. (1R,2'S)-7-Chloro-2'-methyl-1'-prop-2-ynyl-spiro[isochroman-1,4'-piperidine] S5 (10 mg, 0.03451 mmol), TBTA (0.9159 mg, 0.001726 mmol), and sodium (+)-L-ascorbate (6.837 mg, 0.03451 mmol) were added and the reaction was heated at 50°C for 2 hours. The reaction was concentrated and purified by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30 × 150 mm, 5 micron. Gradient: acetonitrile in water with 0.1% trifluoroacetic acid) to give 2-[4-[[(1R,2'S)-7-chloro-2'-methyl-spiro[isochroman-1,4'-piperidin]-1'-yl]methyl]triazol-1-yl]ethanol 141 (10.7 mg, 58%) as the trifluoroacetate salt. 1 H NMR (400MHz, chloroform-d) δ8.28(s,1H),7.29~7.07(m,3H),4.74(d,J=14.4Hz,1H),4.64~4.48(m,3H),4.05~3.93(m,2H),3.88(q,J=6 .0Hz,2H),3.64(dt,J=9.6,3.5Hz,1H),3.47(dd,J=7.3,4.5Hz,2H),2.80(q,J=5.1Hz,2H),2.35~1.92(m,4H),1.60(d,J=6.4Hz,3H). LCMS m / z calculated value 377.35[M+H] + .

[0194] compound 142 (4-((4-(((1R,2'S)-7-chloro-2'-methylspiro[isochroman-1,4'-piperidine]-1'-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)methanol (142) [ka] Synthesis of (4-((4-(((1R,2'S)-7-chloro-2'-methylspiro[isochroman-1,4'-piperidine]-1'-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)methanol (142) Representative procedure for reductive azide transfer click. Method B To a solution of (4-(aminomethyl)pyridin-2-yl)methanol (HCl) C159 (14.57 mg, 0.07040 mmol) in DMSO (200 μL) was added NaHCO3 (110 μL of 1 M, 0.110 mmol). N-diazosulfamoyl fluoride (155 μL of 0.45 M, 0.06975 mmol) was added as a solution in MTBE, and the resulting mixture was stirred at room temperature for 1 h. A solution of (1R,2'S)-7-chloro-2'-methyl-1'-prop-2-ynyl-spiro[isochroman-1,4'-piperidine] S5 (10 mg, 0.03451 mmol) in DMSO (200 μL) was added, followed by aqueous copper(II) sulfate (35 μL of 0.1 M, 0.003500 mmol), aqueous (+)-L-sodium ascorbate (70 μL of 0.2 M, 0.01400 mmol), and a solution of TBTA in DMSO (35 μL of 0.1 M, 0.003500 mmol). The resulting mixture was heated at 50°C for 16 hours. The crude was concentrated and purified by reverse-phase HPLC (Method: Waters XSelect CSH C18 OBD preparative column; 30 x 150 mm, 5 micron. Gradient: acetonitrile in water with 0.2% formic acid) to give (4-((4-(((1R,2'S)-7-chloro-2'-methylspiro[isochroman-1,4'-piperidine]-1'-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)methanol 142 as the formate salt (3.5 mg, 22%). LCMS m / z calculated 454.24 [M+H] + .

[0195] Compounds 143-185 were prepared in a single step using intermediate S5 and the azide transfer click method described for compounds 141-142. Amines were obtained from commercial sources. Any modifications to the method are described in Table 13 and the accompanying footnotes. [Table 13-1] [Table 13-2]

Table 13-3

Table 13-4

Table 13-5

Table 13-6

Table 13-7

Table 13-8

Table 13-9

Table 13-10

Table 13-11

Table 13-12

Table 13-13

Table 13-14

Table 13-15

Table 13-16

Table 13-17

[0196] Compound 190 N-Methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (190) [ka] Step 1. Synthesis of 1-benzyl-4-[2-(dimethoxymethyl)phenyl]piperidin-4-ol (C162) To a stirred solution of 1-bromo-2-(dimethoxymethyl)benzene (5 g, 0.0214 mol) in THF (60 mL) was added n-BuLi (14 mL of 1.6 M, 0.0224 mol) under argon over 10 minutes at −78° C. and stirred for 5 minutes. A solution of 1-benzylpiperidin-4-one (3.4 g, 0.0176 mol) in THF (10 mL) was added and stirred at −78° C. for 2 hours, at which point the solution was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was quenched with water at 0° C., diluted with saturated NH4Cl solution, and extracted with EtOAc (2×50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 1-benzyl-4-[2-(dimethoxymethyl)phenyl]piperidin-4-ol (6.4 g, 35% yield) as a pale yellow semi-solid. LCMS m / z 342.08[M+1] + .

[0197] Step 2. Synthesis of 1'-benzyl-1-methoxy-spiro[1H-isobenzofuran-3,4'-piperidine] (C163) To a stirred solution of 1-benzyl-4-[2-(dimethoxymethyl)phenyl]piperidin-4-ol (6.4 g, 0.0075 mol) in methanol (50 mL), p-TsOH hydrate (4.5 g, 0.0232 mol) was added at room temperature and stirred for 5 days. The reaction mixture was diluted with 2 M NaOH solution to pH 10, and the compound was extracted with DCM (2 × 200 mL). The organic layer was washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 230-400) eluting with 25% EtOAc in pet ether. The collected fractions were concentrated under reduced pressure to give 1'-benzyl-1-methoxy-spiro[1H-isobenzofuran-3,4'-piperidine] (1.9 g, 59% yield) as a yellow liquid. 1 H NMR (300MHz, chloroform-d) δ7.42~7.28(m,8H),7.18(d,J=7.4Hz,1H),6.07(s,1H),3.60(s,2H),3.47(s,3H),2.92~2.8 5(m,2H),2.47(t,J=10.8Hz,2H),2.15~1.98(m,2H),1.81(dd,J=13.5Hz,2.7Hz,1H),1.64(dd,J=13.8Hz,2.7Hz,1H). LCMS m / z 310.38[M+1] + .

[0198] Step 3. Synthesis of 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C164) To a stirred solution of 1'-benzyl-1-methoxy-spiro[1H-isobenzofuran-3,4'-piperidine] (1.9 g, 0.0044 mol) in DCM (100 mL) was added TMSCN (3.8857 g, 5 mL, 0.0384 mol) and BF3.OEt2 (1.0143 g, 0.9 mL, 0.0070 mol) at -25 °C and stirred for 30 min. The mixture was then warmed to 0 °C and stirred for 1 h. The reaction mixture was quenched with methanol (1 mL) followed by 2 M NaOH solution. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 230-400) eluting with 40% EtOAc in pet ether. The collected fractions were concentrated under reduced pressure to give 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (1.4 g, 97% yield) as an off-white semi-solid. 1 H NMR (400 MHz, chloroform-d): δ 7.43–7.25 (m, 8H), 7.20 (d, J = 6 Hz, 1H), 5.87 (s, 1H), 3.59 (s, 2H), 2.88–2.82 (m, 2H), 2.53–2.38 (m, 2H), 2.10–1.91 (m, 3H), 1.73–1.69 (m, 1H). LCMS m / z 305.33 [M+1] + .

[0199] Step 4. Synthesis of ethyl 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylate (C165) To a stirred solution of 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (100 mg, 295 μmol) in EtOH (2 mL) was added H2SO4 (552.00 mg, 0.3000 mL, 0.0055 mol) and two drops of water at room temperature. The reaction mixture was stirred at 90 °C for 20 h. The reaction mixture was cooled to room temperature, diluted with cold water (10 mL), and extracted with EtOAc (2 × 20 mL). The organic layer was washed with 2 M NaOH solution (5 mL), brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 230-400) eluting with 30% EtOAc in pet ether. The collected fractions were concentrated under reduced pressure to give ethyl 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylate (70 mg, 67% yield) as a pale yellow thick liquid. 1 H NMR (400MHz, chloroform-d) δ7.41~7.26(m,8H),7.19(d,J=6.8Hz,1H),5.66(s,1H),4.22(q,J=3.2Hz,2H),3.60(s, 2H), 2.86(t,J=6.4Hz,2H),2.62~2.46(m,2H),2.11~1.97(m,3H),1.76(d,J=13.6Hz,1H),1.28(t,J=7.2Hz,3H). LCMS m / z 352.08[M+1] + .

[0200] Step 5. Synthesis of 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (C166) To a stirred solution of ethyl 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylate (0.9 g, 0.0024 mol) in THF (20 mL) was added a solution of LiOH hydrate (302 mg, 0.0071 mol) in water (6 mL) at room temperature. Methanol (3 mL) was then added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude residue. This was diluted with water (50 mL), acidified with 1 M HCl solution at 0 °C, and the compound was extracted with 10% MeOH in DCM (2 × 100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (780 mg, 99% yield) as an off-white solid. 1 H NMR(300MHz,DMSO-d6)δ7.61(d,J=4.2Hz,2H),7.47~7.39(m,6H),7.20(br s, 1H), 5.66 (s, 1H), 4.31 (s, 2H), 3.29~3.14 (m, 2H), 2.43~2.20 (m, 2H), 1.98~1.90 (m, 2H). LCMS m / z 324.28[M+1] + .

[0201] Step 6. Synthesis of 1'-benzyl-N-methyl-spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (C167) To a stirred solution of 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (780 mg, 0.0024 mol), HATU (1.13 g, 0.0029 mol), and methylamine (2 M in THF) (2.4000 mL of 2 M, 0.0048 mol) in DMF (10 mL), DIPEA (1.5270 g, 2.1 mL, 0.0116 mol) was added at room temperature and stirred for 16 hours. The reaction mass was diluted with cold water, and the compound was extracted with 5% MeOH in DCM (2 × 50 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to give 1'-benzyl-N-methyl-spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (820 mg, 84% yield) as a dark brown liquid. LCMS m / z 337.11[M+1]+ .

[0202] Step 7. Synthesis of N-methylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (C168) A suspension of 1'-benzyl-N-methyl-spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (100 mg, 243.74 μmol) and 10% palladium on carbon (25 mg, 10% w / w, 23 μmol) in methanol (5 mL) was hydrogenated under balloon pressure at room temperature for 16 h. The reaction mixture was filtered through a pad of Celite and washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography (column: C18. Gradient: 0 to 100% 1:1 MeCN:MeOH in water containing 10 mM NH4HCO3). The collected fractions were concentrated under reduced pressure to give N-methylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (16 mg, 26% yield) as an off-white gum. 1 H NMR(400MHz,DMSO-d6):δ7.55(d,J=7.6Hz,1H),7.38(d,J=7.6Hz,1H),7.38~7.26(m,2H),7.22(d,J=7.6Hz,1H),5.39(s,1H), 3.02(t,J=12.4Hz,1H),2.99~2.84(m,3H),2.63(d,J=4.8Hz,3H),1.92~1.84(m,1H),1.88~1.74(m,2H),1.67(d,J=4.8Hz,1H). LCMS m / z 247.1[M+1] + .

[0203] Step 8. Synthesis of N-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (190) A solution of N-methylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (200 mg, 649.60 μmol), 1-phenylpyrazole-4-carbaldehyde (137 mg, 779.75 μmol), and acetic acid (5 drops) in methanol (5 mL) was stirred at room temperature for 16 hours. Then, NaCNBH3 (50 mg, 779.73 μmol) was added to the reaction mixture at 0 °C, and the mixture was allowed to gradually warm to room temperature and stirred for 6 hours. The reaction mass was concentrated under reduced pressure to give the crude compound. This was purified by reverse-phase chromatography (column: C18; gradient: 0-100% 1:1 MeOH:MeCN in water containing 10 mM NH4HCO3). The collected fractions were concentrated under reduced pressure to give N-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (50 mg, 19% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ8.42(s,1H),7.83(d,J=7.6Hz,2H),7.68(s,1H),7.54~7.46(m,3H),7.38~7.25(m,5H),5.39(s,1H),3.52(s,2H),2 .81(t,J=10Hz,2H),2.62(d,J=4.8Hz,3H),2.54(s,1H),2.34(t,J=10Hz,1H),2.09~2.03(m,1H),1.87~1.82(m,2H),1.64(d,J=11.6Hz,1H). LCMS m / z 403.2[M+1] + .

[0204] Preparation S20 1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-one (S20) [ka] To a solution of 4-(chloromethyl)-1-phenyl-pyrazole (8.3 g, 0.0388 mol) in DMF (80 mL) was added piperidin-4-one (hydrochloride (1)) (7.5 g, 0.0387 mol) followed by K2CO3 (14 g, 0.100 mol) at room temperature and stirred at 100 °C for 16 h. The reaction mixture was quenched with ice / water (250 mL), diluted with ethyl acetate (2 × 500 mL), washed with brine (250 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography using 60% ethyl acetate in hexanes, and the pure fractions were concentrated under reduced pressure to give 1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-one (9.1 g, 85% yield) as a solid. 1 H NMR (400 MHz, chloroform-d) δ 7.89 (s, 1H), 7.69-7.66 (m, 3H), 7.47-7.42 (m, 2H), 7.31-7.26 (m, 1H), 3.61 (s, 2H), 2.79 (t, J = 6.0 Hz, 4H), 2.47 (t, J = 6.0 Hz, 4H). LCMS m / z 256.13 [M+1] + .

[0205] Preparation S21 1-(3-trimethylsilylprop-2-ynyl)piperidin-4-one (S21) [ka] To a stirred solution of piperidin-4-one (hydrochloride (1)) (1 g, 0.0066 mol) in MeCN (10 mL) was added KCO (3.0 g, 0.0215 mol) followed by 3-bromoprop-1-ynyl(trimethyl)silane (1.5213 g, 1.3003 mL, 0.0078 mol) at 0 °C and stirred at room temperature for 4 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give crude 1-(3-trimethylsilylprop-2-ynyl)piperidin-4-one (850 mg, 90% purity, 55% yield) as a colorless liquid. 1H NMR (300 MHz, chloroform-d) δ: 3.44 (s, 2H), 2.85 (t, J = 6.3 Hz, 4H), 2.50 (t, J = 5.7 Hz, 4H), 0.16 (s, 9H).

[0206] Preparation S22 1-[[1-(2-pyridyl)pyrazol-4-yl]methyl]piperidin-4-one (S22) [ka] To a stirred solution of piperidin-4-one (2.8 g, 26.833 mmol) in 1,2-dichloroethane (40 mL) was added MeOH (10 mL), 1-(2-pyridyl)pyrazole-4-carbaldehyde (3.5 g, 19.807 mmol), followed by sodium triacetoxyborohydride (9 g, 41.615 mmol) at 0 °C and stirred at room temperature for 1 h. The reaction was diluted with ethyl acetate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography using ethyl acetate, and pure fractions were concentrated under reduced pressure to give 1-[[1-(2-pyridyl)pyrazol-4-yl]methyl]piperidin-4-one (2.5 g, 37% yield) as a yellow sticky gum. 1 H NMR (400 MHz, chloroform-d): δ 8.50 (s, 1H), 8.41–8.39 (m, 1H), 7.97–7.95 (m, 1H), 7.84–7.79 (m, 1H), 7.71 (s, 1H), 7.20–7.17 (m, 1H), 3.65 (s, 2H), 2.81 (t, J = 6.0 Hz, 4H), 2.49 (t, J = 6.4 Hz, 4H). LCMS m / z 257.24 [M+1] + .

[0207] Preparation S23 1-[(1-tetrahydropyran-4-ylpyrazol-4-yl)methyl]piperidin-4-one (S23) [ka] 1-[(1-tetrahydropyran-4-ylpyrazol-4-yl)methyl]piperidin-4-one (S23) was prepared using the same method as used to prepare S22 with starting aldehyde C172.

[0208] Preparation S24 1-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]piperidin-4-one (S24) [ka] 1-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]piperidin-4-one (S24) was prepared using the same method as used to prepare S22 with starting aldehyde C173.

[0209] Preparation S25 2-Bromo-1-(dimethoxymethyl)-4-methyl-benzene (S25) [ka] To a stirred solution of 2-bromo-4-methyl-benzaldehyde (5 g, 0.0226 mol) in MeOH (80 mL) was added p-TsOH (783 mg, 0.7318 mL, 0.0045 mol) followed by trimethyl orthoformate (5.9539 g, 6.2 mL, 0.0555 mol) at room temperature, and the reaction mixture was stirred at 75 °C for 15 h. The reaction was diluted with saturated sodium bicarbonate solution (100 mL), and the methanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (2 × 100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude 2-bromo-1-(dimethoxymethyl)-4-methyl-benzene (5.2 g, 86% yield) as a pale yellow liquid, which was used without further purification. 1 H NMR (400 MHz, chloroform-d) δ ppm: 7.47 (d, J = 8 Hz, 1H), 7.37 (s, 1H), 7.13–7.10 (m, 1H), 5.53 (s, 1H), 3.36 (s, 6H), 2.30 (s, 3H).

[0210] Preparation S26 2-Bromo-1-(dimethoxymethyl)-4-(trifluoromethyl)benzene (S26) [ka] 2-Bromo-1-(dimethoxymethyl)-4-(trifluoromethyl)benzene (S26) was prepared using the same method as used to synthesize S25 with starting aldehyde C175.

[0211] Preparation S27 1-[[1-(3-pyridyl)pyrazol-4-yl]methyl]piperidin-4-one (S27) [ka] 1-[[1-(3-pyridyl)pyrazol-4-yl]methyl]piperidin-4-one (S27) was prepared using the same method as used to prepare S22 with starting aldehyde C176.

[0212] Preparation S28 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (S28) [ka] Step 1. Synthesis of 4-[5-chloro-2-(dimethoxymethyl)phenyl]-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-ol (C178) To a stirred solution of 2-bromo-4-chloro-1-(dimethoxymethyl)benzene (5.0 g, 0.0169 mol) and 1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-one (5.0 g, 0.0180 mol) in THF (100 mL) was added n-butyllithium (10 mL of 2.5 M, 0.0250 mol) at −80° C. and stirred for 2 hours. The reaction was allowed to warm slowly to room temperature and stirred for 4 hours. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (2×250 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give crude 4-[5-chloro-2-(dimethoxymethyl)phenyl]-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-ol (11 g, 86% yield, approximately 60% pure by LC / MS) as a yellow liquid, which was used in the subsequent step without further purification.

[0213] Step 2. Synthesis of 5-chloro-1-methoxy-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine] (C179) To a stirred solution of 4-[5-chloro-2-(dimethoxymethyl)phenyl]-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-ol (10 g, approx. 40% pure by LC / MS, 9.0508 mmol) in MeOH (100 mL) was added p-TsOH (9.2 g, 8.5981 mL, 52.357 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure directly to the crude residue, which was dissolved in DCM (200 mL) and washed with 1 M NaOH solution (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (gradient: 0 to 50% EtOAc in hexanes) to afford 5-chloro-1-methoxy-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine] (4 g, approximately 80% pure by LC / MS, 86% yield) as a brown gum. 1H NMR (300MHz, chloroform-d) δ7.91(s,1H),7.70~7.68(m,3H),7.47~7.41(m,2H),7.28~7.24(m,2H),7.14(s,1H),6.01(s,1H),3.58(s,2 H),3.46(s,3H),2.96~2.87(m,2H),2.52~2.44(m,2H),2.12~2.06(m,2H),2.04~1.94(m,1H),1.86~1.80(m,1H),1.69~1.64(m,1H). LCMS m / z 410.06[M+1] +

[0214] Step 3. Synthesis of 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (S28) To a stirred solution of 5-chloro-1-methoxy-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine] (2 g, 0.0047 mol) in DCM (30 mL) was added TMSCN (3.7302 g, 4.7039 mL, 0.0368 mol) followed by BF3.OEt2 (1.3341 g, 1.1601 mL, 0.0093 mol) at -25 °C and stirred for 30 min. The reaction was then allowed to warm to 0 °C and stirred for 1 h. The reaction mixture was quenched with MeOH (10 mL) and water (100 mL) and then extracted with DCM (2 x 250 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (1.8 g, 95%). 1 H NMR (300MHz, chloroform-d): δ7.90(s,1H),7.71~7.68(m,3H),7.48~7.42(m,2H),7.39~7.26(m,3H),7.17(s ,1H),5.82(s,1H),3.59(s,2H),2.94(brs,2H),2.46~2.43(m,2H),2.06~1.99(m,3H),1.77~1.72(m,1H). LCMS m / z 405.02[M+1] + .

