Spiropiperidine derivatives as inhibitors of APOL1 and methods of use thereof

Abstract

The present disclosure provides at least one compound selected from the group consisting of compounds of Formula I, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, compositions including the same, and methods of using the same, in particular, the present invention relates to the use thereof, including the use thereof in the treatment of APOL1 mediated diseases, including pancreatic cancer, focal segmental glomerular sclerosis (FSGS), and / or non-diabetic kidney disease (NDKD). # imgabs0 #

Description

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 307,926, filed on 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 these compounds to treat APOL1-mediated diseases, such as pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and / or non-diabetic kidney disease (NDKD). In some embodiments, FSGS and / or NDKD are associated with at least one of two common APOL1 genetic variants (G1: S342G: I384M and G2: N388del: Y389del). In some embodiments, pancreatic cancer is associated with elevated levels of APOL1 (e.g., elevated levels of APOL1 in pancreatic cancer tissue).

[0003] FSGS is a rare kidney disease with an estimated global incidence of 0.2 to 1.1 / 100,000 / year. FSGS is a podocyte (glomerular visceral epithelial cell) disease that causes proteinuria and progressive decline in renal function. NDKD is a kidney disease involving damage to the podocyte or glomerular vascular bed that is not caused by diabetes. NDKD is a disease characterized by hypertension and progressive decline in renal function. Human genetics supports the causal role of G1 and G2 APOL1 variants in inducing renal disease. Individuals with 2 APOL1 risk alleles have an increased risk of end-stage renal disease (ESKD), including primary (idiopathic) FSGS, human immunodeficiency virus (HIV)-related FSGS, NDKD, arteriosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. See P. Dummer et al., Semin Nephrol. 35(3):222-236 (2015).

[0004] FSGS and NDKD can be divided into different subgroups based on the underlying etiology. A homogeneous subgroup of FSGS is characterized by the presence of independent common sequence variants called G1 and G2 in the apolipoprotein L1 (APOL1) gene, which are referred to as "APOL1 risk alleles". G1 encodes a pair of related non-synonymous amino acid changes (S342G and I384M), G2 encodes 2 amino acid deletions near the C-terminus of the protein (N388del:Y389del), and G0 is the ancestral (low-risk) allele. A unique phenotype of NDKD has also been found in patients with APOL1 genetic risk variants. In APOL1-mediated FSGS and NDKD, patients with two risk alleles experience higher levels of proteinuria and more rapid loss of renal function compared to patients with no or only 1 APOL1 genetic risk variant. Alternatively, in AMKD, patients with one risk allele may also experience higher levels of proteinuria and accelerated loss of renal function. See G. Vajgel et al., J. Rheumatol., November 2019, jrheum.190684.

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

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

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

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

[0009] People of recent sub-Saharan African ancestry have a significantly higher risk of ESKD compared with people of European ancestry. In the United States, ESKD causes 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, thus leading to proteinuria. Patients with proteinuria are at a higher risk of developing end-stage renal disease (ESKD) and developing proteinuria-related complications such as infection or thromboembolic events. There is no standardized treatment regimen for FSGS or NDKD, and there are no approved drugs. Currently, FSGS and NDKD are managed with symptomatic treatment (including blood pressure control using renin-angiotensin system blockers), and patients with FSGS and severe proteinuria may receive high-dose steroids. Current treatment options for NDKD are based on blood pressure control and blockade of the renin-angiotensin system.

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

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

[0013] One aspect of the present disclosure provides at least one compound selected from the group consisting of a compound of Formula I, a tautomer of Formula I, a deuterated derivative of these compounds or tautomers, and a pharmaceutically acceptable salt of any of the foregoing, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt, 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:

[0014]

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

[0016] Ring A is selected from 6-membered aryl and 6-membered heteroaryl groups, wherein the 6-membered aryl or 6-membered heteroaryl group is optionally substituted by 1, 2, 3 or 4 R 1 Group substitution;

[0017] X is selected from -CR 1a R 1b -、-C(O)-、-S-、-S(O) 2 -、-NR 1c - and -O-;

[0018] Y is selected from -CR 1a R 1b -、-C(O)-、-S(O) 2 -、-NR 1c - and -O-;

[0019] Z is selected from bond, -CR 1a R 1b -、-NR 1c -、-C(O)-、-S(O) 2 - and -O-, where:

[0020] At least one of X and Y is selected from -CR 1a R 1b - and -C(O)-;

[0021] R 1a , R 1b and R 1c is independently selected at each occurrence from hydrogen and R 1 Group;

[0022] R 1 is independently selected at each occurrence from halogen, -OH, cyano, phenyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkenyl, C 1 -C 6 Alkoxy, C 3 -C 6 Carbocyclic group, 4- to 6-membered heterocyclic group, -C(=O)R c 、-C(=O)OR c 、-C(=O)N(R c ) 2 and-OS(=O) 2 R c Group, in which:

[0023] R c is independently selected at each occurrence from hydrogen, C 1 -C 4 Alkyl and C 1 -C 4 haloalkyl groups;

[0024] R 1 The 4- to 6-membered heterocyclyl includes 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and is optionally substituted by a group selected from the group consisting of oxo and -OH;

[0025] R 1 The C 1 -C6 The alkyl group and the C 1 -C 6 Each alkenyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen, cyano, -OH, -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , C 1 -C 4 Alkoxy, 3 to 5 membered heterocyclic group (optionally R c substituted), 3- to 5-membered heteroaryl groups and phenyl;

[0026] R 1 The C 1 -C 6 The alkoxy group is optionally substituted with 1 to 3 groups independently selected from: -OH, cyano and halogen groups;

[0027] R 1 The C 3 -C 6 The carbocyclyl group is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH, -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, -C(=O)NH 2 、-C(=O)NH(C 1 -C 4 Alkoxy) and -C(=O)N(C 1 -C 4 alkyl) 2 group; and

[0028] R 1 The phenyl group is optionally substituted by 1 to 3 groups independently selected from the following: halogen, cyano, -OH, -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , C 1 -C 4 Alkyl, C 1 -C4 Alkoxy, -C(=O)NH 2 、-C(=O)NH(C 1 -C 4 alkyl) and -C(=O)N(C 1 -C 4 alkyl) 2 Group;

[0029] R 2 and R 3 are each independently selected from hydrogen and C 1 -C 4 Alkyl groups;

[0030] R 4 Selected from C 1 -C 6 Alkyl, -C(=O)O(C 1 -C 4 Alkyl) and Group, in which:

[0031] R 4 The C 1 -C 6 The alkyl group is optionally substituted with 1 to 5 groups independently selected from the group consisting of halogen, cyano, -OH, -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 、-C(=O)NH 2 , -C(=O)(C 1 -C 4 alkyl), -C(=O)OH, -C(=O)O(C 1 -C 4 alkyl), -C(=O)NH(C 1 -C 4 alkyl), -C(=O)N(C 1 -C 4 alkyl) 2 , C 1 -C 4 Alkoxy, C 3 -C 6 Carbocyclic group, C 6 Aryl, -O-(C 6 aryl), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein:

[0032] The C 6 Aryl and the -O-(C 6The aryl) groups are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen and C 1 -C 4 haloalkyl groups;

[0033] Ring B is selected from C 3 -C 12 Carbocyclic group, 3 to 12 membered heterocyclic group, C 6 and C 10 aryl and 5 to 10 membered heteroaryl groups, wherein ring B is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution; wherein:

[0034] R a is independently selected at each occurrence from halogen, cyano, oxo, C 1 -C 8 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 8 Alkenyl, C 1 -C 6 Halogenated alkenyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 12 Carbocyclic group, 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 , -C(=O)(C 1 -C 4 Alkylene)OR k 、-C(=O)R k , -C(=O)(C 1 -C 4 Alkylene)S(=O) p R k , -C(=O)(C 1 -C 4 Alkylene)S(=O) p NR h R i , -C(=O)(C 1 -C 4 Alkylene)NR i S(=O) p R k , -C(=O)(C 1 -C 4 Alkylene)NRh C(=O)R k 、 -C(=O)C(=O)R k 、 -NR h R i 、 -NH(CH 2 ) q CHR h R i 、 -NH(CH 2 ) q NR h R i 、 -NR h C(=O)R k 、 -NR h C(=O)OR k 、 -NR h C(=O)(C 1 -C 4 alkylene)OR k 、 -NR h C(=O)O(C 1 -C 4 alkylene)R k 、 -NR h C(=O)NR i R j 、 -NR h C(=O)(C 1 -C 4 alkylene)NR i S(=O) p R k 、 -NR h S(=O) p R k 、 -NR h C(=O)(C 1 -C 4 alkylene)S(=O) p R k 、 -NR h S(=O) p (C 1 -C 4 alkylene)C(=O)OR k 、 -NR h C(=O)[O(CH 2 ) q r OC(=O)NR h R i (CH 2 ) q [O(CH 2 ) q r (C 1 ​​-C 6 alkyl) (optionally replaced by 1 to 3 R m Group substitution), -NR h C(=O)(C 1 -C 6 alkylene)[O(CH 2 ) q ] r OC(=O)NR h R i (CH 2 ) q [O(CH 2 ) q ] r (C 1 -C 6 alkyl) (optionally replaced by 1 to 3 R m Group substitution), -OR k 、-OC(=O)R k 、-OC(=O)OR k 、-OC(=O)NR h R i 、-[O(CH 2 ) q ] r O(C 1 -C 6 Alkyl), -S(=O) p R k and -S(=O) p NR h R i Group, in which:

[0035] R a -C(=O)(C 1 -C 4 Alkylene)S(=O) p R k , -C(=O)(C 1 -C 4 Alkylene)OR k , -C(=O)(C 1 -C 4 Alkylene)S(=O) p NR h R i , -C(=O)(C 1 -C 4 Alkylene)NR i S(=O) p R k , -C(=O)(C 1 -C 4 Alkylene)NR h C(=O)Rk 、-NR h C(=O)O(C 1 -C 4 Alkylene)R k 、-NR h C(=O)(C 1 -C 4 Alkylene)OR k 、-NR h S(=O) p (C 1 -C 4 alkylene)C(=O)OR k and-NR h C(=O)(C 1 -C 4 Alkylene)NR i S(=O) p R k C in each of 1 -C 4 The alkylene group is optionally substituted with 1 to 3 -OH groups;

[0036] R a The C 1 -C 8 Alkyl, the C 1 -C 6 haloalkyl, the C 1 -C 6 The alkoxy group and the C 2 -C 8 Each alkenyl group is optionally substituted with 1 to 3 groups independently selected from the group consisting of 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(CH 2 ) q ] r OH, -OC(=O)R k、-OC(=O)OR k 、-OC(=O)NR h R i 、-SR k 、-S(=O) p R k 、-S(=O) p NR h R i 、-[O(CH 2 ) q ] r O(C 1 -C 4 Alkyl), -O-(C 6 aryl or 5 to 8 membered heteroaryl) (optionally substituted by 1 to 3 R m Group substitution), C 3 -C 6 Carbocyclic group (optionally substituted by 1 to 3 R m Group substitution), C 6 To C 10 Aryl (optionally substituted with 1 to 3 R m substituted with a group), a 4- to 10-membered heterocyclic group (optionally substituted with 1 to 3 R m substituted with 1 to 3 R m group substituted) group;

[0037] R a The C 3 -C 12 The carbocyclic group, the 3 to 12 membered heterocyclic group, the C 6 and C 10 The aryl group and the 5- to 10-membered heteroaryl group are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, oxo, cyano, C 1 -C 6 Alkyl (optionally with 1 to 3 R m Group substitution), -C(=O)R k 、-C(=O)OR k 、-NR h R i 、-OR k 、-S(=O) p R k 、-S(=O) p NR h R i and a 5- to 10-membered heterocyclyl group, wherein:

[0038] R h , R i and R j are independently selected at each occurrence from hydrogen, C1 -C 6 Alkyl, C 6 -C 10 Aryl, C 3 -C 8 Carbocyclic group (optionally substituted by 1 to 3 R m substituted with 1 to 3 R m substituted with 1 to 3 R m A group substituted with a (substituted) group, wherein:

[0039] R h , R i and R j Any of the C 1 -C 6 The alkyl group is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH, C 1 -C 4 Alkoxy, -C(=O)NH(C 1 -C 4 Alkyl), C 3 -C 6 Carbocyclic group (optionally substituted by 1 to 3 R m substituted with 1 to 3 R m substituted with 1 to 3 R m group substituted) group;

[0040] R k is independently selected at each occurrence from hydrogen, C 1 -C 6 Alkyl, benzyl, C 6 Aryl, C 3 -C 6 Carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein:

[0041] R k Any of the C 1 -C 6 The alkyl group is optionally substituted with 1 to 5 groups independently selected from the group consisting of halogen, cyano, -NH 2 、-OH、C 1 -C 4 Alkoxy, C 3 -C 6 cycloalkyl (optionally substituted by 1 to 3 halogen groups), 5 to 10 membered heterocyclyl (optionally substituted by 1 to 3 -OH groups) and 5 to 10 membered heteroaryl (optionally substituted by 1 to 3 -OH groups) groups; and

[0042] R k Any of the C 3 -C 6 Carbocyclic, benzyl and C 6 The aryl groups are each optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, cyano, oxo, -OH, -C(=O)NH 2 、-C(=O)N(CH 3 ) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl (optionally substituted by 1 to 3 halogen groups), C 6 Aryl (optionally substituted by 1 to 3 halogen groups) and 5 to 10 membered heteroaryl (optionally substituted by 1 to 3 halogen groups) groups, wherein:

[0043] The C 1 -C 4 The alkyl group is optionally substituted with 1 to 3 -OH groups; and

[0044] R k The 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl of any one of the above are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -C(=O)CH 3 、-NH 2 、-OH、C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 3 -C 6 Cycloalkyl and C 1 -C 4 An alkoxy group, wherein:

[0045] The C 1 -C 4 The alkyl group is optionally substituted with 1 to 3 -OH groups;

[0046] R m is independently selected at each occurrence from 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, C 1 -C 6 Alkoxy, -C(=O)R k 、-S(=O) p R k 、-OR k , C 3 -C 6 Cycloalkyl and 5- to 10-membered heterocyclyl groups wherein:

[0047] R m Any of the C 1 -C 6 Alkyl, the C 1 -C 6 The alkoxy and the 5- to 10-membered heterocyclic group are optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH and C 1 -C 4 an alkoxy group; and

[0048] n, at each occurrence, is an integer selected from 0, 1, and 2;

[0049] p at each occurrence is an integer independently selected from 1 and 2; and

[0050] q and r are each an integer independently selected from 0, 1, 2 and 3 at each occurrence.

[0051] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is a compound represented by the following structural formulas IA, II, IIA, III, IV, IVA, IVB, IVC, V, VA, VB, VC, VI, VIA, VIB, VIC, VII, VIIA, VIII, VIIIA, IX, and IXA:

[0052]

[0053]

[0054] wherein all variables are as defined above for Formula I.

[0055] In one aspect of the present 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 to 299, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0056] In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt selected from the following: 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 compounds, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical composition may include at least one compound selected from the following: Compounds 1 to 299, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0057] Another aspect of the present disclosure provides a method of treating an APOL1-mediated disease, comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of 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 the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds 1 to 299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0058] Another aspect of the present disclosure provides a method of treating APOL1-mediated cancer (e.g., pancreatic cancer), comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the following: 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 the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the following: compounds 1 to 299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0059] Another aspect of the present disclosure provides a method for treating APOL1-mediated kidney diseases (e.g., ESKD, FSGS and / or NDKD), comprising administering to a subject in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the following: 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 the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the following: compounds 1 to 299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0060] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one additional active agent in the form of the same pharmaceutical composition as at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the following: 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 compounds, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method comprises administering to a subject in need thereof at least one additional active agent in the form of the same pharmaceutical composition as at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the following: Compounds 1 to 299, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing: Compounds 1 to 299, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0061] 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 the group consisting of 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 the 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 to 299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. DETAILED DESCRIPTION

[0062] definition

[0063] As used herein, the term "APOL1" means apolipoprotein L1 protein, and the term "APOL1" means apolipoprotein L1 gene.

[0064] The term "APOL1-mediated disease" refers to a disease or condition associated with abnormal APOL1 (e.g., certain APOL1 genetic variants; elevated levels of APOL1). In some embodiments, the APOL1-mediated disease is an APOL1-mediated kidney disease. In some embodiments, the APOL1-mediated disease is associated with patients having two APOL1 risk alleles (e.g., patients who are homozygous or compound heterozygous for the G1 or G2 alleles). In some embodiments, the APOL1-mediated disease is associated with patients having one APOL1 risk allele.

[0065] The term "APOL1-mediated kidney disease" refers to a disease or condition that impairs kidney function and is attributable to APOL1. In some embodiments, the APOL1-mediated kidney disease is associated with patients with two APOL1 risk alleles (e.g., patients who are homozygous or compound heterozygous for the G1 or G2 alleles). In some embodiments, the APOL1-mediated kidney disease is selected from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOL1-mediated kidney disease is chronic kidney disease or proteinuria.

[0066] As used herein, the term "FSGS" means focal segmental glomerulosclerosis, a disease of podocytes (glomerular lining epithelial cells) that causes proteinuria and progressive decline in kidney function and is associated with 2 common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0067] As used herein, the term "NDKD" means non-diabetic kidney disease, which is characterized by severe hypertension and progressive decline in kidney function and is associated with 2 common APOL1 genetic variants (G1:S342G:I384M and G2:N388del:Y389del).

[0068] The terms "ESKD" and "ESRD" are used interchangeably herein and refer to end-stage renal disease or end-stage renal disease. ESKD / ESRD is the final stage of kidney disease, i.e., kidney failure, and means that the kidneys have stopped working well enough so that the patient cannot survive without dialysis or a kidney transplant. In some embodiments, ESKD / ESRD is associated with two APOL1 risk alleles.

[0069] When referring to the compounds of the present disclosure, the term "compound" refers to a collection of molecules having the same chemical structure except that there may be isotopic variations between the constituent atoms of the molecules, unless otherwise specified as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers). Thus, it will be clear to one skilled in the art that a compound represented by a particular chemical structure containing an indicated deuterium atom will also contain a smaller amount of isotopologues having hydrogen atoms at one or more designated deuterium positions in the structure. The relative amount of such isotopologues in the compounds of the present disclosure will depend on many factors, including the isotopic purity of the reagents used to prepare the compounds and the incorporation efficiency of the isotopes in the various synthetic steps used to prepare the compounds. However, as explained above, the overall relative amount of such isotopologues will be less than 49.9% of the compound. In other embodiments, the overall relative amount of such isotopologues will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1% or less than 0.5% of the compound.

[0070] As used herein, "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise specified, 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 substituent may be the same or different at each position. Combinations of substituents contemplated by the present disclosure are those combinations of substituents that result in the formation of stable or chemically feasible compounds.

[0071] The term "isotopologue" refers to a species in which a chemical structure differs from a reference compound only in its isotopic composition. In addition, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or replacing 13 C or 14 Compounds having the present structures except for C replacing the carbon are within the scope of the present disclosure.

[0072] Unless otherwise stated, structures depicted herein are also meant to include all isomeric forms of the structures, e.g., racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the compounds of the invention are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0073] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that coexist in equilibrium and are easily interchangeable by migration of atoms (eg, hydrogen atoms) or groups within a molecule.

[0074] As used herein, "stereoisomers" refers to enantiomers and diastereomers.

[0075] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as the reference compound but with one or more hydrogen atoms replaced by a deuterium atom ("D" or " 2 H”) substituted. It will be appreciated that, depending on the source of the chemical materials used in the synthesis, there is some variation in the natural isotopic abundance of the synthesized compounds. Despite this variation, the concentration of the naturally abundant stable hydrogen isotopes is small and insignificant compared to the extent of stable isotopic substitution of the deuterated derivatives described herein. Therefore, unless otherwise specified, when referring to a “deuterated derivative” of a compound of the present disclosure, at least one hydrogen has been replaced by deuterium at a level well above its natural isotopic abundance (typically about 0.015%). In some embodiments, the deuterated derivatives of the present disclosure have an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each specified 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) per deuterium atom.

[0076] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0077] As used herein, the term "alkyl" or "aliphatic" means a fully saturated straight chain (i.e., linear or unbranched) or branched, substituted or unsubstituted hydrocarbon chain. Unless otherwise specified, the alkyl group contains 1 to 20 alkyl carbon atoms. In some embodiments, the alkyl group contains 1 to 10 aliphatic carbon atoms. In some embodiments, the alkyl group contains 1 to 8 aliphatic carbon atoms. In some embodiments, the alkyl group contains 1 to 6 alkyl carbon atoms. In some embodiments, the alkyl group contains 1 to 4 alkyl carbon atoms, in other embodiments, the alkyl group contains 1 to 3 alkyl carbon atoms, and in yet other embodiments, the alkyl group contains 1 or 2 alkyl carbon atoms. In some embodiments, the alkyl group is linear or straight chain or unbranched. In some embodiments, the alkyl group is branched.

[0078] 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, the cycloalkyl group is C 3 To C 12 In some embodiments, the cycloalkyl group is C 3 To C 8 In some embodiments, the cycloalkyl group is C 3 To C 6 Cycloalkyl. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0079] As used herein, the term "carbocyclyl" or "alicyclic" encompasses the term "cycloalkyl" or "cyclic alkyl" and refers to a fully saturated or partially saturated monocyclic C 3-8 Hydrocarbon or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14 Hydrocarbons are hydrocarbons because they contain one or more unsaturated units but are not aromatic, wherein any individual ring in the bicyclic system has 3 to 7 members. Bicyclic carbocyclyls include combinations of monocyclic carbocyclic rings fused to phenyl. In some embodiments, carbocyclyls are C 3 To C 12 In some embodiments, the carbocyclic group is C 3 To C 10 In some embodiments, the carbocyclic group is C 3 To C 8 Carbocyclic group.

[0080] As used herein, the term "heteroalkyl" or "heteroaliphatic" means an alkyl or aliphatic group as defined above wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus or silicon.

[0081] As used herein, the term "alkenyl" means a straight (i.e., linear or unbranched) or branched hydrocarbon chain containing one or more double bonds. In some embodiments, the alkenyl group is straight-chain. In some embodiments, the alkenyl group is branched.

[0082] The terms "heterocycle", "heterocyclyl" and "heterocyclic" are used interchangeably herein and refer to a non-aromatic (i.e., fully saturated or partially saturated, as it contains one or more unsaturated units but is not aromatic), monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system in which one or more ring members are independently selected heteroatoms. Bicyclic heterocyclyls include the following monocyclic combinations: a monocyclic heteroaryl fused to a monocyclic heterocyclyl; a monocyclic heterocyclyl fused to another monocyclic heterocyclyl; a monocyclic heterocyclyl fused to a phenyl; a monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and a monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl.

[0083] In some embodiments, the heterocyclic ring includes one or more oxo groups (eg, a C=O group, an S=O group, or a SO 2 A ring atom substituted with a (a) group.

[0084] In some embodiments, a "heterocycle", "heterocyclyl", "heterocycloaliphatic" or "heterocyclic" group has 3 to 14 ring members, one or more of which is a heteroatom independently selected from oxygen, sulfur, nitrogen, silicon and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has one heteroatom independently selected from oxygen, sulfur, nitrogen, silicon and phosphorus, any basic nitrogen or quaternized form of a substitutable nitrogen of the heterocycle, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (such as in N-substituted pyrrolidinyl). In some embodiments, the heterocycle has a heteroatom that is a nitrogen atom. In some embodiments, the heterocycle has a 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 heterocyclic group is a 3 to 12-membered heterocyclic group. In some embodiments, the heterocyclic group is a 3 to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a 3 to 8-membered heterocyclic group. In some embodiments, the heterocyclic group is a 5 to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a 5 to 8-membered heterocyclic group. In some embodiments, the heterocyclic group is a 5 or 6-membered heterocyclic group. Non-limiting examples of monocyclic heterocyclic groups include piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl, tetrahydrothienyl 1,1-dioxide, etc.

[0085] As used herein, the term "unsaturated" means that a moiety has one or more units or degrees of unsaturation. Unsaturation is the state in which not all available valences in a compound are occupied by substituents and thus the compound contains double or triple bonds.

[0086] As used herein, the term "alkoxy" or "thioalkyl" refers to an alkyl group as previously defined, wherein one of the carbons 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 containing at least one alkoxy group but not aromatic. Non-limiting examples of cyclic alkoxy include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo [3.2.1] octyl and oxepanyl.

[0087] As used herein, the terms "haloalkyl", "haloalkenyl" and "haloalkoxy" refer to a linear or branched alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms, respectively. Non-limiting examples of haloalkyl groups include -CHF 2 、-CH 2 F, -CF 3 , -CF 2 - and perhaloalkyl, such as -CF 2 CF 3 Non-limiting examples of haloalkoxy groups include -OCHF 2 、-OCH 2 F, -OCF 3 and-OCF 2 .

[0088] The term "halogen" encompasses F, Cl, Br and I, ie, fluorine, chlorine, bromine and iodine, respectively.

[0089] The term "aminoalkyl" refers to an alkyl group substituted by or containing an amino group.

[0090] As used herein, "amino" refers to a group that is a primary amine, a secondary amine, or a tertiary amine.

[0091] As used herein, a "carbonyl" group refers to C=O.

[0092] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0093] As used herein, a "hydroxy" group refers to -OH.

[0094] As used herein, a "thiol" group refers to -SH.

[0095] As used herein, "tert" and "t-" each refer to tertiary.

[0096] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system having a delocalized π electron orbital consisting of [4n+2]p orbital electrons, where n is an integer ranging from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0097] The term "aryl", used alone or as part of a larger moiety (such as in "arylalkyl", "arylalkoxy", or "aryloxyalkyl"), refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system having a total of five to fourteen ring members, wherein each ring in the system is an aromatic ring containing only carbon atoms, and wherein each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C 6 ) and naphthyl (C 10 )ring.

[0098] The term "heteroaryl", used alone or as part of a larger moiety (such as in "heteroarylalkyl" or "heteroarylalkoxy"), refers to monocyclic or spirocyclic, fused or bridged bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, wherein at least one ring in the system contains one or more heteroatoms, and wherein each ring in the bicyclic or tricyclic system contains 3 to 7 ring members. Bicyclic heteroaryl includes a combination of the following monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl. In some embodiments, the heteroaryl has one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl has one heteroatom. In some embodiments, the heteroaryl has two heteroatoms. In some embodiments, the heteroaryl is a monocyclic ring system with five ring members. In some embodiments, the heteroaryl is a monocyclic ring system with six ring members. In some embodiments, the heteroaryl is a 3 to 12-membered heteroaryl. In some embodiments, the heteroaryl is a 3 to 10-membered heteroaryl. In some embodiments, 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 heteroaryl are pyridyl, pyrimidinyl, thienyl, thiazolyl, isoxazolyl, etc.

[0099] Non-limiting examples of useful protecting groups for nitrogen-containing groups such as amine groups include, for example, tert-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethylcarbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylamine, and p-toluenesulfonamide. Methods for adding (commonly referred to as "protection") and removing (commonly referred to as "deprotection") such amine protecting groups are well known in the art and are available, for example, in PJ Kocienski, Protecting Groups, Thieme, 1994, which is incorporated herein by reference in its entirety, and in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed. (John Wiley & Sons, New York, 1999) and 4th ed. (John Wiley & Sons, New Jersey, 2014).

[0100] Non-limiting examples of suitable solvents that can be used in the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CH 2 Cl 2 ), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropanol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butyl alcohol, diethyl ether (Et 2 O), methyl tert-butyl ether (MTBE), 1,4-dioxane and N-methylpyrrolidone (NMP).

[0101] 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 (K 2 CO 3 ), N-methylmorpholine (NMM), triethylamine (Et 3 N; TEA), diisopropylethylamine (i-Pr 2 EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH 3).

[0102] The present disclosure encompasses pharmaceutically acceptable salts of the disclosed compounds. Salts of compounds 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.

[0103] As used herein, the term "pharmaceutically acceptable" refers to components that are suitable for contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. "Pharmaceutically acceptable salt" means any non-toxic salt that can directly or indirectly provide a compound of the present disclosure when administered to a recipient. Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al., Journal of Pharmaceutical Sciences, 1977, 66, 1 to 19.

[0104] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, ditartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfate, pyrophosphate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, caprate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, Pharmaceutically acceptable acid addition salts include butyrate, succinate ...

[0105] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1-4 alkyl) 4 Salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium. Additional non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0106] The terms "patient" and "subject" are used interchangeably herein and refer to animals, including humans.

[0107] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that produces the desired effect of its administration (e.g., improving symptoms of FSGS and / or NDKD, reducing the severity of FSGS and / or NDKD or symptoms of FSGS and / or NDKD, and / or reducing the progression of FSGS and / or NDKD or symptoms of FSGS and / or NDKD). The exact amount of an effective dose will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0108] As used herein, the term "treat" and its cognate words refer to slowing down or stopping the progression of a disease. As used herein, "treat" and its cognate words include but are not limited to the following: complete or partial relief, reduction of the risk of renal failure (e.g., ESRD) and disease-related complications (e.g., edema, susceptibility to infection or thromboembolic events). The improvement of any of these symptoms or the reduction of their severity can be easily assessed according to methods and techniques known in the art or subsequently developed.

[0109] When used in conjunction with a dose, amount, or weight percentage of an ingredient of a composition or dosage form, the terms "about" and "approximately" encompass a value of the specified dose, amount, or weight percentage, or a range of the specified dose, amount, or weight percentage, that one of ordinary skill in the art would recognize as providing a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percentage.

[0110] At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the following: compounds of Formula I and II, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, may be administered once a day, twice a day, or three times a day, for example, to treat AMKD, including FSGS and / or NDKD. In some embodiments, at least one compound selected from the following: compounds 1 to 299, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for example, to treat AMKD, including FSGS and / or NDKD, may be administered once a day, twice a day, or three times a day. In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds of Formula I, IA, 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, is administered once daily. In some embodiments, at least one compound selected from the group consisting of compounds 1 to 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 the group consisting of 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 and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily. In some embodiments, at least one compound selected from the group consisting of compounds 1 to 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 the group consisting of 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 and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered three times daily.In some embodiments, at least one compound selected from Compounds 1 to 299, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered three times daily.

[0111] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound selected from the following: 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 are administered once a day, twice a day, 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 the following: compounds 1 to 299, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once a day, twice a day, or three times a day.

[0112] One of ordinary skill in the art will recognize that when an amount of a compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. The amounts of the compounds, pharmaceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based on the free base form of the reference compound. For example, "1000 mg of at least one compound or pharmaceutically acceptable salt selected from a compound of Formula I and a pharmaceutically acceptable salt thereof" includes 1000 mg of a compound of Formula I and a pharmaceutically acceptable salt of a compound of Formula I at a concentration equivalent to 1000 mg of the compound of Formula I.

[0113] As used herein, the term "ambient conditions" means room temperature, open air conditions, and uncontrolled humidity conditions.

[0114] Compounds and compositions

[0115] In some embodiments, AMKD (including FSGS and NDKD) can be treated with at least one compound selected from the following: 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 and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, 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 can be selected from compounds 1 to 299, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, AMKD (including FSGS and NDKD) can be treated with a pharmaceutical composition comprising at least one compound selected from the following: 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 and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical composition comprises at least one compound selected from the following: compounds 1 to 299, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0116] In some embodiments of Formula I:

[0117]

[0118] Ring A is an unsubstituted phenyl group. In some embodiments, Ring A is substituted with 1 or 2 R 1 substituted phenyl radical, and each R 1 are independently selected from halogen, cyano, -CH 3 、-CH 2 CH 3 、-CH 2 CF 2 、-CFCF 2 , -CF 2 , -CF 3 、-OCH 3 、-OCF 2 and-OCF 3 In some embodiments, Ring A is surrounded by 1 or 2 R 1substituted phenyl radical, and each R 1 Independently selected from F and Cl.

[0119] In some embodiments of Formula I, X is selected from -C(O)-, -O-, -S-, -CR 1a R 1b -and-NR 1c In some embodiments of Formula I, X is selected from -CH 2 - and -NH- (i.e., R 1a , R 1b and R 1c are each hydrogen). In some embodiments of Formula I, X is -CR 1a R 1b -, where R 1a is hydrogen and R 1b Selected from R 1 In some embodiments of Formula I, X is -CHOH- (ie, wherein R 1a is hydrogen, R 1b YesR 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)-.

[0120] In some embodiments of Formula I, Y is selected from -CR 1a R 1b -and-NR 1c -. In some embodiments of Formula I, Y is -CR 1a R 1b , where R 1a and R 1b In some embodiments of Formula I, Y is -CR 1a R 1b , where R 1a and R 1b Each is R 1 , and R 1 Yes-CH 3 In some embodiments of Formula I, Y is -CR 1a R 1b , where R 1a is hydrogen and R 1b Selected from R 1 In some embodiments of Formula I, Y is -CR 1a R 1b , where R 1a is hydrogen, R 1b YesR 1 , and R 1 Selected from -OH, -CH3, -C(O)NH 2 、C(O)NHCH3 In some embodiments of Formula I, Y is -CR 1a R 1b , where R 1a and R 1b YesR 1 , and R 1 Selected from -OH and -CH3.

[0121] In some embodiments of Formula I, X is selected from -C(O)- and -CR 1a R 1b -, and Y is -NR 1c -, where R 1c In some embodiments of Formula I, X is selected from -C(O)- and -CR 1a R 1b -, and Y is -NR 1c -, where R 1c Selected from R 1 In some embodiments of Formula I, X is selected from -C(O)- and -CR 1a R 1b -, and Y is -NR 1c -, where R 1c YesR 1 , and R 1 is selected from C optionally substituted by 1 to 3 halogen groups 1 -C 6 Alkyl and C 1 -C 6 In some embodiments of Formula I, X is selected from -C(O)- and -CR 1a R 1b -, and Y is -NR 1c -, where R 1c YesR 1 , and R 1 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 In some embodiments of Formula I, Y is -NR 1c -, where R 1c YesR 1 , and R 1 In some embodiments of Formula I, Y is -NR 1c-, where R 1c YesR 1 , and R 1 yes

[0122] In some embodiments of Formula I, Y is -CH(C(O)NH 2 In some embodiments of Formula I, Y is -CH(C(O)NHCH 3 In some embodiments of Formula I, Y is -CH(CH 3 ) 2 -. In some embodiments of Formula I, Y is -CH 2 -. 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(CH 3 In some embodiments of Formula I, Y is -N(C(O)CH 3 )-.

[0123] In some embodiments of Formula I, Z is a bond (ie, Y is directly attached to Ring A). In some embodiments of Formula I, and Z is selected from -CR 1a R 1b -. In some embodiments of Formula I, and Z is -CR 1a R 1b -, where R 1a and R 1b In some embodiments of Formula I, and Z is -CR 1a R 1b -, where R 1a and R 1b In some embodiments of Formula I, and Z is -CR 1a R 1b -, where R 1a is hydrogen and R 1b It is -OH.

[0124] In some embodiments of Formula I, R 2 and R 3 are independently selected from hydrogen and CH 3 In some embodiments of Formula I, R 2 and R 3 Both are hydrogen. In some embodiments of Formula I, R 2 and R 3 One of them is hydrogen and the other is CH 3 .

[0125] In some embodiments of Formula I, contained in 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 Selected from C 1 -C 6 Alkyl, optionally substituted by 1 to 5 groups independently selected from the group consisting of halogen, cyano, -OH, -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 、-C(=O)NH 2 , -C(=O)(C 1 -C 4 alkyl), -C(=O)O(C 1 -C 4 alkyl), -C(=O)NH(C 1 -C 4 alkyl), -C(=O)N(C 1 -C 4 alkyl) 2 , C 1 -C 4 Alkoxy, C 3 -C 6 Carbocyclic group, C 6 Aryl (optionally substituted by 1 to 3 independently selected from halogen and C 1 -C 4 haloalkyl radical), -O-(C 6 Aryl) (optionally substituted by 1 to 3 independently selected from halogen and C 1 -C 4 In some embodiments of Formula I, in the embodiments contained in 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 C substituted by 1 to 2 groups independently selected from 1 -C 6 Alkyl: -OH, phenyl, and phenyl further substituted with halogen. In some embodiments of Formula I, R 4 Selected from C substituted by -OH and phenyl 1 -C 6In some embodiments of Formula I, in embodiments contained in 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 Selected from C substituted by -OH and phenyl substituted by Cl 1 -C 6 In some embodiments of Formula I, R 4 Selected from C substituted by -OH and phenyl substituted by 2F 1 -C 6 In some embodiments of Formula I, R 4 Selected from -C(=O)O(C 1 -C 4 alkyl).

[0126] In some embodiments of Formula I, contained in 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 Selected from In some embodiments of Formula I, in embodiments contained in 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 Selected from In some embodiments, Ring B is selected from

[0127]

[0128] 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 is replaced by 1 R a In some embodiments, ring B is substituted with 2 R a In some embodiments, ring B is substituted with 3 R a In some embodiments, Ring B is substituted with 4 R a Group substitution.

[0129] In some embodiments of Formula I, contained in 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 are independently selected from halogen, cyano, oxo, C 1 -C 8 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 12 Carbocyclic group, 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 Group, in which:

[0130] R a The C 1 -C 8 Alkyl, the C 1 -C 6 haloalkyl, the C 1 -C 6 The alkoxy group and the C 2 -C 8 Each alkenyl group is optionally substituted with 1 to 3 groups independently selected from: -C(=O)NR h R i , =NOR k 、-NR h R i 、-NR h C(=O)NR i R j 、-NRh S(=O) p R k 、-OR k 、-S(=O) p R k 、-S(=O) p NR h R i , C 3 -C 6 Carbocyclic group (optionally substituted by 1 to 3 R m substituted with a group), a 4- to 10-membered heterocyclic group (optionally substituted with 1 to 3 R m substituted with 1 to 3 R m group substituted) group;

[0131] R a The C 3 -C 12 The carbocyclic group, the 3 to 12 membered heterocyclic group, the C 6 and C 10 The aryl group and the 5- to 10-membered heteroaryl group are each optionally substituted by 1 to 3 groups independently selected from the group consisting of oxo, halogen, cyano, C 1 -C 6 Alkyl (optionally with 1 to 3 R m Group substitution), -OR k 、-S(=O) p R k 、-S(=O) p NR h R i and a 5- to 10-membered heterocyclyl group, wherein:

[0132] R h , R i and R j are independently selected at each occurrence from hydrogen, C 1 -C 6 alkyl, 5 to 10 membered heteroaryl (optionally substituted by 1 to 3 R m substituted with 1 to 3 R m Group substitution), wherein:

[0133] R h , R i and R j Any of the C 1 -C 6 The alkyl group is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH, C 3 -C 6 Carbocyclic group (optionally substituted by 1 to 3 Rm group substitution);

[0134] R k is independently selected at each occurrence from hydrogen, C 1 -C 6 Alkyl, C 3 -C 6 Carbocyclyl and 5- to 10-membered heteroaryl groups wherein:

[0135] R k Any of the C 1 -C 6 The alkyl group is optionally substituted with 1 to 5 groups independently selected from the group consisting of halogen, cyano, -NH 2 and -OH; and

[0136] R k The 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl of any one of the above are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH, C 1 -C 4 Alkyl (optionally substituted with 1 to 3 -OH groups), C 1 -C 4 Halogenated alkyl, C3 -C 6 Cycloalkyl and C 1 -C 4 An alkoxy group, wherein:

[0137] R m is independently selected at each occurrence from halogen, cyano, oxo, -C(=O)NH 2 、-NH 2 , -C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, -OR k and C 3 -C 6 Cycloalkyl, wherein:

[0138] R m Any of the C 1 -C 6 Alkyl, the C 1 -C 6 The alkoxy and the 5- to 10-membered heterocyclic group are optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH and C 1 -C 4 Alkoxy groups;

[0139] p is an integer independently selected from 1 and 2 at each occurrence.

[0140] In some embodiments of Formula I, contained in 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 Independently selected from

[0141] -halogen;

[0142] -Oxo;

[0143] - cyano;

[0144] -C 1 Haloalkoxy;

[0145] -CH 3 ;

[0146] -CF 2 ;

[0147] By-OR k Replaced-C 1 Alkyl, where R k Yes-CH 3 ;

[0148] -C(=O)NR h R i Replaced-C 1 Alkyl, where R h and R i Both are CH 3 ;

[0149] -C(=O)NR h R i Replaced-C 1 Alkyl, where R h is hydrogen and R i Yes CH 3 ;

[0150] -C(=O)NR h R i Replaced-C 1 Alkyl, where R h is hydrogen and R i Is C 3 -C 6 carbocyclyl optionally substituted cyano substituted CH 3 ;

[0151] -C(=O)NR h R i Replaced-C 1 Alkyl, where Rh is hydrogen and R i is a CH substituted by a 5-membered heteroaryl 3 ;

[0152] -C substituted by cyclopropyl 1 Alkyl, the cyclopropyl is further R m Substitution, where R m Selected from CH 3 , CH 2 OH and CH 2 C(=O)NH 2 ;

[0153] 4-membered heterocyclic ring Replaced-C 1 Alkyl, the 4-membered heterocyclic ring is further R m Substitution, where R m is C(=O)NH 2 ;

[0154] -C substituted by a 5-membered optionally substituted heterocyclic ring 1 alkyl;

[0155] quilt Replaced-C 1 Alkyl, Optionally oxo and CH 3 replace;

[0156] -C substituted by 5-membered optionally substituted heteroaryl 1 alkyl;

[0157] quilt Replaced-C 1 Alkyl, Optionally -OH or C(=O)NH 2 replace;

[0158] quilt Replaced-C 1 Alkyl, Optionally -C 1 To -C 3 Alkyl substitution;

[0159] quilt Replaced-C 1 Alkyl, Optionally N(CH 3 ) 2 replace;

[0160] quilt Replaced-C 1 Alkyl, Optionally, 1 to 3 R independently selected from the followingm Group substitution: CH 3 , CH 2 OH and C(=O)NH 2 ;

[0161] -C substituted by 6-membered optionally substituted heteroaryl 1 alkyl;

[0162] quilt Replaced-C 1 Alkyl, Optionally, 1 to 3 R independently selected from the following m Group substitution: oxo, CH3 and CH 2 OH;

[0163] quilt Replaced-C 1 Alkyl, Optionally, 1 to 3 R independently selected from the following m Group substitution: oxo, CH 3 , -C 3 Branched alkyl, cyclopropyl and NHCH 3 ;

[0164] quilt Replaced-C 1 Alkyl, Optionally, 1 to 3 R independently selected from the following m Group substitution: -OH, oxo and C 1 -C 3 alkyl;

[0165] quilt Replaced-C 1 Alkyl, Optionally, 1 to 2 R independently selected from the following m Group substitution: oxo and CH 3 ;

[0166] quilt Replaced-C 1 Alkyl, Optionally, 1 to 2 R independently selected from the following m Group substitution: oxo and CH 3 ;

[0167] quilt Replaced-C 1 Alkyl, Optionally 1 to 2 R m Group substitution;

[0168] -C 1 -C3 Alkoxy;

[0169] -C 2 alkyl;

[0170] By -OH and -C 3 -C 6 -C 2 alkyl;

[0171] C 1 Alkoxy substituted -C 2 alkyl;

[0172] -C substituted by -OH 2 alkyl;

[0173] NR h R i Replaced-C 2 Alkyl, where R h is hydrogen, and R i is optionally selected from -C 1 -C 3 The R of the alkyl m a 6-membered heteroaryl substituted with a radical;

[0174] =NOR k Replaced-C 2 Alkyl, where R k Yes-C 2 alkyl;

[0175] NR h S(=O) p R k Replaced-C 2 Alkyl, where R h is hydrogen, p is 2 and R k is cyclopropyl;

[0176] NR h C(=O)NR i R j Replaced-C 2 Alkyl, where R h and R i is hydrogen, and R j Yes-C 2 alkyl;

[0177] S(=O) p R k Replaced-C 2 Alkyl, where p is 2 and R k Yes CH 3 ;

[0178] -S(=O) p NR h R i Replaced-C 2 Alkyl, where p is 2 and R h and R i Both are hydrogen;

[0179] -S(=O) p NR h R i Replaced-C 2 Alkyl, where R h is hydrogen and R i Yes CH 3 ;

[0180] -C substituted by -OH and a 6-membered heterocycle (optionally further substituted by -OH) 2 alkyl;

[0181] 6-membered heterocyclic ring Replaced-C 2 Alkyl, the 6-membered heterocyclic ring is further R m Substitution, where R m Yes-OR k , where R k is -OH;

[0182] -OH and optionally substituted Replaced-C 2 Alkyl, the optionally substituted further substituted by OH;

[0183] -C substituted by 5-membered optionally substituted heteroaryl 2 alkyl;

[0184] 1 to 2 halogen groups and Replaced-C 2 Alkyl, Optionally C 1 -C 3 Alkyl substitution;

[0185] -C substituted by 6-membered optionally substituted heteroaryl 2 alkyl;

[0186] quilt Replaced-C 2 Alkyl, optionally substituted with oxo;

[0187] -C optionally substituted with 1 to 2 -OH groups 3 alkyl;

[0188] -C substituted by -OH3 Haloalkyl;

[0189] -C 3 Carbon ring;

[0190] -C substituted by 5-membered optionally substituted heteroaryl 3 alkyl;

[0191] quilt Replaced-C 3 Alkyl, optionally substituted with oxo;

[0192] -C substituted by 6-membered heteroaryl 3 Alkyl, the 6-membered heteroaryl is optionally substituted with 1 to 2 oxo groups;

[0193] quilt Replaced-C 3 alkyl;

[0194] -C substituted with two -OH groups 4 alkyl;

[0195] -C substituted by -OH 4 Branched chain alkyl;

[0196] NR h S(=O) p R k Replaced-C 4 Branched alkyl, where R h is hydrogen, p is 2 and R k Yes CH 3 ;

[0197] NR h R i Replaced-C 4 Branched alkoxy, wherein R h and R i Both are hydrogen;

[0198] -C substituted with two -OH groups 5 Branched chain alkyl;

[0199] -S(=O) p NR h R i Replaced-C 5 Branched alkyl, where p is 2 and R h and R i Both are hydrogen;

[0200] Optionally CF 3 Replaced-C 6 Aryl;

[0201] -C(=O)OR k , where R k Yes CH 3 ;

[0202] -C(=O)NR h R i , where R h is hydrogen and R i Yes CH 3 ;

[0203] -C(=O)NR h R i , where R h and R i Both are hydrogen;

[0204] -NR h R i , where R h and R i Both are hydrogen;

[0205] -NR h R i , where R h is hydrogen and R i Yes CH 3 ;

[0206] -NR h R i , where R h is hydrogen and R i It is a branched-C substituted by -OH 4 alkyl;

[0207] -NR h C(=O)R k , where R h is hydrogen and R k Yes CH 3 ;

[0208] -NR h C(=O)R k , where R h is hydrogen and R k is a 5-membered heteroaryl substituted by a group selected from Cl and cyclopropyl

[0209] -NR h C(=O)R k , where R h is hydrogen and R k is not replaced Or by CH 3 Replaced

[0210] -NR h S(=O) p R k , where R h is hydrogen, p is 2, and R k Yes-C 2 alkyl;

[0211] -NR h S(=O) p R k , where R h is hydrogen, p is 2, and R k is cyclopropyl;

[0212] -NR h S(=O) p R k , where R h is hydrogen, p is 2, and R k is -cyano;

[0213] -S(=O) p R k , where R k Yes CH 3 ;

[0214] -S(=O) p NR h R i , where p is 2, and R h and R i Both are hydrogen;

[0215] 4-membered heterocyclic ring,

[0216]

[0217] Optionally S(O) 2 CH 3 replace;

[0218] 5-membered heterocyclic ring;

[0219] Optionally CH 3 replace;

[0220] Optionally oxo and CH 3 replace;

[0221] 6-membered heterocyclic ring;

[0222] Optional Substituted

[0223] Optionally substituted with -OH

[0224] 5-membered heteroaryl;

[0225] 6-membered heteroaryl;

[0226] Optionally -C 1 -C 3 Alkyl substituted

[0227] Optionally -C 1 -C 3 Alkyl substituted

[0228] In some embodiments, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is selected from Compounds 1 to 299 depicted in Table 1, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. The wavy lines (i.e., ) depicts a bond between two atoms and indicates the position of a mixed stereochemistry of a collection of molecules, such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. Asterisks near atoms in the compounds in Table 1 (e.g., ) indicates the chiral position in the molecule.

[0229] In some embodiments, the compound of Formula I is selected from the compounds presented in Table 1 below, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0230] Table 1. Compounds 1 to 314

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] Some embodiments of the present disclosure include derivatives of compounds 1 to 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, wherein at least one carbon atom selected from the following compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts has been replaced by silicon: compounds 1 to 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. In some embodiments, the derivative is a boron derivative, wherein at least one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from Compounds 1 to 299 or a 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, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing has been replaced by boron. In other embodiments, the derivative is a phosphorus derivative, wherein at least one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from Compounds 1 to 299 or a 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, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing has been replaced by phosphorus.

[0260] In some embodiments, the derivative is a silicon derivative, wherein one of the carbon atoms selected from the group consisting of the following compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts has been replaced by silicon or a silicon derivative (e.g., -Si(CH 3 ) 2 -or-Si(OH) 2-) is substituted with: Compounds 1 to 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, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. The carbon substituted with silicon can be a non-aromatic carbon. In other embodiments, fluorine has been replaced with a silicon derivative (e.g., -Si(CH 3 ) 3 ) is substituted. In some embodiments, the silicon derivatives of the present disclosure may contain one or more hydrogen atoms replaced by deuterium. In some embodiments, the silicon derivatives selected from the following compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts may incorporate silicon into a heterocycle: Compounds 1 to 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, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing.

[0261] In some embodiments, the derivative is a boron derivative, wherein one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from Compounds 1 to 299 or a 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, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing has been replaced by boron or a boron derivative.

[0262] In some embodiments, the derivative is a phosphorus derivative, wherein one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the following has been replaced by phosphorus or a phosphorus derivative: Compounds 1 to 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.

[0263] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one 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 and compounds 1 to 299, their tautomers, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting 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 compounds 1 to 299, tautomers thereof, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered to a patient in need thereof.

[0264] The pharmaceutical composition may further include at least one pharmaceutically acceptable carrier. In some embodiments, at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, at least one pharmaceutically acceptable is selected from a pharmaceutically acceptable filler, a disintegrant, a surfactant, a binder, and a lubricant.

[0265] It will also be understood that the pharmaceutical compositions of the present disclosure can be used in combination therapy; that is, the pharmaceutical compositions described herein can further include at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one selected from the following compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts can be used as a separate composition simultaneously with, before or after a composition comprising at least one other active therapeutic agent: 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 compounds, their tautomers, deuterated derivatives of these compounds or tautomers and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the following: Compounds 1 to 299, 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, prior to, or after a composition comprising at least one other active therapeutic agent.

[0266] As described above, the pharmaceutical compositions disclosed herein may optionally further include at least one pharmaceutically acceptable carrier. At least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, at least one pharmaceutically acceptable carrier comprises any and all solvents, diluents, other liquid vehicles, dispersing aids, suspending aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders and lubricants suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, disclose various carriers for formulating pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, its use is contemplated to be within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid and potassium sorbate), saturated vegetable fatty acids, water, partial glyceride mixtures of salts and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars (e.g., lactose, glucose and sucrose ), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffered solution, nontoxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavoring agents, aromas, preservatives and antioxidants.

[0267] Uses of compounds and compositions

[0268] 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.

[0269] 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.

[0270] In some embodiments of the present disclosure, the compounds and pharmaceutical compositions described herein are used to treat pancreatic cancer. In some embodiments, pancreatic cancer is mediated by APOL1.

[0271] In some embodiments, the methods of the present disclosure include administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of 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 and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is selected from compounds 1 to 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 has APOL1 genetic variants, i.e., G1: S342G: I384M and G2: N388del: Y389del.

[0272] Another aspect of the present disclosure provides a method of inhibiting APOL1 activity, the method comprising contacting the APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of 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 of inhibiting APOL1 activity comprises contacting the APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the group consisting of compounds 1 to 299, tautomers thereof, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0273] Examples

[0274] In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the present disclosure in any manner.

[0275] The compounds of the present disclosure can be prepared according to standard chemical practices or as described herein. Throughout the following synthetic schemes and in the description of the preparation of 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, compounds 1 to 299, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, the following abbreviations are used:

[0276] abbreviation

[0277] AcOH = acetic acid

[0278] ARP = assay ready plate

[0279] BF 3 .OET 2 = Boron trifluoride etherate

[0280] Boc 2 O = di-tert-butyl dicarbonate

[0281] DAST = Diethylaminosulfur trifluoride

[0282] DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene

[0283] DCE = 1,2-dichloroethane

[0284] DCM = dichloromethane

[0285] DEE = ethyl ether

[0286] DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propane-2-amine

[0287] DMEM = Dulbecco's modified Eagle's medium

[0288] DMF = dimethylformamide

[0289] DMPU=N,N'-dimethylpropyleneurea

[0290] DMSO = dimethyl sulfoxide

[0291] dppb = 1-4-bis[P(Ph)2]-butane

[0292] ESI-MS = Electrospray Ionization Mass Spectrometry

[0293] EtOAc = Ethyl acetate

[0294] EtOH = ethanol

[0295] FBS = fetal bovine serum

[0296] HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphorus hexafluoride ion)

[0297] IPA = Isopropyl Alcohol

[0298] IPAmine=isopropylamine

[0299] LCMS = Liquid Chromatography Mass Spectrometry

[0300] LED = Light Emitting Diode

[0301] mCPBA = meta-chloroperbenzoic acid

[0302] MeCN = acetonitrile

[0303] MeI = Methyl iodide

[0304] MeMgBr = Methylmagnesium bromide

[0305] MeOH = methanol

[0306] MTBE or TBME = methyl tert-butyl ether

[0307] n-BuLi=n-butyllithium

[0308] NMP = N-methylpyrrolidine

[0309] NMR = Nuclear Magnetic Resonance

[0310] Pd(dppf)Cl 2 =[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0311] Pd(PPh 3 ) 4 =Tetrakis(triphenylphosphine)palladium

[0312] PP = Polypropylene

[0313] PPh 3 =Triphenylphosphine

[0314] PTFE = Polytetrafluoroethylene

[0315] PTSA = p-toluenesulfonic acid monohydrate

[0316] rf = retention factor

[0317] rt = room temperature

[0318] SFC = Supercritical Fluid Chromatography

[0319] STAB = Sodium triacetoxyborohydride

[0320] T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide

[0321] TBAF = Tetra-n-butylammonium fluoride

[0322] TBS = Silyl ether

[0323] TBSCl = tert-butyldimethylsilyl chloride

[0324] TBTA = tris((1-benzyl-4-triazolyl)methyl)amine

[0325] tBuBrettPhos Pd G3=[(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II)

[0326] TEA = triethylamine

[0327] Tet = Tetracycline

[0328] TFA or TFAA = trifluoroacetic acid

[0329] Tf 2 O = trifluoroanhydride

[0330] THF = Tetrahydrofuran

[0331] TLC = Thin Layer Chromatography

[0332] TMSCN = trimethylsilyl cyanide

[0333] VT = variable temperature

[0334] Example 1. Synthesis of compounds

[0335] All specific and generic compounds and intermediates disclosed for the preparation of those compounds are considered to be a part of the disclosure disclosed herein.

[0336] Compound 1

[0337] 5-Chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (1)

[0338]

[0339] Step 1: Preparation of 5-chloro-2-oxo-spiro[indoline-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (C2)

[0340] N-chlorosuccinimide (17.8g, 133.3mmol) was added to a solution of C1 (20.1g, 66.58mmol) in chloroform (300mL) at room temperature. The resulting mixture was stirred at 56°C for 24 hours. N-chlorosuccinimide (4.3g, 32.2mmol) was added, and the reaction mixture was continued to be stirred for 12 hours at 56°C. N-chlorosuccinimide (9g, 67.4mmol) was further added, and the reaction mixture was continued to be stirred for 8 hours at 56°C. N-chlorosuccinimide (17g, 127.3mmol) was added, and the reaction mixture was refluxed for 4 hours this time. The reaction mixture was then placed at room temperature and washed with a saturated aqueous solution of sodium bisulfite (200mL) and brine (200mL). The organic layer was concentrated in vacuo, and the product was purified by silica gel chromatography (0-50% EtOAc: hexane) to obtain a mixture of starting material and product. The combined material was purified by reverse phase HPLC (Waters XSelect CSH C18 OBD preparative column; 30 x 150 mm, 5 micron. Gradient: acetonitrile / water with 5 mM hydrochloric acid). Product containing fractions were combined and concentrated to give the title compound (C2) (2.18 g, 9%) as an off-white solid. 1 H 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 / z337.5[M+H] + .