[0215] Preparation of S29 to S36 Intermediate compounds S29-S36 (see Table 14) were prepared from the appropriate aryl bromides and piperidones using the same method as described for S28. All aryl bromides and piperidones were obtained from commercial sources or synthesized as described above. [Table 14-1] [Table 14-2] [Table 14-3]

[0216] Compound 191 5-Chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (191) [ka] To a stirred solution of 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (200 mg, 454.39 μmol) (S9) in water (1.0 mL) and THF (1.0 mL) was added LiOH(aqueous (1)) (40 mg, 943.68 μmol) at room temperature. The reaction mixture was stirred for 16 hours. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by reverse-phase chromatography (column: C18. Gradient: 0 to 100% MeCN in water with 0.1% formic acid) to afford 5-chloro-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide (formate (1)) (30 mg, 14%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ:8.41(s,1H),8.18(s,1H),7.83(d,J=8.8Hz,2H),7 .67(s,1H),7.48(t,J=8.4Hz,2H),7.4~7.33(m,4H),7.28(t,J=7.2Hz,1H),7 .12(brs,1H),5.35(s,1H),3.55(s,2H),2.81~2.61(m,2H),2.46(brs,1H), 2.37~2.32(m,1H),2.10~2.03(m,1H),1.92~1.88(m,2H),1.65~1.04(m,1H). LCMS m / z 423.05[M+1] + .

[0217] 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (192), 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (193), and 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (194). [ka] To a stirred solution of 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (200 mg, 454.39 μmol) in water (1.0 mL) and THF (1.0 mL) was added liOH (40 mg, 943.68 μmol) at ambient temperature. The reaction mixture was stirred for 16 hours, and then the reaction mass was diluted with water (20 mL) and

[0218] Extraction with ethyl acetate (3 × 50 mL) was performed. The organic layer was dried over sodium sulfate, concentrated (aqueous layer reserved for purification of the carboxylic acid), and then purified by reverse-phase HPLC (gradient: 45–99% MeCN in 0.1% aqueous formic acid) to give 5-chloro-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide as a mixture of enantiomers. Separation of the stereoisomers by chiral SFC purification (column: AS-H, 10 × 250 mm, gradient: 60% CO in methanol (5 mM methanolic ammonia), flow rate: 15 mL / min) provided the first eluting peak (193) 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (6.3 mg, 79%). 1 H NMR (300MHz, chloroform-d) δ8.26(s,1H),7.83~7.70(m,3H),7.55~7.42(m,3H),7.41~7.31(m,2H),7.27(d,J=1.9Hz,1H),5 .44(s,1H),3.74(s,2H),3.12~2.97(m,2H),2.83~2.58(m,2H),2.19(td,J=13.3,4.4Hz,1H),2.03~1.78(m,3H).ESI-MS m / z:423.05[M+1] + .

[0219] The second eluting peak was isolated to give compound 194 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (6.2 mg, 78%). 1 H NMR (300MHz, chloroform-d) δ8.26(s,1H),7.79~7.70(m,3H),7.54~7.30(m,5H),7.27(d,J=1.9Hz,1H),5.44(s,1H), 3.74(s,2H),3.04(t,J=11.3Hz,2H),2.80~2.55(m,2H),2.19(td,J=13.3,4.5Hz,1H),2.04~1.74(m,3H).ESI-MS m / z:423.05[M+1] + .

[0220] The aqueous layer from the above reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by reverse-phase HPLC (gradient: 45 to 99% MeCN in 0.1% aqueous formic acid) to give 5-chloro-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxylic acid 192 (20 mg, 10%). 1 I got H. NMR(400MHz,DMSO-d6)δ:8.43(s,1H),7.84(d,J=8.4Hz,2H),7.68(s,1H),7.48(t,J=8.4Hz,2H),7.40~7.34(m,3H),7.30~7.26(m,1H),6.11 (brs,1H),5.52(s,1H),3.57(s,2H),2.82~2.81(m,2H),2.49~2.32(m,2H),2.07~2.00(m,2H),1.98~1.90(m,1H),1.62~1.55(m,1H).ESI-MS m / z:424.03[M+1] + .

[0221] Compound 195 5-Chloro-N-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (195) [ka] Step 1. Synthesis of 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (192) To a stirred solution of 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (400 mg, 0.8513 mmol) in THF (5 mL) was added LiOH .A solution of HO (40 mg, 0.0016 mol) in water (5 mL) was added at room temperature and heated to 60° C. for 16 h. The reaction was cooled to room temperature, acidified with 1 M HCl, and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 5-chloro-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxylic acid (180 mg, 44%) as a yellow gum, which was used in the next step without further purification. LCMS m / z 423.96 [M+1] + .

[0222] Step 2. Synthesis of 5-chloro-N-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (195) To a stirred solution of 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (110 mg, 207.31 μmol) in THF (2.0 mL) was added HATU (320 mg, 833.18 μmol), DIPEA (146.92 mg, 0.2 mL, 0.0011 mol), and methylamine (HCl (1)) (40 mg, 586.51 μmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (50 mL) and extracted with 10% methanol in DCM (2 × 100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography (column: x-select phenylhexyl. Gradient: 0 to 100% MeCN in water with 0.1% formic acid) to give, after lyophilization, 5-chloro-N-methyl-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide (formate (1)) 195 (50 mg, 48%) as a white solid. 1H NMR(400MHz,DMSO-d6):δ8.42(s,1H),8.31(s,1H),7.83(d,J=8.8Hz,2H),7.67(s,1 H),7.62~7.59(m,1H),7.48(t,J=8.4Hz,2H),7.41~7.32(m,3H),7.28(t,J=7.2Hz,1 H),5.39(s,1H),3.55(s,2H),2.86~2.75(m,2H),2.62(d,J=4.8Hz,3H),2.49~2.45( m,1H), 2.36~2.31(m,1H),2.12~2.05(m,1H),1.90~1.78(m,2H),1.65~1.60(m,1H). LCMS m / z 435.19[M-1] - .

[0223] Compounds 196~202 Compounds 196-202 (see Table 15) were prepared from the appropriate nitrile intermediate using the same method as for compound 191, or the method for compound 191 and then compound 192. All nitriles were synthesized as described above. Any modifications to the method are described in Table 15 and the accompanying footnotes. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4]

[0224] compound 203 5-Cyano-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (203) [ka] To a stirred solution of 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (191) (100 mg, 0.2190 mmol) in NMP (3 mL) was added Zn(CN) (60 mg, 500.79 μmol) and Zn dust (700 mg, 0.0981 mL, 10.491 mmol). The reaction mixture was degassed with argon for 10 minutes. Then, bis(tri-tert-butylphosphine)palladium(0) (75 mg, 143.82 μmol) was added, and the solution was degassed again at room temperature for 5 minutes. The reaction mixture was irradiated under microwave conditions at 150 °C for 1 hour. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (30 2 × mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was blended with an additional reaction under the same conditions starting with 50 mg of 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (2) and then purified by reverse-phase chromatography (column: C18. Gradient: 0 to 100% MeCN in 10 mM aqueous ammonium bicarbonate) to give, after lyophilization, 5-cyano-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (17 mg, 12.5% ​​yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ:8.41(s,1H),7.87(s,1H),7.83(dd,J=1.2,8.8Hz,2H),7.77(d d,J=1.2,7.6Hz,1H),7.67(s,1H),7.57(d,J=7.6Hz,1H),7.48(dd,J=2,7.2H,3H),7.28 (t,J=7.6Hz,1H),7.21(s,1H),5.47(s,1H),3.52(s,2H),2.81(d,J=8Hz,2H),2.51~2.4 6(m,1H),2.35(t,J=10Hz,1H),2.12~2.06(m,1H),1.93~1.88(m,2H),1.60~1.50(m,1H). LCMS m / z 414.1[M+1] + .

[0225] compound 204 5-Cyano-N-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (204) [ka] 5-Cyano-N-methyl-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide (204) was prepared using the same method as used to prepare compound 203 using the appropriate starting aryl chloride.

[0226] 1 H NMR(400MHz,DMSO-d6)δ:8.42(s,1H),7.87~7.82(m,3H),7.76(dd,J=1.2,8Hz,1H),7 .68(d,J=6.4Hz,2H),7.56(d,J=8Hz,1H),7.49(t,J=7.6Hz,2H),7.28(t,J=7.6Hz,1H ),5.51(s,1H),3.42(s,2H),2.81(brs,2H),2.62(d,J=4.8Hz,3H),2.54~2.49(m,1H) ,2.37~2.31(m,1H),2.15~2.11(m,1H),1.91~1.82(m,2H),1.65(d,J=11.2Hz,1H)LCMS m / z 428.46[M+1] + .

[0227] Preparation of S37 1'-[(1-phenylpyrazol-4-yl)methyl]-5-vinyl-spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (S37) [ka] To a stirred solution of 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (500 mg, 0.0011 mol) in dioxane (25 mL) and water (7 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (240 mg, 0.0015 mol) and K2CO3 (610 mg, 0.0043 mol). The reaction mixture was degassed with argon for 10 minutes. XPhosPd-G2 (160 mg, 199.03 μmol) was then added in a sealed tube and degassed again at room temperature for 5 minutes. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel column chromatography (gradient: 0 to 50% EtOAc in pet ether) to afford 1'-[(1-phenylpyrazol-4-yl)methyl]-5-vinyl-spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (350 mg, 80% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ:8.43(s,1H),7.83(d,J=7.6Hz,2H),7.68~7.47(m,6H),7.29(t,J=6.8Hz,1H),6.7 8(dd,J=11.2,18Hz,1H),6.20(s,1H),5.95(d,J=17.6Hz,1H),5.33(d,J=10.8Hz,1H),3.52(s,2H),2.85(br s,2H),2.32(br s,2H),2.13~1.98(m,2H),1.76(d,J=12.4Hz,1H),1.63(d,J=12.4Hz,1H). LCMS m / z 397.19[M+1] + .

[0228] Preparation of C181 and 182 Intermediate compounds C181 and C182 (see Table 16) were prepared from nitrile intermediate S37 using either the method used to prepare compound 191 or the method used to prepare compound 195. Any modifications to the method are described in Table 16 and the accompanying footnotes. [Table 16]

[0229] compound 205 5-Ethyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (205) [ka] To a stirred solution of 1'-[(1-phenylpyrazol-4-yl)methyl]-5-vinyl-spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (40 mg, 79.131 μmol) in MeOH (5 mL) was added palladium on carbon (40 mg, 10% w / w, 0.0376 mmol). The reaction mass was stirred at room temperature under a hydrogen balloon for 16 hours. The reaction was filtered through a pad of Celite, washed with MeOH (25 mL), and evaporated in vacuo. The crude residue was purified by reverse-phase chromatography (column: C18. Gradient: 0 to 100% MeCN in 0.1% TFA in water) to give, after lyophilization, 5-ethyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (trifluoroacetic acid (1)) 205 (10 mg, 23% yield) as an off-white sticky solid. 1H NMR(400MHz,DMSO-d6)δ:10.6(brs,1H),8.60(br s,1H),7.85~7.83(m,3H),7.53(t,J=7.6Hz,2H),7.37~7.17(m,5H),6.99(br s,1H),5.38(s,1H),4.19~4.15(m,2H),3.32~2.66(m,4H),2.62(t,J=7.6Hz,2H),2.21(br s,1H),1.90(br s,2H),1.80(d,J=9.2Hz,1H),1.24(s,3H),19F NMR(376.75MHz,DMSO-d6)δ:-73.49. LCMS m / z 417.28[M+1] + .

[0230] compound 206 5-Ethyl-N-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (206) [ka] 5-Ethyl-N-methyl-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide (206) was prepared using the same method as used to prepare compound 205 using the starting methylamide C182. 1 H NMR(400MHz,DMSO-d6)δ:8.40(s,1H),7.82(d,J=8Hz,2H),7.67(s,1H),7.48(t, J=7.6Hz,3H),7.30~7.24(m,2H),7.10(t,J=8Hz,2H),5.34(s,1H),3.52(s,2H), 2.80(t,J=10.8Hz,2H),2.63~2.53(m,5H),2.51~2.49(m,1H),2.34(t,J=11.2Hz ,1H),2.07~2.04(m,1H),1.85~1.78(m,2H),1.63(s,1H),1.16(t,J=7.6Hz,3H). LCMS m / z 431.33[M+1] + .

[0231] compound 207 1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (207) [ka] Step 1. Synthesis of 1'-prop-2-ynyl-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C183) To a stirred solution of 5-(trifluoromethyl)-1'-(3-trimethylsilylprop-2-ynyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (1 g, 0.0025 mol) in DMF (10 mL) was added KF (5 g, 0.0843 mol) at 0 °C and stirred at the same temperature for 6 h. The reaction was quenched with saturated NH4Cl solution (50 mL) and extracted with ethyl acetate (2 × 100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (isocratic: 10% EtOAc in hexane) to give 1'-prop-2-ynyl-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (715 mg, 86% yield) as an off-white sticky solid. 1 H NMR (DMSO-d6, 400MHz): δ7.91(s,1H),7.83~7.77(m,2H),6.36(s,1H),3.35(d,J=2.4Hz,2H),3.18(t,J=2 .4Hz,1H),2.79~2.74(m,2H),2.57~2.52(m,2H),2.17~2.08(m,2H),1.80~1.75(m,1H),1.68~1.64(m,1H). LCMS m / z 321.11[M+1] + .

[0232] Step 2. Synthesis of 1'-prop-2-ynyl-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (C184) To a solution of 1'-prop-2-ynyl-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (32 mg, 0.09990 mmol) in THF (0.5 mL) was added LiOH (12 mg, 0.5011 mmol) and water (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was extracted with DCM (2 x 2 mL), and the organic layer was concentrated in vacuo to give 1'-prop-2-ynyl-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide, which was used in the subsequent step without further purification. LCMS m / z 339.19 [M+1] + .

[0233] Step 3. Synthesis of 1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (207) Crude 1'-prop-2-ynyl-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide was dissolved in MeOH (0.5 mL) and a solution of 1-azido-2-methylsulfonylethane (15 mg, 0.1006 mmol) in MeOH (0.5 mL) containing copper sulfate (0.08 mL of 1% w / v, 0.005012 mmol) was added. Ascorbic acid (sodium salt) (2 mg, 0.01004 mmol) was then added and the mixture was stirred at room temperature for 1 hour. The residue was concentrated in vacuo and purified by reverse-phase HPLC. Method: C18 Waters Sunfire column (30 x 150 mm, 5 microns). Purification by gradient: MeCN in HO containing 0.1% trifluoroacetic acid afforded 1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (trifluoroacetate salt) (14.8 mg, 24% yield over two steps) as a pale yellow sticky solid. 1H NMR (400MHz, DMSO-d6) δ8.41(d,J=17.3Hz,1H),7.78(d,J=8.0Hz,1H),7.67(d,J =8.1Hz,1H),7.54(s,2H),7.47(s,1H),5.58(s,1H),4.92(t,J=6.6Hz,2H),4.57( s,2H),3.85(t,J=6.7Hz,2H),3.73(t,J=7.2Hz,1H),3.28(d,J=12.1Hz,1H),3.0 2(s,3H),2.31(d,J=15.3Hz,1H),2.13(d,J=14.5Hz,2H),1.96(d,J=14.4Hz,1H). LCMS m / z 488.34[M+1] + .

[0234] compound 208 5-Chloro-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (208) [ka] 5-Chloro-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide (208) was prepared using the same method as used to prepare compound 207 using starting nitrile S33, with the modification that the LiOH hydrolysis step was performed after the copper sulfate catalysis in this sequence.

[0235] 1H NMR(300MHz,MeOD)δ8.32(s,1H),7.51(dt,J=8.1,0.8Hz,1H),7.40(dd,J=8.2,1.8Hz,1H),7.28(s,1H),5.53(d,J=1.1Hz,1H),5.08~4.96(m ,2H),4.58(s,2H),3.91~3.73(m,2H),3.61(s,3H),3.46(t,J=12.1Hz,1H),3.00(d,J=6.3Hz,3H),2.32(d,J=17.0Hz,1H),2.22~1.99(m,3H). LCMS m / z 454.29[M+1] + .

[0236] compound 209 5-Chloro-1'-[[1-(2-methylpyrimidin-5-yl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (209) [ka] Step 1. Synthesis of 5-chloro-1'-(1H-pyrazol-4-ylmethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C187) To a stirred solution of 5-chloro-1'-[(1-tetrahydropyran-2-ylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (450 mg, 0.6892 mmol) in MeOH (6 mL) was added p-TsOH (180 mg, 0.1682 mL, 1.0244 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. At this time, the reaction mixture was evaporated under reduced pressure. The crude residue was diluted with water (30 mL), adjusted to pH 9 with 2 M NaOH (20 mL), extracted with EtOAc (2 x 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel column chromatography (gradient: 0-60% acetone / petroleum ether) to afford impure 5-chloro-1'-(1H-pyrazol-4-ylmethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (500 mg, 30% yield) as a sticky yellow gum. LCMS m / z 329.22 [M+1] + .

[0237] Step 2. Synthesis of 5-chloro-1'-[[1-(2-methylpyrimidin-5-yl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C188) To a stirred solution of 5-chloro-1'-(1H-pyrazol-4-ylmethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (300 mg, 0.6202 mmol) in THF (5.0 mL) was added (2-methylpyrimidin-5-yl)boronic acid (200 mg, 1.4355 mmol), pyridine (297.00 mg, 0.3 mL, 3.7172 mmol), and copper(II) acetate (11.375 mg, 0.0620 mmol) at room temperature. The reaction mixture was stirred at 60 °C under an oxygen balloon for 16 h. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 5-chloro-1'-[[1-(2-methylpyrimidin-5-yl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (400 mg, 31%) as a sticky solid, which was used without further purification. LCMS m / z 420.96 [M+1] + .

[0238] Step 3. Synthesis of 5-chloro-1'-[[1-(2-methylpyrimidin-5-yl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (209) To a stirred solution of 5-chloro-1'-[[1-(2-methylpyrimidin-5-yl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (30 mg, 45.011 μmol) in water (1.0 mL) and THF (1.0 mL) was added LiOH·H2O (4.0 mg, 94.368 μmol) at room temperature. The reaction mixture was stirred for 6 h. The reaction was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (isocratic: 60% acetone in hexanes) to afford 5-chloro-1'-[[1-(2-methylpyrimidin-5-yl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (9.0 mg, 41% yield) as an off-white solid. 1H NMR (400MHz, DMSO-d6)δ:9.17(s,2H),8.55(s,1H),7.79(s,1H),7.43(brs,1H),7.41~7.33(m,3H),7.13(brs,1H),5.35(s,1H),3.5 2(s,2H),2.81~2.79(m,2H),2.69(s,3H),2.49(s,1H),2.37~2.32(m,1H),2.11~2.02(m,1H),1.92~1.83(m,2H),1.63~1.60(m,1H). LCMS m / z 439.1[M+1] + .

[0239] compound 210 5-Chloro-N-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (210) [ka] Step 1. Preparation of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C189) To a stirred solution of 5-chloro-1'-(1H-pyrazol-4-ylmethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (400 mg, 0.8029 mmol) in MeCN (5.0 mL) was added DBU (302 mg, 0.3 mL, 1.96 mmol) followed by 1-methylsulfonylethylene (80.005 mg, 0.7462 mmol) at 0°C. The reaction was stirred at room temperature for 16 hours, after which the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over sodium sulfate and concentrated to give 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (200 mg, 25%). ESI-MS m / z 434.87[M+1] + .

[0240] Step 2. Preparation of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (C190) To a stirred solution of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (100 mg, 0.1035 mmol) in water (1.0 mL) and THF (1.0 mL) was added LiOH (50 mg, 1.1796 mmol) at ambient temperature. The reaction mixture was stirred for 6 hours, concentrated, diluted with water (10 mL), acidified with 1 M HCl (pH = 4), and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (120 mg). ESI-MS m / z 454.32 [M+1] + .

[0241] Step 3. Preparation of 5-chloro-N-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (210) To a stirred solution of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (120 mg, 0.2330 mmol) in THF (2.0 mL) was added methylamine (50 mg, 0.7331 mmol), TEA (143.75 mg, 0.2 mL, 1.4064 mmol), and T3P (212.00 mg, 0.2 mL of 50% w / v, 0.3143 mmol) in ethyl acetate at ambient temperature and stirred for 16 h. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over sodium sulfate and concentrated. The crude compound was purified by reverse-phase chromatography (gradient: 10 to 100% MeCN in 10 mM aqueous ammonium bicarbonate) to give 5-chloro-N-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (10 mg, 9%). 1 H NMR(400MHz,DMSO-d6)δ:7.70(s,1H),7.58~7.57(m,1H),7.41~7.40(m,2H),7.3 7~7.32(m,2H),5.38(s,1H),4.51(t,J=6.8Hz,2H),3.68(t,J=6.8Hz,2H),3.41(b rs,2H),2.80(s,3H),2.74(brs,2H),2.61(d,J=4.4Hz,3H),2.50~2.49(m,1H),2. 29~2.24(m,1H),2.08~2.00(m,1H),1.85~1.78(m,2H),1.62~1.58(m,1H).ESI-MS m / z 467.21[M+1] + .

[0242] compound 211 5-Chloro-N-methyl-1'-[[1-(2-methylpyrimidin-5-yl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (211) [ka] Compound 211 was prepared starting from 6-chloro-1′-((1-(2-methylpyrimidin-5-yl)-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-3-carbonitrile (C188) and following the method described in steps 2 and 3 for the preparation of compound 210. This afforded 5-chloro-N-methyl-1′-[[1-(2-methylpyrimidin-5-yl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide 211 (10 mg, 15%). 1 H NMR(400MHz,DMSO-d6)δ:9.17(s,2H),8.55(s,1H),7.79(s,1H),7.61(d,J=4.8Hz,1H),7.40~7.32(m,3H),5.40(s,1H),3.56(s,2H),2.80(brs, 2H),2.66(s,3H),2.62(d,J=4.8Hz,3H),2.54~2.50(m,1H),2.37~2.31( m,1H),2.11~2.08(m,1H),1.90~1.78(m,2H),1.33~1.20(m,1H).ESI-MS m / z 453.2[M+1] + .

[0243] Preparation S38 5-Chlorospiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (S38) [ka] Step 1. Synthesis of tert-butyl 5-chloro-1-methoxy-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (C191) To a solution of 2-bromo-4-chloro-1-(dimethoxymethyl)benzene (29.8 g, 112.2 mmol) in THF (230 mL) was added n-BuLi (48 mL of 2.8 M, 134.4 mmol) under N at −78° C. (dry ice-acetone bath). Stirred at −78° C. for 40 minutes, after which a solution of tert-butyl 4-oxopiperidine-1-carboxylate (24.7 g, 124.0 mmol) in THF (115 mL) was added. The reaction was stirred at −78° C. for 30 minutes, then warmed to 0° C. and stirred for 30 minutes, at which point the reaction was quenched with saturated aqueous ammonium chloride (200 mL). Partitioned between MTBE and water (400 mL each). The organic layer was separated, washed with water, then brine (500 mL each), dried over magnesium sulfate, filtered, and concentrated. The resulting residue was dissolved in MeOH (300 mL) and treated with 4-methylbenzenesulfonic acid (hydrate (1)) (350 mg, 1.840 mmol). The mixture was heated to 60 °C and stirred for 16 h. The reaction was quenched with saturated aqueous sodium bicarbonate (300 mL) and then partitioned between water (200 mL) and MTBE (1 L). The organic layer was separated, washed with brine (300 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (gradient: 0 to 50% EtOAc in heptane) to afford tert-butyl 5-chloro-1-methoxy-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (25.8 g, 65% yield) as a viscous oil / glass. 1 H NMR (400 MHz, chloroform-d) δ 7.30 (t, J = 1.3 Hz, 2H), 7.10 (t, J = 1.1 Hz, 1H), 6.02 (s, 1H), 4.12 (s, 1H), 3.48 (s, 3H), 3.28–3.14 (m, 2H), 1.97–1.72 (m, 3H), 1.65–1.55 (m, 2H), 1.49 (s, 9H).

[0244] Step 2. Synthesis of tert-butyl 5-chloro-1-cyano-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (C192) To a solution of tert-butyl 5-chloro-1-methoxy-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (3.7 g, 10.46 mmol) in DCM (50 mL) was added trimethylsilyl cyanide (2.0 mL, 15.00 mmol) followed by diethyloxonio(trifluoro)boranide (1.4 mL, 11.34 mmol) at -78 °C under N2. Stirred at -78 °C for 30 minutes and then warmed to 0 °C. After 1 hour at 0 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (100 mL). The reaction was warmed to room temperature and treated with BocO (1.1 g, 5.040 mmol). The resulting biphasic mixture was stirred for 1 hour, then diluted with DCM (50 mL), and the layers were separated. The organic layer was washed successively with saturated aqueous sodium bicarbonate, 0.5 M aqueous NaOH, and brine (100 mL each), dried (MgSO), filtered, and concentrated. The crude residue was purified by silica gel chromatography (gradient: 0 to 50% EtOAc in heptane) to afford tert-butyl 5-chloro-1-cyano-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (3.0 g, 82% yield) as a clear, colorless glass. 1 H NMR (400MHz, chloroform-d) δ7.39(dd,J=8.2,1.8Hz,1H),7.35(dt,J=8.2,0.7Hz,1H),7.14(d,J=1.7Hz,1H),5.8 5(d,J=0.8Hz,1H),4.25~4.02(m,2H),3.31~3.04(m,2H),2.00~1.76(m,3H),1.74~1.62(m,1H),1.49(s,9H).

[0245] Step 3. Synthesis of tert-butyl 1-carbamoyl-5-chloro-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (C193) To a flask containing tert-butyl 5-chloro-1-cyano-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (1.125 g, 2.580 mmol), THF (45 mL) was added and diluted with water (45 mL). To this solution was added lithium hydroxide monohydrate (237 mg, 5.648 mmol) and stirred at room temperature overnight. The reaction was quenched with 100 mL of saturated aqueous NH4Cl and DCM (100 mL). After extraction with DCM (3x), the pooled organics were passed through a phase separator and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (gradient: 0-20% MeOH in DCM) to afford tert-butyl 1-carbamoyl-5-chloro-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (962.7 mg, 92% yield) as a waxy, foamy white solid. 1 H NMR (400MHz, chloroform-d) δ7.59(d,J=8.2Hz,1H),7.33(dd,J=8.2,1.8Hz,1H),7.09(d,J=1.9Hz,1H),6.61(s,1H),5.49(d,J=1.1Hz,1 H),5.46(s,1H),4.20(s,2H),3.22(s,2H),2.03(td,J=13.3,5.1Hz,1H),1.79(d,J=16.0Hz,2H),1.52(s,9H),0.91(t,J=6.7Hz,1H). LCMS m / z 311.1[M+1] + .

[0246] Step 4. Synthesis of 5-chlorospiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (S38) To a flask containing tert-butyl 1-carbamoyl-5-chloro-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (1.28 g, 3.140 mmol) was added DCM (10 mL) and TFA (2 mL, 25.96 mmol). The reaction was stirred for 3 hours. The reaction was concentrated and azeotroped with DCM and MTBE to give crude 5-chlorospiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (trifluoroacetic acid (1)) (1.19 g, 89% yield), which was used in the next step without further purification.

[0247] 1 H NMR (300MHz, chloroform-d) δ9.36(d,J=71.2Hz,2H),7.64~7.59(m,1H),7.40(dd,J=8.2,1.8Hz,1H),7.21(d,J=1.8Hz,1H),6.68( s,1H),6.33(s,1H),5.55(s,1H),3.70~3.39(m,4H),2.53(td,J=14.0,5.3Hz,1H),2.37~2.20(m,1H),2.01(t,J=15.4Hz,2H). LCMS m / z 267.18[M+1] + .

[0248] compound 212 5-chloro-1'-[[1-[3-(trifluoromethyl)phenyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (212) [ka] To a vial containing 5-chlorospiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (hydrochloride) (8.8 mg, 0.02903 mmol) was added DCM (500 μL), followed by 1-[3-(trifluoromethyl)phenyl]pyrazole-4-carbaldehyde (10 mg, 0.04164 mmol). To this was added EtN (20 μL, 0.1435 mmol), followed by triacetoxyboranide (sodium salt) (22 mg, 0.1038 mmol) and stirred overnight. The reaction was quenched with saturated NaHCO and extracted with DCM (3×). The pooled organics were passed through a phase separator and concentrated. The resulting crude residue was redissolved in DMSO and purified by reverse-phase HPLC (Method: Waters XBridge Prep C8 column; 30 × 150 mm, 5 microns. Gradient: acetonitrile in water containing 10 mM ammonium hydroxide) to give 5-chloro-1′-[[1-[3-(trifluoromethyl)phenyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide 212 (5.7 mg, 40% yield). 1 H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.17(d,J=9.4Hz,2H),7.80~7.62(m,3H),7.46~7.30(m,4H),7.17(s,1H),5.36 (s,1H),3.59(s,2H),2.86(s,2H),2.47~2.34(m,1H),2.16~2.03(m,1H),1.97~1.78(m,2H),1.65(d,J=13.4Hz,1H). LCMS m / z 491.32[M+1] + .

[0249] Compounds 213~276 Compounds 213-276 (see Table 17) were prepared from S38 and the appropriate aldehyde using the same method as compound 212. All aryl bromides and piperidones were obtained from commercial sources or synthesized as described above. Any modifications to the method are described in Table 17 and the accompanying footnotes. [Table 17-1]

Table 17-2

Table 17-3

Table 17-4

Table 17-5

Table 17-6

Table 17-7

Table 17-8

Table 17-9

Table 17-10

Table 17-11

Table 17-12

Table 17-13

Table 17-14

Table 17-15

Table 17-16

Table 17-17

Table 17-18

[0250] compound 277 5-chloro-1'-[[1-[(2S)-2,3-dihydroxy-3-methyl-butyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (277) [ka] To a vial containing 5-chlorospiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (trifluoroacetate salt) (107 mg, 0.2445 mmol) in DCM (1.9 mL) and TEA (70 μL, 0.5022 mmol) was added 1-[[(4S)-2,2,5,5-tetramethyl-1,3-dioxolan-4-yl]methyl]pyrazole-4-carbaldehyde (90 mg, 0.3777 mmol). To the resulting mixture was added triacetoxyboranide (sodium salt) (185 mg, 0.8729 mmol) and stirred for 2 days. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM (3x). The pooled organics were passed through a phase separator and concentrated. The resulting crude residue was diluted with THF (5 mL) and hydrogen chloride (500 μL of 4 M in dioxane, 2.000 mmol) was added. The reaction was stirred overnight, then water (500 μL, 27.75 mmol) was added and the reaction was stirred overnight again. The reaction was then concentrated under reduced pressure. Purification of the residue by reverse-phase HPLC (Method: Waters XBridge Preparative C8 column; 30 × 150 mm, 5 micron. Gradient: acetonitrile in water with 10 mM ammonium hydroxide) gave 5-chloro-1′-[[1-[(2S)-2,3-dihydroxy-3-methyl-butyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide 277 (21.7 mg, 18%). 1H NMR(400MHz,DMSO-d6)δ7.57(s,1H),7.49~7.29(m,5H),7.12(s,1H),5.35(s,1H),4.9 2(d,J=6.1Hz,1H),4.46(s,1H),4.33(dd,J=13.7,1.9Hz,1H),3.90~3.79(m,1H),3.52( t,J=7.7Hz,1H),3.39(s,2H),3.31(s,1H),2.83~2.72(m,2H),2.46~2.20(m,1H),2.03( t,J=11.3Hz,1H),1.91~1.75(m,2H),1.60(d,J=13.1Hz,1H),1.08(d,J=21.7Hz,6H).). LCMS m / z 449.28[M+1] + .

[0251] compound 278 5-Chloro-1'-[[1-[(2R)-2,3-dihydroxy-3-methyl-butyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (278) [ka] 5-Chloro-1′-[[1-[(2R)-2,3-dihydroxy-3-methyl-butyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide (278) was prepared using the same method as used to prepare compound 277 using starting aldehyde C196.

[0252] 1H NMR(400MHz,DMSO-d6)δ7.57(s,1H),7.48~7.28(m,5H),7.12(s,1H),5.35(s ,1H),4.92(d,J=6.1Hz,1H),4.46(s,1H),4.38~4.29(m,1H),3.85(dd,J=13.8 ,9.6Hz,1H),3.52(t,J=7.6Hz,1H),3.40(s,2H),2.82~2.74(m,2H),2.47~2. 20(m,2H),2.04(t,J=14.9Hz,1H),1.94~1.55(m,3H),1.09(d,J=21.7Hz,6H). LCMS m / z 449.33[M+1] + .

[0253] Preparation S39 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (S39) [ka] Step 1: 2-(Bromomethyl)-2-methyl-propane-1,3-diol (C198) To a mixture of (3-methyloxetan-3-yl)methanol C197 (10 mL, 100.3 mmol) in THF (70 mL) was added hydrogen bromide (14 mL of 48% w / w, 123.7 mmol) at 0 °C. After stirring for 24 h, the mixture was concentrated to a minimum volume, diluted with DCM / methanol, and excess HBr was quenched with saturated sodium bicarbonate. The layers were split, and the organic layer was dried over sodium sulfate, filtered, rinsed with methanol, and concentrated to give 2-(bromomethyl)-2-methyl-propane-1,3-diol C198 (13.6682 g, 74%). 1 H NMR (400 MHz, chloroform-d) δ 3.47 (d, J = 1.1 Hz, 6H), 0.96 (s, 3H).

[0254] Step 2: [2-(Bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propoxy]-tert-butyl-dimethyl-silane (C199) To a mixture of 2-(bromomethyl)-2-methyl-propane-1,3-diol C198 (10 g, 54.09 mmol) in DCM (200 mL) was added imidazole (7.7 g, 113.1 mmol), followed by TBSCl (17 g, 112.8 mmol). After 5 minutes, the mixture precipitated a white crystalline solid. The mixture was filtered, rinsed with DCM, and concentrated. The mixture was diluted with heptane (25 mL) to further precipitate imidazole / imidazole HCl, filtered, and the solid was rinsed with additional heptane (10 mL). The mixture was concentrated to precipitate additional solid. The mixture was diluted and concentrated twice more with heptane (50 mL) to give [2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propoxy]-tert-butyl-dimethyl-silane C199 (22246 mg, 100%). 1 H NMR (400 MHz, chloroform-d) δ 3.44 (s, 4H), 3.40 (s, 2H), 0.94 (s, 3H), 0.89 (s, 18H), 0.04 (d, J = 1.2 Hz, 12H).

[0255] Step 3: 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (S39) To a vial was added 1H-pyrazole-4-carbaldehyde (2 g, 20.81 mmol), dipotassium carbonate (4 g, 28.94 mmol), and [2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propoxy]-tert-butyl-dimethyl-silane C199 (9.5 g, 23.08 mmol) in DMF (20 mL). The mixture was heated to 130 °C. After 3 h, the mixture was cooled to room temperature and diluted with water (100 mL) and heptane (100 mL). The layers were mixed, and the aqueous layer was washed with heptane (2 × 100 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL), and the organic layer was dried over sodium sulfate and concentrated. Purification by silica gel chromatography (gradient: 0 to 60% EtOAc:heptane) afforded the product 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde S39 (2390 mg, 23%). 1 H NMR (400 MHz, chloroform-d) δ 9.85 (s, 1H), 7.98–7.91 (m, 2H), 4.12 (s, 2H), 3.43–3.29 (m, 4H), 0.91 (s, 18H), 0.84 (s, 3H), 0.05 (d, J = 0.6 Hz, 12H). LCMS m / z 427.31 [M+H] + .

[0256] compound 279 5-Chloro-1'-[[1-[3-hydroxy-2-(hydroxymethyl)-2-methyl-propyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (279) [ka] 5-Chloro-1′-[[1-[3-hydroxy-2-(hydroxymethyl)-2-methyl-propyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide (279) was prepared using the same method as used to prepare compound 278 with starting aldehyde S39, except that MeOH was used instead of THF / HO used as the solvent during the reaction with HCl.

[0257] 1 H NMR(400MHz,DMSO-d6)δ7.55(s,1H),7.49~7.29(m,5H),7.12(s,1H),5.34(s,1H),4.58(t,J=5.3Hz,2H),3.98(s, 2H), 3.27~3.09(m,4H),2.86~2.68(m,2H),2.48~2.22(m,2H),2.15~1.96(m,1H),1.93~1.55(m,3H),0.68(s,3H). LCMS m / z 449.33[M+1] + .

[0258] compound 280 5-chloro-1'-[[1-[2-hydroxy-2-(1-hydroxycyclobutyl)ethyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (280) [ka] To a suspension of 5-chloro-1'-(1H-pyrazol-4-ylmethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (30 mg, 0.08650 mmol) (compound 226), CsCO (114 mg, 0.3499 mmol) in DMF (1.0 mL) was added 1-(oxiran-2-yl)cyclobutanol (11 mg, 0.09637 mmol) and stirred at 75° C. for 5 h. The reaction was filtered through a PTFE 0.45 um syringe filter and concentrated. The crude residue was purified by reverse-phase HPLC (column: C18. Gradient: 0 to 100% MeCN in 10 mM ammonium bicarbonate in water) to give 5-chloro-1′-[[1-[2-hydroxy-2-(1-hydroxycyclobutyl)ethyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide 280 (17.8 mg, 41%). 1 H NMR(400MHz,DMSO-d6)δ8.47~7.29(m,5H),7.57(s,1H),7.12(s,1H),5.34(s,1H),5.04(s,1H),4.89(d,J=6.7Hz,1H),4.21~4.1 1(m,1H),3.99~3.86(m,1H),3.70(t,J=8.9Hz,1H),3.39(s,2H),2.81~2.72(m,2H),2.43~2.17(m,2H),2.05~1.41(m,8H).ESI-MS m / z 461.29[M+1] + .

[0259] Compound 281-285 Compounds 281-285 (see Table 18) were prepared from compound 226 and the appropriate electrophile using the same method as compound 280. Any modifications to the method are described in Table 18 and the accompanying footnotes. [Table 18-1] [Table 18-2]

[0260] compound 286 5-Methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine] (286) [ka] Step 1: Preparation of tert-butyl 4-hydroxy-4-[2-(hydroxymethyl)-5-methyl-phenyl]piperidine-1-carboxylate (C201) To a stirred solution of (2-bromo-4-methyl-phenyl)methanol (300 mg, 0.0013 mol) in THF (6 mL) was added n-BuLi (1.2800 mL of 2.5 M, 0.0032 mol) at −78° C., and the solution was stirred for 10 minutes. To this was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (278.95 mg, 0.0014 mol) in diethyl ether (2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was allowed to warm to ambient temperature, quenched with saturated NH4Cl solution, and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give tert-butyl 4-hydroxy-4-[2-(hydroxymethyl)-5-methyl-phenyl]piperidine-1-carboxylate (550 mg, 45%). ESI-MS m / z: 322.23 [M+1] +

[0261] Step 2: Preparation of tert-butyl 5-methylspiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (C202) To a stirred solution of tert-butyl 4-hydroxy-4-[2-(hydroxymethyl)-5-methyl-phenyl]piperidine-1-carboxylate (370 mg, 1.1512 mmol) in DCM (10 mL) was added EtN (582.45 mg, 0.8023 mL, 5.7560 mmol) at 0 °C, followed by MsCl (197.81 mg, 0.1337 mL, 1.7268 mmol). The reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with DCM (30 mL) and washed three times with water (10 mL). The solvent was evaporated, and the crude residue was purified by normal-phase flash column chromatography (gradient: 10–20% EtOAc / hexanes) to give tert-butyl 5-methylspiro[1H-isobenzofuran-3,4′-piperidine]-1′-carboxylate (150 mg, 43%). 1 H NMR (DMSO-d6): δ7.15(d, J=8Hz, 1H), 7.09(d, J=4.24, 2H), 4.94(s, 2H), 3.93(brs, 2H) , 3.05 (brs, 2H), 2.30 (s, 3H), 1.78~1.72 (m, 2H), 1.57 (d, J=12.4Hz, 2H), 1.42 (s, 9H). ESI-MS m / z:304.0[M+1] + .