[0341] Step 2: Preparation of 5-chlorospiro[indoline-3,4'-piperidin]-2-one (C3)

[0342] A solution of DCM (5 mL) and HCl in dioxane (15 mL, 4 M, 60.0 mmol) was 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 (2.1 g, 110%), which was used in the subsequent step without any further purification.

[0343] Step 3: Preparation of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (1)

[0344] 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 was added sodium triacetoxyborohydride (420 mg, 1.99 mmol), and the mixture was stirred at room temperature for 20 hours.

[0345] At this time, the mixture was evaporated to remove volatiles. The material was purified by reverse phase HPLC (Waters XSelect CSHC18 OBD preparative column; 30×150 mm, 5 microns. Gradient: acetonitrile / water with 0.1% trifluoroacetic acid). The product-containing fractions were combined and the final product was converted to the HCl salt by treatment with HCl (4 M in dioxane), and the resulting suspension was filtered and dried to give the title compound 1 dihydrochloride (304 mg, 92%). 1 H NMR (300 MHz, chloroform-d) δ8.01 (d, J=0.7 Hz, 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] +

[0346] Table 2. Using the listed intermediates and modified intermediates available to those skilled in the art of organic chemistry, the following reactions can be carried out by, for example, copper-mediated cross coupling, Suzuki coupling, Negishi coupling, S N Ar, S N 2. Chemical transformations such as lithiation, acylation, halogenation, silylation, desilylation, 1,4-addition and reduction were used to prepare compounds 2-36 in a similar manner.

[0347] Table 2: Compounds 2-36

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358] Compound 37

[0359] 5-Chloro-1-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (37)

[0360]

[0361] Step 1: Preparation of 5-chloro-1-methyl-2-oxo-spiro[indoline-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (C28)

[0362] To a solution of C2 (199 mg, 0.591 mmol) and MeI (100 μL, 1.61 mmol) in 4 ml THF was added NaH (71 mg, 60% w / w, 1.78 mmol) and the mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and absorbed onto SiO 2 The product was purified by column chromatography (SiO 2 , 0-50% EtOAc:heptane). The product containing fractions were combined and concentrated to give the title compound C28 (199 mg, 93%) as a white solid. 1 H NMR (300MHz, chloroform-d) δ7.43(d,J=2.1Hz,1H),7.32(dd,J=8.3,2.1Hz,1H),6.98(d,J =8.3Hz,1H),3.79(d,J=6.0Hz,4H),3.19(s,3H),1.84-1.68(m,4H),1.50(s,9H). LCMS m / z 351.03[M+H] +

[0363] Step 2: Preparation of 5-chloro-1-methyl-spiro[indoline-3,4'-piperidin]-2-one (C29)

[0364] To a solution of C28 (192 mg, 0.528 mmol) in 3 ml methanol was added HCl (3 ml, 4M / dioxane, 12 mmol) and stirred at 50° C. for 40 minutes. At this time, the mixture was evaporated to give the title compound C29 hydrochloride (156 mg, 101%) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 7.45-7.23 (m, 2H), 7.03 (d, J = 8.3 Hz, 1H), 3.82 (ddd, J = 12.8, 11.9, 3.6 Hz, 2H), 3.39 (dt, J = 13.0, 4.1 Hz, 2H), 3.21 (s, 3H), 2.17 (ddd, J = 14.8, 12.0, 4.3 Hz, 2H), 2.06-1.90 (m, 2H). LCMS m / z 251.05 [M+H] +

[0365] Step 3: Preparation of 5-chloro-1-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (37)

[0366] 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 hours. At this time, the mixture was concentrated under vacuum. The material was purified by reverse phase HPLC (C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN / H 2 The product-containing fractions were combined and concentrated to give the title compound (37) (16.4 mg, 68%) as a clear oil. 1H 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=6.3Hz ,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] +

[0367] The intermediates listed and modified intermediates available to those skilled in the art of organic chemistry are prepared by S N Ar Compounds 38-40 in Table 3 were prepared in a similar manner.

[0368] Table 3: Compounds 38-40

[0369]

[0370] Compound 41

[0371] 5-Chloro-1'-[[1-[3-hydroxy-2-(hydroxymethyl)-2-methyl-propyl]triazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (41)

[0372]

[0373] Step 1: Preparation of 5-chloro-1'-prop-2-ynyl-spiro[indoline-3,4'-piperidin]-2-one (C31)

[0374] 3-bromoprop-1-yne (100 μL, 80% w / w, 0.898mmol) is added to a mixture of C3 hydrochloride (200mg, 0.732mmol) and potassium carbonate (200mg, 1.45mmol) in acetonitrile (5mL) and the mixture is stirred for 70 minutes. At this time, the mixture is diluted with DCM (20mL) and water (10mL). The aqueous layer is extracted with DCM (10mL), and the organic layer is combined and passed through a phase separator. The mixture is concentrated to dryness, diluted to a minimum in EtOAc, and purified by silica gel column chromatography (100% EtOAc). The product fractions are combined and concentrated to obtain the title compound C31 (171mg, 83%) as a clear oil. 1H 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] +

[0375] 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)

[0376] To a mixture of 2-(aminomethyl)-2-methylpropane-1,3-diol (C32) (20 mg, 0.327 mmol) in methanol (3 mL) was added a solution containing CuSO 4 (1 mg, 0.0063 mmol) in water (0.125 mL) was added, followed by sodium bicarbonate (30 mg, 0.357 mmol) in water (0.5 mL) and trifluoroazide (0.75 mL, 0.452 M) in DCM. This mixture was stirred for 1 hour. At this time, methanol (0.5 mL) containing C31 (35 mg, 0.127 mmol), water (0.25 mL) containing ascorbic acid (25 mg, 0.142 mmol) and methanol (0.35 mL) containing TBTA (3.5 mg, 0.0066 mmol) were added, and the mixture was heated to 55 ° C and stirred for 18 hours. The material was purified by reverse phase HPLC (Waters XSelect CSH C18 OBD preparative column; 30×150 mm, 5 microns. Gradient: acetonitrile / water with 0.1% trifluoroacetic acid). Product containing fractions were combined and 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. 1H 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] +

[0377] Compounds 42-44 shown in Table 4 were prepared in a similar manner from intermediate C29 instead of C3.

[0378] Table 4: Compounds 42-44

[0379]

[0380]

[0381] Compound 45

[0382] 5-Chloro-1-(2-hydroxyethyl)-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one(45)

[0383]

[0384] Preparation of 5-chloro-1-(2-hydroxyethyl)-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (45)

[0385] 1 dihydrochloride (36 mg, 0.0713 mmol), Cs 2 CO 3 (140 mg, 0.430 mmol), ethylene oxide in THF (1000 μL, 3 M, 3.00 mmol) and Cs 2 CO 3 A suspension of (140 mg, 0.430 mmol) in DMF (2 mL) was stirred at 75 ° C for 16 hours. At this time, DCM (10 mL) was added, and the suspension was filtered, and the filtrate was evaporated to remove volatiles. The crude residue was dissolved in DMSO, and the material was passed through reverse phase HPLC (C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN / H 2The product containing fractions were combined 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=2.1H z,1H),6.90(d,J=8.3Hz,1H),4.66(t,J=6.3Hz,2H),4.10(s,2H),3.88(tt, J=8.2,4.1Hz,4H),3.67(t,J=6.3Hz,2H),3.57(td,J=12.5,3.1Hz,2H),3.3 6(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] +

[0386] Compounds 46-51 shown in Table 5 were prepared in a similar manner from compound 1 using alternative electrophiles. Note that compound 46 was isolated as a byproduct from the same reaction to generate 45.

[0387] Table 5: Compounds 46-51

[0388]

[0389]

[0390]

[0391] Compound 52

[0392] 5-Chloro-1'-[[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]methyl]-1-methyl-spiro[indoline-3,4'-piperidin]-2-one (52)

[0393]

[0394] 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)

[0395] 38 (10 mg, 0.022 mmol), Cs 2 CO 3A suspension of 2-(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 hours. At this time, DCM (10 mL) was added and the mixture was filtered, concentrated under vacuum, and diluted with DMSO (1 mL). The material was passed through a reverse phase HPLC (C18 Waters Sunfire column (30×150 mm, 5 microns). Gradient: MeCN / H 2 The product containing fractions were combined and concentrated to give the title compound 52 (5.8 mg, 63%) as a white solid. 1 H 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 / z403.17[M+H] +

[0396] Compounds 53-59 shown in Table 6 were prepared in a similar manner from compound 38 using alternative epoxides.

[0397] Table 6: Compounds 53-59

[0398]

[0399]

[0400]

[0401] Compound 60

[0402] N-[3-[(5-chloro-1-methyl-2-oxo-spiro[indoline-3,4'-piperidinyl]-1'-yl)methyl]cyclobutyl]-3-cyclopropyl-isoxazole-5-carboxamide (60)

[0403]

[0404] Step 1: Preparation of 1'-[(3-aminocyclobutyl)methyl]-5-chloro-1-methyl-spiro[indoline-3,4'-piperidin]-2-one (C46)

[0405] 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, which was then extracted with DCM (3×5 mL). The combined organic fractions were washed with H 2 O (1 x 2 mL), brine (1 x 2 mL), dried over sodium sulfate, filtered and concentrated in vacuo.

[0406] The crude material was diluted with dioxane containing HCl (4 mL, 4 M, 16.00 mmol) and stirred for 1 hour. At this time, the solvent was removed under vacuum and the material was isolated as is. The title compound (C46) trifluoroacetate salt was isolated as a yellow oil. LCMS m / z 334.15 [M+H] +

[0407] Step 2: Preparation of N-[3-[(5-chloro-1-methyl-2-oxo-spiro[indoline-3,4'-piperidinyl]-1'-yl)methyl]cyclobutyl]-3-cyclopropyl-isoxazole-5-carboxamide (60)

[0408] 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 Et 3 N (24 μL, 0.171 mmol) and PyBop (35.6 mg, 0.068 mmol) were added and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum and diluted in 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 / water with 0.1% trifluoroacetic acid). The product-containing fractions were combined and concentrated to give the title compound (60) difluoroacetate salt (7.5 mg, 22%) as a clear oil.

[0409] Compounds 61-71 shown in Table 7 were prepared in a similar manner from compound C46 or the trans-cyclobutyl analog using alternative acids, sulfonyl chlorides and carbamoyl chlorides.

[0410] Table 7: Compounds 61-71

[0411]

[0412]

[0413]

[0414]

[0415] Compound 72

[0416] 2-(4-((1-methyl-2-oxospiro[indoline-3,4'-piperidinyl]-1'-yl)methyl)-1H-pyrazol-1-yl)ethane-1-sulfonamide (72)

[0417]

[0418] Step 1: Preparation of 1-methylspiro[indoline-3,4'-piperidin]-2-one (C55)

[0419] A stirring 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 layer was dried over sodium sulfate, filtered, and evaporated under vacuum to obtain a crude residue (600 mg). The crude residue was purified by column chromatography using (SiO 2 The product containing fractions were combined and concentrated.

[0420] The residue was dissolved in 1,4-dioxane (5 mL), and 1,4-dioxane (1.625 mL, 4 M, 0.0065 mol) containing HCl was added to the solution at 0 ° C. The reaction mass was stirred for 5 hours. At this time, the reaction was evaporated under vacuum to give a crude residue. The crude residue was washed with ether (3 × 5 mL) to give the title compound (C55) hydrochloride (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] +

[0421] Step 2. 2-(4-((1-methyl-2-oxospiro[indoline-3,4'-piperidinyl]-1'-yl)methyl)-1H-pyrazol-1-yl)ethane-1-sulfonamide (72)

[0422] To a stirred solution of C55 hydrochloride (75 mg, 287 μmol) in DMF (5 mL) was added K 2 CO 3 (594mg, 4.2mmol), KI (9.5mg, 56.8μmol) and 2-[4-(chloromethyl)pyrazol-1-yl]ethanesulfonamide (C56) hydrochloride (200mg, 384μmol). The reaction mixture was stirred at 100°C for 16 hours. At this time, the reaction was filtered and washed with methanol (15mL). The filtrate was evaporated under vacuum to give a crude compound (200mg) in the form of a brown jelly. The crude compound was purified by preparative HPLC (gradient: 0-98% MeCN / 0.1% aqueous TFA) to give the title compound (72) trifluoroacetate (15mg, 10%) in the form of a light brown jelly. 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=7.6Hz ,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] +

[0423] 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.

[0424] Table 8: Compound 73

[0425]

[0426] Compound 74

[0427] (2'S,3R)-5-Chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (74)

[0428]

[0429] Step 1: Preparation of (2S,4S)-4-[(2-bromo-4-chloro-phenyl)carbamoyl]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (C59)

[0430] 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) was added a solution of T3P (50 wt% in EtOAc, 500 μL, 0.841 mmol), and the mixture was stirred for 3.5 hours. At this time, the mixture was quenched with saturated aqueous sodium bicarbonate solution (3 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were concentrated in the presence of silica gel and analyzed by chromatography (silica gel, 0-50% EtOAc: heptane). The product-containing fractions were combined and concentrated to give the title compound (C59) (153 mg, 81%) as a white solid. LCMS m / z 431.0 [M+H] +

[0431] Step 2: Preparation of (2S,4S)-4-[(2-bromo-4-chloro-phenyl)-[(4-methoxyphenyl)methyl]carbamoyl]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (C60)

[0432] 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.

[0433] After stirring for 10 minutes, PMB-Br (600 μL, 4.12 mmol) was added, and after stirring for another 10 minutes, the reaction was warmed to room temperature and stirred for 18 hours. At this time, the reaction was quenched with saturated sodium bicarbonate aqueous solution (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with Na 2 SO 4 Dried, filtered, and concentrated. The crude material was dissolved in SiO2 and loaded onto a silica gel column for purification (0-50% EtOAc in heptane). Product-containing fractions were combined and concentrated, and then purified for an additional time to afford the title compound (C60) (797 mg, 60%) as a white solid. 1 H NMR (300 MHz, CDCl 3)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,1H),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] +

[0434] Step 3: Preparation of (2'S)-5-chloro-1-[(4-methoxyphenyl)methyl]-2'-methyl-2-oxo-spiro[indoline-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (C61)

[0435] A mixture of C60 (200 mg, 0.36 mmol), racemic BINAP Pd G3 (36 mg, 0.0363 mmol) and sodium tert-butoxide (104 mg, 1.08 mmol) was purged with N2 for 15 min, at which time dioxane (3.6 mL) was added and the mixture was heated to 100 °C and stirred for 16 h. At this time, the mixture was washed with saturated NaHCO 3 (5 mL) and the solution was quenched and extracted with EtOAc (4×5 mL). The combined organic layers were washed with Na 2 SO 4 Dry, filter, and concentrate. The crude material was purified by silica gel column chromatography (0-30% EtOAc / heptane) to give the product at 1.8:1 dr. The title compound (C61) (153 mg, 88%) was isolated as a clear oil. LCMS m / z 471.18 [M+H] +

[0436] Step 4: Preparation of (2'S,3R)-5-chloro-2'-methylspiro[indoline-3,4'-piperidin]-2-one (C62)

[0437] 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 hour, and then heated to 80 ° C for 1 hour. At this time, trifluoromethane (34 μL, 0.384 mmol) was added and the mixture was stirred for 18 hours. At this time, the reaction was cooled to room temperature and quenched with saturated sodium bicarbonate aqueous solution (2 mL) and extracted with DCM (4×2 mL). The combined organic layer was purified by Na 2 SO 4 Dried, filtered, and concentrated. The crude material was purified by silica gel column chromatography (0-20% MeOH:DCM), and the product-containing fractions were combined and re-purified as above. The title compound (C62) (4.5 mg, 21%) was isolated as a clear oil. 1 H NMR (300 MHz, CDCl 3 )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 / z251.11[M+H] +

[0438] 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)

[0439] 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 minutes. At this time, the mixture was quenched with saturated aqueous sodium bicarbonate (1 mL) and extracted with DCM (8×1 mL). The combined organic layers were washed with Na 2 SO 4Dry, filter and concentrate. The crude material was purified by silica gel column chromatography (0-100% 3:1 EtOAc / EtOH:heptane). The product containing fractions were combined and 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] +

[0440] Using intermediate C65 with commercial aldehyde and modified intermediates available to those skilled in the art of organic chemistry, the reaction is carried out by, for example, S N 2. Chemical transformations such as silylation and desilylation were used to prepare compounds 75-76 in a similar manner.

[0441] Table 9: Compounds 75-76

[0442]

[0443]

[0444] Compound 77

[0445] 5-Chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one trifluoroacetic acid (77)

[0446]

[0447] Step 1: Preparation of 4-[(2-bromo-4-chloro-phenyl)carbamoyl]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (C63)

[0448] To a solution of 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, 2 M, 17.60 mmol). At this point, a drop of DMF was added, and the mixture was stirred at room temperature for 2 hours. At this point, 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 warmed to room temperature and stirred for 18 hours. At this point, EtOAc (300 mL) was added, and the organic layer was washed with brine (300 mL), cold 1 M HCl (2×300 mL), NaHCO 3 (300 mL) and brine (300 mL). The organic layer was washed with Na 2 SO 4Dried and concentrated over silica gel and loaded onto a silica gel column for purification (0-50% EtOAc:heptane) to give the title compound (C63) (1.47 g, 41%) as a white solid. 1 HNMR (300MHz, chloroform-d) δ8.31(d,J=8.9Hz,1H),7.68(s,1H),7.56(d,J=2.4Hz,1H),7.31(dd,J=8.9,2.4Hz,1H),4.13(q,J=6.8Hz,1H),3.98-3 .79(m,1H),3.28-3.04(m,1H),2.61(dtd,J=9.1,7.3,4.4Hz,1H),2.21-1.90(m,3H),1.90-1.65(m,1H),1.49(s,9H),1.19(d,J=6.5Hz,3H). LCMS m / z 431.08[M+H] +

[0449] Step 2: Preparation of 5-chloro-2'-methyl-2-oxo-spiro[indoline-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (C64)

[0450] To C63 (107 mg, 0.245 mmol), Pd 2 dba 3 To a suspension of 4-(21 mg, 0.0365 mmol) and racemic BINAP (46 mg, 0.074 mmol) in dioxane (3 mL) was added sodium tert-butoxide (71 mg, 0.74 mmol) and the reaction was heated to 170 °C for 2 hours. At this time, the crude mixture was adsorbed onto silica gel and loaded onto a silica gel column for purification (0-50% EtOAc: heptane). The product-containing fractions were combined and concentrated to give 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) δ9.05 (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] +

[0451] Step 3: Preparation of 5-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidin]-2-one (77)

[0452] To a mixture of C64 in MeOH (2 mL) was added dioxane containing HCl (1 mL, 4 M, 4.00 mmol), and the solution was heated to 50 ° C for 1 hour. At this time, the mixture was evaporated. C4 (48 mg, 0.204 mmol), DCE (4 mL), AcOH (35 μL, 0.616 mmol) and sodium triacetoxyborohydride (64 mg, 0.303 mmol) were added to the crude solid, and the reaction was stirred at room temperature for 12 hours. At this time, additional sodium triacetoxyborohydride (32 mg, 0.150 mmol) was added, and the mixture was heated to 60 ° C for 3 hours. At this time, the mixture was concentrated to dryness, diluted in 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 / water, containing 0.1% trifluoroacetic acid). The product containing fractions were combined 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),4.2 3(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] +

[0453] During step 1, compounds 78 and 79 were prepared in a manner similar to compound 77 using alternative anilines.

[0454] Table 10: Compounds 78 and 79

[0455]

[0456] Compound 80

[0457] (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)

[0458]

[0459] Step 1: Preparation of 4-[(2-bromo-4-chloro-phenyl)carbamoyl]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (C63)

[0460] See the procedure for the preparation of intermediate C63 in the preparation of compound 77 above.

[0461] Step 2: Preparation of 4-[(2-bromo-4-chloro-phenyl)-methyl-carbamoyl]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (C67)

[0462] To a solution of C63 (310 mg, 0.711 mmol) and MeI (135 μL, 2.17 mmol) in 4 ml THF was added NaH (90 mg, 60% w / w, 2.25 mmol), 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). The product-containing fractions were combined and concentrated to give the title compound (C67) (294 mg, 89%) as a yellow oil. LCMS m / z 445.08 [M+H] +

[0463] Step 3: Preparation of (2'S,3R)-5-chloro-1,2'-dimethyl-spiro[indoline-3,4'-piperidin]-2-one (68)

[0464] C67 (285 mg, 0.615 mmol), Pd 2 dba 3To a suspension of (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 hours. At this time, the reaction was concentrated and diluted with 3 ml of MeOH and HCl (3 mL, 4 M, 12.00 mmol) in dioxane, and the reaction was heated to 50 °C for 40 minutes. The mixture was concentrated and diluted in DMSO (1 mL) and loaded onto a C18 column for reverse phase purification (10%-100% MeCN:water, 0.1% TFA modifier). The product containing fractions were concentrated and diluted in HCl dioxane to give the HCl salt. Title compound (C68) hydrochloride (49.9 mg, 25%) 1 H NMR (300 MHz, chloroform-d) δ 7.41-7.25 (m, 2H), 7.01 (dd, J = 8.2, 0.5 Hz, 1H), 4.13 (h, J = 6.8 Hz, 1H), 3.96-3.80 (m, 1H), 3.39 (ddd, J = 12.7, 4.6, 2.0 Hz, 1H), 3.31 (p, J = 1.7 Hz, 3H), 2.17 (ddd, J = 14.9, 13.6, 4.6 Hz, 1H), 2.06-1.89 (m, 3H), 1.34 (d, J = 6.6 Hz, 3H). LCMS m / z 265.01 [M+H] + Retention time: 0.61 min. Final purity was determined by reverse phase UPLC using Acquity UPLC Acquity CSHC18 manufactured by Waters (2.1 x 50 mm, 1.7 μm particles) and a dual gradient run from 5% to 95% mobile phase B in 0.6 min. Mobile phase A = H 2 O(0.1% CF 3 CO 2 H). Mobile phase B = CH3CN (0.1% CF 3 CO 2 H). Flow rate = 0.6 mL / min, injection volume = 2.0 μL.

[0465] 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)

[0466] To a solution of C68 (12 mg, 0.037 mmol) in 2 ml of DCE was added C4 (20 mg, 0.085 mmol). After 5 minutes, sodium triacetoxyborohydride (28 mg, 0.133 mmol) was added and the mixture was stirred at room temperature for 14 hours. At this time, the mixture was evaporated, diluted in 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 / water with 0.1% trifluoroacetic acid). The product containing fractions were combined and concentrated to give the title compound (80) trifluoroacetate salt (4.9 mg, 22%) LCMS m / z 451.09 [M+H] +

[0467] Compounds 81 to 87 were prepared in a manner analogous to compound 80 utilizing an alternative aniline in step 1 and an alternative piperidine.

[0468] Table 11: Compounds 81-87

[0469]

[0470]

[0471]

[0472] Compound S1

[0473] (1R,2'S)-7-Chloro-2'-methyl-spiro[isochromane-1,4'-piperidine](S1)

[0474]

[0475] Step 1. Synthesis of (1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidin]-6-ol (C85)

[0476] A solution of (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester C83 (9.21 g, 38.00 mmol) in DCM (125 mL) was cooled to approximately 6 ° C with an ice bath. Methanesulfonic acid (10.8 mL, 166.4 mmol) was added in 4 portions over a 5-minute process. After the addition was complete, the reaction was warmed with a water bath at 35 ° C, and then the bath was removed, and the reaction was stirred at room temperature for 15 minutes. The internal vacuum was drawn for 2 minutes to remove any residual isobutylene. 2-chloro-5-(2-hydroxyethyl)phenol C84 (7 g, 40.55 mmol) was added to this solution, and the reaction mixture was warmed to 36 ° C with the aid of a heating jacket. The reaction was stirred at this temperature under a reflux condenser for 15 hours. The reaction was warmed to ambient temperature, poured into a 1L conical flask, and cooled on a brine / ice bath while stirring. 6M NaOH was slowly added until the pH was adjusted to 9. A white colorless precipitate was formed. Stirring was continued under ice-cold conditions for 30 minutes. The solid was filtered, air-dried, and then vacuum-dried to give (1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-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] + .

[0477] Step 2. Synthesis of (1R,2'S)-7-chloro-6-hydroxy-2'-methyl-spiro[isochromane-1,4'-piperidinyl]-1'-carboxylic acid tert-butyl ester (C86)

[0478] To a solution of (1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidin]-6-ol C85 (3.6 g, 12.77 mmol) in DCM (45 mL) was added Boc 2 O (2.9 g, 13.29 mmol), and then sodium bicarbonate (33 mL, 1.8 M, 59.40 mmol) was added and stirred at room temperature for 16 hours. The aqueous layer was extracted with DCM (50 ml) through a phase separator and then back-extracted three times with DCM (50 mL) each time. The combined organic extracts were washed with brine and purified by Na 2 SO 4Dry, filter, and concentrate under vacuum to give the crude product (1R,2'S)-7-chloro-6-hydroxy-2'-methyl-spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester C86 (4.8 g, 97%) LCMS m / z 268.03 [M-100+H] + .

[0479] Step 2. Synthesis of tert-butyl (1R,2'S)-7-chloro-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochromane-1,4'-piperidine]-1'-carboxylate (C87)

[0480] To a suspension of (1R,2'S)-7-chloro-6-hydroxy-2'-methyl-spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester C86 (5.7 g, 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, 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 hours. 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 2M HCl. Extracted with DCM (3×50 ml). The combined organic extracts were washed with brine and purified by Na 2 SO 4 Dried, filtered, and concentrated in vacuo to give the crude material as a gummy solid. The crude was purified by silica gel chromatography using 0 to 50% ethyl acetate / heptane to give (1R,2'S)-tert-butyl 7-chloro-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochromane-1,4'-piperidine]-1'-carboxylate C87 (7.9 g, 97%) 1 H NMR (400 MHz, chloroform-d) δ 7.44-7.27 (m, 2H), 7.21 (s, 1H), 7.08 (s, 1H), 4.03 (ddd, J = 11.7, 6.8, 5.4 Hz, 1H), 3.94-3.74 (m, 3H), 3.38 (ddd, J = 14.3, 9.4, 5.3 Hz, 1H), 2.89-2.67 (m, 2H), 2.15 (dddd, J = 15.6, 9.4, 6.2, 1.7 Hz, 1H), 2.08-1.98 (m, 1H), 1.89-1.69 (m, 3H), 1.51 (s, 9H), 1.28 (d, J = 6.5 Hz, 4H). LCMS m / z 400.05 [M-Boc+H] + .

[0481] Step 4. Synthesis of (1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (C88)

[0482] To a suspension of (1R,2'S)-7-chloro-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester C87 (375 mg, 0.7501 mmol) in DMF (7 mL) was added Pd(dppf)Cl 2 (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 hours. 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 purified by Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude material was purified by silica gel chromatography eluting with 0-30% EtOAc / heptane to give (1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester C88 (270 mg, 97%) 1 H NMR (400 MHz, CHLOROFORM-d) δ7.13 (dd, J = 8.1, 2.1 Hz, 1H), 7.07-6.99 (m, 2H), 4.02 (ddd, J = 11.7, 6.7, 5.4 Hz, 1H), 3.92-3.74 (m, 3H), 3.39 (ddd, J = 14.3, 9.4, 5.3 Hz, 1H), 2.87-2.66 (m, 2H), 2.14 (dddd, J = 15.5, 9.4, 6.1, 1.7 Hz, 1H), 2.02 (ddd, J = 14.2, 5.2, 1.7 Hz, 1H), 1.93-1.74 (m, 2H), 1.52 (s, 9H), 1.28 (d, J = 6.5 Hz, 3H). LCMS m / z 252.06[M-Boc+H] + .

[0483] Step 5. Synthesis of (1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidine] (S1)

[0484] To (1R, 2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester C88 (4 g, 10.80 mmol) was added hydrochloric acid (45 mL, 4M, 180.0 mmol) 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 dried under vacuum to give the white HCl salt (1R, 2'S)-7-chloro-2'-methyl-spiro[isochromane-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] + .

[0485] Preparation of S2

[0486] ((1R,2'S)-7-Chloro-2'-methyl-spiro[isochromane-1,4'-piperidin]-4-ol (S2)

[0487]

[0488] Steps 1 and 2. Synthesis of (1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidin]-4-ol (S2)

[0489] To a solution of (1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidine](HCl salt) S1 (50 mg, 0.1735 mmol) in acetonitrile (430 μL) and water (1.3 mL) was added ammonium bisulfate (80 mg, 0.3506 mmol) and Mn(OAc) 2 (13.7 mg, 0.07918 mmol). The reaction was stirred at 70 °C for 16 hours. Cooled to room temperature and concentrated in vacuo. The crude material was carried over to the material as a mixture of ketone C89 and alcohol S2 without further purification. To the crude mixture was added methanol (2.7 mL), NaBH4 (7.9 mg, 0.2088 mmol) and stirred at 23°C with the needle outlet open to the air 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 microns. Gradient: acetonitrile / water with 0.2% formic acid) to give S1 as a formate salt (20.70 mg, 89%) LCMS m / z 268.23 [M+H] + .

[0490] Preparation of S3

[0491] (1R,2'S)-7-Chloro-4,4-difluoro-2'-methyl-spiro[isochromane-1,4'-piperidine](S3)

[0492]

[0493] Step 1. Synthesis of 1-[(1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidinyl]-1'-yl]-2,2,2-trifluoroethanone (C90)

[0494] To a solution of (1R, 2'S)-7-chloro-2'-methyl-spiro[isochromane-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 hours. The crude reaction was diluted with DCM (3 ml) and quenched with 3 ml of saturated ammonium chloride. A phase separator was used to extract with DCM (3×10 ml). The organic layer was washed with 1.5 ml of 1M HCl, followed by 1 ml of water and 1.5 ml of brine. The organic matter 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 / heptane to give a clear gum 1-[(1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone C90 (362 mg, 77%) LCMS m / z 348.15 [M+H] + .

[0495] Step 2. Synthesis of 1-[(1R,2'S)-7-chloro-4-hydroxy-2'-methyl-spiro[isochromane-1,4'-piperidinyl]-1'-yl]-2,2,2-trifluoroethanone (C91)

[0496] To a solution of 1-[(1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone C90 (1.77 g, 5.090 mmol) in water (31.5 mL) and acetonitrile (11 mL) was added ammonium bisulfate (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 (3×25 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 / heptane to afford C91(1R,2'S)-7-chloro-2'-methyl-1'-(2,2,2-trifluoroacetyl)spiro[isochromane-1,4'-piperidin]-4-one (1.58 g, 85%) as a light yellow solid. LCMS m / z 362.05 [M+H] + .

[0497] Step 3. Synthesis of 1-[(1R,2'S)-7-chloro-4,4-difluoro-2'-methyl-spiro[isochromane-1,4'-piperidinyl]-1'-yl]-2,2,2-trifluoroethanone (C92)

[0498] DAST (200 μL, 1.514 mmol) was added to (1R, 2'S)-7-chloro-2'-methyl-1'-(2,2,2-trifluoroacetyl)spiro[isochromane-1,4'-piperidin]-4-one C91 (30.2 mg, 0.08348 mmol) sequentially over 3 days and stirring was continued at 40 °C for 3 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[isochromane-1,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone C92 without further purification.

[0499] Step 4. Synthesis of (1R,2'S)-7-chloro-4,4-difluoro-2'-methyl-spiro[isochromane-1,4'-piperidine] (S3)

[0500] To a solution of 1-[(1R,2'S)-7-chloro-4,4-difluoro-2'-methyl-spiro[isochromane-1,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone C92 in methanol (1 ml) was slowly added NaOH (600 μL, 2M, 1.200 mmol) at 0°C. The reaction was allowed to warm to ambient temperature for 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 Preparative C8 column; 30×150 mm, 5 microns. Gradient: acetonitrile / water with 10 mM ammonium hydroxide) to give (1R,2'S)-7-chloro-4,4-difluoro-2'-methyl-spiro[isochromane-1,4'-piperidin] S3 as a white solid (10.2 mg, 41%) 1 H NMR (300 MHz, chloroform-d) δ7.66 (d, J = 8.4 Hz, 1H), 7.51-7.29 (m, 2H), 4.11 (t, J = 10.6 Hz, 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] + .

[0501] Compound S4

[0502] (1R,2'S,4S)-7-Chloro-2'-methyl-spiro[isochromane-1,4'-piperidinyl]-4-ol (S4)

[0503]

[0504] Steps 1 and 2. Synthesis of (1R,2'S,4S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidin]-4-ol (S4).

[0505] To a premixed 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 premixed solution of triethylamine:formic acid (240 μL, 0.5716 mmol). The solution turned bright red and some slight effervescence was observed. After 10 minutes, the mixture was cooled to 0 °C and treated with a solution of (1R,2'S)-7-chloro-2'-methyl-1'-(2,2,2-trifluoroacetyl)spiro[isochromane-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 warmed to room temperature within 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[isochromane-1,4'-piperidin]-1'-yl]-2,2,2-trifluoroethanone C93 in methanol (6.9 mL) was added NaOH (950 μL, 2M, 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 micron. Gradient: acetonitrile / water with 0.2% formic acid) to give the formate salt of (1R,2'S,4S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidin]-4-ol S4 (78 mg, 65%, >99:1 dr) 1R,2'S,4S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidin]-4-ol (formic acid (1)) (78 mg, 65%) as a white solid 1 H 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] + .

[0506] It should be noted that the stereochemistry of alcohol S4 was assigned based on literature understanding of reduction using this catalyst and ligand system. (Reference: New Chiral Rhodium and Iridium Complexes with Chiral Diamine Ligands for Asymmetric Transfer Hydrogenation of Aromatic Ketones. Kunihiko Murata, Takao Ikariya and Ryoji Noyori. The Journal of Organic Chemistry 1999 64(7), 2186-2187).

[0507] Preparation of S5

[0508] (1R,2'S)-7-Chloro-2'-methyl-1'-prop-2-ynyl-spiro[isochromane-1,4'-piperidine](S5)

[0509]

[0510] To a solution of (1R, 2'S)-7-chloro-2'-methyl-spiro[isochromane-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 minutes. 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 / DCM to afford (1R,2'S)-7-chloro-2'-methyl-1'-prop-2-ynyl-spiro[isochromane-1,4'-piperidine] S5 as a white solid (137.8 mg, 86%) 1H NMR (400MHz, chloroform-d) δ7.20(d,J=2.1Hz,1H),7.13(dd,J=8.2,2.1Hz,1H),7.04(d,J =8.2Hz,1H),4.03-3.83(m,2H),3.69(dd,J=17.3,2.4Hz,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),2.08-1.9 6(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] + .

[0511] Preparation of S6

[0512] 5-Methylspiro[isochromane-1,4'-piperidine](S6)

[0513]

[0514] Step 1. Synthesis of 5-methylspiro[isochromane-1,4'-piperidine]

[0515] TFA (2.5 mL) was added to a solution of 2- (o- tolyl) ethanol C94 (410 mg, 2.4084 mmol) and tert-butyl 4-oxopiperidin-1-carboxylate C95 (576 mg, 2.8331 mmol) in DCM (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 trifluoromethane (678.16 mg, 0.4 mL, 4.4284 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with 1M NaOH (150 ml), and the aqueous layer was extracted with ethyl acetate (250 × 2 ml). The combined organic extracts were purified by Na 2 SO 4 Dry, filter and concentrate in vacuo to give 5-methylspiro[isochromane-1,4'-piperidine]S6 as a yellow gum (350 mg, 16%) LCMS m / z 218.21 [M+H] + .

[0516] Preparation of S7

[0517] 7-Chlorospiro[isochromane-1,4'-piperidinyl]S7

[0518]

[0519] Step 1. Synthesis of 2-(2-bromo-4-chloro-phenyl)ethoxy-tert-butyl-dimethyl-silane C97

[0520] To a solution of 2-(2-bromo-4-chloro-phenyl)ethanol C96 (1860 mg, 7.898 mmol) in DCM (16 mL), TBSCl (1.80 g, 11.94 mmol) and imidazole (1.08 g, 15.86 mmol) were added. The resulting white slurry was stirred at room temperature for 2.5 hours. The reaction was diluted with DCM and quenched with 1MN 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 / heptane to obtain a colorless oil 2-(2-bromo-4-chloro-phenyl)ethoxy-tert-butyl-dimethyl-silane C97 (2738 mg, 99%). 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.54 (d, J = 1.6 Hz, 1H), 7.20 (d, J = 1.8 Hz, 2H), 3.80 (t, J = 6.7 Hz, 2H), 2.93 (t, J = 6.7 Hz, 2H), 0.86 (s, 9H), -0.03 (s, 6H).

[0521] Step 2. Synthesis of 4-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-phenyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester C98

[0522] 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, 2.3 M, 42.886 mmol) dropwise at -78 °C and stirred for 4 hours. The reaction mixture was washed with saturated NH 4 Cl solution (200mL) is diluted and allowed to warm to room temperature. The reaction mixture is extracted with ethyl acetate (3×250ml). The organic layer is washed with water (200mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material is purified by silica gel chromatography using 0-40% ethyl acetate / heptane to obtain 4-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-phenyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester C98 (4g, 30%) LCMS m / z 470.00[M+H] + .

[0523] Step 3. Synthesis of tert-butyl 4-[5-chloro-2-(2-hydroxyethyl)phenyl]-4-hydroxy-piperidine-1-carboxylate C99

[0524] To a solution of 4-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-phenyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester C98 (4 g, 8.5085 mmol) in THF (10 mL) at room temperature, TBAF (12.763 mL, 1 M, 12.763 mmol) was added and the reaction was stirred 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 / heptane to obtain 4-[5-chloro-2-(2-hydroxyethyl)phenyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 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] + .

[0525] Step 4. Synthesis of tert-butyl 7-chlorospiro[isochromane-1,4'-piperidinyl]-1'-carboxylate C100

[0526] Triethylamine (853.08 mg, 1.1750 mL, 8.4305 mmol) and methanesulfonyl chloride (579.44 mg, 0.3915 mL, 5.0583 mmol) were added to a solution of 4-[5-chloro-2-(2-hydroxyethyl)phenyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester C99 (1.2 g, 3.3722 mmol) in DCM (30 mL). 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 × 2). The organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude material 7-chlorospiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester C100 (650 mg, 57%) LCMS m / z 338.00 [M+H]+ .

[0527] Step 5. Synthesis of 7-chlorospiro[isochromane-1,4'-piperidine]S7

[0528] To a solution of tert-butyl 7-chlorospiro[isochromane-1,4'-piperidine]-1'-carboxylate C100 (1 g, 2.960 mmol) in dioxane (23 ml) was added HCl (7.4 mL, 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[isochromane-1,4'-piperidine] S7 (700 mg, 70%) LCMS m / z 238.44 [M+H] + .

[0529] Preparation of S8

[0530] Chlorospiro[isochromane-1,4'-piperidine](S6)

[0531]

[0532] Synthesis of Spiro[isochromane-1,4'-piperidine]S8

[0533] The compound was prepared following the procedure described for compound S7 using commercially available C101. The reaction was evaporated to give spiro[isochromane-1,4'-piperidine] S8 as a white HCl salt (985 mg, 89%) 1 H 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] + .

[0534] Preparation of S9

[0535] 6-Methoxyspiro[isochromane-1,4'-piperidine](S9)

[0536]

[0537] Synthesis of 6-methoxyspiro[isochromane-1,4'-piperidine](S9)

[0538] The compound was prepared using commercially available C106 as described for compound S7. The reaction mixture was concentrated under reduced pressure. Saturated Na 2 CO 3 The solution was diluted with cold (50 mL) to maintain pH 10 and extracted with DCM (50 mL×2). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6-methoxyspiro[isochromane-1,4′-piperidine] S9 (120 mg, 65%) LCMS m / z 234.17 [M+H] + .

[0539] Preparation of S10

[0540] 7-(Trifluoromethyl)spiro[isochromane-1,4'-piperidine](S10)

[0541]

[0542] Synthesis of 7-(Trifluoromethyl)spiro[isochromane-1,4'-piperidine]S10

[0543] 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[isochromane-1,4'-piperidine]S10 (110 mg, 41%) as a trifluoroacetate salt. LCMS m / z 272.00 [M+H] + .

[0544] Preparation of S11

[0545] 7-Chlorospiro[isochromane-1,4'-piperidinyl]-4-ol (S11)

[0546]

[0547] Step 1. Synthesis of tert-butyl 4-(2-bromo-5-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (C118)

[0548] 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) was added Pd(dppf)Cl 2 (1.2 g, 1.640 mmol), K 2 CO 3(6.7g, 48.48mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester C117 (5000mg, 16.17mmol). Nitrogen was bubbled by stirring the reaction mixture for 15 minutes. The reaction mixture was then stirred for 16 hours at 80°C. The reaction was warmed to room temperature, quenched with water (25ml), extracted with ethyl acetate (3×25ml), and washed with brine (75ml). 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 0-15% ethyl acetate / heptane to give the product 4-(2-bromo-5-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester C118 (4.42g, 71%) as a yellow oil 1 H NMR (300MHz, chloroform-d) δ7.49(d,J=8.5Hz,1H),7.18(d,J=2.6Hz,1H),7.12(dd,J=8.4,2.6Hz, 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] + .

[0549] Step 2. Synthesis of 4-(2-bromo-5-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (C119)

[0550] To a solution of 4-(2-bromo-5-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester C118 (500 mg, 1.342 mmol) in THF (10 mL) under oxygen was added Co(acac) 2 (38 mg, 0.2147 mmol), followed by the addition of PhSiH 3 The mixture was stirred for 1 day at 4 °C for 2 hours at 4 °C for 3 hours at 5 °C for 1 hour. The mixture was stirred for 1 day at 4 °C for 2 hours at 5 °C for 3 hours at 5 °C for 1 hour at 5 °C for 2 hours. The mixture was stirred for 1 day at 4 °C for 2 hours at 5 °C for 3 hours at 5 °C for 1 hour at 5 °C for 3 hours ...2 hours. The mixture was stirred for 1 day at 4 °C for 2 hours at 5 ° 1H 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).

[0551] Step 3. Synthesis of 4-(5-chloro-2-vinyl-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (C120)

[0552] To a solution of 4-(2-bromo-5-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester C119 (2000 mg, 5.119 mmol) in toluene (30 mL) under nitrogen was added tributyl(vinyl)thiophene (2.5 mL, 8.554 mmol) and Pd(PPh 3 ) 4 The product was purified by HPLC-MS / MS (10% by volume, 1% by weight). The product was quenched with 4-(5-chloro-2-vinyl-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 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).

[0553] Step 4. Synthesis of tert-butyl 7-chloro-4-hydroxy-spiro[isochromane-1,4'-piperidinyl]-1'-carboxylate (C121)

[0554] To a solution of 4-(5-chloro-2-vinyl-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (315 mg, 0.9324 mmol) in DCM (5 mL) was added mCPBA (270 mg, 1.173 mmol). The reaction was stirred for 16 hours. It was quenched with 1M NaOH, extracted with DCM (2×10 ml) on a PTFE glass frit, and injected directly on a silica gel column. It was eluted with 0-60% ethyl acetate / heptane to obtain 7-chloro-4-hydroxy-spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester C121 (200 mg, 61%) 1 HNMR (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,2H ), 1.86 (td, J = 13.2, 5.0 Hz, 1H), 1.65 ( q, J = 11.1, 9.2 Hz, 3H), 1.42 ( s, 9H). LCMS m / z 353.73[M+H] + .

[0555] Step 5. Synthesis of 7-chlorospiro[isochromane-1,4'-piperidinyl]-4-ol S11

[0556] To a solution of 7-chloro-4-hydroxy-spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (25 mg, 0.07065 mmol) in dioxane (1 mL) was added HCl (250 μL, 4 M, 1.000 mmol) and stirred for 3 hours. The crude reaction was purified by reverse phase HPLC (method: C18 Waters Sunfire column (30×150 mm, 5 microns), gradient: MeCN / H 2 O, containing 0.1% trifluoroacetic acid) to give 7-chlorospiro[isochromane-1,4′-piperidin]-4-ol S11 as a trifluoroacetate salt (17 mg, 62%) 1HNMR(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] + .

[0557] Compound S12

[0558] (2'S)-7-Chloro-2'-methyl-spiro[isochromane-1,4'-piperidine](S12)

[0559]

[0560] Step 1. Synthesis of 2-(4-chloro-3-nitro-phenyl)acetic acid C123

[0561] 2-(4-Chlorophenyl)acetic acid C122 (10 g, 0.0586 mol) was dissolved in H at 0 °C. 2 SO 4 Potassium nitrate (6.6 g, 0.0646 mol) was added in batches to a solution in (50 mL) and stirred for 2 hours. The progress of the reaction was monitored by TLC with 50% ethyl acetate / hexane (0.4 rf). After completion, the reaction mass was poured into ice-cold water (500 mL), the solid was filtered, washed with water and dried under reduced pressure to obtain an off-white solid 2-(4-chloro-3-nitro-phenyl)acetic acid C123 (10 g, 71%) 1 H NMR (400 MHz, CDCl 3 )δ7.82(s,1H),7.52(d,J=8.0Hz,1H),7.46-7.43(m,1H),3.72(s,2H).

[0562] Step 2. Synthesis of 2-(4-chloro-3-nitro-phenyl)ethanol C124

[0563] 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 BH 3The product was stirred for 2 hours at 4 ℃ for 15 minutes.Then the mixture was stirred for 2 hours at 4 ℃ for 3 hours.(Solution in THF) (55.700mL, 1M, 0.0557mol).The reaction was heated at 60 ℃ for 16 hours.The reaction was cooled to ambient temperature, quenched with 1M HCl (50ml), added with water (250ml) and extracted with ethyl acetate (2×300ml).The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure.The crude product was purified using silica gel chromatography using 0-20% ethyl acetate / petroleum ether to obtain yellow oil 2-(4-chloro-3-nitro-phenyl)ethanol C124 (7g, 92%) (400MHz, CDCl 3 ), δppm 7.77(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).

[0564] Step 3. Synthesis of 2-(3-amino-4-chloro-phenyl)ethanol C125

[0565] Fe (503 mg, 0.0090 mol) was added to a solution of 2- (4- chloro-3-nitro-phenyl) ethanol C124 (420 mg, 0.0015 mol) in acetic acid (5.0 mL) 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 / 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), 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 / hexane to obtain 2- (3-amino-4-chloro-phenyl) ethanol C125 (200 mg, 76%) 1 H NMR (400 MHz, CDCl 3 )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 / z172.13[M+H] + .

[0566] Step 4. Synthesis of (2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidinyl]-6-amine C126

[0567] To a solution of 2-(3-amino-4-chloro-phenyl)ethanol C125 (100 mg, 582.67 μmol) in toluene (1.5 mL) at ambient temperature was added (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester C1 (149.12 mg, 699.20 μmol), followed by BF 3 .OET 2 (411.59 mg, 0.3642 mL, 0.0029 mol). The reaction was stirred at 120 °C for 16 hours. The reaction was concentrated under reduced pressure and 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[isochromane-1,4'-piperidin]-6-amine C126 (150 mg, 49%) LCMS m / z 267.00 [M+H] + .

[0568] Step 6. Synthesis of (2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidine]S12

[0569] To a solution of (2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidin]-6-amine C126 (50 mg, 129.33 μmol) in HCl (3.0000 mL, 2 M, 0.0060 mol) was added NaNO at ambient temperature 2 (11.896 mg, 129.33 μmol), then cooled to 0 ° C. Fluoroboric acid (0.0341 mL, 50% w / v, 194.00 μmol) was slowly added at 0 ° C, and the reaction was warmed to ambient temperature and stirred for 16 hours. 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[isochromane-1,4'-piperidine] 3 (25 mg, 28%) LCMS m / z 252.00 [M + H] + .

[0570] Preparation of S13

[0571] 7-Chloro-3'-methylspiro[isochromane-1,4'-piperidine](S13)

[0572]

[0573] Step 2. Synthesis of 4-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-phenyl]-4-hydroxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester C128

[0574] t-BuLi (2.0588mL, 1.7M, 0.0035mol) was slowly added to a solution of 2-(2-bromo-4-chloro-phenyl)ethoxy-tert-butyl-dimethyl-silane C97 (1g, 0.0029mol) in THF (15.000mL) at -100°C in 10 minutes. The reaction was stirred at -100°C for 30 minutes, and then 3-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester C127 (746.46mg, 0.0035mol) (in 1ml THF) was slowly added at -100°C in 15 minutes. 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 (20ml) and extracted with ethyl acetate (2×100ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-phenyl]-4-hydroxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester C128 (1.5 g, 31%) LCMS m / z 484.00 [M+H] + .

[0575] Step 3. Synthesis of 7-chloro-3'-methyl-spiro[isochromane-1,4'-piperidine]S13

[0576] To a solution of 4-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-chloro-phenyl]-4-hydroxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester C128 (100 mg, 206.55 μmol) in toluene (1.5 mL) was added BF 3. OE 2 (298.05 mg, 0.2638 mL, 0.0021 mol), the reaction was then stirred at ambient temperature for 16 hours while being 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 (2×100 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 7-chloro-3'-methyl-spiro[isochromane-1,4'-piperidine] S13 (40 mg, 42%) LCMS m / z 252.00 [M+H] + .

[0577] Compound S14

[0578] (2'S)-2'-Methylspiro[isochromane-1,4'-piperidine](S14)

[0579]

[0580] Compound S14 was prepared from compound C13 following the procedure described for compound S1. The crude reaction was purified by reverse phase HPLC (method: Waters XSelect CSH C18 OBD preparative column; 30×150 mm, 5 microns. Gradient: acetonitrile / water with 5 mM hydrochloric acid) to afford (2′S)-2′-methylspiro[isochromane-1,4′-piperidine] S14 (26 mg, 47%) as an 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 (dd, 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] + .

[0581] Preparation of C136 and C137

[0582] (1R,2'S)-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (C136) and (1S,2'S)-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (C137)

[0583]

[0584] Synthesis of tert-butyl (1R,2'S)-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochromane-1,4'-piperidine]-1'-carboxylate (C136) and tert-butyl (1S,2'S)-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochromane-1,4'-piperidine]-1'-carboxylate (C137).

[0585] To a solution of (2'S)-6-hydroxy-2'-methyl-spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester 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), followed by NaOH (8.5 mL, 2M, 17.00 mmol). Stir at room temperature for 16 hours. 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 product was purified using silica gel chromatography using 0-10% ethyl acetate / hexane to obtain two diastereomers. Absolute stereochemistry was confirmed by 1HNMR analysis. (1R,2'S)-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester C136 (425.6 mg, 79%) LCMS m / z 366.01 [M-Boc+H] + and (1S,2'S)-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester C137 (240.8 mg, 42%) LCMS m / z 366.01 [M-Boc+H] +

[0586] Compound S15

[0587] (1R,2'S)-6-Chloro-2'-methyl-spiro[isochromane-1,4'-piperidine](S15)

[0588]

[0589] Steps 1 and 2. Synthesis of (1R,2'S)-6-chloro-2'-methyl-spiro[isochromane-1,4'-piperidine] (S15)

[0590] To (2'S)-2'-methyl-6-(trifluoromethylsulfonyloxy)spiro[isochromane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (307 mg, 0.6595 mmol) was added tBuBrettPhos Pd G3 (59.34 mg, 0.06945 mmol), KCl (127 mg, 1.704 mmol), KF (25.42 mg, 0.4375 mmol) and purged with nitrogen three times. Dioxane (3.4 mL) was added and heated to 130 °C for 24 hours. The reaction was cooled to 23 °C, HCl (4.397 mL, 6M, 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 x 150 mm, 5 micron. Gradient: acetonitrile / water with 10 mM ammonium hydroxide) to afford (1R,2'S)-6-chloro-2'-methyl-spiro[isochromane-1,4'-piperidine] S15 (27 mg, 16%) 1 H NMR (300 MHz, 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 = 7.0 Hz, 3H). LCMS m / z 252.20 [M+H] + .

[0591] Preparation of C140

[0592] (2'S)-2',7-Dimethylspiro[isochromane-1,4'-piperidine](C140)

[0593]

[0594] 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 (2×100 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[isochromane-1,4'-piperidine] C140 (180 mg, 36%) LCMS m / z 232.00 [M+H] + .

[0595] Preparation of compound S16

[0596] 2',7-Dimethylspiro[isochromane-1,4'-piperidine](S16)

[0597]

[0598] Step 1. Synthesis of 5-(2-hydroxyethyl)-2-methyl-phenol (C142)

[0599] To a solution of 2-(3-hydroxy-4-methyl-phenyl)acetic acid C141 (890 mg, 5.356 mmol) in THF (11 mL) was slowly added BH 3 To the 4-thiazolyl-1-yl pyridine-2-ol (5-(2-hydroxyethyl)-2-methyl-phenol C142, 800 mg, 98%) of 5-(2-hydroxyethyl)-2-methyl-phenol C142 was added to 4-thiazolyl-1-ol (1-thiazolyl-1-ol, 800 mg, 98%) of 3 ... 1 H 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] + .

[0600] Step 2. Synthesis of 1'-benzyl-2',7-dimethyl-spiro[isochromane-1,4'-piperidin]-6-ol (C144)

[0601] To a solution of 1-benzyl-2-methyl-piperidin-4-one C142 (150 mg, 0.7379 mmol) and 1-benzylpiperidin-4-one C143 (124 mg, 0.8148 mmol) in dioxane (2.3 mL) was slowly added trifluoroformic acid (221 mg, 1.473 mmol) at 0°C. The reaction was warmed to room temperature and stirred for 2.5 hours. The reaction was heated with saturated NaHCO 3 Quench and extract with DCM (15 ml x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The material was carried as a mixture of diastereomers. 1'-Benzyl-2',7-dimethyl-spiro[isochromane-1,4'-piperidin]-6-ol C61 (310 mg, 125%) LCMS m / z 338.00 [M+H] + .

[0602] Step 3. Synthesis of (1'-benzyl-2',7-dimethyl-spiro[isochromane-1,4'-piperidin]-6-yl) trifluoromethanesulfonate (C145)

[0603] To a solution of 1'-benzyl-2',7-dimethyl-spiro[isochromane-1,4'-piperidin]-6-ol C144 (249 mg, 0.7379 mmol) in DCM (3.7 mL) was added pyridine (134 μL, 1.2587 mmol) followed by trifluoroanhydride (149 μL, 0.8856 mmol) at 0°C. The resulting yellow solution was warmed to room temperature and stirred for 16 hours. The reaction was heated with saturated NaHCO 3 Quench and extract with DCM (8 ml xc3) 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[isochromane-1,4'-piperidin]-6-yl) trifluoromethanesulfonate C145 (346 mg, >99%) LCMS m / z 470.00 [M+H] + .