[0262] Step 3: Preparation of 5-methylspiro[1H-isobenzofuran-3,4'-piperidine] (C203) To a stirred solution of tert-butyl 5-methylspiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (150 mg, 0.4944 mmol) in DCM (5 mL) was added TFA (281.86 mg, 0.1904 mL, 2.4720 mmol) at 0 °C and stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM (30 mL) and washed three times with saturated aqueous sodium carbonate (10 mL) and water (10 mL). Evaporation of the solvent gave 5-methylspiro[1H-isobenzofuran-3,4'-piperidine] (95 mg, 95%), which was used in the next step without further purification. ESI-MS m / z: 204.0 [M+1] + .

[0263] Step 4: Preparation of 5-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine] (286) To a stirred solution of 5-methylspiro[1H-isobenzofuran-3,4'-piperidine] (90 mg, 0.4067 mmol) in methanol (2 mL) was added 1-methyl-1H-pyrazole-4-carbaldehyde (67.170 mg, 0.6100 mmol). The mixture was stirred for 30 minutes, followed by the addition of NaCNBH3 (76.674 mg, 1.2201 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was quenched with ice, and then the excess ethanol was evaporated. The crude residue was diluted with DCM (50 mL) and washed three times with water (20 mL). The excess solvent was evaporated, and the crude residue was purified by reverse-phase column chromatography (column: YMC Triart Actus C18 (250 × 20 mm, 5 μ), gradient: 30–95% MeCN / 20 mM ammonium bicarbonate in water) to give 5-methyl-1′-[(1-methylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine] 286 (45 mg, 36%). 1 H NMR (DMSO-d6): δ7.56(s,1H),7.30(s,1H),7.12(d,J=7.6Hz,1H),7.06(d,J=7.68Hz,1H),7.02(s,2H),4.88(s,2H),3.79(s,3 ESI-MS m / z:298.0[M+1] + .

[0264] compound 287 5-Chloro-1,1-dimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isobenzofuran-3,4'-piperidine] (287) [ka] Step 1: Preparation of 2-(2-bromo-4-chloro-phenyl)propan-2-ol (C206) To a stirred solution of methyl 2-bromo-4-chlorobenzoate (10 g, 40.082 mmol) in THF (200 mL) cooled to 0 °C, MeMgBr (19.118 g, 160.33 mmol) was added slowly while maintaining the temperature at 0 °C. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3 × 300 ml). The organic layer was washed with brine (400 mL) and dried over anhydrous NaSO. The organic layer was filtered and concentrated to give 2-(2-bromo-4-chloro-phenyl)propan-2-ol (10 g, 100%). 1 H NMR (CDCl3, 400MHz): δ=7.65~7.63 (d, 1H, J=8.8Hz), 7.598~7.592 (d, 1H, J=2.4Hz), 2.55 (m, 1H), 1.69~1.73ppm (m, 6H).

[0265] Step 2: Preparation of tert-butyl 4-[5-chloro-2-(1-hydroxy-1-methyl-ethyl)phenyl]-4-hydroxy-piperidine-1-carboxylate (C207) To a stirred solution of 2-(2-bromo-4-chloro-phenyl)propan-2-ol (2.5 g, 0.0089 mol) in THF (37.5 mL) was added n-BuLi (2.0 g, 3 mL, 0.0318 mol) at −78° C. The reaction mixture was stirred at the same temperature for 30 minutes, and then tert-butyl 4-oxopiperidine-1-carboxylate (2.2 g, 0.0110 mol) in THF (5 mL) was added. The reaction mixture was allowed to warm to room temperature and continued stirring for 3 hours. The reaction mixture was quenched with saturated ammonium chloride solution (200 ml) and then extracted with EtOAc (3×100 ml). The combined organic layers were dried over Na2SO4 and concentrated to give tert-butyl 4-[5-chloro-2-(1-hydroxy-1-methyl-ethyl)phenyl]-4-hydroxy-piperidine-1-carboxylate (5 g, 21%), which was carried on without further purification.

[0266] Step 3: Preparation of 5-chloro-1,1-dimethyl-spiro[isobenzofuran-3,4'-piperidine] (C208) To a stirred solution of tert-butyl 4-[5-chloro-2-(1-hydroxy-1-methyl-ethyl)phenyl]-4-hydroxy-piperidine-1-carboxylate (1.5 g, 0.7300 mmol) in toluene (15 mL) was slowly added BF3.OEt2 (2.8779 g, 2.5468 mL, 20.277 mmol) at room temperature. The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated, neutralized with sodium bicarbonate solution, then added to water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were concentrated to give 5-chloro-1,1-dimethyl-spiro[isobenzofuran-3,4'-piperidine] (190 mg, 103%) as a crude intermediate, which was carried on directly to the next step without further purification. ESI-MS m / z: 252.0 [M+1] + .

[0267] Step 4: Preparation of 5-chloro-1,1-dimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isobenzofuran-3,4'-piperidine] (287) To a stirred solution of 5-chloro-1,1-dimethyl-spiro[isobenzofuran-3,4'-piperidine] (100 mg, 293.94 μmol) and 4-(chloromethyl)-1-(2-methylsulfonylethyl)pyrazole (82 mg, 294.58 μmol) in MeCN (2.0 mL) and DMF (1.0 mL) was added KCO (207 mg, 0.0015 mol) followed by KI (10 mg, 60.24 μmol) at ambient temperature. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (2 × 200 mL). The filtrate was concentrated to give a crude residue, which was purified by reverse-phase HPLC (column: -xselect phenylhexyl (150 × 25) mm, 5 u, gradient: 2 to 25% MeCN:MeOH (1:1) in 0.1% aqueous TFA) to give 5-chloro-1,1-dimethyl-1′-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isobenzofuran-3,4′-piperidine] (287) (23 mg, 14%). 1 H NMR(400MHz,DMSO-d6)δ8.00(d,J=12.0Hz,1H),7.67(d,J=8.0Hz,1H),7.42(dd,J=8.0Hz,1.6Hz,1H ),7.36(d,J=4.8Hz,1H),7.33~6.52(m,1H),4.59(t,J=6.4Hz,2H),4.41(d,J=6.0Hz,2H),3.70(t,J=6.8Hz ,2H),3.37(s,2H),3.12(s,2H)2.89(s,3H),2.17~2.07(m,2H),1.81(d,J=13.6Hz,2H),1.46(s,6H).ESI-MS m / z: 438.0 [M+1] + .

[0268] compound 288 2-Methyl-1-[[5-[(1,1,5-trimethylspiro[isobenzofuran-3,4'-piperidine]-1'-yl)methyl]-2-pyridyl]oxy]propan-2-amine (288) [ka] Step 1: Preparation of 2-(2-bromo-4-methyl-phenyl)propan-2-ol (C210) To a stirred solution of methyl 2-bromo-4-methylbenzoate (5.0 g, 21.83 mmol) in THF (50 mL) was slowly added MeMgBr (21.83 mL of 3 M, 65.481 mmol) at ambient temperature, and the resulting reaction mixture was stirred for 16 hours. The reaction mixture was quenched with ammonium chloride solution (200 ml), extracted with ethyl acetate (200 ml), and the organic layer was dried over sodium sulfate. The solution was concentrated to give 2-(2-bromo-4-methyl-phenyl)propan-2-ol (5.5 g, 93%). 1 H NMR (400MHz, CDCl3), δppm 7.51(d, J=8.4MHz, 1H), 7.41(s, 1H), 7.09(d, J=6.8MHz, 1H), 2.29(s, 3H), 1.72(s, 6H).

[0269] Step 2: Preparation of 1-benzyl-4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-phenyl]piperidin-4-ol (C211) To a stirred solution of 2-(2-bromo-4-methyl-phenyl)propan-2-ol (5.5 g, 24.0 mmol) in THF (45 mL), n-BuLi (22.1 mL of 2.5 M, 55.2 mmol) was slowly added over 15 minutes at −78° C., and the mixture was stirred at the same temperature for 1 hour. To the mixture, a solution of 1-benzylpiperidin-4-one (6.36 g, 33.6 mmol) in tetrahydrofuran (10 mL) was slowly added over 10 minutes at −78° C. The resulting mixture was slowly warmed to ambient temperature and stirred for 18 hours. The reaction mixture was quenched by the addition of ammonium chloride solution (100 ml), extracted with ethyl acetate (200 ml), and the organic layer was dried over sodium sulfate and then concentrated. The crude residue was purified by flash column chromatography (gradient: 5% methanol in DCM) to give 1-benzyl-4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-phenyl]piperidin-4-ol (3.2 g, 32%). 1H NMR(400MHz,CDCl3),δppm 7.63(s,1H),7.43~7.32(m,5H),7.16(d,J=7.6Hz,1H),6.97(d,J=7.6Hz,1H),4.07(s,2H),3.21(br,s,4H), 2.87(br,s,2H),2.30(s,3H),2.69~2.03(m,2H),1.76(s,6H),1.33~1.30(m,1H),0.91~0.88(m,1H).ESI-MS m / z 340.0[M+1] + .

[0270] Step 3: Preparation of 1'-benzyl-1,1,5-trimethyl-spiro[isobenzofuran-3,4'-piperidine] (C212) To a stirred solution of 1-benzyl-4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-phenyl]piperidin-4-ol (3.2 g, 9.43 mmol) in toluene (64 mL) was added boron trifluoride diethyl etherate (30.1 g, 26.6 mL, 212.1 mmol), and the reaction mixture was stirred for 16 h. The solvent was evaporated under reduced pressure to give a crude residue, which was quenched with water (200 mL), extracted with ethyl acetate (3 × 100 mL), dried over sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography (gradient: 30-40% ethyl acetate in hexanes) to give 1'-benzyl-1,1,5-trimethyl-spiro[isobenzofuran-3,4'-piperidine] (2.9 g, 78%). 1 H NMR(400MHz,CDCl3),δppm 7.48~7.43(m,5H),7.12(d,J=8Hz,1H),7.02(s,1H),6.97(d,J=8Hz,1H),4.23(s,2H),3.49~3.45( m,2H),3.23~3.17(m,2H),2.71~2.61(m,2H),2.35(s,3H),1.77~1.75(m,2H),1.46(s,6H).ESI-MS m / z:322.0[M+1] + .

[0271] Step 4: Preparation of 1,1,5-trimethylspiro[isobenzofuran-3,4'-piperidine] (C213) To a stirred solution of 1'-benzyl-1,1,5-trimethyl-spiro[isobenzofuran-3,4'-piperidine] (2.3 g, 7.15 mmol) in methanol (46 mL) was added Pd / C (1.5 g, 10% w / w, 1.4095 mmol) and AcOH (214 mg, 0.203 mL, 3.58 mmol). The reaction mixture was stirred under a hydrogen atmosphere (30 psi) at ambient temperature for 24 hours. The reaction mixture was filtered through a wet Celite pad, ensuring that the pad and palladium by-product remained wet. The pad was washed with methanol (50 mL), and the filtrate was concentrated. The crude residue was triturated with diethyl ether (3 x 50 mL) and concentrated to give 1,1,5-trimethylspiro[isobenzofuran-3,4'-piperidine] (1.429 g, 86%). 1 H NMR(400MHz,DMSO-d6),δppm 8.27(br,s,1H),7.15(s,2H),6.92(s,1H),3.32~3.29(m,2H),3.15~3.08(m, 2H),2.34(s,3H),2.17~2.06(m,2H),1.79~1.67(m,2H),1.44(s,6H).ESI-MS m / z:232.2[M+1] + .

[0272] Step 5: Preparation of 1'-[(6-chloro-3-pyridyl)methyl]-1,1,5-trimethyl-spiro[isobenzofuran-3,4'-piperidine] (C214) A solution of 1,1,5-trimethylspiro[isobenzofuran-3,4'-piperidine] (200 mg, 0.865 mmol) in DCE (5 mL) was treated with 2-chloro-5-(chloromethyl)pyridine (142 mg, 0.878 mmol), followed by DIPEA (407 μL, 2.337 mmol). The resulting solution was heated at 60 °C overnight. The reaction was cooled to ambient temperature and then quenched by partitioning between 1 M NaOH and DCE. The combined organics were collected through a phase separator tube and then concentrated in vacuo. The crude residue was purified by flash column chromatography (gradient: 0 to 100% EtOAc in heptane) to give 1'-[(6-chloro-3-pyridyl)methyl]-1,1,5-trimethyl-spiro[isobenzofuran-3,4'-piperidine] (130 mg, 42%). 1 H NMR (400 MHz, chloroform-d) δ 8.35 (dd, J = 2.4, 0.7 Hz, 1H), 7.69 (dd, J = 8.2, 2.4 Hz, 1H), 7.30 (dd, J = 8.2, 0.7 Hz, 1H), 7.10 (ddd, J = 7.7, 1.6, 0.7 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6 .91(dt,J=1.6,0.8Hz,1H),3.56(s,2H),2.78~2.72(m,2H),2.52(td,J=11.9,11.5,2 .5Hz, 2H), 2.37 (d, J=0.8Hz, 3H), 2.01~1.93 (m, 2H), 1.70~1.64 (m, 2H), 1.48 (s, 6H). ESI-MS m / z:357.32[M+1] + .

[0273] Step 6: Preparation of 2-methyl-1-[[5-[(1,1,5-trimethylspiro[isobenzofuran-3,4'-piperidine]-1'-yl)methyl]-2-pyridyl]oxy]propan-2-amine (288) A 2 mL microwave vial was charged with 1'-[(6-chloro-3-pyridyl)methyl]-1,1,5-trimethyl-spiro[isobenzofuran-3,4'-piperidine] (50 mg, 0.1398 mmol), 2-amino-2-methyl-propan-1-ol (9 μL, 0.1677 mmol), and tBu-XPhos Pd G1 precatalyst (5 mg, 0.008 mmol) in tBuOH (1.5 mL). The mixture was degassed under a nitrogen balloon, followed by the addition of 2-methylpropan-2-olate (sodium salt) (154 μL of 2 M, 0.3080 mmol). The vial was sealed and heated at 80 °C for 1 h, then quenched by the addition of methanol. The solution was concentrated and purified by reverse-phase HPLC (gradient: 10 to 90% MeCN in aqueous HCl (0.1% HCl)) to give 2-methyl-1-[[5-[(1,1,5-trimethylspiro[isobenzofuran-3,4′-piperidine]-1′-yl)methyl]-2-pyridyl]oxy]propan-2-amine 288 (6.7 mg, 11%). 1 H NMR (300MHz, chloroform-d) δ8.10(dd,J=2.5,0.7Hz,1H),7.76(dd,J=8.5,2.4Hz,1 H),7.09(ddd,J=7.7,1.5,0.8Hz,1H),7.01(d,J=7.7Hz,1H),6.93~6.88(m,2H) ,4.18(s,2H),3.59(s,2H),2.81(d,J=11.0Hz,2H),2.58~2.48(m,2H),2.34(s, 3H), 2.00(td,J=13.1,4.5Hz,2H),1.68~1.60(m,2H),1.39(d,J=33.6Hz,12H). ESI-MS m / z: 410.47 [M+1] + .

[0274] compound 289 1,1,5-trimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isobenzofuran-3,4'-piperidine] (289) [ka] 1,1,5-Trimethylspiro[isobenzofuran-3,4'-piperidine] C213 (100 mg, 0.4323 mmol) and 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (131 mg, 0.6478 mmol) were dissolved in dichloromethane (2.25 mL). Acetic acid (130 mg, 2.165 mmol) was added, and the solution was transferred to a microwave tube (5 mL). PS-(trimethylammonio)methyl(cyanoborohydride) (650 mg, 2 mmol / g, 1.300 mmol) was added, and the solution was capped and heated to 110 °C in a microwave reactor for 1 h. The solution was filtered and concentrated. The crude product was purified by reverse-phase chromatography (gradient: 20 to 80% MeCN in aqueous HCl (0.1% HCl)) to give 1,1,5-trimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isobenzofuran-3,4'-piperidine] (hydrochloride salt) 289 (120 mg, 61%). ESI-MS m / z: 418.18 [M+1] + .

[0275] compound 290 (2'S)-2',3,3,6-tetramethyl-1'-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4'-piperidine] (290) [ka] Step 1: Preparation of (2S)-4-hydroxy-4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-phenyl]-2-methyl-piperidine-1-carboxylate tert-butyl ester (C215) To a stirred solution of 2-(2-bromo-4-methyl-phenyl)propan-2-ol (460 mg, 2.0 mmol) in THF (10 mL) was slowly added n-BuLi (1.85 mL of 2.5 M, 4.62 mmol) under nitrogen at −78° C. The reaction mixture was stirred at the same temperature for 1 hour, after which a solution of (S)-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (557 mg, 2.61 mmol) in THF (2 mL) was added. The reaction was stirred at ambient temperature for 16 hours. The reaction was quenched with saturated ammonium chloride, extracted with EtOAc (2×50 ml), dried over sodium sulfate, and concentrated to give tert-butyl (2S)-4-hydroxy-4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-phenyl]-2-methyl-piperidine-1-carboxylate (550 mg, 25%). ESI-MS m / z: 364.0 [M+1] + The crude product was used directly in the next reaction without purification.

[0276] Step 2: Preparation of (2'S)-1,1,2',5-tetramethylspiro[isobenzofuran-3,4'-piperidine] (C216) To a stirred solution of tert-butyl (2S)-4-hydroxy-4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-phenyl]-2-methyl-piperidine-1-carboxylate (3.2 g, 8.8 mmol) in toluene (32 mL) was added BF3.OEt2 (6.24 g, 44.0 mmol) slowly at room temperature, and the reaction was then stirred at ambient temperature for 3 hours. The mixture was then concentrated, washed with saturated NaHCO3 (50 ml), extracted with EtOAc (2 x 50 ml), dried over sodium sulfate, concentrated, and the crude was triturated with DEE (2 x 30 ml) to give a crude solid, which was purified by chiral SFC chromatography for isomer separation (Column: Chiralcel OX-H (30 x 250 mm), 5μ, Gradient: 70% CO2 in methanol (15 mM methanolic ammonia), Flow rate: 100 g / min, Temperature: 30.0 °C) to give the following:

[0277] First eluting peak (2'S)-1,1,2',5-tetramethylspiro[isobenzofuran-3,4'-piperidine] C216 (59 mg, 3%) 1 H NMR(400MHz,DMSO-d6),δppm 7.08(s,2H),6.91(s,1H),2.91~2.79(m,3H),2.31(s,3H),1.78(s,1H),1.70~1.62(m,1H),1.49~1.33(m,9H),0.95(d,J=6.4Hz,3H).ESI-MS m / z:246.0[M+1] + .

[0278] Second eluting peak (2'S)-1,1,2',5-tetramethylspiro[isobenzofuran-3,4'-piperidine] C217 (607 mg, 27%) 1 H NMR(400MHz,DMSO-d6),δppm 7.33(s,1H),7.09(s,2H),3.07~2.88(m,3H),2.32(s,3H),1.86(s,1H),1.72~1.65(m,3H),1.40~1.38(m,7H),0.99(d,J=6.4Hz,3H).ESI-MS m / z:246.0[M+1] + .