[0604] Step 4. Synthesis of (cis) 1'-benzyl-2',7-dimethyl-spiro[isochromane-1,4'-piperidine] C146 and (trans) 1'-benzyl-2',7-dimethyl-spiro[isochromane-1,4'-piperidine] C147

[0605] To (1'-benzyl-2',7-dimethyl-spiro[isochromane-1,4'-piperidin]-6-yl) trifluoromethanesulfonate C145 (346 mg, 0.7369 mmol) was added Pd(dppf)Cl 2 (60mg, 0.07347mmol). Purge with nitrogen three times. Under nitrogen, DMF (3.7mL), triethylamine (308μL, 2.210mmol) and formic acid (56μL, 1.484mmol) were added. The resulting solution was stirred at 60°C for 16 hours. The reaction was concentrated under vacuum. The crude material was diluted with DCM (5mL) and quenched with saturated sodium bicarbonate. The organic layer was extracted with DCM (5mL×2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. 20mg of the crude material was purified by reverse phase HPLC (method: C18 Waters Sunfire column (30×150mm, 5 microns), gradient: MeCN / H 2 O, containing 0.1% trifluoroacetic acid) to give cis- and trans-diastereomers C146 and C147 as a mixture of 1'-benzyl-2',7-dimethyl-spiro[isochromane-1,4'-piperidine] (trifluoroacetate) (11.8 mg, 3%) 1H NMR (300 MHz, chloroform-d) δ7.52 (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),2.29 (s, 3H), 2.18 (d, J = 9.9 Hz, 2H), 2.09 (dd, J = 11.5, 4.1 Hz, 2H), 1.61 (d, J = 6.5 Hz, 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 μm), gradient: MeCN / H 2 O, containing 0.1% trifluoroacetic acid) to give the cis- and trans-diastereomers (cis) 1'-benzyl-2',7-dimethyl-spiro[isochromane-1,4'-piperidine] (trifluoroacetate) C146 as trifluoroacetate salt (11.8 mg, 3%) 1 HNMR (300 MHz, chloroform-d) δ7.52 (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, 6.1H z,1H),3.25-3.35(m,1H),3.18(dt,J=12.4,3.5Hz,1H),2.77(q,J=5.3Hz,2H),2.29 (s, 3H), 2.18 (d, J = 9.9 Hz, 2H), 2.09 (dd, J = 11.5, 4.1 Hz, 2H), 1.61 (d, J = 6.5 Hz, 3H). LCMS m / z 322.31[M+H] + and (trans)1'-benzyl-2',7-dimethyl-spiro[isochromane-1,4'-piperidine](trifluoroacetate) C147 (4.1 mg, 1%) 1H NMR (300 MHz, chloroform-d) δ7.61 (dd, J = 6.6, 2.9 Hz, 2H), 7.52 (q, J = 3.4, 2.8 Hz, 3H), 7.02 (d, J = 10.4 Hz, 2H), 6.91 (s, 1H), 4.44-4.28 (m, 2H), 3.92 (dd, J = 6.5, 4.6 Hz, 2H), 3.79 ( 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). LCMSm / z 322.00[M+H] + .

[0606] Step 5. Synthesis of 2',7-dimethylspiro[isochromane-1,4'-piperidine] (S16)

[0607] To a solution of (trans)1'-benzyl-2',7-dimethyl-spiro[isochromane-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 washed with H 2 The mixture was bubbling for 1 minute and then stirred with a balloon under a hydrogen atmosphere for 4 hours. The reaction was filtered through diatomaceous earth, washed with MeOH, and concentrated in vacuo to give a white solid. 14 mg of the crude product was purified by reverse phase HPLC (method: C18 Waters Sunfire column (30×150 mm, 5 microns), gradient: MeCN / H 2 O, containing 0.1% trifluoroacetic acid) to give 4:1 trans:cis 2',7-dimethylspiro[isochromane-1,4'-piperidine]S16 as a trifluoro salt (12.6 mg, 7%) LCMS m / z 232.00 [M+H] + .

[0608] Preparation of S17

[0609] 4-Methylspiro[isochromane-1,4'-piperidine](S17)

[0610]

[0611] 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 reach pH 10, diluted with cold water (50 mL) and extracted with DCM (50 mL x 2). The organic layer was washed with Na 2 SO 4干燥， Filter and concentrate under reduced pressure to give crude 4-methylspiro[isochromane-1,4'-piperidine]S17 (170 mg, 87%) LCMS LCMS m / z 218.2 (M+H) + .

[0612] Preparation of S18

[0613] 1-(2-Methylsulfonylethyl)triazole-4-carbaldehyde (S18)

[0614]

[0615] Synthesis of 1-(2-methylsulfonylethyl)triazole-4-carboxaldehyde (S18)

[0616] To 1-azido-2-methylsulfonyl-ethane C154 (2 g, 0.0134 mol) in MeOH (80.000 mL) and H 2 O (10.000 mL) was added with 3,3-diethoxyprop-1-yne C153 (1.6662 g, 0.0130 mol), (+)-sodium L-ascorbate (2.6348 g, 0.0133 mol) and CuSO 4 (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. The material was suspended in 1 M HCl (80 mL) and stirred at ambient temperature for 24 hours. 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] + .

[0617] Compound 88

[0618] (1R,2'S)-7-Chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isochromane-1,4'-piperidine](88)

[0619]

[0620] Reductive Amination: Standard Method A

[0621] Synthesis of (1R,2'S)-7-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isochromane-1,4'-piperidine](88)

[0622] To a solution of (1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidine]1 (24.4 mg, 0.084 mmol) in 1,2-dichloroethane (1.7 ml) were added 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde S12 (23.7 mg), NaBH(OAc) and 3 (53 mg) and stirred at 80 °C for 16 hours. The reaction was warmed to room temperature, filtered through a plug of silica gel and concentrated. The crude material was purified by reverse phase HPLC (Method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 micron. Gradient: acetonitrile / water with 0.1% trifluoroacetic acid) to give (1R,2'S)-7-chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isochromane-1,4'-piperidine] 88 as a trifluoroacetate salt (28.2 mg, 59%) 1 HNMR (300MHz, chloroform-d) δ8.01 (s, 1H), 7.75 (d, J = 0.8Hz, 1H), 7.28-7.10 (m, 3 H),4.76-4.66(m,2H),4.55(d,J=14.1Hz,1H),4.31(d,J=14.1Hz,1H),3.9 7-3.81(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] + .

[0623] Preparation of compound 89

[0624] 4-Methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isochromane-1,4'-piperidine](89)

[0625]

[0626] Synthesis of 4-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isochromane-1,4'-piperidine](89)

[0627] Reductive Amination: Standard Method B

[0628] To a solution of 4-methylspiro[isochromane-1,4'-piperidine]S17 (300 mg, 1.3805 mmol) in methanol (3 mL) was added 1-methylpyrazole-3-carboxaldehyde C74 (152.01 mg, 1.3805 mmol) and a catalytic amount of acetic acid. After 1 hour, sodium cyanoborohydride (260.26 mg, 4.1415 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with cold water (50 mL) and extracted with DCM (50 mL×2). The organic layer Na 2 SO 4干燥， The crude material was purified by reverse phase HPLC (Waters auto-purification instrument, column name: YMC Triart Actus C18 (250×20 mm, 5 μ), operated at ambient temperature and with a flow rate of 16 ml / min, mobile phase: A=20 mM ammonium bicarbonate / water, B=acetonitrile; gradient profile: mobile phase initial composition is 80% A and 20% B, then 70% A and 30% B in 3 minutes, then 45% A and 55% B in 20 minutes, then 5% A and 95% B in 21 minutes, keep this composition for up to 23 minutes for column washing, then return to the initial composition in 24 minutes and keep until 26 minutes) to obtain 4-methyl-1′-[(1-methylpyrazol-4-yl)methyl]spiro[isochromane-1,4′-piperidine] 89 (150 mg, 34%). 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] + .

[0629] Preparation of Compound 90

[0630] (1R,2'S)-7-Chloro-2'-methyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[isochromane-1,4'-piperidine](90)

[0631]

[0632] Reductive Amination Representative Procedure 3

[0633] A solution of (2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidine](trifluoromethanesulfonic acid) (15 mg, 0.03733 mmol) in DCM (1 mL) was washed with a saturated bicarbonate solution on a phase separator (3×2 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude was dissolved in DCM (1 mL), and 1-(2-methylsulfonylethyl)triazole-4-carboxaldehyde S13 (23 mg, 0.1132 mmol) and (trimethylcarbamoyl)methylcyanoborohydride (100 mg, 1.2 mmol / g, 0.1200 mmol) were added under nitrogen. The mixture was capped and irradiated at 110° C. for 30 minutes. The resin was filtered off and concentrated in vacuo. The crude material was purified by reverse phase HPLC (method: Waters XSelect CSH C18 OBD preparative column; 30×150 mm, 5 micron. Gradient: acetonitrile / water with 0.1% trifluoroacetic acid) to afford (1R,2′S)-7-chloro-2′-methyl-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[isochromane-1,4′-piperidine] 90 as a trifluoroacetate salt (10.3 mg, 63%) LCMS m / z 439.22 [M+H] + .

[0634] Compounds 91-139 were prepared in a single step using appropriate intermediates and reagents and using the reductive amination formation method described for compounds 88-90. Aldehydes were prepared by the methods described above or obtained from commercial sources. Any modifications to the methods are identified in Table 12 and the accompanying footnotes.

[0635] Table 12. Compounds 91-139

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654] Compound 140

[0655] 7-Chloro-3'-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isochromane-1,4'-piperidine](140)

[0656]

[0657] Synthesis of 7-chloro-3'-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isochromane-1,4'-piperidine](140)

[0658] To a stirred solution of 7-chloro-3'-methyl-spiro[isochromane-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 K 2 CO 3 (179.67 mg, 0.0013 mol). The reaction was heated at 80 ° C for 16 hours. The reaction was cooled to room temperature and 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 phase HPLC (method: Waters XSelect CSH C18 OBD prep column; 30×150 mm, 5 microns. Gradient: acetonitrile / water with 0.1% trifluoroacetic acid) to give 7-chloro-3'-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isochromane-1,4'-piperidine] 140 (18 mg, 9%) as a trifluoroacetate salt (400 MHz, DMSO d6), δ ppm 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] + .

[0659] Preparation of S19

[0660] N-diazo-1,1,1-trifluoro-methanesulfonamide (S19)

[0661]

[0662] Synthesis of N-diazo-1,1,1-trifluoro-methanesulfonamide (S19)

[0663] 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 Tf 2OC156 (380 μL, 2.259 mmol) was added and stirred for 2 hours. At this time, 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 with additional DCM up to 5 mL to produce a stock solution (0.452 M) that was used on the same day and the reaction was not further characterized.

[0664] Compound 141

[0665] 2-[4-[[(1R,2'S)-7-Chloro-2'-methyl-spiro[isochromane-1,4'-piperidinyl]-1'-yl]methyl]triazol-1-yl]ethanol (141)

[0667]

[0668] Synthesis of 2-[4-[[(1R,2'S)-7-chloro-2'-methyl-spiro[isochromane-1,4'-piperidinyl]-1'-yl]methyl]triazol-1-yl]ethanol (141)

[0669] Representative procedure for azido transfer click. Method A

[0670] The substrate 2-aminoethanol C158 (8.348 mg, 0.1367 mmol), CuSO 4 (0.2755 mg, 0.07646 μL, 0.001726 mmol) and NaHCO 3 (6.175 mg, 0.07351 mmol) was suspended in a volume with the TfN to be used 3 The solution was then diluted with water (380 μL). TfN 3(370 μL, 0.452M, 0.1672mmol) solution, followed by methanol (700 μL) was added 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[isochromane-1,4'-piperidine] S5 (10 mg, 0.03451mmol), TBTA (0.9159mg, 0.001726mmol) and (+)-L-sodium ascorbate (6.837mg, 0.03451mmol) 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 prep column; 30×150 mm, 5 μm. Gradient: acetonitrile / water with 0.1% trifluoroacetic acid) to give 2-[4-[[(1R,2′S)-7-chloro-2′-methyl-spiro[isochromane-1,4′-piperidinyl]-1′-yl]methyl]triazol-1-yl]ethanol 141 as a trifluoroacetate salt (10.7 mg, 58%) 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=6.0 Hz, 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 calc377.35[M+H] + .

[0671] Compound 142

[0672] (4-((4-(((1R,2'S)-7-chloro-2'-methylspiro[isochromane-1,4'-piperidinyl]-1'-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)methanol (142)

[0673]

[0674] Synthesis of (4-((4-(((1R,2'S)-7-chloro-2'-methylspiro[isochromane-1,4'-piperidinyl]-1'-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)methanol 142

[0675] Representative procedure for reductive azido transfer click. Method B

[0676] To a solution of (4-(aminomethyl)pyridin-2-yl)methanol(HCl) C159 (14.57 mg, 0.07040 mmol) in DMSO (200 μL) was added NaHCO 3 (110 μL, 1M, 0.110mmol). N-diazoaminosulfonyl fluoride (155 μL, 0.45M, 0.06975mmol) was added as a solution in MTBE, and the resulting mixture was stirred at room temperature for 1 hour. (1R, 2'S)-7-chloro-2'-methyl-1'-prop-2-ynyl-spiro[isochromane-1,4'-piperidine] S5 (10mg, 0.03451mmol) was added in DMSO (200 μL), followed by addition of a solution of copper (II) sulfate (35 μL, 0.1M, 0.003500mmol), (+)-L-sodium ascorbate (70 μL, 0.2M, 0.01400mmol) and TBTA (35 μL, 0.1M, 0.003500mmol) in DMSO. 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; 30×150 mm, 5 micron. Gradient: acetonitrile / water with 0.2% formic acid) to give (4-((4-(((1R,2′S)-7-chloro-2′-methylspiro[isochromane-1,4′-piperidinyl]-1′-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)methanol 142 as formate salt (3.5 mg, 22%) LCMS m / z calc 454.24 [M+H] + .

[0677] Compounds 143-185 were prepared in a single step using intermediate S5 and the azido transfer click method described for compounds 141-142. Amines were obtained from commercial sources. Any modifications to the methods are identified in Table 13 and the accompanying footnotes.

[0678] Table 13. Compounds 143-185

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697] 1 Purification of stereoisomers from product mixtures by chiral SFC

[0698] Compound 190

[0699] N-Methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (190)

[0700]

[0701] Step 1. Synthesis of 1-benzyl-4-[2-(dimethoxymethyl)phenyl]piperidin-4-ol (C162)

[0702] 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, 1.6 M, 0.0224 mol) under argon at -78 ° C in 10 minutes and stirred for 5 minutes. A solution of 1-benzylpiperidin-4-one (3.4 g, 0.0176 mol) in THF (10 mL) was added to the reaction mixture and stirred at -78 ° C for 2 hours, at which time the solution was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was quenched with water at 0 ° C and washed with saturated NH 4The organic layer was washed with brine and purified by Na 2 SO 4 Dry and concentrate under reduced pressure to give 1-benzyl-4-[2-(dimethoxymethyl)phenyl]piperidin-4-ol (6.4 g, 35% yield) as a light yellow semisolid. LCMS m / z 342.08 [M+1] + .

[0703] Step 2. Synthesis of 1'-benzyl-1-methoxy-spiro[1H-isobenzofuran-3,4'-piperidine](C163)

[0704] To a stirred solution of 1-benzyl-4-[2-(dimethoxymethyl)phenyl]piperidin-4-ol (6.4 g, 0.0075 mol) in methanol (50 mL) was added p-TsOH hydrate (4.5 g, 0.0232 mol) at room temperature and stirred for 5 days. The reaction mixture was diluted with 2M NaOH solution to pH 10, and the compound was extracted with DCM (2×200 mL). The organic layer was washed with brine and purified by Na 2 SO 4 The residue was purified by column chromatography (silica, 230-400) and eluted with 25% EtOAc / petroleum 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),2.92-2.85( 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] + .

[0705] Step 3. Synthesis of 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C164)

[0706] 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) at -25 °C were added TMSCN (3.8857 g, 5 mL, 0.0384 mol) and BF3 .OET 2 (1.0143 g, 0.9 mL, 0.0070 mol) and stirred for 30 minutes. Then it was allowed to warm to 0 °C and stirred for 1 hour. The reaction mixture was quenched with methanol (1 mL) and then quenched with 2M NaOH solution. The organic layer was separated and purified by Na 2 SO 4 The product was dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 230-400) and eluted with 40% EtOAc / petroleum ether. The collected fractions were concentrated under reduced pressure to give 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-nitrile (1.4 g, 97% yield) as an off-white semisolid. 1 H NMR (400 MHz, chloroform-d) δ7.43-7.25 (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] + .

[0707] Step 4. Synthesis of ethyl 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylate (C165)

[0708] To a stirred solution of 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (100 mg, 295 μmol) in EtOH (2 mL) was added H 2 SO 4 (552.00 mg, 0.3000 mL, 0.0055 mol) and two drops of water. The reaction mixture was stirred at 90 ° C for 20 hours. The reaction mixture was cooled to room temperature, diluted with chilled water (10 mL), and extracted with EtOAc (2×20 mL). The organic layer was washed with 2M NaOH solution (5 mL), brine, and Na 2 SO 4 The product was dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 230-400) and eluted with 30% EtOAc / petroleum ether. The collected fractions were concentrated under reduced pressure to obtain 1'-benzyl spiro [1H-isobenzofuran-3,4'-piperidine] -1-carboxylic acid ethyl ester (70 mg, 67% yield) as a light yellow viscous liquid. 1H NMR (400 MHz, chloroform-d) δ 7.41-7.26 (m, 8H), 7.19 (d, J = 6.8 Hz, 1H), 5.66 (s, 1H), 4.22 (q, J = 3.2 Hz, 2H), 3.60 (s, 2H), 2.86 (t, J = 6.4 Hz, 2H), 2.62-2.46 (m, 2H), 2.11-1.97 (m, 3H), 1.76 (d, J = 13.6 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H). LCMS m / z 352.08 [M+1] + .

[0709] Step 5. Synthesis of 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (C166)

[0710] To a stirred solution of 1'-benzylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid ethyl ester (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. Then, methanol (3 mL) was added to the reaction mixture and it was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude residue. It was diluted with water (50 mL), acidified with 1M HCl solution at 0 ° C, and the compound was extracted with 10% MeOH / DCM (2 × 100 mL). The organic layer was washed with Na 2 SO 4 Dry and concentrate 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 / z324.28[M+1] + .

[0711] Step 6. Synthesis of 1'-benzyl-N-methyl-spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (C167)

[0712] 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 (2M in THF) (2.4000 mL, 2M, 0.0048 mol) in DMF (10 mL) was added DIPEA (1.5270 g, 2.1 mL, 0.0116 mol) at room temperature and stirred for 16 hours. The reaction mass was diluted with chilled water and the compound was extracted with 5% MeOH / DCM (2×50 mL). The organic layer was washed with Na 2 SO 4 Dried 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 viscous brown liquid. LCMS m / z 337.11 [M+1] + .

[0713] Step 7. Synthesis of N-methylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (C168)

[0714] A suspension of 1'-benzyl-N-methyl-spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (100 mg, 243.74 μmol) and 10% palladium / carbon (25 mg, 10% w / w, 23 μmol) in methanol (5 mL) was hydrogenated under balloon pressure for 16 hours at room temperature. 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: 0-100% 1:1 MeCN:MeOH / water with 10 mM NH 4 HCO 3 ) was purified. The collected pure 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] +.

[0715] Step 8. Synthesis of N-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (190)

[0716] A solution of N-methylspiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (200 mg, 649.60 μmol), 1-phenylpyrazole-4-carboxaldehyde (137 mg, 779.75 μmol) and acetic acid (5 drops) in methanol (5 mL) was stirred at room temperature for 16 hours. NaCNBH was then added to the reaction mixture at 0°C. 3 (50 mg, 779.73 μmol), 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. The crude compound was purified by reverse phase chromatography (column: C18. Gradient: 0-100% 1:1 MeOH:MeCN / water, containing 10 mM NH 4 HCO 3 ) was purified by HPLC-MS / MS. 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] + .

[0717] Preparation of S20

[0718] 1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-one (S20)

[0719]

[0720] To a solution of 4-(chloromethyl)-1-phenyl-pyrazole (8.3 g, 0.0388 mol) in DMF (80 mL) was added piperidin-4-one (hydrochloric acid (1)) (7.5 g, 0.0387 mol) at room temperature, followed by K2 CO 3 To the mixture of 4-[(1-phenylpyrazole-4-yl)methyl]piperidin-4-one (9.1 g, 85% yield) was added 4-[(1-phenylpyrazole-4-yl)methyl]piperidin-4-one (10.3 g, 1.25% yield) and 1-[(1-phenylpyrazole-4-yl)methyl]piperidin-4-one (10.3 g, 1.25% yield) at 100 °C. The mixture was quenched with ice / water (250 mL), extracted with ethyl acetate (2 × 500 mL), washed with brine (250 mL) and dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography with 60% ethyl acetate / hexane, and the pure fractions were concentrated under reduced pressure to obtain 1-[(1-phenylpyrazole-4-yl)methyl]piperidin-4-one (9.1 g, 85% yield) as a solid. 1 H NMR (400MHz, chloroform-d) δ7.89(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=6.0Hz,4H),2.47(t,J=6.0Hz,4H). LCMS m / z 256.13[M+1] + .

[0721] Preparation of S21

[0722] 1-(3-Trimethylsilylprop-2-ynyl)piperidin-4-one (S21)

[0723]

[0724] To a stirred solution of piperidin-4-one (hydrochloric acid (1)) (1 g, 0.0066 mol) in MeCN (10 mL) was added K 2 CO 3 (3.0 g, 0.0215 mol), followed by the addition of 3-bromoprop-1-ynyl(trimethyl)silane (1.5213 g, 1.3003 mL, 0.0078 mol) and stirring at room temperature for 4 hours. 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 1 H 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).

[0725] Preparation of S22

[0726] 1-[[1-(2-Pyridinyl)pyrazol-4-yl]methyl]piperidin-4-one (S22)

[0727]

[0728] To a stirred solution of piperidine-4-one (2.8 g, 26.833 mmol) in 1,2-dichloroethane (40 mL), MeOH (10 mL) at 0 ° C., 1- (2-pyridyl) pyrazole-4-carboxaldehyde (3.5 g, 19.807 mmol) was added, followed by sodium triacetoxyborohydride (9 g, 41.615 mmol), and stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography with ethyl acetate, and the pure fractions were concentrated under reduced pressure to give 1- [[1- (2-pyridyl) pyrazol-4-yl] methyl] piperidine-4-one (2.5 g, 37% yield) as a yellow viscous gum. 1 H NMR (400MHz, chloroform-d) δ8.50(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=6.0Hz,4H),2.49(t,J=6.4Hz,4H). LCMS m / z 257.24[M+1] + .

[0729] Preparation of S23

[0730] 1-[(1-Tetrahydropyran-4-ylpyrazol-4-yl)methyl]piperidin-4-one (S23)

[0731]

[0732] 1-[(1-Tetrahydropyran-4-ylpyrazol-4-yl)methyl]piperidin-4-one (S23) was prepared using the same procedure used to prepare S22 with starting aldehyde C172.

[0733] Preparation of S24

[0734] 1-[(1-Tetrahydropyran-2-ylpyrazol-4-yl)methyl]piperidin-4-one (S24)

[0735]

[0736] 1-[(1-Tetrahydropyran-2-ylpyrazol-4-yl)methyl]piperidin-4-one (S24) was prepared using the same procedure used to prepare S22 with starting aldehyde C173.

[0737] Preparation of S25

[0738] 2-Bromo-1-(dimethoxymethyl)-4-methyl-benzene (S25)

[0739]

[0740] 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) at room temperature followed by trimethyl orthoformate (5.9539 g, 6.2 mL, 0.0555 mol) and the reaction mixture was stirred at 75 °C for 15 hours. The reaction was diluted with saturated sodium bicarbonate solution (100 mL) and methanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (2 x 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 light yellow liquid which was used without additional 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).

[0741] Preparation of S26

[0742] 2-Bromo-1-(dimethoxymethyl)-4-(trifluoromethyl)benzene (S26)

[0743]

[0744] 2-Bromo-1-(dimethoxymethyl)-4-(trifluoromethyl)benzene (S26) was prepared using the same procedure used for the synthesis of S25 with starting aldehyde C175.

[0745] Preparation of S27

[0746] 1-[[1-(3-Pyridinyl)pyrazol-4-yl]methyl]piperidin-4-one (S27)

[0747]

[0748] 1-[[1-(3-Pyridinyl)pyrazol-4-yl]methyl]piperidin-4-one (S27) was prepared using the same procedure used to prepare S22 with starting aldehyde C176.

[0749] Preparation of S28

[0750] 5-Chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (S28)

[0751]

[0752] Step 1. Synthesis of 4-[5-chloro-2-(dimethoxymethyl)phenyl]-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-ol (C178)

[0753] 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-butyl lithium (10 mL, 2.5 M, 0.0250 mol) and stirred for 2 hours at -80 ° C, and the reaction was slowly warmed 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, about 60% purity by LC / MS) as a yellow liquid, which was used for continuous steps without further steps.

[0754] Step 2. Synthesis of 5-chloro-1-methoxy-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine] (C179)

[0755] To a stirred solution of 4-[5-chloro-2-(dimethoxymethyl)phenyl]-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-ol (10 g, ca. 40% purity 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 warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated directly under reduced pressure to a 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 under vacuum. The resulting crude residue was purified by silica gel chromatography (Gradient: 0-50% EtOAc / hexanes) to afford 5-chloro-1-methoxy-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine] (4 g, -80% pure by LC / MS, 86% yield) as a brown gum. 1HNMR (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, 2H), 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] +

[0756] Step 3. Synthesis of 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (S28)

[0757] 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) at -25 °C was added TMSCN (3.7302 g, 4.7039 mL, 0.0368 mol) followed by BF 3 .OET 2 (1.3341g, 1.1601mL, 0.0093mol) and stirred for 30 minutes. The reaction was then warmed to 0°C and stirred for 1 hour. The reaction mixture was quenched with MeOH (10mL) and water (100mL) and extracted with DCM (2×250mL). 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 (1.8g, 95%), 1 H NMR (300 MHz, 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] + .

[0758] Preparation of S29-S36

[0759] Intermediate compounds S29-S36 (see Table 14) were prepared using the same method as described for S28 with the appropriate aryl bromide and the appropriate piperidone. All aryl bromides and piperidones were obtained from commercial sources or synthesized as described above.

[0760] Table 14. Structural and physicochemical data of intermediates S29-S36

[0761]

[0762]

[0763]

[0764] Compound 191

[0765] 5-Chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (191)

[0766]

[0767] 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(water (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 x 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: 0-100% MeCN / water with 0.1% formic acid) to give 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (formic acid (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] + .

[0768] 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)

[0769]

[0770] 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

[0771] Extracted with ethyl acetate (3×50 mL). The organic layer was dried over sodium sulfate and concentrated (the aqueous layer was set aside for purification of the carboxylic acid), then purified by reverse phase HPLC (gradient: 45%-99% MeCN / 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. Purified by chiral SFC (column: AS-H, 10×250 mm; gradient: 60% CO 2 / methanol (5 mM methanolic ammonia; flow rate: 15 mL / min) to separate the stereoisomers provided the first eluting peak 1935-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (6.3 mg, 79%). 1 H NMR (300 MHz, 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 = 1.9 Hz, 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, 4.4 Hz, 1H), 2.03-1.78 (m, 3H). ESI-MS m / z: 423.05 [M+1] + .

[0772] The second eluting peak was isolated to provide compound 1945-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (6.2 mg, 78%) 1 H NMR (300 MHz, chloroform) δ8.26 (s, 1H), 7.79-7.70 (m, 3H), 7.54-7.30 (m, 5H), 7.27 (d, J = 1.9 Hz, 1H), 5.44 (s, 1H), 3.74 (s, 2H), 3.04 (t, J = 11.3 Hz, 2H), 2.80-2.55 (m, 2H), 2.19 (td, J = 13.3, 4.5 Hz, 1H), 2.04-1.74 (m, 3H). ESI-MS m / z: 423.05 [M+1] + .

[0773] The aqueous layer from the reaction mixture was concentrated under reduced pressure to give a crude residue which was purified by reverse phase HPLC (gradient: 45%-99% MeCN / 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%) 1H 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] + .

[0774] Compound 195

[0775] 5-Chloro-N-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (195)

[0776]

[0777] Step 1. Synthesis of 5-chloro-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (192)

[0778] 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·H 2 O (40 mg, 0.0016 mol) in water (5 mL) and heated to 60 ° C for 16 hours. The reaction was cooled to room temperature, acidified with 1M 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 subsequent step without further purification. LCMS m / z 423.96[M+1] + .

[0779] Step 2. Synthesis of 5-chloro-N-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (195)

[0780] 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 (hydrochloric acid (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 / 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: 0-100% MeCN / water with 0.1% formic acid) to afford after lyophilization 5-chloro-N-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (formic acid (1)) 195 as a white solid (50 mg, 48%). 1 H 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). LCMSm / z 435.19[M-1] - .