[0279] Step 3: Preparation of (2'S)-2',3,3,6-tetramethyl-1'-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4'-piperidine] (290) To a stirred solution of (2'S)-1,1,2',5-tetramethylspiro[isobenzofuran-3,4'-piperidine]C216 (27.43 mg, 0.11 mmol) and 4-(chloromethyl)-1-(2-methylsulfonylethyl)triazole (25 mg, 0.1118 mmol) in DMF was added K2CO3 (15.45 mg, 0.11 mmol). The solution was stirred at 60 °C for 16 h. The reaction was extracted with DCM and water on a phase separator, then concentrated and purified by flash column chromatography (gradient: 0 to 20% MeOH / DCM) to give (2'S)-2',3,3,6-tetramethyl-1'-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4'-piperidine] 290 (17.2 mg, 35%). ESI-MS m / z: 433.64 [M+1] + .

[0280] Compound 291 (2'S)-5-chloro-1,1,2'-trimethyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[isobenzofuran-3,4'-piperidine] (291) [ka] Compound 291 was prepared by the method described for compound 290 with the following modifications. In step 1, 2-(2-bromo-4-chlorophenyl)propan-2-ol was used instead of 2-(2-bromo-4-methylphenyl)propan-2-ol. In step 2, peak 2 was isolated and carried to the next step by chiral SFC chromatography for isomer separation (column: Chiralcel OX-H (30 × 250 mm), 5 μm; gradient: 80% CO in methanol (15 mM methanolic ammonia); flow rate: 90 g / min; temperature: 30.0 °C). In step 3, (2'S)-5-chloro-1,1,2'-trimethyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[isobenzofuran-3,4'-piperidine] 291 (4.3 mg, 19%) was obtained. ESI-MS m / z: 453.18 [M+1] + .

[0281] compound 292 (2'S)-5-Chloro-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (292) [ka]

[0282] Step 1: Preparation of (2S)-2-methyl-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-one (C219) To a stirred solution of 1-phenylpyrazole-4-carbaldehyde (2 g, 0.01 mol) in DCE (30 mL) was added (2S)-2-methylpiperidin-4-one (810 mg, 0.007 mol) followed by sodium triacetoxyborohydride (2.3 g, 0.01 mol) at 0 °C. The reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2 × 100 mL). The organic layer was dried over sodium sulfate and concentrated to give crude compound (2S)-2-methyl-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-one (2.2 g). This was carried on directly to the next step without further purification. ESI-MS m / z: 270.06 [M+1] + .

[0283] Step 2: Preparation of (2S)-4-[5-chloro-2-(dimethoxymethyl)phenyl]-2-methyl-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-ol (C220) To a stirred solution of 2-bromo-4-chloro-1-(dimethoxymethyl)benzene (1.5 g, 0.005 mol) and (2S)-2-methyl-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-one (1.6 g, 0.006 mol) in THF (15 mL) was added n-butyllithium (5.5 mL of 2.5 M, 0.014 mol) at −78° C. and maintained at the same temperature for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over NaSO and concentrated to give (2S)-4-[5-chloro-2-(dimethoxymethyl)phenyl]-2-methyl-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-ol (2.5 g, 59%). ESI-MS m / z: 456.36 [M+1] + .

[0284] Step 3: Preparation of (2'S)-5-chloro-1-methoxy-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine] (C221) To a stirred solution of (2S)-4-[5-chloro-2-(dimethoxymethyl)phenyl]-2-methyl-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-ol (2.5 g, 0.0030 mol) in MeOH (50 mL) was added PTSA (4.6 g, 0.0264 mol) at 0° C., and the reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was concentrated, diluted with water (100 mL), extracted with DCM (2×200 mL), and the organic layer was washed with 2 M NaOH solution (30 mL, pH=9), dried over sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography (gradient: 60 to 100% EtOAc in hexanes) to afford (2'S)-5-chloro-1-methoxy-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine] (1.1 g, 80%). 1 H NMR(400MHz,DMSO-d6)δ8.43(d,J=8.0Hz,1H),7.84(d,J=8.4Hz,2H),7.69(d,J=11.2Hz,1H),7.51~7.36(m,5H),7.28(t,J=8.0Hz,1H),6.01~5.97( m,1H),3.32~2.89(m,1H),3.89~3.51(m,2H),3.37~3.28(m,3H),2.85~2. 79(m,1H),2.56~2.49(m,1H),2.06~1.46(m,4H),1.22~1.55(m,3H)ESI-MS m / z:424.32[M+1] + .

[0285] Step 4: Preparation of (2'S)-5-chloro-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C222) To a stirred solution of (2'S)-5-chloro-1-methoxy-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine] (1.6 g, 0.0035 mol) in CHCl (50 mL) was added TMSCN (2.27 g, 3.2 mL, 0.0206 mol) followed by BF.OEt (1.13 g, 1 mL, 0.008 mol) at -25 °C. The solution was stirred at 0 °C for 1 h. The reaction mixture was quenched with methanol (5 mL), followed by the addition of 2 M NaOH solution (pH = 9). The organic layer was separated, dried over NaSO, and concentrated. The crude residue was purified by flash column chromatography (gradient: 30–40% EtOAc in hexanes) to give (2′S)-5-chloro-2′-methyl-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carbonitrile (300 mg, 20%). 1 H NMR(300MHz,DMSO-d6)δ8.42(s,1H),8.44(s,1H),7.84(d,J=8.4Hz,2H),7.70(s 1H),7.58~7.46(m,5H),7.28(t,J=7.5Hz,1H),6.23(s,1H),3.66(d,J=3.9Hz,1H),3.05~3.01(m,1H), 2.85~2.80(m,1H),2.65~2.69(m,1H),2.12~1.92(m,2H),1.77~1.65(m,2H),1.23~1.15(m,3H).ESI-MS m / z 419.33[M+1] + .

[0286] Step 5: Preparation of (2'S)-5-chloro-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (292) To a stirred solution of (2'S)-5-chloro-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (100 mg, 226.77 μmol) in THF (2 mL) was added a solution of LiOH (60 mg, 0.0014 mol) in HO (0.5 mL) at ambient temperature. The solution was stirred for 16 h. The reaction was concentrated, and the crude residue was dissolved in EtOAc (50 mL). The organic layer was dried over NaSO and concentrated. The crude compound was purified by reverse-phase HPLC (gradient: 30–90% MeCN in 10 mM ammonium bicarbonate) to give (2′S)-5-chloro-2′-methyl-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide 292 (20 mg, 19%). 1 H NMR (400MHz, DMSO-d6): δ8.45(s,1H),7.84(d,J=8.0Hz,2H),7.71(s,1H),7.48(t,J=7.6Hz,2H),7.41~7.26(m,5H),7. 19~6.98(m,1H),5.34(s,1H),3.72(s,2H),2.98~2.81(m,2H),2.67~2.51(m,1H),1.94~1.66(m,4H),1.30~1.10(m,3H). ESI-MS m / z:437.39[M+1] + .

[0287] compound 293 (2'S)-5-Chloro-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (293) [ka] Compound 292 was purified by chiral SFC purification (Column: Chiralpak IC (250 x 30 x 5μ); Gradient: 50% CO in methanol (0.5% IPA amine in IPA; Flow rate: 70 g / min; Temperature: 30.0 °C) to give (2'S)-5-chloro-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide 293 (5 mg, 4%). ESI-MS m / z 437.42 [M+1] + .

[0288] compound 294 (2'S)-5-chloro-N,2'-dimethyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (294) [ka] Step 1: Preparation of (2'S)-5-chloro-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (C223) To a stirred solution of (2'S)-5-chloro-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (350 mg, 818.77 μmol) in THF (2 mL) was added a solution of LiOH (710 mg, 0.0166 mol) in HO (0.5 mL) at ambient temperature, followed by stirring at 80 °C for 24 h. The reaction was concentrated, and the crude residue was dissolved in water (50 mL) and extracted with EtOAc (30 mL). The separated organic and aqueous layers were acidified with 1 M HCl and extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layers were dried over NaSO and concentrated to give (2'S)-5-chloro-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (300 mg, 67%). ESI-MS m / z 438.12 [M+1] + .

[0289] Step 2: Preparation of (2'S)-5-chloro-N,2'-dimethyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (294) To a stirred solution of (2'S)-5-chloro-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (200 mg, 431.59 μmol) in THF (4 mL) was added methylamine (20 mg, 290.29 μmol) and TEA (294.00 mg, 0.4 mL, 0.0028 mol), followed by T3P (0.9 mL of 50% w / v, 0.0014 mol) at 0°C, and the solution was then allowed to warm to ambient temperature for 16 h. The reaction mixture was dissolved in EtOAc (50 mL), and the organic layer was then washed with 1 M NaOH solution (2 × 10 mL), dried over Na2SO4, and concentrated. The crude residue was purified by chiral SFC purification (column: Lux, cellulose-4 (250 × 30 × 5μ), gradient: 60% CO in methanol (30 mM methanolic ammonia in ethanol), flow rate: 70 g / min, temperature: 30.0 °C), and the first eluting peak was isolated to give (2'S)-5-chloro-N,2'-dimethyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide 294 (10 mg, 5%). 1 H NMR(400MHz,DMSO-d6):δ8.45(s,1H),7.84(d,J=8.0Hz,2H),7.71~7.68(m,2H),7.49(t,J =8.0Hz,2H),7.40(d,J=8.0Hz,1H),7.34~7.27(m,3H),5.39(s,1H),3.69(s,2H),2.93(br s,2H),2.61(d,J=4.4Hz,4H),1.94~1.90(m,3H),1.66(br s 1H),1.19(s,3H),ESI-MS m / z:451.2[M+1] + .

[0290] compound 295 5-Chloro-N-methyl-1'-[[1-[3-(trifluoromethyl)phenyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (295) [ka] 5-Chloro-N-methyl-1′-[[1-[3-(trifluoromethyl)phenyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide (295) was prepared using the same HATU amide coupling method used to prepare compound 294 with the appropriate carboxylic acid.

[0291] 1 H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.18(d,J=9.3Hz,2H),7.81~7.57(m,4H),7.42~7.31(m,3H),5.40(s,1H),3. 58(s,3H),2.85(s,2H),2.62(d,J=4.7Hz,3H),2.43~2.05(m,2H),1.85(d,J=13.6Hz,2H),1.66(d,J=13.7Hz,1H). LCMS m / z 505.27[M+1] + .

[0292] compound 296 6-Methoxy-1'-((1-phenyl-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carboxamide (296) [ka] 6-Methoxy-1′-((1-phenyl-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-3-carboxamide 296 was prepared in a manner similar to that of compound 191 using 2-bromo-1-(dimethoxymethyl)-4-methoxybenzene to give 14 mg of the final product.

[0293] 1H NMR (400MHz, DMSO-d6): δ8.41(s,1H),7.83(d,J=8.8Hz,2H),7.67(s,1H),7.48(t,J=7.6Hz,2H),7.32~7.24(m,3H),7.0(brs,1H),6.85~6.8 3(m,2H),5.26(s,1H),3.74(s,3H),3.51(s,2H),2.80(brs,2H),2.49~ 2.32(m,2H), 2.10~2.02(m,1H), 1.92~1.79(m,2H), 1.65~1.62(m,1H). LCMS m / z 419.2[M+1] + .

[0294] compound 297 6-Methoxy-N-methyl-1'-((1-phenyl-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carboxamide (297) [ka] 6-Methoxy-N-methyl-1'-((1-phenyl-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carboxamide was prepared similarly to compound 195 using 2-bromo-1-(dimethoxymethyl)-4-methoxybenzene to give 30 mg of the final product 297.

[0295] 1 H NMR(400MHz,DMSO-d6)δ8.41(s,1H),7.83(d,J=8.0,2H),7.67(s,1H),7.48(t,J=8.0Hz,3H),7.30~7.22(m,2H),6.84~6.82(m,2H),5.31(s,1H),3 .74(s,3H),3.52(s,2H),2.80(t,J=12.0Hz,2H),2.61(d,J=8.0Hz,3H),2 .52~2.47(m,1H),2.33(t,J=11.2Hz,1H),2.11~2.04(m,2H),1.89(s,1H). LCMS m / z 433.51[M+1] + .

[0296] compound 298 6-chloro-1'-((1-isopropyl-1H-pyrazol-4-yl)methyl)-N-methyl-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carboxamide (298) [ka] Compound 298 was prepared similarly to compound 195 using 1-isopropyl-1H-pyrazole-4-carbaldehyde to give the final product 6-chloro-1′-((1-isopropyl-1H-pyrazol-4-yl)methyl)-N-methyl-3H-spiro[isobenzofuran-1,4′-piperidine]-3-carboxamide (12 mg). 1 H NMR(400MHz,DMSO-d6):δ7.63(s,1H),7.60~7.48(m,1H),7.40(d,J=1.6Hz, 1H),7.38~7.32(m,3H),5.39(s,1H),4.47~4.41(m,1H),3.39(s,2H),2.74( brs,2H),2.62(d,J=4.8Hz,3H),2.51~2.49(m,1H),2.46~2.40(m,1H),2.07 ~2.01(m,1H),1.84~1.79(m,2H),1.62~1.59(m,1H),1.39(d,J=6.8Hz,6H). LCMS m / z 403.42[M+1] + .

[0297] compound 299 6-chloro-N-methyl-1'-((5-methyl-1-phenyl-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carboxamide (299) [ka] Compound 299 was prepared similarly to compound 190 using 2-bromo-4-chloro-1-(dimethoxymethyl)benzene and 5-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde to give the final product 6-chloro-N-methyl-1'-((5-methyl-1-phenyl-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carboxamide (2 mg). LCMS m / z 451.27 [M+1] + .

[0298] Compounds 300 and 301 5-Chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indan-3,4'-piperidin]-1-ol (300) and 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indan-1,4'-piperidin]-2-ol (301) [ka] Step 1: Preparation of 6-chloro-1H-indene (C225) To a stirred solution of 5-chloroindan-1-ol (10.0 g, 0.0593 mol) in benzene (100 mL) was added pTSA (206 mg, 0.193 mL, 0.0012 mol) at ambient temperature, and the reaction was then stirred at 80 °C for 1 hour. The reaction mixture was cooled to ambient temperature, basified with saturated sodium bicarbonate solution (100 mL), water (50 mL) was added, extracted with ethyl acetate (2 × 200 mL), and the organic layers were combined and dried over sodium sulfate. The organic layers were filtered and concentrated. The crude residue was purified by column chromatography (gradient: 100% hexane) to give 6-chloro-1H-indene (6.2 g, 68%). 1 H NMR (400MHz, CDCl3), δppm 7.43(s,1H),7.29~7.27(m,1H),7.24~7.22(m,1H),6.84~6.81(m,1H),6.55~6.53(m,1H),3.37(s,2H).

[0299] Step 2: Preparation of tert-butyl 6-chlorospiro[indene-1,4'-piperidine]-1'-carboxylate (C226) To a stirred solution of 6-chloro-1H-indene (4.0 g, 0.01 mol) in THF (40 mL) was added LHMDS (23.2 mL of 1 M, 0.0232 mol) over 20 minutes at 0° C. The reaction was stirred at 0° C. for 1 hour, then tert-butyl N,N-bis(2-chloroethyl)carbamate (2.25 g, 0.01 mol) in THF (10 mL) was added slowly over 10 minutes at 0° C., then stirred at 0° C. for 2 hours. The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was concentrated and purified by column chromatography (gradient: 5% ethyl acetate in hexanes) to give tert-butyl 6-chlorospiro[indene-1,4′-piperidine]-1′-carboxylate (5.0 g, 44%). 1 H NMR(400MHz,CDCl3),δppm 7.30~7.26(m,1H),7.23~7.15(m,2H),6.90~6.83(m,1H),6.74~6.72(m,1H),4.18~4.1 3(m,2H),3.13~3.07(m,2H),2.10~1.93(m,2H),1.15~1.45(m,9H),1.34~1.31(m,2H). LCMS m / z 264.0[M-55] + .

[0300] Step 3: Preparation of 6-chlorospiro[indene-1,4'-piperidine] (C227) To a stirred solution of tert-butyl 6-chlorospiro[indene-1,4'-piperidine]-1'-carboxylate (300 mg, 919.25 μmol) in 1,4-dioxane (3.0 mL) was added HCl (4 M in 1,4-dioxane) (2.30 mL of 4 M, 0.0092 mol) at ambient temperature, and the reaction was stirred for 3 hours. The reaction mixture was concentrated to give 6-chlorospiro[indene-1,4'-piperidine] (hydrochloride salt) (230 mg, 95%). 1H NMR(300MHz,DMSO d6),δppm 9.12(br,s,1H),7.41~7.32(m,3H),7.18(d,J=5.7Hz,1H),6.86(d,J=5.4Hz,1H),3. 42~3.38(m,2H),3.27~3.19(m,2H),2.34(t,J=11.1Hz,2H),1.34(d,J=14.1Hz,2H). LCMS m / z:220.0[M+1] + .

[0301] Step 4: Preparation of 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indene-1,4'-piperidine] (C228) To a stirred solution of 6-chlorospiro[indene-1,4'-piperidine] (hydrochloride) (230 mg, 869.92 μmol) in DMF (4.6 mL) was added 4-(chloromethyl)-1-methyl-pyrazole (hydrochloride) (145.31 mg, 869.92 μmol), KI (144.41 mg, 869.92 μmol), and KCO (594.29 mg, 0.0043 mol) at ambient temperature. The reaction was then stirred at 80°C for 16 hours. The reaction was quenched with water (50 mL), extracted with ethyl acetate (2 x 50 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated to give 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indene-1,4'-piperidine] (240 mg, 58%). LCMS m / z: 314.0 [M+1] + .

[0302] Step 5: Preparation of 5-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indan-3,4'-piperidin]-1-ol (300) and 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indan-1,4'-piperidin]-2-ol (301) To a stirred solution of 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indene-1,4'-piperidine] (240 mg, 749.46 μmol) in THF (3.6 mL) was added BH3 (solution in THF) (1.9 mL of 1 M, 0.0019 mol) at -5 °C. The reaction mixture was stirred at ambient temperature for 1 h. NaOH (5.0 mL of 3 M, 0.0150 mol) and HO2 (2.55 mL of 30% w / v, 0.0225 mol) were added over 10 min at 0 °C. The reaction was stirred at ambient temperature for 2 h. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (2 x 30 ml), and the combined organic layers were washed with water (50 ml), dried over sodium sulfate, and concentrated. The regioisomers were separated and purified by preparative HPLC (gradient: 0-20% MeCN in 10 mM ammonium bicarbonate) to give:

[0303] First eluting peak as 5-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indan-3,4'-piperidin]-1-ol (300) (8 mg, 3%). 1 H NMR(400MHz,DMSO d6),δppm 7.56(s,1H),7.31~7.29(m,2H),7.25~7.23(m,2H),5.30(br s,1H),5.02(t,J=6.4Hz,1H),3.79(s,3H),3.34(s,2H),2.74~2.76(m,2H),2.49~2.35(m, 1H), 2.09~1.92(m,3H), 1.68~1.61(m,2H), 1.50(d,J=11.6Hz,1H),1.32(d,J=11.2Hz,1H). LCMS m / z:332.0[M+1] + .

[0304] The second eluting peak was 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indan-1,4'-piperidin]-2-ol (301) (16 mg, 6%). 1H NMR(400MHz,DMSO d6),δppm 7.55(s,1H),7.29(s,1H),7.20~7.13(m,3H),4.79(br s,1H),4.27(d,J=4Hz,1H),3.79(s,3H),3.32(s,2H),3.16~3.09(m,1H),2.68~2.62(m ,3H),2.24~2.19(m,2H),1.95(d,J=13.2Hz,1H),1.78~1.71(m,1H),1.43~1.41(m,2H). LCMS m / z:332.0[M+1] + Both regioisomers were confirmed by nuclear Overhauser effect analysis.