[0781] Compound 196-202

[0782] Compounds 196-202 (see Table 15) were prepared using the same method as for compound 191 or the method for compound 191 followed by the method for compound 192 using the appropriate nitrile intermediates. All nitriles were synthesized as described above. Any modifications to the methods are identified in Table 15 and the accompanying footnotes.

[0783] Table 15. Structural and physicochemical data of compounds 196-202

[0784]

[0785]

[0786]

[0787]

[0788]

[0789] 1) Using T3P and Et 3 N replaces HATU and DIPEA to carry out amide coupling of compound 203

[0790] 5-Cyano-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (203)

[0792]

[0793] 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) 2 To the 4-thiazolyl-1-yl pyridine-2 ... The crude residue was combined with another reaction of the same conditions starting from 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: 0-100% MeCN / 10 mM ammonium bicarbonate in water) 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. 1H 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] + .

[0794] Compound 204

[0795] 5-Cyano-N-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (204)

[0796]

[0797] 5-Cyano-N-methyl-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide (204) was prepared using the same procedure used to prepare compound 203 with the appropriate starting aryl chloride.

[0798] 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)LCMSm / z 428.46[M+1] + .

[0799] Preparation of S37

[0800] 1'-[(1-phenylpyrazol-4-yl)methyl]-5-vinyl-spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile

[0801] (S37)

[0802]

[0803] 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 K 2 CO 3 (610mg, 0.0043mol). The reaction mixture was degassed with argon for 10 minutes. XPhosPd-G2 (160mg, 199.03 μmol) was then added and degassed again in a sealed tube at room temperature for 5 minutes. The reaction mixture was stirred at 100 ° C for 16 hours. The reaction mixture was diluted with water (50mL), extracted with EtOAC (2×50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel column chromatography silica gel chromatography (gradient: 0-50% EtOAc / petroleum ether) to obtain 1'-[(1-phenylpyrazole-4-yl)methyl]-5-vinyl-spiro[1H-isobenzofuran-3,4'-piperidine]-1-nitrile (350mg, 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] + .

[0804] Preparation of C181 and 182

[0805] Intermediate compounds C181 and C182 (see Table 16) were prepared using either the method used to prepare compound 191 or the method used to prepare compound 195 with nitrile intermediate S37. Any modifications to the methods are identified in Table 16 and the accompanying footnotes.

[0806] Table 16. Structural and physicochemical data of compounds C181 and C182

[0807]

[0808]

[0809] 1) T3P replaces HATU for amide coupling

[0810] Compound 205

[0811] 5-Ethyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (205)

[0812]

[0813] 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 hydrogen balloon pressure for 16 hours. The reaction was filtered through a pad of celite, washed with MeOH (25 mL) and evaporated under vacuum. The crude residue was purified by reverse phase chromatography (column: C18. Gradient: 0-100% MeCN / 0.1% TFA in water) to afford 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 after lyophilization. 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] + .

[0814] Compound 206

[0815] 5-Ethyl-N-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (206)

[0816]

[0817] 5-Ethyl-N-methyl-1′-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide (206) was prepared using the same procedure used to prepare compound 205 with starting methyl amide 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] + .

[0818] Compound 207

[0819] 1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]-5-(trifluoromethyl)spiro[1H-isobenzofuran-

[0820] 3,4'-Piperidine]-1-carboxamide (207)

[0821]

[0822] Step 1. Synthesis of 1'-prop-2-ynyl-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C183)

[0823] 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 hours. The reaction was washed with saturated NH 4 Cl solution (50mL) was quenched and extracted with ethyl acetate (2×100mL). 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 / 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). LCMSm / z 321.11[M+1] + .

[0824] Step 2. Synthesis of 1'-prop-2-ynyl-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (C184)

[0825] 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 (2×2 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] + .

[0826] Step 3. Synthesis of 1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (207)

[0827] The 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-methylsulfonyl-ethane (15 mg, 0.1006 mmol) in MeOH (0.5 mL) containing copper sulfate (0.08 mL, 1% w / v, 0.005012 mmol) was added. Then, ascorbic acid (sodium salt) (2 mg, 0.01004 mmol) was 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 (30×150 mm, 5 microns). Gradient: MeCN / H 2 (0.1% trifluoroacetic acid) to give 1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]-5-(trifluoromethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (trifluoroacetate) (14.8 mg, 24% yield over 2 steps) as a light 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] + .

[0828] Compound 208

[0829] 5-Chloro-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (208)

[0830]

[0831] 5-Chloro-1′-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4′-piperidine]-1-carboxamide (208) was prepared using the same procedure used to prepare compound 207 from starting nitrile S33 with the modification that the LiOH hydrolysis step was performed in this order after the copper sulfate catalyzed reaction.

[0832] 1 H 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] + .

[0833] Compound 209

[0834] 5-Chloro-1'-[[1-(2-methylpyrimidin-5-yl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (209)

[0835]

[0836] Step 1. Synthesis of 5-chloro-1'-(1H-pyrazol-4-ylmethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C187)

[0837] 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), brought to pH ~ 9 with 2M NaOH (20 mL), extracted with EtOAc (2×30 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] + .

[0838] 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)

[0839] 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 for 16 hours under an oxygen balloon. The reaction mixture was diluted with ice-cold water (50 mL) and then 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] + .

[0840] 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)

[0841] 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·H 2 0 (4.0 mg, 94.368 μmol). The reaction mixture was stirred for 6 hours. The reaction was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (isocratic: 60% acetone / hexane) to give 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] + .

[0842] Compound 210

[0843] 5-Chloro-N-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (210)

[0844]

[0845] Step 1. Preparation of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carbonitrile (C189)

[0846] 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) at 0°C was added DBU (302 mg, 0.3 mL, 1.96 mmol) followed by 1-methylsulfonylethylene (80.005 mg, 0.7462 mmol). The reaction was stirred at room temperature for 16 hours, then 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] + .

[0847] Step 2. Preparation of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxylic acid (C190)

[0848] 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, and the reaction was concentrated, diluted with water (10 mL), acidified with 1M 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] + .

[0849] 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)

[0850] 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 in ethyl acetate (212.00 mg, 0.2 mL, 50% w / v, 0.3143 mmol) at ambient temperature and stirred for 16 hours. 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%-100% MeCN / 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%) 1H NMR(400MHz,DMSO-d6)δ:7.70(s,1H),7.58-7.57(m,1H),7.41-7.40(m,2H),7. 37-7.32(m,2H),5.38(s,1H),4.51(t,J=6.8Hz,2H),3.68(t,J=6.8Hz,2H),3.4 1(brs,2H),2.80(s,3H),2.74(brs,2H),2.61(d,J=4.4Hz,3H),2.50-2.49(m,1 H),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] + .

[0851] Compound 211

[0852] 5-Chloro-N-methyl-1'-[[1-(2-methylpyrimidin-5-yl)pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (211)

[0853]

[0854] Compound 211 was prepared following the procedure described for the preparation of compound 210 starting from 6-chloro-1′-((1-(2-methylpyrimidin-5-yl)-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-3-carbonitrile (C188) in steps 2 and 3. 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 (b rs,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] + .

[0855] Preparation of S38

[0856] 5-Chlorospiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (S38)

[0857]

[0858] Step 1. Synthesis of 5-chloro-1-methoxy-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (C191)

[0859] At -78 °C (dry ice-acetone bath) under N 2 nBuLi (48 mL, 2.8 M, 134.4 mmol) was added to a solution of 2-bromo-4-chloro-1-(dimethoxymethyl)benzene (29.8 g, 112.2 mmol) in THF (230 mL) under reduced pressure. Stirred at -78 °C for 40 minutes, a solution of tert-butyl 4-oxopiperidin-1-carboxylate (24.7 g, 124.0 mmol) in THF (115 mL) was then 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 a saturated aqueous solution of ammonium chloride (200 mL). Distributed between MTBE and water (400 mL each). The organic layer was separated, washed with water and 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 product was heated to 60 ° C and stirred for 16 hours. The reaction was quenched with saturated sodium bicarbonate aqueous solution (300 mL), then distributed 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: 0-50% EtOAc / heptane) to obtain 5-chloro-1-methoxy-spiro [1H-isobenzofuran-3,4'-piperidine] -1'-carboxylic acid tert-butyl ester (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).

[0860] Step 2. Synthesis of 5-chloro-1-cyano-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (C192)

[0861] at -78 °C in N 2 To a solution of 5-chloro-1-methoxy-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (3.7g, 10.46mmol) in DCM (50mL) was added trimethylsilyl cyanide (2.0mL, 15.00mmol), followed by diethyloxonium (trifluoro) boron tincture (1.4mL, 11.34mmol). Stir at -78°C for 30 minutes and then warm to 0°C. After 1 hour at 0°C, the reaction was quenched with saturated aqueous sodium bicarbonate solution (100mL). The reaction was warmed to room temperature and quenched with Boc 2 O (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 sequentially with saturated aqueous sodium bicarbonate, 0.5 M aqueous NaOH, and brine (100 mL each), and dried (MgSO 4 ), filtered, and concentrated. The crude residue was purified by silica gel chromatography (Gradient: 0-50% EtOAc / heptane) to give 5-chloro-1-cyano-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (3.0 g, 82% yield) as a clear colorless glass. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.39 (dd, J = 8.2, 1.8 Hz, 1H), 7.35 (dt, J = 8.2, 0.7 Hz, 1H), 7.14 (d, J = 1.7 Hz, 1H), 5.85 (d, J = 0.8 Hz, 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).

[0862] Step 3. Synthesis of tert-butyl 1-carbamoyl-5-chloro-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (C193)

[0863] To a flask containing 5-chloro-1-cyano-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (1.125 g, 2.580 mmol) was added THF (45 mL) and diluted with water (45 mL). To the solution was added lithium hydroxide monohydrate (237 mg, 5.648 mmol) and stirred at room temperature overnight. The reaction was quenched into 100 mL of saturated NH 4Cl aqueous solution and DCM (100mL).Extracted with DCM (3x), the combined organic matter is passed through a phase separator and concentrated under reduced pressure.The crude residue is purified by silica gel chromatography (gradient: 0-20% MeOH / DCM) to obtain 1-carbamoyl-5-chloro-spiro [1H-isobenzofuran-3,4'-piperidine] -1'-carboxylic acid tert-butyl ester (962.7mg, 92% yield) as a waxy foam white solid. 1 HNMR (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,1H) ,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] + .

[0864] Step 4. Synthesis of 5-chlorospiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (S38)

[0865] DCM (10 mL) and TFA (2 mL, 25.96 mmol) were added to a flask containing 1-carbamoyl-5-chloro-spiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (1.28 g, 3.140 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 another step without further purification.

[0866] 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] + .

[0867] Compound 212

[0868] 5-Chloro-1'-[[1-[3-(trifluoromethyl)phenyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (212)

[0869]

[0870] 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) and then 1-[3-(trifluoromethyl)phenyl]pyrazole-4-carbaldehyde (10 mg, 0.04164 mmol). To this was added Et 3 N (20 μL, 0.1435 mmol), and then triacetoxyborate (sodium salt) (22 mg, 0.1038 mmol) was added and stirred overnight. The reaction was quenched into saturated NaHCO 3 The product was added into 4% paraformaldehyde and extracted with DCM (3x). The combined organics were passed through a phase separator and concentrated. The crude residue was dissolved in DMSO and purified by reverse phase HPLC (method: Waters XBridge Preparative C8 column; 30×150 mm, 5 microns. Gradient: acetonitrile / water with 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] + .

[0871] Compounds 213-276

[0872] Compounds 213-276 (see Table 17) were prepared using 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 methods are identified in Table 17 and the accompanying footnotes.

[0873] Table 17. Structural and physicochemical data of compounds 213-276

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893] Compound 277

[0894] 5-Chloro-1'-[[1-[(2S)-2,3-dihydroxy-3-methyl-butyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (277)

[0895]

[0896] To a vial containing a solution of 5-chlorospiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (trifluoroacetate) (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). Triacetoxyborate (sodium salt) (185 mg, 0.8729 mmol) was added to the resulting mixture and stirred for 2 days. The reaction was quenched into saturated NaHCO 3 The product was stirred overnight, and then water (500 μL, 27.75 mmol) was added, and the reaction was stirred again overnight. The reaction was then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (method: Waters XBridge preparative C8 column; 30 × 150 mm, 5 microns. Gradient: acetonitrile / water, containing 10 mM ammonium hydroxide) to obtain 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% yield). 1 H 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).). LCMSm / z 449.28[M+1] + .

[0897] Compound 278

[0898] 5-Chloro-1'-[[1-[(2R)-2,3-dihydroxy-3-methyl-butyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (278)

[0899]

[0900] 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 procedure used to prepare compound 277 with starting aldehyde C196.

[0901] 1 H 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] + .

[0902] Preparation of S39

[0903] 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (S39)

[0904]

[0905] Step 1: 2-(Bromomethyl)-2-methyl-propane-1,3-diol (C198)

[0906] To a mixture of (3-methyloxetane-3-yl)methanol C197 (10 mL, 100.3 mmol) in THF (70 mL) was added hydrogen bromide (14 mL, 48% w / w, 123.7 mmol) at 0°C. After stirring for 24 h, the mixture was concentrated to minimum volume, diluted with DCM / methanol, and excess HBr was quenched with saturated sodium bicarbonate. The layers were separated, 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%) 1H NMR (400 MHz, CHLOROFORM-d) δ 3.47 (d, J = 1.1 Hz, 6H), 0.96 (s, 3H).

[0907] Step 2: [2-(Bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propoxy]-tert-butyl-dimethyl-silane (C199)

[0908] 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 solids. 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).

[0909] Step 3: 1-[3-[tert-butyl(dimethyl)silyl]oxy-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-propyl]pyrazole-4-carbaldehyde (S39)

[0910] To a vial was added 1H-pyrazole-4-carboxaldehyde (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 hours, 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 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), and the organic layer was dried over sodium sulfate and concentrated. Purification by silica gel chromatography (gradient: 0-60% 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] + .

[0911] Compound 279

[0912] 5-Chloro-1'-[[1-[3-hydroxy-2-(hydroxymethyl)-2-methyl-propyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (279)

[0913]

[0914] 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 procedure used to prepare compound 278 with starting aldehyde S39, except that MeOH was used instead of THF / H2O as solvent during the reaction with HCl. 2 O.

[0915] 1H 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] + .

[0916] Compound 280

[0917] 5-Chloro-1'-[[1-[2-hydroxy-2-(1-hydroxycyclobutyl)ethyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (280)

[0918]

[0919] To 5-chloro-1'-(1H-pyrazol-4-ylmethyl)spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (30 mg, 0.08650 mmol) (Compound 226), Cs 2 CO 3 To a suspension of 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%) was added 1-(oxiran-2-yl)cyclobutanol (11 mg, 0.09637 mmol) (114 mg, 0.3499 mmol) in DMF (1.0 mL) and stirred at 75 °C for 5 hours. 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: 0-100% MeCN / 10 mM aqueous ammonium bicarbonate solution) 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%). 1H 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- 4.11(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-MSm / z 461.29[M+1] + .

[0920] Compounds 281-285

[0921] Compounds 281-285 (see Table 18) were prepared using compound 226 and appropriate electrophiles using the same method as for compound 280. Any modifications to the method are identified in Table 18 and the accompanying footnotes.

[0922] Table 18. Structural and physicochemical data of compounds 281-285

[0923]

[0924]

[0925]

[0926] Compound 286

[0927] 5-Methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine](286)

[0928]

[0929] Step 1: Preparation of tert-butyl 4-hydroxy-4-[2-(hydroxymethyl)-5-methyl-phenyl]piperidine-1-carboxylate (C201)

[0930] 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, 2.5 M, 0.0032 mol) at -78 ° C, and the solution was stirred for 10 minutes. A solution of tert-butyl 4-oxopiperidin-1-carboxylate (278.95 mg, 0.0014 mol) in ether (2 mL) was added thereto at -78 ° C. The reaction mixture was stirred at -78 ° C for 2 hours. The reaction mixture was allowed to warm to ambient temperature and saturated NH 4The solution was quenched with Cl solution and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry and concentrate to give 4-hydroxy-4-[2-(hydroxymethyl)-5-methyl-phenyl]piperidine-1-carboxylic acid tert-butyl ester (550 mg, 45%). ESI-MS m / z: 322.23 [M+1] +

[0931] Step 2: Preparation of tert-butyl 5-methylspiro[1H-isobenzofuran-3,4'-piperidine]-1'-carboxylate (C202)

[0932] To a stirred solution of 4-hydroxy-4-[2-(hydroxymethyl)-5-methyl-phenyl]piperidine-1-carboxylic acid tert-butyl ester (370 mg, 1.1512 mmol) in DCM (10 mL) was added Et 3 To 5- methyl spiro [1H- isobenzofuran -3,4 '- piperidine] -1 '- carboxylic acid tert-butyl ester (150mg, 43%) was added to 4- methyl spiro [1H- isobenzofuran -3,4 '- piperidine] -1 '- carboxylic acid tert-butyl ester (150mg, 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] + .

[0933] Step 3: Preparation of 5-methylspiro[1H-isobenzofuran-3,4'-piperidine](C203)

[0934] TFA (281.86 mg, 0.1904 mL, 2.4720 mmol) was added to a stirred solution of 5-methylspiro [1H-isobenzofuran-3,4'-piperidine] -1'-carboxylic acid tert-butyl ester (150 mg, 0.4944 mmol) in DCM (5 mL) at 0 ° C and stirred for 1 hour at ambient temperature. The reaction mixture was diluted with DCM (30 mL) and washed 3 times with saturated sodium carbonate solution (10 mL) and water (10 mL). The solvent was evaporated to give 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] + .

[0935] Step 4: Preparation of 5-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine] (286)

[0936] 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 before the addition of NaCNBH at 0°C. 3 The reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was quenched with ice, and then the excess methanol was evaporated. The crude residue was diluted with DCM (50 mL) and washed 3 times with water (20 mL). Excess solvent was evaporated, and the crude residue was purified by reverse phase column chromatography (column: YMCTriart Actus C18 (250 × 20 mm, 5 μ); gradient: 30%-95% MeCN / 20 mM aqueous ammonium bicarbonate solution) to obtain 5-methyl-1'-[(1-methylpyrazole-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,3H),3.37(s,3H),2.70(d,J=10.84Hz,2H),2.30(s,3H),2.27-2.21(m,2H),1.87-1.79(m,2H),1.56(d,J=12.64Hz,2H). ESI-MS m / z:298.0[M+1]+ .

[0937] Compound 287

[0938] 5-Chloro-1,1-dimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isobenzofuran-3,4'-

[0939] Piperidine](287)

[0940]

[0941] Step 1: Preparation of 2-(2-bromo-4-chloro-phenyl)propan-2-ol (C206)

[0942] To a stirred solution of 2-bromo-4-chloro-benzoic acid methyl ester (10 g, 40.082 mmol) in THF (200 mL) cooled to 0°C was slowly added MeMgBr (19.118 g, 160.33 mmol) 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 purified by anhydrous Na 2 SO 4 The organic layer was filtered and concentrated to give 2-(2-bromo-4-chloro-phenyl)propan-2-ol (10 g, 100%) 1 HNMR (CDCl 3 , 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).

[0943] Step 2: Preparation of 4-[5-chloro-2-(1-hydroxy-1-methyl-ethyl)phenyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (C207)

[0944] n-BuLi (2.0 g, 3 mL, 0.0318 mol) was added 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) at -78 ° C. The reaction mixture was stirred at the same temperature for 30 minutes, and then THF (5 mL) containing tert-butyl 4-oxopiperidin-1-carboxylate (2.2 g, 0.0110 mol) was added. The reaction mixture was allowed to warm to room temperature and then stirred 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 layer was purified by Na 2 SO4 Drying and concentration gave 4-[5-chloro-2-(1-hydroxy-1-methyl-ethyl)phenyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5 g, 21%) which was carried forward without further purification.

[0945] Step 3: Preparation of 5-chloro-1,1-dimethyl-spiro[isobenzofuran-3,4'-piperidine](C208)

[0946] To a stirred solution of 4-[5-chloro-2-(1-hydroxy-1-methyl-ethyl)phenyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 0.7300 mmol) in toluene (15 mL) was slowly added BF 3 .OET 2 (2.8779 g, 2.5468 mL, 20.277 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated and neutralized with sodium bicarbonate solution, then added to water (100 ml) and extracted with EtOAc (2×100 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 without further purification, which was carried directly to the next step. ESI-MS m / z: 252.0 [M+1] + .

[0947] Step 4: Preparation of 5-chloro-1,1-dimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isobenzofuran-3,4'-piperidine] (287)

[0948] 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 K 2 CO 3(207mg, 0.0015mol), followed by addition of KI (10mg, 60.24μmol). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was filtered through a celite pad and washed with EtOAc (2×200mL). The filtrate was concentrated to give a crude residue, which was purified by reverse phase HPLC (column: -xselect phenylhexene (150×25) mm, 5u; gradient: 2%-25% MeCN:MeOH (1:1) / 0.1% TFA aqueous solution) to give 5-chloro-1,1-dimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isobenzofuran-3,4'-piperidine] (287) (23mg, 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] + .

[0949] Compound 288

[0950] 2-Methyl-1-[[5-[(1,1,5-trimethylspiro[isobenzofuran-3,4'-piperidinyl]-1'-yl)methyl]-2-pyridinyl]

[0951] [Oxy]propan-2-amine (288)

[0952]

[0953] Step 1: Preparation of 2-(2-bromo-4-methyl-phenyl)propan-2-ol (C210)

[0954] MeMgBr (21.83 mL, 3 M, 65.481 mmol) was slowly added to a stirred solution of 2-bromo-4-methyl-benzoic acid methyl ester (5.0 g, 21.83 mmol) in THF (50 mL) 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 obtain 2- (2-bromo-4-methyl-phenyl) propan-2-ol (5.5 g, 93%). 1 H NMR (400 MHz, CDCl 3 ), 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).

[0955] Step 2: Preparation of 1-benzyl-4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-phenyl]piperidin-4-ol (C211)

[0956] n-BuLi (22.1mL, 2.5M, 55.2mmol) was slowly added to a stirred solution of 2-(2-bromo-4-methyl-phenyl) propan-2-ol (5.5g, 24.0mmol) in THF (45mL) at -78 ° C in 15 minutes, and the mixture was stirred at the same temperature for 1 hour. A tetrahydrofuran solution (10mL) of 1-benzylpiperidin-4-one (6.36g, 33.6mmol) was slowly added to the mixture at -78 ° C for 10 minutes. The resulting mixture was slowly warmed to ambient temperature and stirred for 18 hours. The reaction mixture was quenched by adding ammonium chloride solution (100ml), extracted with ethyl acetate (200ml), and the organic layer was dried over sodium sulfate and then concentrated. The crude residue was purified by flash column chromatography (Gradient: 5% methanol / DCM) to give 1-benzyl-4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-phenyl]piperidin-4-ol (3.2 g, 32%). 1 H NMR (400 MHz, CDCl 3),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,4 H),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] + .

[0957] Step 3: Preparation of 1'-benzyl-1,1,5-trimethyl-spiro[isobenzofuran-3,4'-piperidine](C212)

[0958] 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 ether (30.1 g, 26.6 mL, 212.1 mmol), and the reaction mixture was stirred for 16 hours. The solvent was evaporated under reduced pressure to obtain 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 / hexane) to give 1'-benzyl-1,1,5-trimethyl-spiro[isobenzofuran-3,4'-piperidine] (2.9 g, 78%) 1 H NMR (400 MHz, CDCl 3 ),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-MSm / z:322.0[M+1] + .

[0959] Step 4: Preparation of 1,1,5-trimethylspiro[isobenzofuran-3,4'-piperidine](C213)

[0960] Pd / C (1.5 g, 10% w / w, 1.4095 mmol) and AcOH (214 mg, 0.203 mL, 3.58 mmol) were added 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). The reaction mixture was stirred at ambient temperature for 24 hours under a hydrogen atmosphere (30 psi). The reaction mixture was filtered through a wetted celite pad, ensuring that the pad and palladium byproduct remained wet. The pad was washed with methanol (50 ml), and the filtrate was concentrated. The crude residue was triturated with ether (3×50 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] + .

[0961] Step 5: Preparation of 1'-[(6-chloro-3-pyridyl)methyl]-1,1,5-trimethyl-spiro[isobenzofuran-3,4'-piperidine] (C214)

[0962] 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) and subsequently treated with 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 1M NaOH and DCE. The combined organics were collected by a phase separation tube and then concentrated in vacuo. The crude residue was purified by flash column chromatography (gradient: 0-100% EtOAc / heptane) to give 1'-[(6-chloro-3-pyridyl)methyl]-1,1,5-trimethyl-spiro[isobenzofuran-3,4'-piperidine] (130 mg, 42%) 1H 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), 6.9 1(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] + .

[0963] Step 6: Preparation of 2-methyl-1-[[5-[(1,1,5-trimethylspiro[isobenzofuran-3,4'-piperidinyl]-1'-yl)methyl]-2-pyridinyl]oxy]propan-2-amine (288)

[0964] 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), 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, 2M, 0.3080 mmol). The vial was sealed and heated at 80 °C for 1 hour and then quenched by the addition of methanol. The solution was concentrated and purified by reverse phase HPLC (gradient: 10%-90% MeCN / aq. HCl (0.1% HCl)) to give 2-methyl-1-[[5-[(1,1,5-trimethylspiro[isobenzofuran-3,4′-piperidinyl]-1′-yl)methyl]-2-pyridinyl]oxy]propan-2-amine 288 (6.7 mg, 11%) 1H NMR (300MHz, chloroform-d) δ8.10 (dd, J=2.5, 0.7Hz, 1H), 7.76 (dd, J=8.5, 2.4Hz, 1H), 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,3 H), 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] + .

[0965] Compound 289

[0966] 1,1,5-Trimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[isobenzofuran-3,4'-piperidine](289)

[0967]

[0968] 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-(trimethylcarbamoyl)methyl(cyanoborohydride) (650 mg, 2 mmol / g, 1.300 mmol) was added, the solution was capped, and heated to 110 °C in a microwave reactor for 1 hour. The solution was filtered and concentrated. The crude product was purified by reverse phase chromatography (gradient: 20%-80% MeCN / 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) 289 (120 mg, 61%) ESI-MS m / z: 418.18 [M+1] + .

[0969] Compound 290

[0970] (2'S)-2',3,3,6-tetramethyl-1'-((1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-3H-

[0971] Spiro[isobenzofuran-1,4'-piperidine](290)

[0972]

[0973] Step 1: Preparation of (2S)-4-hydroxy-4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-phenyl]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (C215)

[0974] 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, 2.5 M, 4.62 mmol) at -78 ° C under nitrogen. The reaction mixture was stirred at the same temperature for 1 hour, and then a solution of (S)-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (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 (2S)-4-hydroxy-4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-phenyl]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (550 mg, 25%) ESI-MS m / z: 364.0 [M+1] + The crude product was used directly in the next reaction without purification.

[0975] Step 2: Preparation of (2'S)-1,1,2',5-tetramethylspiro[isobenzofuran-3,4'-piperidine](C216)

[0976] To a stirred solution of (2S)-4-hydroxy-4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-phenyl]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (3.2 g, 8.8 mmol) in toluene (32 mL) was slowly added BF 3 .OET 2 (6.24 g, 44.0 mmol), and the reaction was then stirred at ambient temperature for 3 hours. The mixture was then concentrated and washed with saturated NaHCO 3 The product was washed with 4% paraformaldehyde (50 ml), extracted with EtOAc (2×50 ml), dried over sodium sulfate and concentrated, and the crude was triturated with DEE (2×30 ml) to give a crude solid which was purified by chiral SFC chromatography for isomer separation (column: Chiralcel OX-H (30×250 mm), 5 μ; gradient: 70% CO 2 / methanol (15 mM methanolic ammonia); flow rate: 100 g / min; temperature: 30.0°C) to obtain:

[0977] The 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] + .

[0978] 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-MSm / z:246.0[M+1] + .

[0979] 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)

[0980] 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 K 2 CO 3(15.45 mg, 0.11 mmol). The solution was stirred at 60 ° C for 16 hours. The reaction was extracted with DCM and water on a phase separator, then concentrated and purified by flash column chromatography (gradient: 0-20% 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] + .

[0981] Compound 291

[0982] (2'S)-5-Chloro-1,1,2'-trimethyl-1'-[[1-(2-methylsulfonylethyl)triazol-4-yl]methyl]spiro[isobenzofuran-3,4'-piperidine](291)

[0983]

[0984] Compound 291 was prepared according to the method described for compound 290 with the following modifications. In step 1, 2-(2-bromo-4-chloro-phenyl)propan-2-ol was used instead of 2-(2-bromo-4-methyl-phenyl)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), 5μ; gradient: 80% CO 2 / methanol (15 mM methanolic ammonia); flow rate: 90 g / min; temperature: 30.0°C). Step 3 provided (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%). ESI-MS m / z: 453.18 [M+1] + .

[0985] Compound 292

[0986] (2'S)-5-Chloro-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (292)

[0987]

[0988] Step 1: Preparation of (2S)-2-methyl-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-one (C219)

[0989] To a stirred solution of 1-phenylpyrazole-4-carboxaldehyde (2 g, 0.01 mol) in DCE (30 mL) was added (2S)-2-methylpiperidin-4-one (810 mg, 0.007 mol) at 0 ° C, followed by sodium triacetoxyborohydride (2.3 g, 0.01 mol). The reaction mixture was stirred at ambient temperature for 4 hours. The reaction was diluted with ethyl acetate (100 mL), washed with water (2 × 100 mL), and the organic layer was dried over sodium sulfate and concentrated to give a crude compound (2S)-2-methyl-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-one (2.2 g). It can be directly carried to the next step without further purification. ESI-MS m / z: 270.06[M+1] + .

[0990] Step 2: Preparation of (2S)-4-[5-chloro-2-(dimethoxymethyl)phenyl]-2-methyl-1-[(1-phenylpyrazol-4-yl)methyl]piperidin-4-ol (C220)

[0991] 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, 2.5 M, 0.014 mol) at -78 °C and the same temperature was maintained for 3 hours. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were purified by Na 2 O 4 3-naphthalene pyridine-1-yl pyridine-4-yl pyridine-1-yl pyridine-4-yl pyridine-1-yl pyridine-4-one (1.6 g, 0.006 mol). 2 SO 4 The reaction mixture was dried and concentrated to obtain (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] + .

[0992] 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)

[0993] 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 hours. The reaction mixture was concentrated, diluted with water (100 mL) and extracted with DCM (2×200 mL), the organic layer was washed with 2M NaOH solution (30 mL, pH=9), dried over sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography (Gradient: 60%-100% EtOAc / hexanes) to give (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] + .

[0994] 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)

[0995] To (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) was added to CH 2 Cl 2 To a stirred solution of 1% paraformaldehyde (50 mL) was added TMSCN (2.27 g, 3.2 mL, 0.0206 mol), followed by BF3.OEt 2(1.13 g, 1 mL, 0.008 mol). The solution was stirred at 0 °C for 1 hour. The reaction mixture was quenched with methanol (5 mL), and then 2 M NaOH solution (pH = 9) was added. The organic layer was separated and purified by Na 2 SO 4 The crude residue was purified by flash column chromatography (gradient: 30%-40% EtOAc / 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,1 H),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] + .

[0996] 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)

[0997] 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 LiOH (60 mg, 0.0014 mol) in H 2 O (0.5 mL). The solution was stirred for 16 hours. The reaction was concentrated and the crude residue was dissolved in EtOAc (50 mL). The organic layer was washed with Na 2 SO 4 The crude compound was purified by reverse phase HPLC (gradient: 30%-90% MeCN / 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%), 1H 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] + .

[0998] Compound 293

[0999] (2'S)-5-Chloro-2'-methyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (293)

[1000]

[1001] Compound 292 was purified by chiral SFC (column: Chiralpak IC (250×30×5μ); gradient: 50% CO 2 (0.5% IPAmine / IPA) / methanol; 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] + .

[1002] Compound 294

[1003] (2'S)-5-Chloro-N,2'-dimethyl-1'-[(1-phenylpyrazol-4-yl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (294)

[1004]

[1005] 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)

[1006] 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 LiOH (710 mg, 0.0166 mol) in H 2 O (0.5 mL), and then stirred at 80 ° C for 24 hours. The reaction was concentrated, and the crude residue was dissolved in water (50 mL) and extracted with EtOAc (30 mL). The separated organic layer and aqueous layer were acidified with 1M HCl and extracted with 10% MeOH / DCM (2×50 mL). The combined organic layer was purified by Na 2 SO 4 Dry and concentrate 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] + .

[1007] 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)

[1008] 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) at 0°C 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, 50% w / v, 0.0014 mol), and the solution was then allowed to warm to ambient temperature for 16 hours. The reaction mixture was dissolved in EtOAc (50 mL), and the organic layer was then washed with 1 M NaOH solution (2×10 mL) and purified by Na 2 SO 4 The crude residue was purified by chiral SFC (column: Lux; cellulose-4 (250×30×5μ); gradient: 60% CO 2(30 mM methanolic ammonia / ethanol) / methanol; flow rate: 70 g / min; temperature: 30.0°C) was used to purify and isolate the first elution peak to obtain (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 s1H),1.19(s,3H),ESI-MS m / z:451.2[M+1] + .

[1009] Compound 295

[1010] 5-Chloro-N-methyl-1'-[[1-[3-(trifluoromethyl)phenyl]pyrazol-4-yl]methyl]spiro[1H-isobenzofuran-3,4'-piperidine]-1-carboxamide (295)

[1011]

[1012] 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.

[1013] 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] + .

[1014] Compound 296

[1015] 6-Methoxy-1'-((1-phenyl-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carboxamide (296)

[1016]

[1017] 6-Methoxy-1′-((1-phenyl-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-3-carboxamide 296 was prepared in a similar manner to compound 191 using 2-bromo-1-(dimethoxymethyl)-4-methoxybenzene to give 14 mg of the final product.

[1018] 1 H 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] + .

[1019] Compound 297

[1020] 6-Methoxy-N-methyl-1'-((1-phenyl-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carboxamide (297)

[1021]

[1022] 6-Methoxy-N-methyl-1′-((1-phenyl-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-3-carboxamide was prepared in a manner similar to compound 195 using 2-bromo-1-(dimethoxymethyl)-4-methoxybenzene to give 30 mg of the final product 297.

[1023] 1H 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] + .

[1024] Compound 298

[1025] 6-Chloro-1'-((1-isopropyl-1H-pyrazol-4-yl)methyl)-N-methyl-3H-spiro[isobenzofuran-1,4'-piperidine]-3-carboxamide (298)

[1026]

[1027] Compound 298 was prepared in a manner similar 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] + .

[1028] Compound 299

[1029] 6-Chloro-N-methyl-1'-((5-methyl-1-phenyl-1H-pyrazol-4-yl)methyl)-3H-spiro[isobenzofuran-1,4'-

[1030] [Piperidine]-3-carboxamide(299)

[1031]

[1032] Compound 299 was prepared in a manner similar 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] + .

[1033] Compounds 300 and 301

[1034] 5-Chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indan-3,4'-piperidin]-1-ol (300) and 6-chloro-1'-

[1035] [(1-Methylpyrazol-4-yl)methyl]spiro[indan-1,4'-piperidin]-2-ol (301)

[1036]

[1037] Step 1: Preparation of 6-chloro-1H-indene (C225)

[1038] 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 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 x 200 ml), the organic layers were combined and dried over sodium sulfate. The organic layers were filtered and concentrated. The crude residue was purified by column (gradient: 100% hexanes) to give 6-chloro-1H-indene (6.2 g, 68%). 1 H NMR (400 MHz, CDCl 3 ), 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).

[1039] Step 2: Preparation of tert-butyl 6-chlorospiro[indene-1,4'-piperidine]-1'-carboxylate (C226)

[1040] 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, 1 M, 0.0232 mol) at 0°C within 20 minutes. The reaction was stirred at 0°C for 1 hour, then THF (10 ml) containing tert-butyl N,N-bis(2-chloroethyl)carbamate (2.25 g, 0.01 mol) was slowly added at 0°C within 10 minutes, and 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 / hexane) to give tert-butyl 6-chlorospiro[indene-1,4'-piperidine]-1'-carboxylate (5.0 g, 44%). 1 H NMR (400 MHz, CDCl 3 ),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 / z264.0[M-55] + .

[1041] Step 3: Preparation of 6-chlorospiro[indene-1,4'-piperidine](C227)

[1042] 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 (4M / 1,4-dioxane) (2.30 mL, 4M, 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) (230 mg, 95%). 1 H NMR (300 MHz, DMSO d 6 ),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] + .

[1043] Step 4: Preparation of 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indene-1,4'-piperidine] (C228)

[1044] To a stirred solution of 6-chlorospiro[indene-1,4′-piperidine](hydrochloride) (230 mg, 869.92 μmol) in DMF (4.6 mL) at ambient temperature were added 4-(chloromethyl)-1-methyl-pyrazole(hydrochloride) (145.31 mg, 869.92 μmol), KI (144.41 mg, 869.92 μmol) and K 2 CO 3 (594.29 mg, 0.0043 mol). 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] + .

[1045] 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)

[1046] 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 BH 3 (solution in THF) (1.9 mL, 1 M, 0.0019 mol). The reaction mixture was stirred at ambient temperature for 1 hour. NaOH (5.0 mL, 3 M, 0.0150 mol) and H were added at 0 °C over 10 minutes. 2 O 2 (2.55mL, 30% w / v, 0.0225mol). The reaction was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with water (30ml), extracted with ethyl acetate (2×30ml), and the combined organic layers were washed with water (50ml), dried over sodium sulfate, and concentrated. The positional isomers were separated and purified by preparative HPLC (gradient: 0-20% MeCN / 10mM ammonium bicarbonate) to give:

[1047] The first eluting peak was 5-chloro-1′-[(1-methylpyrazol-4-yl)methyl]spiro[indan-3,4′-piperidin]-1-ol (300) (8 mg, 3%). 1 H NMR (400 MHz, DMSO d 6 ), 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] + .

[1048] The second eluting peak was 6-chloro-1′-[(1-methylpyrazol-4-yl)methyl]spiro[indan-1,4′-piperidin]-2-ol (301) (16 mg, 6%). 1 H NMR (400 MHz, DMSO d 6 ), 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 positional isomers were confirmed by the nuclear Overhauser effect.

[1049] Compound 302

[1050] 5-Chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (302)

[1051]

[1052] Step 1: Preparation of 5-chlorospiro[indan-3,4'-piperidin]-1-one (C230)

[1053] A solution of 6-chloro-3-oxo-spiro[indan-1,4'-piperidin]-1'-carboxylic acid tert-butyl ester (540 mg, 1.61 mmol) in 4 mL of methanol and HCl (2 mL, 4M, 8.000 mmol)-dioxane solution 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) (435 mg, 98%). LCMS m / z: 236.11 [M+1] + .

[1054] Step 2: Preparation of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-one (C231)

[1055] To 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 DCE was added STAB (386 mg, 1.830 mmol) and stirred at ambient temperature for 6 hours. The solution was neutralized and concentrated, 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] + .

[1056] Step 3: Preparation of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (302)

[1057] 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 LiBH 4 (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 / 0.1% formic acid) gave 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidine]-1-ol 302 (20.4 mg, 87%). 1H NMR (300MHz, chloroform-d) δ8.45 (s, 1H), 7.95 (s, 1H), 7.70 (s, 1H), 7.37 (d, J = 8.0Hz, 1H), 7.33-7. 18(m,2H),5.19(dd,J=7.1,5.0Hz,1H),4.69(dd,J=6.9,5.6Hz,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] + .

[1058] Compound 303

[1059] 5-Chloro-1-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (303)

[1060]

[1061] 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 ether was added (methyl)magnesium bromide (280 μL, 1.4 M, 0.3920 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. Two drops of saturated ammonium chloride and DCM (10 ml) were added, followed by Na 2 SO 4 The organic layer was filtered, concentrated, and the crude residue was purified by reverse phase HPLC (gradient: 0-50% MeCN / 0.1% TFA in water) to give 5-chloro-1-methyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (trifluoroacetate) 303 (0.6 mg, 5%) ESI-MS m / z: 438.09 [M+1] + .

[1062] Compound 304

[1063] 5-Methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[1H-2-benzothiophene-3,4'-piperidine](304)

[1064]

[1065] Step 1: Synthesis of tert-butyl 4-hydroxy-4-[5-methyl-2-(sulfanylmethyl)phenyl]piperidine-1-carboxylate (C233)

[1066] To a stirred solution of (2-bromo-4-methyl-phenyl)methanethiol (C232) (2.0 g, 0.0083 mol) in THF (20 mL) was added n-BuLi in hexane (8.32 mL, 2.5 M, 0.0208 mol) at -78 °C. The reaction mixture was stirred for 1 hour. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.6538 g, 0.0083 mol) in ether (6 mL) was added to the reaction mixture, and the reaction mixture was stirred at -78 °C for 2 hours. The reaction was heated with NH 4 The mixture was quenched with Cl solution and extracted with EtOAc (2×80 mL). The organic layer was washed with brine (50 mL) and purified by Na 2 SO 4 Dry and concentrate.The crude residue was purified by reverse phase HPLC (gradient: 0-20% MeCN / 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) + .

[1067] Step 2: Preparation of 5-methylspiro[1H-2-benzothiophene-3,4'-piperidine](C234)

[1068] 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. OE 2(2.0580 g, 1.8212 mL, 0.0145 mol). 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(br s,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] + .

[1069] Step 3: Preparation of 5-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[1H-2-benzothiophene-3,4'-piperidine] (304)

[1070] 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) was added 4-(chloromethyl)-1-methyl-pyrazole (160 mg, 0.0011 mol) at room temperature, followed by K 2 CO 3 (830 mg, 0.0060 mol) and a catalytic amount of KI (40 mg, 240.96 μmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the crude compound was purified by reverse phase HPLC (gradient: 0-20% MeCN / 0.1% TFA) to give 5-methyl-1'-[(1-methylpyrazol-4-yl)methyl]spiro[1H-2-benzothiophene-3,4'-piperidine] 304 (32 mg, 8%). 1 H 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] + .

[1071] Compound 305

[1072] 5-Chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidine](305)

[1073]

[1074] Step 1: Preparation of tert-butyl 5-chlorospiro[indoline-3,4'-piperidine]-1-carboxylate (C236)

[1075] To a solution of 5-chlorospiro[indoline-3,4'-piperidine] C235 (170 mg, 0.7633 mmol) in AcOH (6.5 mL, 10% w / w) (aq.) was added a Boc 2 O (174.9 mg, 184.1 μL, 0.8015 mmol) in 1,4-dioxane (6.5 mL), and the mixture was vigorously stirred for 16 hours. It was diluted with water (10 mL), extracted with ethyl acetate (2×10 mL), and dried over MgSO 4 Drying and evaporation gave tert-butyl 5-chlorospiro[indoline-3,4'-piperidine]-1-carboxylate (160 mg, 65%) as a yellow oil which was used directly without further purification.

[1076] Step 2: Preparation of tert-butyl 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidine]-1-carboxylate (C237)

[1077] 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 hours. 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%) 1H 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 = 13. 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] + .

[1078] Step 3: Preparation of 5-chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indoline-3,4'-piperidine] (305)

[1079] 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 4M 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] + .

[1080] Compounds 306 and 307

[1081] (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)

[1082]

[1083] Step 1: Preparation of (2S)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (C238)

[1084] To a stirred solution of (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (25 g, 0.1172 mol) in ethyl acetate (550 mL) at room temperature was added 2,2-dimethyl-1,3-dioxane-4,6-dione (17 g, 0.1180 mol). After 5 minutes, triisopropyl borate (37.490 g, 46 mL, 0.1993 mol), NH 4 To the product of 4- (2S) -4- (2,2- dimethyl -4,6- dioxo -1,3- dioxane -5- subunit) -2- methyl -piperidine -1- carboxylic acid tert-butyl ester (21g, 40%) LCMS m / z: 338.28 [M-1] - .

[1085] Step 2: Preparation of (2S)-4-(3-chlorophenyl)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (C239)

[1086] To a stirred solution of magnesium (1.2g, 0.0494mol) in THF (250mL) was added iodine (388mg, 0.0787mL, 0.0015mol) and 1-bromo-3-chloro-benzene (4.2885g, 7mL, 0.0224mol) 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. (2S)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (10g, 0.0222mol) and CuI (2g, 0.0105mol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0°C and washed with saturated NH 4 Cl solution (250mL) was quenched. It was then extracted with EtOAc (250mL×3). The organic layer was washed with brine solution (150mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain (2S)-4-(3-chlorophenyl)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (9g, 30%). LCMS m / z 452.19[M+1]+ .

[1087] Step 3: Preparation of 2-[(2S)-1-tert-butoxycarbonyl-4-(3-chlorophenyl)-2-methyl-4-piperidinyl]acetic acid (C240)

[1088] To a stirred solution of (2S)-4-(3-chlorophenyl)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 0.0043 mol) in water (12 mL) in a microwave vial at room temperature, 3-pentanone (15 mL) was added. 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), the organic layer was separated and concentrated to obtain 2-[(2S)-1-tert-butoxycarbonyl-4-(3-chlorophenyl)-2-methyl-4-piperidinyl]acetic acid (1.9 g, 44%). LCMSMS m / z: 368.21[M+1] + .

[1089] Step 4: Preparation of (2S)-4-(2-chloro-2-oxo-ethyl)-4-(3-chlorophenyl)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (C241)

[1090] A stirred solution of 2-[(2S)-1-tert-butoxycarbonyl-4-(3-chlorophenyl)-2-methyl-4-piperidinyl]acetic acid (2.25 g, 0.0043 mol) in MTBE (35 mL) was cooled to -10 ° C. 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 then added. After 20 minutes, the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched in dry methanol and then distilled under vacuum to obtain (2S)-4-(2-chloro-2-oxo-ethyl)-4-(3-chlorophenyl)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (2.5 g, 90%).

[1091] Step 5: Preparation of (2'S)-6-chloro-2'-methyl-3-oxo-spiro[indan-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (C242)

[1092] AlCl 3 A stirred solution of (62 mg, 464.97 μmol) in DCM (8 mL) was cooled to -30 °C and then added with AlCl 3The mixture was stirred at -20 °C for 1 hour, then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was poured into ice-cold water (10 mL) and stirred for 30 minutes. The aqueous layer was separated and added to another flask containing MTBE (10 mL). The solution was cooled to -10 °C, NaOH (10 M aqueous solution) (0.1 mL, 10 M, 0.0010 mol) and Boc 2 The mixture was stirred for 16 hours at room temperature. 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: 0-20% MeCN / 10 mM ammonium bicarbonate) to give (2'S)-6-chloro-2'-methyl-3-oxo-spiro[indane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (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,1H) LCMS m / z:350.18[M+1] + .

[1093] Step 6: Preparation of (2'S)-6-chloro-3-hydroxy-2'-methyl-spiro[indan-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (C243)

[1094] A stirred solution of (2'S)-6-chloro-2'-methyl-3-oxo-spiro[indane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (500 mg, 0.0014 mol) in MeOH (30 mL) was cooled to -10 °C and NaBH 4(200mg, 0.2116mL, 0.0053mol). After 20 minutes, the reaction was slowly warmed to room temperature and stirred for 4 hours. The reaction mixture was quenched with ice-cold water (60mL), then extracted with DCM (150mL×3). The organic layer was washed with saline solution (40mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (2'S)-6-chloro-3-hydroxy-2'-methyl-spiro[indane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (450mg, 87%) LCMS m / z 352.07[M+1] + .

[1095] Step 7: Preparation of (2'S)-5-chloro-2'-methyl-spiro[indan-3,4'-piperidin]-1-ol (C244)

[1096] A stirred solution of (2'S)-6-chloro-3-hydroxy-2'-methyl-spiro[indane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (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 minutes, the reaction was slowly allowed to reach room temperature and stirred for 4 hours. The reaction mixture was concentrated to give (2'S)-5-chloro-2'-methyl-spiro[indane-3,4'-piperidine]-1-ol (trifluoroacetate) (350 mg, 70%) LCMS m / z 252.17 [M+1] + .

[1097] 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)

[1098] 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 K 2 CO 3(580 mg, 0.0042 mol), 4-(chloromethyl)-1-(2-methylsulfonylethyl)pyrazole (hydrochloride) (200 mg, 655.98 μmol) and KI (120 mg, 722.88 μmol). 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 to obtain a crude residue, which was purified by chiral SFC chromatography (column: ChiralcelOX-H (30×250 mm), 5 μ; gradient: 40% (0.5% DEA / MeOH) / CO 2 ; temperature: 30°C; flow rate: 60.0 g / min) to obtain:

[1099] 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] + .

[1100] 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] + .

[1101] Compound 308

[1102] (2'S)-2',5-dimethyl-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-ol (308)

[1103]

[1104] Compound 308 was prepared using 1-bromo-3-methylbenzene in a manner similar to compounds 306 and 307. This provided (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) δ8.40 (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), 4.29 ( 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] + .

[1105] Compound 309

[1106] (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)

[1107]

[1108] Compound 309 was prepared using 1-bromo-3-methylbenzene in a manner similar to compounds 306 and 307. This provided (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 (300MHz, chloroform-d) δ8.41(s,1H),8.00(s,1H),7.74(s,1H),7.24(t,J=7.5Hz,1H),7.07(dd,J=7.4,5.6Hz,2H),5.28(dd,J=6.9,2.4Hz,1H),4.71( dd,J=6.9,5.3Hz,2H),4.50(dd,J=14.2,1.8Hz,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] + .

[1109] Compound 310

[1110] 6-Chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indan-1,4'-piperidine]

[1111]

[1112] Step 1: Preparation of 6-chlorospiro[indan-1,4'-piperidine](C246)

[1113] A solution of tert-butyl 6-chlorospiro[indane-1,4'-piperidine]-1'-carboxylate (50 mg, 0.1554 mmol) in DCM (2 mL) was treated with HCl (200 μL, 4 M, 0.8000 mmol) and the reaction was stirred at ambient temperature for 3 hours. The reaction was concentrated to give 6-chlorospiro[indane-1,4'-piperidine] (hydrochloride) (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] + .

[1114] Step 2: Preparation of 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[indan-1,4'-piperidine] (310)

[1115] A solution of 6-chlorospiro[indane-1,4'-piperidine](hydrochloride) (28mg, 0.1035mmol) and 1-methylpyrazole-4-carboxaldehyde (20mg, 0.1816mmol) in DCM (1.3mL) was treated with STAB (70mg, 0.3319mmol). After 3 hours, the reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM (3x) by a phase separator. The organic matter was concentrated and purified by reverse phase HPLC (gradient: 0-20% MeCN / 0.1% TFA aqueous solution) to obtain 6-chloro-1'-[(1-methylpyrazole-4-yl)methyl]spiro[indane-1,4'-piperidine](trifluoroacetate) (30.5mg, 59%). 1 H 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] + .

[1116] Compound 311

[1117] 6-Chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isoindoline-1,4'-piperidine](311)

[1118]

[1119] Step 1: Preparation of 4-[(4-chloro-2-iodo-benzoyl)-[(4-methoxyphenyl)methyl]amino]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (C248)

[1120] Prepare a solution of tert-butyl 4-oxopiperidine-1-carboxylate (22g, 110.42mmol), (4-methoxyphenyl)methylamine (15.2g, 110.80mmol) and toluene (250mL). The mixture is heated to reflux overnight. After cooling to room temperature, the solvent is evaporated. The obtained residue can be directly used in the next step without further purification. The crude residue is redissolved in toluene (500mL), then 4-chloro-2-iodo-benzoic acid (25g, 86.737mmol) and triethylamine (14.520g, 20mL, 143.49mmol) are added. The resulting solution is heated under reflux overnight. After cooling to room temperature, 100mL of 0.5MHCl aqueous solution is added to the mixture, and each layer is vibrated and separated. The organic layer is washed with brine (200mL), dried over anhydrous sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography (gradient: 0-40% EtOAc / hexanes) to give 4-[(4-chloro-2-iodo-benzoyl)-[(4-methoxyphenyl)methyl]amino]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (41 g, 49%). LCMS m / z: 583.4 [M+1] + .

[1121] Step 2: Preparation of 6'-chloro-2'-[(4-methoxyphenyl)methyl]-3'-oxo-spiro[2,3-dihydropyridine-4,1'-isoindoline]-1-carboxylic acid tert-butyl ester (C249

[1122] In a 500-mL round-bottom flask equipped with a condenser, 4-[(4-chloro-2-iodo-benzoyl)-[(4-methoxyphenyl)methyl]amino]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (23g, 23.676mmol) was dissolved in acetonitrile (300mL), and the mixture was purged with nitrogen for 1 hour. Palladium acetate (1.77g, 7.8839mmol), triphenylphosphine (4.14g, 15.784mmol), potassium carbonate (11g, 79.591mmol) and tetrabutylammonium bromide (12.7g, 39.396mmol) were added. The mixture was heated under reflux overnight. The mixture was cooled to room temperature and rotary evaporated. The residue was dissolved in EtOAc (100mL) and water (100mL). 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: 0-40% EtOAc / hexanes) to yield 6'-chloro-2'-[(4-methoxyphenyl)methyl]-3'-oxo-spiro[2,3-dihydropyridine-4,1'-isoindoline]-1-carboxylic acid tert-butyl ester (6 g, 55%). LCMS m / z: 455.4 [M+1] + .

[1123] Step 3: Preparation of 5'-chlorospiro[2,3-dihydro-1H-pyridine-4,3'-isoindolin]-1'-one (C250)

[1124] A solution of 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 was at pH = 7. The aqueous solution was saturated with NaCl and extracted with EtOAc (3 x 100 mL). The combined organic solution was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to produce crude 5'-chlorospiro[2,3-dihydro-1H-pyridine-4,3'-isoindoline]-1'-one (13 g). This product was used in the next step without further purification. LCMS m / z: 235.2 [M+1] + .

[1125] Step 4: Preparation of 5-chlorospiro[isoindoline-3,4'-piperidin]-1-one (C251)

[1126] To a solution of crude 5'-chlorospiro[2,3-dihydro-1H-pyridine-4,3'-isoindolin]-1'-one (13 g, 43.207 mmol) in acetic acid (100 mL) was added PtO 2 (1 g, 4.4037 mmol), and the mixture was purged with nitrogen, evacuated and refilled with hydrogen. 2 Stir overnight under a 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 saturated aqueous sodium bicarbonate solution was added to the residue until pH=7. It 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 produce 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] + .

[1127] Step 5: Preparation of 5-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isoindoline-3,4'-piperidin]-1-one (C252)

[1128] MP-sodium cyanoborohydride (145 mg, 2 mmol / g, 0.2900 mmol) was added 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). The vial was capped and heated to 110 °C for 30 minutes using a microwave reactor. After cooling, the solid phase reagent was filtered off and washed with 15 mL of dichloromethane. The combined filtrates were removed by rotary evaporation and the residue was purified by reverse phase HPLC (Gradient: 0-20% MeCN / 0.1% TFA in water) to yield 5-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isoindoline-3,4'-piperidin]-1-one (trifluoroacetate salt) (28.6 mg, 30%). 1H 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] + .

[1129] Step 6: Preparation of 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isoindoline-1,4'-piperidine] (311)

[1130] 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 BH 3 -DMS (1.7 mL, 2 M, 3.4000 mmol) was added and the suspension was stirred at room temperature for 1 hour and at 110 ° C (reflux) for 2 hours. THF (6 mL) was added to help dissolve the starting material. Heating was continued overnight. After cooling to room temperature, MeOH (20 mL) was added and the solution was refluxed for 15 minutes. The solvent was removed by rotary evaporation. Purification by reverse phase HPLC (gradient: 0-20% MeCN / 0.1% TFA in water) provided 6-chloro-1'-[(1-methylpyrazol-4-yl)methyl]spiro[isoindoline-1,4'-piperidine](trifluoroacetic acid (2)) 311 (27 mg, 2%). 1 HNMR(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),4.72–4.52(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] + .