[0305] Compound 302 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (302) [ka] Step 1: Preparation of 5-chlorospiro[indan-3,4'-piperidin]-1-one (C230) A solution of tert-butyl 6-chloro-3-oxo-spiro[indan-1,4'-piperidine]-1'-carboxylate (540 mg, 1.61 mmol) in 4 mL of methanol and HCl (2 mL of 4 M, 8.000 mmol) in dioxane was stirred at 50°C for 1 hour. The reaction mixture was concentrated to give the product 5-chlorospiro[indan-3,4'-piperidin]-1-one (hydrochloride salt) (435 mg, 98%). LCMS m / z: 236.11 [M+1] + .

[0306] Step 2: Preparation of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-one (C231) To a solution of 5-chlorospiro[indan-3,4'-piperidin]-1-one (HCl salt) (165 mg, 0.6002 mmol), 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (145 mg, 0.6173 mmol), and AcOH (120 μL, 2.110 mmol) in 4 mL of DCE, STAB (386 mg, 1.830 mmol) was added and stirred at ambient temperature for 6 h. The solution was neutralized, concentrated, and then purified by flash column chromatography (gradient: 0-20% MeOH / DCM) to give 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-one (110 mg, 40%). LCMS m / z: 422.22 [M+1] + .

[0307] Step 3: Preparation of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (302) To 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-one (24 mg, 0.05462 mmol) in methanol (2 mL) was added LiBH4 (15 mg, 0.6886 mmol). The reaction was stirred at ambient temperature for 12 h and then concentrated. Purification by reverse-phase HPLC (0–50% MeCN in 0.1% formic acid) gave 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol 302 (20.4 mg, 87%). 1H NMR (300 MHz, chloroform-d) δ 8.45 (s, 1H), 7.95 (s, 1H), 7.70 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.33–7.18 (m, 2H), 5.19 (dd, J = 7.1, 5.0 Hz, 1H), 4.69 (dd, J = 6.9, 5.6 Hz, 2H), 4.24 (s, 2H), 3.71 (t, J=6.2Hz,2H),3.48(d,J=12.3Hz,2H),3.08(ddt,J=12.9,9.3,5.2Hz,1H),2.88(s,3H),2.54 (dd,J=13.6,7.2Hz,1H),2.22(td,J=13.8,4.0Hz,1H),2.12~1.83(m,3H),1.78~1.55(m,1H). LCMS m / z:423.98[M+1] + .

[0308] Compound 303 5-Chloro-1-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (303) [ka] To 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-one (9.4 mg, 0.02139 mmol) in 2 mL of diethyl ether was added bromo(methyl)magnesium (280 μL of 1.4 M, 0.3920 mmol). The reaction mixture was stirred at ambient temperature for 16 h. Two drops of saturated ammonium chloride and DCM (10 mL) were added, followed by drying over Na2SO4. The organic layer was filtered and concentrated, and the crude residue was purified by reverse-phase HPLC (gradient: 0 to 50% MeCN in 0.1% aqueous TFA) to give 5-chloro-1-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (trifluoroacetate salt) 303 (0.6 mg, 5%). ESI-MS m / z: 438.09 [M+1] + .

[0309] Compound 304 5-Methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[1H-2-benzothiophene-3,4'-piperidine] (304) [ka] Step 1: Synthesis of tert-butyl 4-hydroxy-4-[5-methyl-2-(sulfanylmethyl)phenyl]piperidine-1-carboxylate (C233) To a stirred solution of (2-bromo-4-methyl-phenyl)methanethiol (C232) (2.0 g, 0.0083 mol) in THF (20 mL) was added a hexane solution of n-BuLi (8.32 mL of 2.5 M, 0.0208 mol) at −78° C. The reaction mixture was stirred for 1 hour. To the reaction mixture was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.6538 g, 0.0083 mol) in diethyl ether (6 mL), and the reaction mixture was stirred at −78° C. for 2 hours. The reaction was quenched with NH4Cl solution, extracted with EtOAc (2×80 mL), and the organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated. The crude residue was purified by reverse-phase HPLC (gradient: 0-20% MeCN in 10 mM ammonium bicarbonate) to give tert-butyl 4-hydroxy-4-[5-methyl-2-(sulfanylmethyl)phenyl]piperidine-1-carboxylate (0.8 g, 28%). 1 H NMR(400MHz,DMSO-d6)δ7.25(d,J=7.6Hz,1H),7.12(s,1H),7.03(d,J=8Hz,1H),5.12(s,1H),4.09~4.06(m,2H) ,3.84~3.82(m,2H),3.167(d,J=5.2Hz,2H),2.67(t,J=7.6Hz,1H),2.26(s,3H),1.86~1.80(m,4H),1.41(s,9H). LCMS m / z:338.2(M+1) + . Step 2: Preparation of 5-methylspiro[1H-2-benzothiophene-3,4'-piperidine] (C234)

[0310] To a stirred solution of tert-butyl 4-hydroxy-4-[5-methyl-2-(sulfanylmethyl)phenyl]piperidine-1-carboxylate (1.2 g, 0.0034 mol) in toluene (15 mL) was added BF 3. OEt (2.0580 g, 1.8212 mL, 0.0145 mol) was added at ambient temperature. The reaction mixture was stirred for 4 hours. The reaction mixture was concentrated. The crude residue was triturated with diethyl ether (2 × 10 mL) to give 5-methylspiro[1H-2-benzothiophene-3,4′-piperidine] (875 mg, 100%). 1 H NMR(400MHz,DMSO-d6)δ8.52(brs,1H),8.35(br s,1H),7.21(d,J=8Hz,1H),7.12(d,J=7.6Hz,1H),6.98(s,1H),4.16(s,2H),3.45 (d,J=13.2Hz,2H),3.0(q,J=12Hz,2H),2.35~2.28(m,5H),1.93(d,J=13.6Hz,2H). LCMS m / z 220.36[M+1] + .

[0311] Step 3: Preparation of 5-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[1H-2-benzothiophene-3,4'-piperidine] (304) To a stirred solution of 5-methylspiro[1H-2-benzothiophene-3,4'-piperidine] (300 mg, 0.0012 mol) in MeCN (6 mL) and DMF (1 mL), 4-(chloromethyl)-1-methyl-pyrazole (160 mg, 0.0011 mol) was added, followed by KCO (830 mg, 0.0060 mol) and a catalytic amount of KI (40 mg, 240.96 μmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated, and the crude compound was purified by reverse-phase HPLC (gradient: 0 to 20% MeCN in 0.1% TFA) to give 5-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[1H-2-benzothiophene-3,4'-piperidine] 304 (32 mg, 8%). 1H NMR(400MHz,DMSO-d6)δ7.60(br s,1H),7.34(br s,1H),7.14(d,J=7.6Hz,1H),7.07~7.04(m,2H),4.07(s,2H),3.80(s,3H),3.31(s,2H),2.91(br s, 2H), 2.32~2.14 (m, 7H), 1.75 (br s, 2H). LCMS m / z:314.2[M+1] + .

[0312] Compound 305 5-Chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidine] (305) [ka] Step 1: Preparation of tert-butyl 5-chlorospiro[indoline-3,4'-piperidine]-1-carboxylate (C236) To a solution of 5-chlorospiro[indoline-3,4'-piperidine]C235 (170 mg, 0.7633 mmol) in AcOH (6.5 mL of 10% w / w) (aqueous solution) was added BocO (174.9 mg, 184.1 μL, 0.8015 mmol) in 1,4-dioxane (6.5 mL), and the mixture was stirred vigorously for 16 h. It was diluted with water (10 mL), extracted with ethyl acetate (2 × 10 mL), dried over MgSO4, and evaporated to give tert-butyl 5-chlorospiro[indoline-3,4'-piperidine]-1-carboxylate (160 mg, 65%) as a yellow oil, which was used directly without further purification.

[0313] Step 2: Preparation of tert-butyl 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidine]-1-carboxylate (C237) To tert-butyl 5-chlorospiro[indoline-3,4'-piperidine]-1-carboxylate (hydrochloride) (182 mg, 0.5066 mmol) in 3 mL of DCE was added 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (126 mg, 0.5364 mmol), followed by STAB (214 mg, 1.015 mmol). The resulting mixture was stirred for 16 h. The reaction was neutralized, concentrated, and purified by flash column chromatography (gradient: 0 to 20% MeOH / DCM) to give tert-butyl 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidine]-1-carboxylate (acetate) (60 mg, 20%). 1 H NMR (300MHz, chloroform-d) δ9.74(s,3H),7.57(d,J=13.3Hz,2H),7.19~7.02(m,2H),4.64(dd,J=6.8,5.5Hz,2H),3.79(s,2H),3.67(dd,J=1 3.9,7.7Hz,4H),3.14(d,J=11.8Hz,2H),2.60(s,3H),2.30(t,J=12.2Hz,2H),2.10(s,5H),2.08(s,2H),1.85~1.63(m,2H),1.58(s,9H). LCMS m / z:509.21[M+1] + .

[0314] Step 3: Preparation of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidine] (305) A solution of tert-butyl 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4 yl]methyl]spiro[indoline-3,4'-piperidine]-1-carboxylate (acetate) (4 mg, 0.006788 mmol) in 1 mL of methanol and 0.5 mL of 4 M HCl was stirred at 50° C. for 30 minutes. The solution was concentrated to give 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4 yl]methyl]spiro[indoline-3,4'-piperidine] (dihydrochloride) 305 (3.2 mg, 93%). LCMS m / z: 409.12 [M+1]+ .

[0315] Compounds 306 and 307 (2'S)-5-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (306) and (2'S)-5-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (307) [ka] Step 1: Preparation of (2S)-tert-butyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2-methyl-piperidine-1-carboxylate (C238) To a stirred solution of tert-butyl (2S)-2-methyl-4-oxo-piperidine-1-carboxylate (25 g, 0.1172 mol) in ethyl acetate (550 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (17 g, 0.1180 mol) at room temperature. After 5 minutes, triisopropyl borate (37.490 g, 46 mL, 0.1993 mol), NHOH (10.8 g, 12 mL of 25% w / v, 0.3082 mol), and acetic acid (6.33 g, 6 mL, 0.1055 mol) were slowly added. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was cooled to 0° C., stirred for 20 minutes, filtered, and the filtrate was concentrated under reduced pressure to give a crude residue. The crude residue was purified by flash column chromatography (gradient: 15% EtOAc in pet ether) to give tert-butyl (2S)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2-methyl-piperidine-1-carboxylate (21 g, 40%). LCMS m / z: 338.28 [M-1] - .

[0316] Step 2: Preparation of (2S)-4-(3-chlorophenyl)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methyl-piperidine-1-carboxylate tert-butyl ester (C239) To a stirred solution of magnesium (1.2 g, 0.0494 mol) in THF (250 mL) was added iodine (388 mg, 0.0787 mL, 0.0015 mol) and 1-bromo-3-chloro-benzene (4.2885 g, 7 mL, 0.0224 mol) at room temperature. The reaction mixture was heated to 85° C. and stirred at 85° C. for 2 hours. The reaction mixture was then cooled to room temperature. To the reaction mixture was added tert-butyl (2S)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2-methyl-piperidine-1-carboxylate (10 g, 0.0222 mol) and CuI (2 g, 0.0105 mol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0° C. and quenched with saturated NH4Cl solution (250 mL). It was then extracted with EtOAc (250 mL x 3). The organic layer was washed with brine solution (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl (2S)-4-(3-chlorophenyl)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methyl-piperidine-1-carboxylate (9 g, 30%). LCMS m / z 452.19 [M+1] + .

[0317] Step 3: Preparation of 2-[(2S)-1-tert-butoxycarbonyl-4-(3-chlorophenyl)-2-methyl-4-piperidyl]acetic acid (C240) To a stirred solution of tert-butyl (2S)-4-(3-chlorophenyl)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methyl-piperidine-1-carboxylate (2.5 g, 0.0043 mol) in water (12 mL) in a microwave vial, 3-pentanone (15 mL) was added at room temperature. The reaction mixture was heated to 140° C. (under microwave conditions) and maintained at 140° C. for 20 minutes. The reaction mixture was diluted with EtOAc (50 mL), and the organic layer was separated and concentrated to give 2-[(2S)-1-tert-butoxycarbonyl-4-(3-chlorophenyl)-2-methyl-4-piperidyl]acetic acid (1.9 g, 44%). LCMSMS m / z: 368.21 [M+1] + .

[0318] Step 4: Preparation of (2S)-tert-butyl 4-(2-chloro-2-oxo-ethyl)-4-(3-chlorophenyl)-2-methyl-piperidine-1-carboxylate (C241) A stirred solution of 2-[(2S)-1-tert-butoxycarbonyl-4-(3-chlorophenyl)-2-methyl-4-piperidyl]acetic acid (2.25 g, 0.0043 mol) in MTBE (35 mL) was cooled to −10° C. Then, DMF (94.400 mg, 0.1 mL, 0.0013 mol), pyridine (586.80 mg, 0.6 mL, 0.0074 mol), and oxalyl chloride (873.00 mg, 0.6 mL, 0.0069 mol) were added. After 20 min, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with dry methanol and then distilled under vacuum to give tert-butyl (2S)-4-(2-chloro-2-oxo-ethyl)-4-(3-chlorophenyl)-2-methyl-piperidine-1-carboxylate (2.5 g, 90%).

[0319] Step 5: Preparation of (2'S)-6-chloro-2'-methyl-3-oxo-spiro[indan-1,4'-piperidine]-1'-carboxylate tert-butyl ester (C242) A stirred solution of AlCl3 (62 mg, 464.97 μmol) in DCM (8 mL) was cooled to −30° C., and then AlCl3 (62 mg, 464.97 μmol) in DCM (8 mL) was added. The reaction mixture was stirred at −20° C. for 1 h, then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was poured into ice-cold water (10 mL) and stirred for 30 min. The aqueous layer was separated and added to another flask containing MTBE (10 mL). This solution was cooled to −10° C., and NaOH (10 M aqueous solution) (0.1 mL of 10 M, 0.0010 mol) and BocO (47.500 mg, 0.05 mL, 217.64 μmol) were added. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with EtOAc (70 mL). The organic layer was separated and extracted with EtOAc (40 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude residue, which was purified by reverse-phase HPLC (gradient: 0 to 20% MeCN in 10 mM ammonium bicarbonate) to give tert-butyl (2'S)-6-chloro-2'-methyl-3-oxo-spiro[indan-1,4'-piperidine]-1'-carboxylate (9 mg, 16%). 1 H NMR(400MHz,DMSO-d6)δ7.676(t,J=8.8Hz,2H),7.475(s,2H),7.388~7.356(m,2H),4.62(brs,1H),4.017~3.62(m,3H),3.42~3.31(m,1) H),3.01~2.95(m,1H),2.75(d,J=2.4Hz,3H),2.32~2.21(m,1H),2.008(s,6H),1.92~1.85(m,1H),1.608(s,18H),1.278~1.242(m,5H). LCMS m / z:350.18[M+1] + .

[0320] Step 6: Preparation of tert-butyl (2'S)-6-chloro-3-hydroxy-2'-methyl-spiro[indan-1,4'-piperidine]-1'-carboxylate (C243) A stirred solution of tert-butyl (2'S)-6-chloro-2'-methyl-3-oxo-spiro[indan-1,4'-piperidine]-1'-carboxylate (500 mg, 0.0014 mol) in MeOH (30 mL) was cooled to -10 °C, and NaBH (200 mg, 0.2116 mL, 0.0053 mol) was added. After 20 min, the reaction was allowed to slowly warm to room temperature and stirred for 4 h. The reaction mixture was quenched with ice-cold water (60 mL) and then extracted with DCM (150 mL x 3). The organic layer was washed with brine solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (2'S)-6-chloro-3-hydroxy-2'-methyl-spiro[indan-1,4'-piperidine]-1'-carboxylate (450 mg, 87%). LCMS m / z 352.07[M+1] + .

[0321] Step 7: Preparation of (2'S)-5-chloro-2'-methyl-spiro[indan-3,4'-piperidin]-1-ol (C244) A stirred solution of tert-butyl (2'S)-6-chloro-3-hydroxy-2'-methyl-spiro[indan-1,4'-piperidine]-1'-carboxylate (410 mg, 0.0011 mol) in DCM (15 mL) was cooled to 0 °C and TFA (2.2200 g, 1.5 mL, 0.0195 mol) was added. After 10 min, the reaction was allowed to warm slowly to room temperature and stirred for 4 h. The reaction mixture was concentrated to give (2'S)-5-chloro-2'-methyl-spiro[indan-3,4'-piperidin]-1-ol (trifluoroacetate) (350 mg, 70%). LCMS m / z 252.17 [M+1] + .

[0322] Step 8: Preparation of (2'S)-5-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (306) and (2'S)-5-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (307) To a stirred solution of (2'S)-5-chloro-2'-methyl-spiro[indan-3,4'-piperidin]-1-ol (trifluoroacetate) (350 mg, 773.25 μmol) in DMF (15 mL) was added KCO (580 mg, 0.0042 mol), 4-(chloromethyl)-1-(2-methylsulfonylethyl)pyrazole (hydrochloride) (200 mg, 655.98 μmol), and KI (120 mg, 722.88 μmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite and washed with EtOAc (20 mL). The filtrate was concentrated and the resulting crude residue was purified by chiral SFC chromatography (column: Chiralcel OX-H (30 × 250 mm), 5μ; gradient: 40% (0.5% DEA in MeOH) in CO; temperature 30 °C; flow rate: 60.0 g / min) to give:

[0323] First eluting peak: (2'S)-5-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol 306 (6.1 mg, 2%). 1 H NMR(400MHz,DMSO-d6)δ7.722(s,1H),7.408(s,1H),7.300~7.223(m,3H),5.32(brs,1H),5.003~4.970(m,1H),4.533~4.500(m,2H),3.737~ 3.436(m,4H),2.838~2.793(m,3H),2.750~2.61(m,1H),2.318~2.156( m,3H), 1.781~1.490(m,3H),1.35~1.210(m,2H),1.137~1.044(m,3H). LCMS m / z:438.1[M+1] + .

[0324] Second eluting peak: (2'S)-5-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol 307 (4.3 mg, 1%). 1H NMR(400MHz,DMSO-d6)δ7.725(s,1H),7.410(s,1H),7.300~7.223(m,3H),5.32(brs,1H),5.003~4.970(m,1H),4.533~4.500(m,2H),3.737~ 3.456(m,4H),2.838~2.793(m,3H),2.750~2.61(m,1H),2.318~2.156( m,3H), 1.781~1.690(m,3H),1.35~1.210(m,2H),1.137~1.044(m,3H). LCMS m / z:438.1[M+1] + .

[0325] Compound 308 (2'S)-2',5-Dimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (308) [ka] Compound 308 was prepared similarly to compounds 306 and 307 using 1-bromo-3-methylbenzene, yielding (2'S)-2',5-dimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (4.9 mg). 1 H NMR (300 MHz, chloroform-d) δ 8.40 (s, 1H), 8.00 (s, 1H), 7.78–7.72 (m, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.05 (s, 1H), 5.14 (d, J = 7.5 Hz, 1H), 4.72 (t, J = 6.2 Hz, 2H), 4.50 (d, J = 14.1 Hz, 1H), 4.2 9(d,J=14.1Hz,1H),3.72(t,J=6.2Hz,2H),3.44(d,J=13.1Hz,1H),3.07(t,J=13.5Hz,1H),2.90(d,J =1.1Hz,3H),2.48~2.31(m,4H),2.26~1.80(m,4H),1.67(dd,J=23.2,14.6Hz,1H),1.57~1.47(m,3H). LCMS m / z:438.1[M+1]+ .

[0326] Compound 309 (2'S)-2',4-Dimethyl-1'-((1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)methyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-ol (309) [ka] Compound 309 was prepared in the same manner as compounds 306 and 307 using 1-bromo-3-methylbenzene, to give (2'S)-2',4-dimethyl-1'-((1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)methyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-ol (6.6 mg). 1 H NMR (300 MHz, chloroform-d) δ 8.41 (s, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.07 (dd, J = 7.4, 5.6 Hz, 2H), 5.28 (dd, J = 6.9, 2.4 Hz, 1H), 4.71 (dd, J = 6.9, 5.3 Hz, 2H), 4.50 (dd, J = 14.2, 1H). 8Hz,1H),4.29(d,J=14.1Hz,1H),3.72(t,J=6.1Hz,2H),3.44(d,J=12.7Hz,1H),3.31(p,J=1.7Hz , under MeOD, 1H), 3.19~2.96 (m, 1H), 2.90 (s, 3H), 2.39 (s, 3H), 2.30 ~ 1.90 (m, 4H), 1.73 ~ 1.45 (m, 4H). LCMS m / z:438.3[M+1] + .

[0327] compound 310 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indan-1,4'-piperidine] [ka] Step 1: Preparation of 6-chlorospiro[indan-1,4'-piperidine] (C246) A solution of tert-butyl 6-chlorospiro[indan-1,4'-piperidine]-1'-carboxylate (50 mg, 0.1554 mmol) in DCM (2 mL) was treated with HCl (200 μL of 4 M, 0.8000 mmol) and the reaction was stirred at ambient temperature for 3 h. The reaction was concentrated to give 6-chlorospiro[indan-1,4'-piperidine] (hydrochloride salt) (37 mg, 88%). 1 H NMR (300MHz, DMSO-d6) δ8.81 (s, 2H), 7.30~7.20 (m, 2H), 7.11 (d, J=1.8Hz, 1H), 3.29 (d, J=14.1Hz, underwater, 2H), 3.10~ 2.92(m,2H),2.86(t,J=7.3Hz,2H),2.09(t,J=7.3Hz,2H),2.00(td,J=13.7,4.4Hz,2H),1.63(d,J=13.9Hz,2H). LCMS m / z:222.06[M+1] + .

[0328] Step 2: Preparation of 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indan-1,4'-piperidine] (310) A solution of 6-chlorospiro[indan-1,4'-piperidine] (hydrochloride) (28 mg, 0.1035 mmol) and 1-methylpyrazole-4-carbaldehyde (20 mg, 0.1816 mmol) in DCM (1.3 mL) was treated with STAB (70 mg, 0.3319 mmol). After 3 h, the reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM (3x) through a phase separator. The organics were concentrated and purified by reverse-phase HPLC (gradient: 0 to 20% MeCN in 0.1% aqueous TFA) to give 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indan-1,4'-piperidine] (trifluoroacetate) (30.5 mg, 59%). 1H NMR(300MHz,DMSO-d6)δ9.70(s,1H),7.86(s,1H),7.56(d,J=0.7Hz,3H),7.31~7.19(m,2H),7.09(d,J=1.7Hz,1H),4.24(d, J=4.6Hz,2H), 3.46~3.34(m,2H),3.05(q,J=11.8Hz,2H),2.87(t,J=7.2Hz,2H),2.12~1.91(m,5H),1.71(d,J=14.2Hz,2H). LCMS m / z:316.31[M+1] + .

[0329] Compound 311 6-Chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isoindoline-1,4'-piperidine] (311) [ka] Step 1: Preparation of tert-butyl 4-[(4-chloro-2-iodo-benzoyl)-[(4-methoxyphenyl)methyl]amino]-3,6-dihydro-2H-pyridine-1-carboxylate (C248) A solution of tert-butyl 4-oxopiperidine-1-carboxylate (22 g, 110.42 mmol), (4-methoxyphenyl)methanamine (15.2 g, 110.80 mmol), and toluene (250 mL) was prepared. The mixture was heated to reflux overnight. After cooling to room temperature, the solvent was evaporated. The resulting residue was used directly in the next step without further purification. The crude residue was redissolved in toluene (500 mL), and then 4-chloro-2-iodo-benzoic acid (25 g, 86.737 mmol) and triethylamine (14.520 g, 20 mL, 143.49 mmol) were added. The resulting solution was heated under reflux overnight. After cooling to room temperature, 100 mL of 0.5 M aqueous HCl was added to the mixture, and the layers were shaken and separated. The organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography (gradient: 0-40% EtOAc in hexanes) to give tert-butyl 4-[(4-chloro-2-iodo-benzoyl)-[(4-methoxyphenyl)methyl]amino]-3,6-dihydro-2H-pyridine-1-carboxylate (41 g, 49%). LCMS m / z: 583.4 [M+1] + .

[0330] Step 2: Preparation of tert-butyl 6'-chloro-2'-[(4-methoxyphenyl)methyl]-3'-oxo-spiro[2,3-dihydropyridine-4,1'-isoindoline]-1-carboxylate (C249) tert-Butyl 4-[(4-chloro-2-iodo-benzoyl)-[(4-methoxyphenyl)methyl]amino]-3,6-dihydro-2H-pyridine-1-carboxylate (23 g, 23.676 mmol) was dissolved in acetonitrile (300 mL) in a 500 mL round-bottom flask equipped with a condenser, and the mixture was purged with nitrogen gas for 1 hour. Palladium acetate (1.77 g, 7.8839 mmol), triphenylphosphine (4.14 g, 15.784 mmol), potassium carbonate (11 g, 79.591 mmol), and tetrabutylammonium bromide (12.7 g, 39.396 mmol) were added. The mixture was heated to reflux overnight. The mixture was cooled to room temperature and rotary evaporated. The residue was dissolved in EtOAc (100 mL) and water (100 mL). The mixture was shaken, and the layers were separated. The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by flash column chromatography (gradient: 0 to 40% EtOAc in hexanes) to give tert-butyl 6'-chloro-2'-[(4-methoxyphenyl)methyl]-3'-oxo-spiro[2,3-dihydropyridine-4,1'-isoindoline]-1-carboxylate (6 g, 55%). LCMS m / z: 455.4 [M+1] + .

[0331] Step 3: Preparation of 5'-chlorospiro[2,3-dihydro-1H-pyridin-4,3'-isoindolin]-1'-one (C250) tert-Butyl 6'-chloro-2'-[(4-methoxyphenyl)methyl]-3'-oxo-spiro[2,3-dihydropyridine-4,1'-isoindoline]-1-carboxylate (6 g, 12.925 mmol) in trifluoroacetic acid (65 mL) and trifluoromethanesulfonic acid (11.900 g, 7 mL, 79.293 mmol) was heated to 60 °C overnight. The solvent was removed by rotary evaporation, and saturated aqueous sodium bicarbonate was added until the solution reached pH = 7. The aqueous solution was saturated with NaCl and extracted with EtOAc (3 × 100 mL). The combined organic solution was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give crude 5'-chlorospiro[2,3-dihydro-1H-pyridin-4,3'-isoindolin]-1'-one (13 g), which was used in the next step without further purification. LCMS m / z: 235.2 [M+1] + .

[0332] Step 4: Preparation of 5-chlorospiro[isoindoline-3,4'-piperidin]-1-one (C251) To a solution of crude 5'-chlorospiro[2,3-dihydro-1H-pyridin-4,3'-isoindolin]-1'-one (13 g, 43.207 mmol) in acetic acid (100 mL) was added PtO (1 g, 4.4037 mmol), and the mixture was purged with nitrogen, evacuated, and refilled with hydrogen. This was stirred overnight under a H balloon. The mixture was filtered, and the filter cake was washed with acetic acid (3 × 50 mL). The combined filtrate was concentrated by rotary evaporation, and the residue was added with saturated aqueous sodium bicarbonate solution until pH = 7. This was saturated with sodium chloride and extracted with EtOAc (3 × 80 mL). The combined organic solution was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give crude 5-chlorospiro[isoindoline-3,4'-piperidin]-1-one (13 g). The crude material was used in the next step without further purification. LCMS m / z: 237.2 [M+1] + .

[0333] Step 5: Preparation of 5-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isoindoline-3,4'-piperidin]-1-one (C252) To a microwave vial containing 5-chlorospiro[isoindoline-3,4'-piperidin]-1-one (50 mg, 0.2112 mmol), 1-methylpyrazole-4-carbaldehyde (30 mg, 0.2724 mmol), dichloromethane (1 mL), and acetic acid (63.360 mg, 0.06 mL, 1.0551 mmol), sodium MP-cyanoborohydride (145 mg, 2 mmol / g, 0.2900 mmol) was added. The vial was capped and heated to 110 °C for 30 min using a microwave reactor. After cooling, the solid phase reagent was filtered and washed with 15 mL of dichloromethane. The combined filtrate was removed by rotary evaporation, and the residue was purified by reverse-phase HPLC (gradient: 0 to 20% MeCN in 0.1% aqueous TFA) to give 5-chloro-1′-[(1-methylpyrazol-4-yl)methyl]spiro[isoindoline-3,4′-piperidin]-1-one (trifluoroacetate salt) (28.6 mg, 30%). 1 H NMR(500MHz,DMSO-d6)δ10.26(s,1H),9.57(s,1H),7.90(s,1H),7.72~7.64(m,1H),7.63~7.55(m,3H),4.24~4. 14(m,2H),3.92~3.83(m,3H),3.57~3.44(m,2H),3.36~3.16(m,2H),2.49~2.43(m,2H),1.69(d,J=14.0Hz,2H). LCMS m / z:331.2[M+1] + .

[0334] Step 6: Preparation of 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isoindoline-1,4'-piperidine] (311) To a suspension of 5-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isoindoline-3,4'-piperidin]-1-one (800 mg, 2.2974 mmol) in toluene (45 mL) was added BH3-DMS (1.7 mL of 2 M, 3.4000 mmol), and the suspension was stirred at room temperature for 1 h and at 110 °C (reflux) for 2 h. THF (6 mL) was added to aid in dissolution of the starting material. Heating was continued overnight. After cooling to room temperature, MeOH (20 mL) was added, and the solution was refluxed for 15 min. The solvent was removed by rotary evaporation. Purification by reverse-phase HPLC (gradient: 0 to 20% MeCN in 0.1% aqueous TFA) gave 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isoindoline-1,4'-piperidine](trifluoroacetic acid (2)) 311 (27 mg, 2%). 1 H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.59(s,1H),7.50(d,J=13.3Hz,2H),7.30(s,1H),6.51(s ,2H),4.724.52(m,1H),4.34~4.21(m,1H),3.88(s,3H),3.25~3.11(m,2H),2.41~2.18(m,3H). LCMS m / z:317.1[M+1] + .

[0335] Compound 312 1-[5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-yl]imidazolidin-2-one (312) [ka] Step 1: Preparation of tert-butyl 3-[2-(tert-butoxycarbonylamino)ethylamino]-6-chloro-spiro[indan-1,4'-piperidine]-1'-carboxylate (C253) A solution of tert-butyl N-(2-aminoethyl)carbamate (650 mg, 4.057 mmol) and tert-butyl 6-chloro-3-oxo-spiro[indan-1,4'-piperidine]-1'-carboxylate (430 mg, 1.280 mmol) in MeOH (4 mL) was treated with NaBHCN (500 mg, 7.956 mmol) followed by AcOH (400 μL, 7.034 mmol) and heated to 65 °C. After 2 h, the reaction was cooled to room temperature, concentrated via rotovap, and the residue was stirred with DCM and saturated sodium bicarbonate overnight. The reaction mixture was passed through a phase separator and extracted with DCM (3x). The organics were concentrated via rotovap and the material was purified by flash column chromatography (gradient: 0 to 100% EtOAc in heptane) to afford tert-butyl 3-[2-(tert-butoxycarbonylamino)ethylamino]-6-chloro-spiro[indan-1,4′-piperidine]-1′-carboxylate (500 mg, 79%). 1 H NMR (300MHz, chloroform-d) δ7.28(s,1H),7.22(dd,J=8.1,1.9Hz,1H),7.14(d,J=1.9Hz,1H),4.96(s,1H),4.27(t,J=7.1Hz,1H),4.14(d,J=9 .3Hz,2H), 3.28(d,J=6.6Hz,2H),3.06~2.77(m,4H),2.58(dd,J=12.9,7.2Hz,1H),1.96(td,J=12.9,4.5Hz,1H),1.49(d,J=10.5Hz,21H). LCMS m / z:480.28[M+1] + .

[0336] Step 2: Preparation of tert-butyl 6-chloro-3-(2-oxoimidazolidin-1-yl)spiro[indan-1,4'-piperidine]-1'-carboxylate (C254) A solution of tert-butyl 3-[2-(tert-butoxycarbonylamino)ethylamino]-6-chloro-spiro[indan-1,4'-piperidine]-1'-carboxylate (500 mg, 1.011 mmol) in THF (8.5 mL) was treated with KtBuO (370 mg, 3.297 mmol) and heated to 60 °C for 30 min. The reaction was cooled to room temperature, diluted with water, and extracted with DCM (3x) through a phase separator. The organics were concentrated via rotovap to give tert-butyl 6-chloro-3-(2-oxoimidazolidin-1-yl)spiro[indan-1,4'-piperidine]-1'-carboxylate (440 mg, 97%). 1 H NMR (300MHz, chloroform-d) δ7.24(dd,J=8.0,1.9Hz,1H),7.17(d,J=1.9Hz,1H),7.11(dd,J=8 .0,1.0Hz,1H),5.63(t,J=8.5Hz,1H),4.68(s,1H),4.14(s,2H),3.48(td,J=8.1,1.2Hz,2 H),3.29(q,J=8.1Hz,1H),3.23~3.09(m,1H),2.89(dd,J=30.1,15.0Hz,2H),2.58(dd,J=1 3.1,8.1Hz,1H),2.04(td,J=13.0,4.5Hz,1H),1.75(dd,J=13.0,8.9Hz,1H),1.51(s,12H). LCMS m / z:406.09[M+1] + .

[0337] Step 3: Preparation of 1-(5-chlorospiro[indan-3,4'-piperidin]-1-yl)imidazolidin-2-one (C255) tert-Butyl 6-chloro-3-(2-oxoimidazolidin-1-yl)spiro[indan-1,4'-piperidine]-1'-carboxylate (441 mg, 0.9778 mmol) in DCM (8 mL) was treated with HCl (2.2 mL of 4 M, 8.800 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated to give 1-(5-chlorospiro[indan-3,4'-piperidin]-1-yl)imidazolidin-2-one (dihydrochloride salt) (360 mg, 91%). 1H NMR (300MHz, DMSO-d6) δ8.90(s, 2H), 7.34(dd, J=8.1, 2.0Hz, 1H), 7.19(d, J=2.0Hz, 1H), 7.09(dd, J=8.1, 1.0Hz, 1H), 6.83~6.31(m, 1H), 5.42(t, J =8.5Hz, 1H), 3.39~2.82(m, 9H), 2.50(p, J=1.9Hz, under DMSO, 1H), DMSO,1H), 2.40~2.21(m,1H), 1.83(dd,J=13.2,9.1Hz,2H),1.68(d,J=13.8Hz,2H). LCMS m / z:306.05[M+1] + .

[0338] Step 4: Preparation of 1-[5-chloro-1′-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4′-piperidin]-1-yl]imidazolidin-2-one (312) 1-(5-chlorospiro[indan-3,4'-piperidin]-1-yl)imidazolidin-2-one (dihydrochloride) (54.5 mg, 0.1353 mmol) and 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (37 mg, 0.1575 mmol) in DCM (2 mL) were treated with TEA (0.1 mL, 0.7175 mmol). STAB (95 mg, 0.4504 mmol) was then added and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM (3x) using a phase separator. The organics were concentrated via rotovap and purified by reverse-phase HPLC (gradient: 0 to 20% MeCN in 0.1% aqueous TFA) to give 1-[5-chloro-1′-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4′-piperidin]-1-yl]imidazolidin-2-one (trifluoroacetate) 312 (93.8 mg, 93%). 1H NMR (300MHz, chloroform-d) δ7.97(d,J=0.8Hz,1H),7.71(d,J=0.8Hz,1H),7.31(dd,J=8.0,1.9Hz,1H ),7.26(d,J=1.9Hz,1H),7.15(dd,J=8.0,1.0Hz,1H),5.51(t,J=8.4Hz,1H),4.76~4.64(m,2H),4 .31(s,2H),3.71(t,J=6.2Hz,2H),3.62~3.48(m,2H),3.47~3.32(m,3H),3.28~3.01(m,3H),2.90 (s,3H),2.57(dd,J=13.4,8.2Hz,1H),2.35(td,J=14.1,4.0Hz,1H),1.89(dd,J=9.7,6.6Hz,5H). LCMS m / z:492.36[M+1] + .

[0339] compound 313 6-chloro-3-(difluoromethylene)-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-1,4'-piperidine] (313) [ka] Step 1: Preparation of tert-butyl 6-chloro-3-(difluoromethylene)spiro[indan-1,4'-piperidine]-1'-carboxylate (C256) To a solution of tert-butyl 6-chloro-3-oxo-spiro[indan-1,4'-piperidine]-1'-carboxylate (518 mg, 1.542 mmol) in MeCN (6 mL) was added DMPU (372 μL, 3.088 mmol), followed by [bromo(difluoro)methyl]-trimethyl-silane (564 mg, 2.777 mmol), followed by PPh3 (486 mg, 1.853 mmol). The reaction was stirred at 60° C. for 30 minutes. The solution was brought to room temperature and KOH (8 mL of 1 M, 8.000 mmol) was added, followed by stirring overnight. The reaction was further diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (gradient: 0 to 50% EtOAc in hepatane) to give tert-butyl 6-chloro-3-(difluoromethylene)spiro[indan-1,4′-piperidine]-1′-carboxylate (18.5 mg, 3%). 1 H NMR (300MHz, chloroform-d) δ7.27(dd, J=8.3, 1.1Hz, 1H), 7.15(dd, J=8.2, 2.0Hz, 1H), 7.06(d, J=2.0Hz, 1H), 4.07(s, 2 H), 2.80(t, J=13.3Hz, 2H), 2.65(t, J=3.2Hz, 2H), 1.71(td, J=13.2, 4.7Hz, 2H), 1.46(d, J=2.6Hz, 2H), 1.42(s, 9H). 19 F NMR (282 MHz, chloroform-d) δ -86.64 (d, J = 45.6 Hz), -87.02 (d, J = 45.9 Hz). LCMS m / z 371.09 [M+1] + .

[0340] Step 2: Preparation of 6-chloro-3-(difluoromethylene)spiro[indan-1,4'-piperidine] (C257) To tert-butyl 6-chloro-3-(difluoromethylene)spiro[indan-1,4'-piperidine]-1'-carboxylate (19 mg, 0.05059 mmol) in 1 mL of methanol was added 1 mL of 4 M HCl. The solution was heated to 50°C for 20 minutes. The solution was evaporated to give 6-chloro-3-(difluoromethylene)spiro[indan-1,4'-piperidine] (hydrochloride) (16 mg, 100%). 1 H NMR (300MHz, chloroform-d) δ7.41 (dt, J=8.0, 1.1Hz, 1H), 7.36~7.28 (m, 2H), 3.52~3.39 (m, 2H) , 3.28~3.10(m, 2H), 2.90(t, J=3.2Hz, 2H), 2.10(td, J=14.1, 4.4Hz, 2H), 1.87~1.70(m, 2H). 19 F NMR (282 MHz, chloroform-d) δ −88.90 (d, J = 47.5 Hz), −89.33 (d, J = 47.2 Hz).

[0341] Step 3: Preparation of 6-chloro-3-(difluoromethylene)-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-1,4'-piperidine] (313) To a mixture of 6-chloro-3-(difluoromethylene)spiro[indan-1,4'-piperidine] (hydrochloride) (12 mg, 0.03919 mmol), 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (20 mg, 0.08514 mmol), and HOAc (20 μL, 0.3517 mmol) in 4 mL of DCE, STAB (40 mg, 0.1896 mmol) was added and stirred at ambient temperature for 16 h. The reaction mixture was concentrated and purified by reverse-phase HPLC (gradient: 0 to 20% MeCN in 0.1% FA in water) to give 6-chloro-3-(difluoromethylene)-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-1,4'-piperidine] (formate) 313 (10.1 mg, 51%). LCMS m / z: 456.15[M+1] + .

[0342] Compound 314 1-[5-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indoline-3,4'-piperidin]-1-yl]ethenone (314) [ka] Step 1: Preparation of benzyl 5-chlorospiro[indoline-3,4'-piperidine]-1'-carboxylate (C260) To a stirred solution of (4-chlorophenyl)hydrazine (3.1654 g, 0.0222 mol) in toluene (122.5 mL) and MeCN (2.5 mL), TFA (7.6053 g, 5.1387 mL, 0.0667 mol) was added, which was degassed with argon for 15 minutes. A solution of benzyl 4-formylpiperidine-1-carboxylate (5 g, 0.0202 mol) in toluene (4.9 mL) and MeCN (0.1 mL) was slowly added to the above reaction mixture over 20 minutes. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to give benzyl 5-chlorospiro[indoline-3,4'-piperidine]-1'-carboxylate (10 g, 30%). LCMS m / z:...

Claims

1. A compound represented by the following structural formula: 【Chemistry 135】 a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring A is one or two R １ phenyl substituted with a group; X is -CR １ａ R １ｂ -, -C(O)-, -S-, -S(O) ２ -, -NR １ｃ -, and -O-; Y is -CR １ａ R １ｂ -, -C(O)-, -S(O) ２ -, -NR １ｃ -, and -O-; Z is a bond, -CR １ａ R １ｂ -, -NR １ｃ -, -C(O)-, -S(O) ２ -, and -O-, wherein At least one of X and Y is -CR １ａ R １ｂ - and -C(O)-; R １ａ , R １ｂ , and R １ｃ are hydrogen and R １ are independently selected from the group R １ For each occurrence, halogen, —OH, cyano, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, 4- to 6-membered heterocyclyl, —C(═O)OR ｃ , —C(═O)R c, and —C(═O)N(R ｃ ) independently selected from two groups; R ｃ For each occurrence, hydrogen, and C １ -C ４ independently selected from alkyl, R １ wherein said 4- to 6-membered heterocyclyl contains one heteroatom selected from nitrogen and oxygen; R １ The above C １ -C ６ Alkyl is halogen, cyano, —OH, C １ -C ４ optionally substituted with 1 to 4 groups independently selected from alkoxy, 3- to 5-membered heterocyclyl, and 3- to 5-membered heteroaryl groups; R １ The above C １ -C ６ the alkoxy is optionally substituted with 1 to 3 groups independently selected from halogen groups; R ２ and R ３ are hydrogen and C, respectively. １ -C ４ independently selected from alkyl groups, R ４ but, 【Transformation 136】 where: Ring B is C ３ -C １２ carbocyclyl, 3- to 12-membered heterocyclyl, C aryl, and 5- to 10-membered heteroaryl groups, and Ring B is selected from 1, 2, or 3 R ａ is substituted with a group, R ａ For each occurrence, halogen, cyano, C １ -C ８ Alkyl, C １ -C ６ Haloalkyl, C ２ -C ８ Alkenyl, C １ -C ６ Haloalkenyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, C ３ -C １２ Carbocyclyl, C ６ and C １０ Aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, —C(═O)NR ｈ R ｉ , -C(=O)OR ｋ , -NR ｈ R ｉ , -NR ｈ C(=O)R ｋ , -NR ｈ C(=O)OR ｋ , -NR ｈ S (= O) ｐ R ｋ , -S(=O) ｐ R ｋ , and -S(=O) ｐ NR ｈ R ｉ are independently selected from the group R ａ The above C １ -C ８ alkyl, the C １ -C ６ haloalkyl, the C １ -C ６ Alkoxy, and the C ２ -C ８ Each alkenyl is —C(═O)R ｋ , -C(=O)OR ｋ , —C(═O)NR ｈ R ｉ , -NR ｈ R ｉ , -NR ｈ C(=O)R ｋ , -NR ｈ C(=O)OR ｋ , -NR ｈ C(=O)NR ｉ R ｊ , -NR ｈ S (= O) ｐ R ｋ 、 -OR ｋ , -OC(=O)R ｋ , -OC(=O)OR ｋ , -OC(=O)NR ｈ R ｉ , -SR ｋ , -S(=O) ｐ R ｋ , -S(=O) ｐ NR ｈ R ｉ , C ３ -C ６ Carbocyclyl (1 to 3 R ｍ optionally substituted with a group), C ６ -C １０ Aryl (1 to 3 R ｍ group), 4- to 10-membered heterocyclyl (1 to 3 R ｍ and 5- to 10-membered heteroaryl (optionally substituted with 1-3 R ｍ optionally substituted with 1 to 3 groups independently selected from the group R ａ The above C ３ -C １２ carbocyclyl, the 3- to 12-membered heterocyclyl, the C ６ and C １０ The aryl and the 5- to 10-membered heteroaryl are each independently selected from halogen, C １ -C ６ Alkyl (1 to 3 R ｍ group), —NR ｈ R ｉ , -S(=O) ｐ R ｋ , and -S(=O) ｐ NR ｈ optionally substituted with 1 to 3 groups independently selected from Ri groups, wherein R ｈ , R ｉ , and R ｊ are, for each occurrence, hydrogen, C, １ -C ６ alkyl, 5- to 10-membered heteroaryl (1 to 3 R ｍ and 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 R ｍ and R ｈ , R ｉ , and R ｊ Any one of the C １ -C ６ the alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH groups; R ｋ For each occurrence, hydrogen, C １ -C ６ Alkyl, benzyl, C ６ Aryl, C ３ -C ６ independently selected from carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein R ｋ Any one of the C １ -C ６ The alkyl is halogen, cyano, -NH ２ , -OH, C １ -C ４ Alkoxy, C ３ -C ６ optionally substituted with 1 to 5 groups independently selected from cycloalkyl (optionally substituted with 1 to 3 halogen groups), 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 —OH groups), and 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 —OH groups); R ｋ wherein any one of the 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl is selected from halogen, C １ -C4 alkyl, C １ -C4 haloalkyl, C １ -C4 alkoxy, and C ３ -C ６ optionally substituted with 1 to 3 groups independently selected from cycloalkyl groups; R ｍ For each occurrence, halogen, cyano, oxo, -(CH ２ ) ｎ C(=O)NH ２ , -NH ２ , —NH(C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , C １ -C ６ Alkyl, -OR ｋ , and C ３ -C ６ cycloalkyl groups, R ｍ Any one of the C １ -C ６ the alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and —OH groups; n, for each occurrence, is an integer selected from 0, 1, and 2; A compound, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein p, for each occurrence, is an integer independently selected from 1 and 2.

2. X is -CR １ａ R １ｂ -, -C(O)-, and -O-; Y is -CR １ａ R １ｂ - and -NR １ｃ - is selected from, Z is a bond and -CR １ａ R １ｂ - is selected from the formula: At least one of X and Y is -CR １ａ R １ｂ 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein the compound is selected from - and -C(O)-.

3. The compound is represented by one of the following structural formulas: 【Chemistry 143】 tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is a ring having one or two R １ 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1 , substituted by a group. (a) The compound is represented by one of the following structural formulas: 【Chemistry 145】 tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: R １ａ is selected from hydrogen, halogen, and an —OH group; R １ｄ and R １ｅ are hydrogen, halogen, —OH, cyano, and C １ -C ４ Alkyl, C １ -C ４ Alkoxy, —C(═O)OR ｃ and —C(═O)N(R ｃ ) independently selected from R ｃ For each occurrence, hydrogen and C １ -C ４ independently selected from alkyl groups, R １ｄ and / or R １ｅ The above C １ -C4 alkyl is optionally substituted with 1 to 3 groups independently selected from halogen and -OH groups; (b) the compound is represented by one of the following structural formulas: 【Chemistry 146】 tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein: R 1a is selected from hydrogen and a C(═O)N(R c1 ) 2 group; R c1 , for each occurrence, is independently selected from hydrogen and a C 1 -C 4 alkyl group; R 1d and R 1e are each independently selected from hydrogen and a halogen group; or (c) the compound is represented by one of the following structural formulas: 【Chemistry 147】 tautomers thereof, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, wherein:

2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein R 1d and R 1e are each independently selected from hydrogen, halogen, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl groups.

5. Each R １ is halogen, cyano, -CH ３ , -CH ２ CH ３ , -CH ２ CHF ２ , -CHFCHF ２ , -CHF ２ , -CF ３ , -OCH ３ , -OCHF ２ , and -OCF ３ 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, independently selected from:

6. (a) X is -CH ２ - and -NH-, or (b) X is —CR 1a R 1b —, where R 1a is hydrogen and R 1b is selected from R 1 groups; or (c) X is —CHOH—, or (d) X is —O—, or (e) The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein X is —C(O)—.

7. (a) Y is -CR １ａ R １ｂ - and -NR １ｃ - selected from, or (b) Y is —CH 2 , or (c) Y is —CR 1a R 1b , R 1a and R 1b are each R 1 , and R 1 is —CH 3 ; or (d) Y is —CR 1a R 1b , where R 1a is hydrogen and R 1b is selected from R 1 groups; or (e) Y is -CR 1a R 1b , R 1a is hydrogen, R 1b is R 1 , and R 1 is selected from -OH, -CH 3 , -C(O)NH 2 , -C(O)NHCH 3 , or (f) Y is —CR 1a R 1b , R 1a and R 1b are both R 1 , and R 1 is selected from —OH and —CH 3 , or (g) Y is —NR 1c —, R 1c is R 1 , and R 1 is selected from 4- to 6-membered heterocyclyl; or (h) Y is —NR 1c —, R 1c is R 1 , and R 1 is 【Chemistry 148】 is, or (i) Y is —N(CH 3 )—; or (j) Y is —CH(OH)—, or (k) Y is —NH—, or (l) The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein Y is -N(C(O)CH 3 )-.

8. (a) X is -C(O)- and -CR １ａ R １ｂ -, and Y is selected from -NR １ｃ - and R １ｃ is hydrogen, or (b) X is selected from —C(O)— and —CR 1a R 1b —; Y is —NR 1c —; R 1c is R 1 ; and R 1 is selected from C 1 -C 6 alkyl and C 1 -C 6 alkoxy optionally substituted with 1 to 3 halogen groups; or (c) The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein X is selected from -C(O)- and -CR 1a R 1b -; Y is -NR 1c -; R 1c is R 1; and R E is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -CH 2 CF 2 , -CH 2 CF 3 , and -CH 2 CH 2 OCH 3 .

9. Z is -CR １ａ R １ｂ - and (a) R 1a and R 1b are hydrogen, or (b) R 1a and R 1b are fluorine, or (c) The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein R 1a is hydrogen and R 1b is —OH.

10. R ２ and R ３ One of the groups is hydrogen and the other is —CH ３ 2. The compound of claim 1, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein:

11. Ring B is 【Chemistry 151】 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1 selected from:

12. Each R ａ The base is halogen; Cyano; C １ Haloalkoxy; -CH ３ ; -CHF ２ ; R ｋ But -CH ３ -OR ｋ C substituted with １ Alkyl; R ｈ and R ｉ are both -CH ３ -C(=O)NR ｈ R ｉ C substituted with １ Alkyl; R ｈ is hydrogen, and R ｉ Ha-CH ３ -C(=O)NR ｈ R ｉ C substituted with １ Alkyl; R ｍ and R ｍ But -CH ３ , -CH ２ OH, and -CH ２ C(=O)NH ２ cyclopropyl-substituted C selected from １ Alkyl; R ｍ and R ｍ is -C(=O)NH ２ a four-membered heterocycle, 【Chemistry 152】 C substituted with １ Alkyl; C substituted with a 5-membered optionally substituted heterocycle １ Alkyl; oxo and —CH ３ optionally substituted with 【Chemistry 153】 C substituted with １ Alkyl; C substituted with 5-membered optionally substituted heteroaryl １ Alkyl; —OH or —C(═O)NH ２ optionally substituted with 【Chemistry 154】 C substituted with １ Alkyl; C1-C ３ optionally substituted with alkyl, 【Chemistry 155】 C substituted with １ Alkyl; -N(CH ３ ) ２ optionally substituted with 【Chemistry 156】 C substituted with １ Alkyl; -CH ３ , -CH ２ OH, and —C(═O)NH ２ 1 to 3 R independently selected from ｍ optionally substituted with a group, 【Chemistry 157】 C substituted with １ Alkyl; C substituted with 6-membered optionally substituted heteroaryl １ Alkyl; oxo, -CH ３ , and -CH ２ 1 to 3 R independently selected from OH ｍ optionally substituted with a group, 【Chemistry 158】 C substituted with １ Alkyl; oxo, -CH ３ , C ３ Branched alkyl, cyclopropyl, and —NHCH ３ 1 to 3 R independently selected from ｍ optionally substituted with a group, 【Chemistry 159】 C substituted with １ Alkyl; -OH, oxo, and C １ -C ３ 1 to 3 R independently selected from alkyl ｍ optionally substituted with a group, [Chemical 160] C substituted with １ Alkyl; oxo and —CH ３ one to two R independently selected from ｍ optionally substituted with a group, 【Chemistry 161】 C substituted with １ Alkyl; oxo and —CH ３ one to two R independently selected from ｍ optionally substituted with a group, 【Chemistry 162】 C substituted with １ Alkyl; 1-2 R ｍ optionally substituted with a group, 【Chemical 163】 C substituted with １ Alkyl; C １ -C ３ Alkoxy; C ２ Alkyl; —OH and C ３ -C ６ C substituted with carbocyclyl (optionally substituted with —OH) ２ Alkyl; C １ Alkoxy-substituted C ２ Alkyl; C substituted with —OH ２ Alkyl; R ｈ is hydrogen, and R ｉ is C １ -C ３ R selected from alkyl ｍ -NR is a 6-membered heteroaryl optionally substituted with a -NR group. ｈ R ｉ C substituted with ２ Alkyl; R ｋ is C ２ alkyl, =NOR ｋ C substituted with ２ Alkyl; R ｈ is hydrogen, p is 2, and R ｋ is cyclopropyl, —NR ｈ S (= O) ｐ R ｋ C substituted with ２ Alkyl; R ｈ and R ｉ is hydrogen, and R ｊ Ha-C ２ alkyl, -NR ｈ C(=O)NR ｉ R ｊ C substituted with ２ Alkyl; p is 2 and R ｋ Ha-CH ３ -S(=O) ｐ R ｋ C substituted with ２ Alkyl; p is 2 and R ｈ and R ｉ are both hydrogen, -S(=O) ｐ NR ｈ R ｉ C substituted with ２ Alkyl; R ｈ is hydrogen, and R ｉ Ha-CH ３ -S(=O) ｐ NR ｈ R ｉ C substituted with ２ Alkyl; C substituted with —OH and a 6-membered heterocycle (optionally further substituted with —OH) ２ Alkyl; R ｍ and R ｍ But, -OR ｋ and R ｋ is —OH, 【Chemistry 164】 C substituted with ２ Alkyl; -OH and optionally substituted -OH further substituted 【Chemistry 165】 C substituted with ２ Alkyl; C substituted with 5-membered optionally substituted heteroaryl ２ Alkyl; C １ -C ３ 1 to 2 halogen groups optionally substituted with alkyl, and 【Chemistry 166】 C substituted with ２ Alkyl; C substituted with 6-membered optionally substituted heteroaryl ２ Alkyl; optionally substituted with oxo; 【Chemistry 167】 C substituted with ２ Alkyl; C optionally substituted with 1 to 2 —OH groups ３ Alkyl; C substituted with —OH ３ haloalkyl; C ３ Carbon rings; C substituted with 5-membered optionally substituted heteroaryl ３ Alkyl; optionally substituted with oxo; 【Chemical 168】 C substituted with ３ Alkyl; C substituted with 6-membered heteroaryl optionally substituted with 1 to 2 oxo groups ３ Alkyl; 【Chemistry 169】 C substituted with ３ Alkyl; C substituted with two -OH groups ４ Alkyl; C substituted with —OH ４ Branched alkyl; R ｈ is hydrogen, p is 2, and R ｋ Ha-CH ３ -NR ｈ S (= O) ｐ R ｋ C substituted with ４ Branched alkyl; R ｈ and R ｉ are both hydrogen, -NR ｈ R ｉ C substituted with ４ branched alkoxy; C substituted with two -OH groups ５ Branched alkyl; p is 2 and R ｈ and R ｉ are both hydrogen, -S(=O) ｐ NR ｈ R ｉ C substituted with ５ Branched alkyl; -CF ３ C optionally substituted with ６ aryl; R ｋ Ha-CH ３ -C(=O)OR ｋ ; R ｈ is hydrogen, and R ｉ Ha-CH ３ -C(=O)NR ｈ R ｉ ; R ｈ and R ｉ are both hydrogen, -C(=O)NR ｈ R ｉ ; R ｈ and R ｉ are both hydrogen, -NR ｈ R ｉ ; R ｈ is hydrogen, and R ｉ Ha-CH ３ -NR ｈ R ｉ ; R ｈ is hydrogen, and R ｉ is a branched C substituted with —OH ４ alkyl, -NR ｈ R ｉ ; R ｈ is hydrogen, and R ｋ Ha-CH ３ -NR ｈ C(=O)R ｋ ; R ｈ is hydrogen, and R ｋ is a 5-membered heteroaryl substituted with a group selected from Cl and cyclopropyl 【Chemistry 170】 -NR ｈ C(=O)R ｋ ; R ｈ is hydrogen, and R ｋ is non-substitutive 【Chemistry 171】 or -CH ３ replaced with 【Chemistry 172】 -NR ｈ C(=O)R ｋ ; R ｈ is hydrogen, p is 2, and R ｋ is C ２ alkyl, -NR ｈ S (= O) ｐ R ｋ ; R ｈ is hydrogen, p is 2, and R ｋ is cyclopropyl, —NR ｈ S (= O) ｐ R ｋ ; R ｈ is hydrogen, p is 2, and R ｋ is -cyano, -NR ｈ S (= O) ｐ R ｋ ; R ｋ is CH ３ -S(=O) ｐ R ｋ ; p is 2 and R ｈ and R ｉ are both hydrogen, -S(=O) ｐ NR ｈ R ｉ ; a four-membered heterocycle, 【Chemistry 173】 -S(O) ２ CH ３ optionally replaced with 【Chemistry 174】 5-membered heterocycle; -CH ３ optionally replaced with 【Chemistry 175】 oxo and —CH ３ optionally replaced with 【Chemistry 176】 6-membered heterocycle; Optionally substituted 【Chemistry 177】 optionally substituted with —OH 【Chemistry 178】 5-membered heteroaryl; 6-membered heteroaryl; C １ -C ３ Optionally substituted with alkyl 【Chemistry 179】 and C １ -C ３ Optionally substituted with alkyl 【Transformation 180】 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, independently selected from: 【Request Item 13】 【Table 21-1】 Table 21-2 Table 21-3 Table 21-4 Table 21-5 Table 21-6 Table 21-7 Table 21-8 Table 21-9 Table 21-10 Table 21-11 Table 21-12 Table 21-13 Table 21-14 Table 21-15 Table 21-16 Table 21-17 Table 21-18 Table 21-19 Table 21-20 Table 21-21 Table 21-22 Table 21-23 Table 21-24 Table 21-25 Table 21-26 Table 21-27 A compound selected from tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13.

15. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for treating an ApoL1 mediated disease.

16. Use of a compound described in any one of claims 1 to 13 in the manufacture of a pharmaceutical for treating focal segmental glomerulosclerosis (FSGS) and / or non-diabetic kidney disease (NDKD).

17. A composition for use in the treatment of an ApoL1 mediated disorder, the composition comprising a compound according to any one of claims 1 to 13.

18. A composition for use in the treatment of focal segmental glomerulosclerosis (FSGS) and / or non-diabetic kidney disease (NDKD), comprising a compound described in any one of claims 1 to 13.

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