[1131] Compound 312

[1132] 1-[5-Chloro-1'-[[1-(2-methylsulfonylethyl)pyrazol-4-yl]methyl]spiro[indan-3,4'-piperidin]-1-yl]imidazolidin-2-one (312)

[1133]

[1134] Step 1: Preparation of tert-butyl 3-[2-(tert-butoxycarbonylamino)ethylamino]-6-chloro-spiro[indan-1,4'-piperidine]-1'-carboxylate (C253)

[1135] 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 heated with NaBH 3 CN (500mg, 7.956mmol) is processed, then AcOH (400 μ L, 7.034mmol) is processed and heated to 65 ° C. After 2 hours, the reaction is cooled to room temperature, concentrated by rotary evaporator, and the residue is stirred overnight with DCM and saturated sodium bicarbonate. The reaction mixture is extracted with DCM (3x) by phase separator. Organic matter is concentrated by rotary evaporator, and material is purified by flash column chromatography (gradient: 0-100% EtOAc / heptane), to provide 3- [2- (tert-butoxycarbonylamino) ethylamino] -6- chloro-spiro [indane -1,4 '- piperidine] -1 '- carboxylic acid tert-butyl ester (500mg, 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=9.3 Hz,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] + .

[1136] Step 2: Preparation of tert-butyl 6-chloro-3-(2-oxoimidazolidin-1-yl)spiro[indan-1,4'-piperidine]-1'-carboxylate (C254)

[1137] THF (8.5 mL) containing 3-[2-(tert-butoxycarbonylamino)ethylamino]-6-chloro-spiro[indane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (500 mg, 1.011 mmol) was treated with KtBuO (370 mg, 3.297 mmol) and heated to 60 ° C for 30 minutes. The reaction was cooled to room temperature, diluted with water, and extracted with DCM (3x) through a phase separator. The organics were concentrated by rotary evaporator to give 6-chloro-3-(2-oxoimidazolidin-1-yl)spiro[indane-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (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...

Claims

1. A compound represented by the following structural formula: Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein: Ring A is selected from 6-membered aryl and 6-membered heteroaryl groups, wherein the 6-membered aryl or 6-membered heteroaryl group is optionally substituted by 1, 2, 3 or 4 R 1 Group substitution; X is selected from -CR 1a R 1b -, -C(O)-, -S-, -S(O)2-, -NR 1c - and -O-; Y is selected from -CR 1a R 1b -、-C(O)-、-S(O)2-、-NR 1c - and -O-; Z is selected from bond, -CR 1a R 1b -、-NR 1c -, -C(O)-, -S(O)2- and -O-, among which: At least one of X and Y is selected from -CR 1a R 1b - and -C(O)-; R 1a , R 1b and R 1c is independently selected at each occurrence from hydrogen and R 1 Group; R 1 is independently selected at each occurrence from halogen, -OH, cyano, phenyl, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)R c 、-C(=O)OR c 、-C(=O)N(R c )2 and -OS(=O)2R c Group, in which: R c is independently selected at each occurrence from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl groups; R 1 The 4- to 6-membered heterocyclyl includes 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and is optionally substituted by a group selected from the group consisting of oxo and -OH; R 1 The C1-C6 alkyl and the C1-C6 alkenyl are each optionally substituted by 1 to 4 groups independently selected from the following: halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkoxy, 3 to 5 membered heterocyclyl (optionally further substituted by R c substituted), 3- to 5-membered heteroaryl groups and C6 aryl groups; R 1 The C1-C6 alkoxy group is optionally substituted by 1 to 3 groups independently selected from the following: -OH, cyano and halogen groups; R 1 The C3-C6 carbocyclyl is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl) and -C(=O)N(C1-C4 alkyl)2 groups; and R 1 The phenyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl) and -C(=O)N(C1-C4 alkyl)2 groups; R 2 and R 3 are each independently selected from hydrogen and a C1-C4 alkyl group; R 4 Selected from C1-C6 alkyl, -C(=O)O(C1-C4 alkyl) and Group, in which: R 4 The C1-C6 alkyl is optionally substituted by 1 to 5 groups independently selected from the following: halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C1-C4 alkoxy, C3-C6 carbocyclyl, C6 aryl, -O-(C6 aryl), 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl groups, wherein: The C6 aryl group and the -O-(C6 aryl) group are each optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen and C1-C4 haloalkyl groups; Ring B is selected from C3-C 12 Carbocyclic group, 3 to 12 membered heterocyclic group, C6 and C 10 aryl and 5 to 10 membered heteroaryl groups, wherein ring B is optionally substituted by 1, 2, 3, 4 or 5 R a Group substitution; wherein: R a is independently selected at each occurrence from halogen, cyano, oxo, C1-C8 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C1-C6 haloalkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Carbocyclic, C6 and C 10 aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(=O)NR h R i 、-C(=O)OR k , -C(=O)(C1-C4alkylene)OR k 、-C(=O)R k 、-C(=O)(C1-C4alkylene)S(=O) p R k 、-C(=O)(C1-C4alkylene)S(=O) p NR h R i 、-C(=O)(C1-C4alkylene)NR i S(=O) p R k 、-C(=O)(C1-C4alkylene)NR h C(=O)R k 、-C(=O)C(=O)R k 、-NR h R i 、-NH(CH2) q CHR h R i 、-NH(CH2) q NR h R i 、-NR h C(=O)R k 、-NR h C(=O)OR k 、-NR h C(=O)(C1-C4 alkylene)OR k 、-NR h C(=O)O(C1-C4 alkylene)R k 、-NR h C(=O)NR i R j 、-NR h C(=O)(C1-C4alkylene)NR i S(=O) p R k 、-NR h S(=O) p R k 、 -NR h C(=O)(C1-C4 alkylene)S(=O) p R k 、-NR h S(=O) p (C1-C4 alkylene)C(=O)OR k 、-NR h C(=O)[O(CH2) q ] r OC(=O)NR h R i (CH2) q [O(CH2) q ] r (C1-C6 alkyl) (optionally with 1 to 3 R m Group substitution), -NR h C(=O)(C1-C6 alkylene)[O(CH2) q ] r OC(=O)NR h R i (CH2) q [O(CH2) q ] r (C1-C6 alkyl) (optionally with 1 to 3 R m Group substitution), -OR k 、-OC(=O)R k 、-OC(=O)OR k 、-OC(=O)NR h R i 、-[O(CH2) q ] r O(C1-C6 alkyl), -S(=O) p R k and -S(=O) p NR h R i Group, in which: R a -C(=O)(C1-C4alkylene)S(=O) p R k , -C(=O)(C1-C4alkylene)OR k 、-C(=O)(C1-C4alkylene)S(=O) p NR h R i 、-C(=O)(C1-C4alkylene)NR i S(=O) p R k 、-C(=O)(C1-C4alkylene)NR h C(=O)R k 、-NR h C(=O)O(C1-C4 alkylene)R k 、-NR h C(=O)(C1-C4 alkylene)S(=O) p R k、 -NR h C(=O)(C1-C4 alkylene)OR k 、-NR h S(=O) p (C1-C4 alkylene)C(=O)OR k and-NR h C(=O)(C1-C4alkylene)NR i S(=O) p R k The C1-C4 alkylene in each of is optionally substituted with 1 to 3 -OH groups; R a The C1-C8 alkyl, the C1-C6 haloalkyl, the C1-C6 alkoxy and the C2-C8 alkenyl are each optionally substituted by 1 to 3 groups independently selected from the following: cyano, -C(=O)R k 、-C(=O)OR k 、-C(=O)NR h R i , =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- to 8-membered heteroaryl) (optionally substituted with 1 to 3 R m group), C3-C6 carbocyclic group (optionally substituted with 1 to 3 R m C6 to C 10 Aryl (optionally substituted with 1 to 3 R m substituted with a group), a 4- to 10-membered heterocyclic group (optionally substituted with 1 to 3 R m substituted with 1 to 3 R m group substituted) group; R a The C3-C 12 The carbocyclic group, the 3 to 12 membered heterocyclic group, the C6 and C 10 The aryl group and the 5- to 10-membered heteroaryl group are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, oxo, cyano, C1-C6 alkyl (optionally substituted by 1 to 3 R m Group substitution), -C(=O)R k 、-C(=O)OR k 、-NR h R i 、-OR k 、-S(=O) p R k 、-S(=O) p NR h R i and a 5- to 10-membered heterocyclyl group, wherein: R h , R i and R j Each occurrence is independently selected from hydrogen, C1-C6 alkyl, C6-C 10 Aryl, C3-C8 carbocyclic group (optionally substituted by 1 to 3 R m substituted with 1 to 3 R m substituted with 1 to 3 R m A group substituted with a (substituted) group, wherein: R h , R i and R j The C1-C6 alkyl group of any one of the following is optionally substituted by 1 to 3 groups independently selected from the following: halogen, cyano, -OH, C1-C4 alkoxy, -C(=O)NH(C1-C4 alkyl), C3-C6 carbocyclyl (optionally substituted by 1 to 3 R m substituted with 1 to 3 R m substituted with 1 to 3 R m group substituted) group; R k is independently selected at each occurrence from hydrogen, C1-C6 alkyl, benzyl, C6 aryl, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein: R k The C1-C6 alkyl of any one of is optionally substituted by 1 to 5 groups independently selected from the following: halogen, cyano, -NH2, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl (optionally substituted by 1 to 3 halogen groups), 5 to 10 membered heterocyclyl (optionally substituted by 1 to 3 -OH groups) and 5 to 10 membered heteroaryl (optionally substituted by 1 to 3 -OH groups) groups; and R k The C3-C6 carbocyclyl, benzyl and C6 aryl of any one of the above are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, oxo, -OH, -C(=O)NH2, -C(=O)N(CH3)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl (optionally substituted by 1 to 3 halogen groups), C6 aryl (optionally substituted by 1 to 3 halogen groups) and 5 to 10 membered heteroaryl (optionally substituted by 1 to 3 halogen groups), wherein: The C1-C4 alkyl group is optionally substituted with 1 to 3 -OH groups; and R k The 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl of any one of the above are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -C(=O)CH3, -NH2, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl and C1-C4 alkoxy groups, wherein: The C1-C4 alkyl group is optionally substituted with 1 to 3 -OH groups; R m is independently selected at each occurrence from halogen, cyano, oxo, -(CH2) n C(=O)NH2、-NH2、-NH(C1-C4 alkyl)2、-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, wherein: R m The C1-C6 alkyl, the C1-C6 alkoxy and the 5- to 10-membered heterocyclyl of any one of are optionally substituted by 1 to 3 groups independently selected from the following: halogen, cyano, -OH and C1-C4 alkoxy groups; and n, at each occurrence, is an integer selected from 0, 1, and 2; p at each occurrence is an integer independently selected from 1 and 2; and q and r are integers independently selected from 0, 1, 2 and 3 at each occurrence.

2. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein: Ring A is optionally substituted by 1, 2 or 3 R 1 phenyl substituted with a radical; R 1a , R 1b and R 1c is independently selected at each occurrence from hydrogen and R 1 Group; R 1 is independently selected at each occurrence from halogen, -OH, cyano, C1-C6 alkyl, C1-C6 alkoxy, 4- to 6-membered heterocyclyl, -C(=O)OR c 、-C(=O)R c and -C(=O)N(R c )2 groups, wherein: R c is independently selected at each occurrence from hydrogen and a C1-C4 alkyl group; R 1 The 4- to 6-membered heterocyclic group includes a heteroatom selected from nitrogen and oxygen; R 1 The C1-C6 alkyl is optionally substituted by 1 to 4 groups independently selected from the group consisting of halogen, cyano, -OH, C1-C4 alkoxy, 3 to 5 membered heterocyclyl, and 3 to 5 membered heteroaryl groups; and R 1 The C1-C6 alkoxy group is optionally substituted by 1 to 3 independently selected halogen atoms; R 2 and R 3 are each independently selected from hydrogen and a C1-C4 alkyl group; R 4 Selected from C1-C6 alkyl and Group, in which: R 4 The C1-C6 alkyl is optionally substituted by 1 to 3 groups independently selected from halogen, cyano, -OH, C6 aryl, 5 to 10 membered heterocyclyl and 5 to 10 membered heteroaryl groups, wherein: The C6 aryl group is optionally substituted by 1 to 3 independently selected halogen atoms; Ring B is selected from C3-C 12 carbocyclyl, 3 to 12 membered heterocyclyl, C6 aryl and 5 to 10 membered heteroaryl groups, wherein Ring B is optionally substituted by 1, 2 or 3 R a Group substitution; wherein: R a is independently selected at each occurrence from halogen, cyano, C1-C8 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C1-C6 haloalkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Carbocyclic, C6 and C 10 aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(=O)NR h R i 、-C(=O)OR k 、-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 Group, in which: R a The C1-C8 alkyl, the C1-C6 haloalkyl, the C1-C6 alkoxy and the C2-C8 alkenyl are each optionally substituted by 1 to 3 groups independently selected from the following: -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 , C3-C6 carbocyclic group (optionally substituted by 1 to 3 R m C6 to C 10 Aryl (optionally substituted with 1 to 3 R m substituted with a group), a 4- to 10-membered heterocyclic group (optionally substituted with 1 to 3 R m substituted with 1 to 3 R m group substituted) group; R a The C3-C 12 The carbocyclic group, the 3 to 12 membered heterocyclic group, the C6 and C 10 The aryl and 5- to 10-membered heteroaryl groups are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted by 1 to 3 R m Group substitution), -NR h R i 、-S(=O) p R k and -S(=O) p NR h R i Group, in which: R h , R i and R j is independently selected at each occurrence from hydrogen, C1-C6 alkyl, 5- to 10-membered heteroaryl (optionally substituted by 1 to 3 R m substituted with 1 to 3 R m Group substitution), wherein: R h , R i and R j The C1-C6 alkyl group of any one of is optionally substituted by 1 to 3 groups independently selected from halogen and -OH groups; R k is independently selected at each occurrence from hydrogen, C1-C6 alkyl, benzyl, C6 aryl, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein: R k The C1-C6 alkyl of any one of is optionally substituted by 1 to 5 groups independently selected from the following: halogen, cyano, -NH2, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl (optionally substituted by 1 to 3 halogen groups), 5 to 10 membered heterocyclyl (optionally substituted by 1 to 3 -OH groups) and 5 to 10 membered heteroaryl (optionally substituted by 1 to 3 -OH groups) groups; and R k The 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl of any one of the above are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl and C1-C4 alkoxy groups; R m is independently selected at each occurrence from oxo, halogen, cyano, -(CH2) n C(=O)NH2、-NH2、-NH(C1-C4 alkyl)、-N(C1-C4 alkyl)2、C1-C6 alkyl、-OR k and a C3-C6 cycloalkyl group, wherein: R m The C1-C6 alkyl of any one of is optionally substituted by 1 to 3 groups independently selected from: halogen and -OH group; and n, at each occurrence, is an integer selected from 0, 1, and 2; p at each occurrence is an integer independently selected from 1 and 2; and All other variables not specifically defined herein are as defined in claim 1.

3. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1 or 2, wherein: Ring A is optionally substituted by 1, 2 or 3 R 1 phenyl substituted with a radical; R 1a , R 1b and R 1c is independently selected at each occurrence from hydrogen and R 1 Group; R 1 is independently selected at each occurrence from halogen, -OH, cyano, C1-C6 alkyl, C1-C6 alkoxy, 4- to 6-membered heterocyclyl, -C(=O)OR c 、-C(=O)R c and -C(=O)N(R c )2 groups, wherein: R c is independently selected at each occurrence from hydrogen and a C1-C4 alkyl group; R 1 The 4- to 6-membered heterocyclic group includes a heteroatom selected from nitrogen and oxygen; R 1 The C1-C6 alkyl is optionally substituted by 1 to 4 groups independently selected from the group consisting of halogen, -OH, C1-C4 alkoxy, 3 to 5 membered heterocyclyl, and 3 to 5 membered heteroaryl groups; and R 1 The C1-C6 alkoxy group is optionally substituted by 1 to 3 independently selected halogen atoms; R 2 and R 3 are each independently selected from hydrogen and a C1-C2 alkyl group; R 4 Selected from C1-C6 alkyl and Group, in which: R 4 The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from: -OH and C6 aryl groups, wherein: The C6 aryl group is optionally substituted by 1 to 3 independently selected halogen atoms; Ring B is selected from C3-C 12 carbocyclyl, 3 to 12 membered heterocyclyl, C6 aryl and 5 to 10 membered heteroaryl groups, wherein Ring B is optionally substituted by 1, 2 or 3 R a Group substitution; wherein: R a is independently selected at each occurrence from halogen, cyano, C1-C8 alkyl, C1-C6 haloalkyl, C2-C8 alkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 carbocyclyl, C6 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 Group, in which: R a The C1-C8 alkyl, the C1-C6 haloalkyl, the C1-C6 alkoxy and the C2-C8 alkenyl are each optionally substituted by 1 to 3 groups independently selected from the following: -C(=O)NR h R i 、-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 , 5 to 10 membered heterocyclic group (optionally substituted by 1 to 3 R m substituted with 1 to 3 R m group substituted) group; R a The C3-C 12 The carbocyclyl, the 3 to 12 membered heterocyclyl, the C6 aryl and the 5 to 10 membered heteroaryl are each optionally substituted by 1 to 3 groups independently selected from the following: C1-C6 alkyl (optionally substituted by 1 to 3 R m -S(=O) p R k Group, in which: R h , R i and R j Each of the following occurrences is independently selected from hydrogen, C1-C6 alkyl and 5- to 10-membered heteroaryl (optionally replaced by 1 to 3 R m Group substitution), wherein: R h , R i and R j The C1-C6 alkyl of any one of is optionally substituted with 1 to 3 -OH groups; R k is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl groups, wherein: R k The C1-C6 alkyl group of any one of is optionally substituted by a cyano group; and R k The 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl of any one of are each optionally substituted by 1 to 3 groups independently selected from halogen, C1-C4 alkyl and C3-C6 cycloalkyl groups; R m is independently selected at each occurrence from halogen, cyano, -(CH2) n C(=O)NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C6 alkyl, -OR k and a C3-C6 cycloalkyl group, wherein: R m The C1-C6 alkyl of any one of is optionally substituted with 1 to 3 -OH groups; and n, at each occurrence, is an integer selected from 0 and 1; p is 2 at every occurrence; and All other variables not specifically defined herein are as defined in claim 1.

4. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein: R 4 Selected from A group in which ring B is optionally substituted by 1, 2 or 3 R a group substitution; and All other variables not specifically defined herein are as defined in any one of Claims 1 to 3.

5. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein: X is selected from -CR 1a R 1b -, -C(O)-, and -O-; Y is selected from -CR 1a R 1b -and-NR 1c -; Z is selected from the bond and -CR 1a R 1b -,in: At least one of X and Y is selected from -CR 1a R 1b - and -C(O)-; and All other variables not specifically defined herein are as defined in any one of Claims 1 to 4.

6. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein the compound is represented by the following structural formula: A tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein all variables not specifically defined herein are as defined in any one of claims 1 to 5.

7. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein the compound is represented by one of the following structural formulas: Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein: Ring A is optionally substituted with 1 or 2 R 1 group substitution; and All variables not specifically defined herein are as defined in any one of Claims 1 to 5.

8. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claims 1 to 5, wherein the compound is represented by the following structural formula: Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein: Ring A is optionally substituted with 1 or 2 R 1 group substitution; and All variables not specifically defined herein are as defined in any one of Claims 1 to 5.

9. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claims 1 to 5, wherein the compound is represented by one of the following structural formulas: Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein: Ring A is optionally substituted with 1 or 2 R 1 group substitution; and All variables not specifically defined herein are as defined in any one of Claims 1 to 5.

10. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claims 1 to 5, wherein the compound is represented by one of the following structural formulas: Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein: Ring A is optionally substituted with 1 or 2 R 1 group substitution; and All variables not specifically defined herein are as defined in any one of Claims 1 to 5.

11. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein the compound is represented by one of the following structural formulas: Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein: R 1a is selected from hydrogen, halogen, -OH and phenyl groups, wherein: R 1a The phenyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl) and -C(=O)N(C1-C4 alkyl)2 groups; R 1d and R 1e are each independently selected from hydrogen, halogen, -OH, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)OR c 、-C(=O)N(R c )2 and -OS(=O)2R c Group, in which: R c is independently selected at each occurrence from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl groups; and R 1d and / or R 1e The C1-C6 alkyl group is optionally substituted by 1 to 3 groups independently selected from halogen and -OH groups; and All variables not specifically defined herein are as defined in any one of Claims 1 to 5.

12. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein the compound is represented by one of the following structural formulas: Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein: R 1a is selected from hydrogen, phenyl and C(=O)N(R c1 )2 groups, wherein: R 1a The phenyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl) and -C(=O)N(C1-C4 alkyl)2 groups; R c1 is independently selected at each occurrence from hydrogen and a C1-C4 alkyl group; R 1d and R 1e are each independently selected from hydrogen and halogen groups; and All variables not specifically defined herein are as defined in any one of Claims 1 to 5.

13. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein the compound is represented by one of the following structural formulas: Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any one of the foregoing, wherein: R 1d and R 1e are each independently selected from hydrogen, halogen, C1-C4 alkyl and C1-C4 haloalkyl groups; and All variables not specifically defined herein are as defined in any one of Claims 1 to 5.

14. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein ring A is an unsubstituted phenyl group.

15. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein Ring A is surrounded by 1 or 2 R 1 A phenyl group substituted with a group.

16. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 15, wherein each R 1 Independently selected from halogen, cyano, -CH3, -CH2CH3, -CH2CF2, -CFCF2, -CF2, -CF3, -OCH3, -OCF2 and -OCF3.

17. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 15, wherein each R 1 Independently selected from Cl and F.

18. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 and 14 to 17, wherein X is selected from -C(O)-, -O-, -S-, -CR 1a R 1b -and-NR 1c -, where R 1a , R 1b and R 1c As defined in claim 1.

19. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 18, wherein X is selected from -CH2- and -NH-.

20. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 18, wherein X is -CR 1a R 1b -, where R 1a is hydrogen, and R 1b Selected from R 1 Group.

21. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 18, wherein X is -CHOH-.

22. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 18, wherein X is -O-.

23. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 18, wherein X is -C(O)-.

24. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 and 14 to 22, wherein Y is selected from -CR 1a R 1b -and-NR 1c -.

25. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 23, wherein Y is -CH2.

26. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 23, wherein Y is -CR 1a R 1b , where R 1a and R 1b Each is R 1 , and R 1 It is -CH3.

27. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 23, wherein Y is -CR 1a R 1b , R 1a is hydrogen, and R 1b Selected from R as defined in claim 1 1 Group.

28. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 23, wherein Y is -CR 1a R 1b , R 1a is hydrogen, R 1b YesR 1 , and R 1 Selected from -OH, -CH3, -C(O)NH2, C(O)NHCH3.

29. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 23, wherein Y is -CR 1a R 1b , R 1a and R 1b Both are R 1 , and R 1 Selected from -OH and -CH3.

30. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 23, wherein Y is -NR 1c -, where R 1c YesR 1 , and R 1 is selected from 4 to 6 membered heterocyclic groups.

31. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 23, wherein Y is -NR 1c -, where R 1c YesR 1 , and R 1 yes 32. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 23, wherein Y is -N(CH3)-.

33. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 23, wherein Y is -CH(OH)-.

34. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 23, wherein Y is -NH-.

35. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 23, wherein Y is -N(C(O)CH3)-.

36. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 1, wherein X is selected from -C(O)- and -CR 1a R 1b -, and Y is -NR 1c -, where R 1c It's hydrogen.

37. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1, wherein X is selected from -C(O)- and -CR 1a R 1b -, and Y is -NR 1c -, where R 1c YesR 1 , and R 1 Selected from C1-C6 alkyl and C1-C6 alkoxy groups optionally substituted by 1 to 3 halogen groups.

38. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 1, wherein X is selected from -C(O)- and -CR 1a R 1b -, and Y is -NR 1c -, where R 1c YesR 1 , and R E Selected from -CH3, -CH2CH3, -CH2CH2OH, -CH2CF2, -CH2CF3 and -CH2CH2OCH3.

39. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 4 to 36, wherein Z is selected from a bond, -CR 1a R 1b -、-NR 1c -, -C(O)-, -S(O)2- and -O-.

40. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 37, wherein Z is a bond.

41. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 37, wherein Z is selected from -CR 1a R 1b -.

42. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 39, wherein R 1a and R 1b It's hydrogen.

43. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 39, wherein R 1a and R 1b It's fluorine.

44. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 39, wherein R 1a is hydrogen and R 1b It is -OH.

45. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 39, wherein R 2 and R 3 are independently selected from hydrogen and CH3.

46. ​​The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 39, wherein R 2 and R 3 One of them is hydrogen and the other is CH3.

47. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 44, wherein R 4 selected from C1-C6 alkyl, the alkyl being optionally substituted by 1 to 5 groups independently selected from the following: halogen, cyano, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, C1-C4 alkoxy, C3-C6 carbocyclyl, C6 aryl (optionally substituted by 1 to 3 groups independently selected from halogen and C1-C4 haloalkyl groups), -O-(C6 aryl) (optionally substituted by 1 to 3 groups independently selected from halogen and C1-C4 haloalkyl groups), 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl groups.

48. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 45, wherein R 4 Selected from C1-C6 alkyl substituted by 1 to 2 groups independently selected from -OH, phenyl and phenyl further substituted by halogen.

49. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 45, wherein R 4 Selected from C1-C6 alkyl substituted by -OH and phenyl substituted by Cl.

50. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 45, wherein R 4 Selected from C1-C6 alkyl substituted by -OH and phenyl substituted by 2F.

51. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 45, wherein R 4 Selected from -C(=O)O(C1-C4 alkyl).

52. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 44, wherein R 4 Selected from Group.

53. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 50, wherein R 4 Selected from Group.

54. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of claim 50 or claim 51, wherein ring B is selected from 55. The compound, tautomer, deuterated derivative or pharmaceutically acceptable salt of any one of claims 1 to 44 and 50 to 52, wherein Ring B is unsubstituted.

56. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 44 and 50 to 52, wherein Ring B is replaced by 1, 2 or 3 R a Group substitution.

57. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 44 and 50 to 52, wherein each R a The groups are independently selected from halogen, cyano, oxo, C1-C8 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 12 Carbocyclic, C6 and C 10 aryl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(=O)NR h R i 、-C(=O)OR k 、-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 Group, in which: R a The C1-C8 alkyl, the C1-C6 haloalkyl, the C1-C6 alkoxy and the C2-C8 alkenyl are each optionally substituted by 1 to 3 groups independently selected from the following: -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 carbocyclic group (optionally substituted by 1 to 3 R m substituted with a group), a 4- to 10-membered heterocyclic group (optionally substituted with 1 to 3 R m substituted with 1 to 3 R m group substituted) group; R a The C3-C 12 The carbocyclic group, the 3 to 12 membered heterocyclic group, the C6 and C 10 The aryl group and the 5- to 10-membered heteroaryl group are each optionally substituted by 1 to 3 groups independently selected from the group consisting of oxo, halogen, cyano, C1-C6 alkyl (optionally substituted by 1 to 3 R m Group substitution), -OR k 、-S(=O) p R k 、-S(=O) p NR h R i and a 5- to 10-membered heterocyclyl group, wherein: R h , R i and R j is independently selected at each occurrence from hydrogen, C1-C6 alkyl, 5- to 10-membered heteroaryl (optionally substituted by 1 to 3 R m substituted with 1 to 3 R m Group substitution), wherein: R h , R i and R j The C1-C6 alkyl group of any one of the above is optionally substituted by 1 to 3 groups independently selected from the following: halogen, cyano, -OH, C3-C6 carbocyclyl (optionally substituted by 1 to 3 R m group substitution); R k is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C3-C6 carbocyclyl, and a 5- to 10-membered heteroaryl group, wherein: R k The C1-C6 alkyl of any one of is optionally substituted by 1 to 5 groups independently selected from the group consisting of halogen, cyano, -NH2 and -OH; and R k The 5- to 10-membered heteroaryl and the 5- to 10-membered heterocyclyl of any one of the above are each optionally substituted by 1 to 3 groups independently selected from the group consisting of halogen, cyano, -OH, C1-C4 alkyl (optionally substituted by 1 to 3 -OH groups), C1-C4 haloalkyl, C3 -C6 cycloalkyl and C1-C4 alkoxy groups, wherein: R m is independently selected at each occurrence from halogen, cyano, oxo, -C(=O)NH2, -NH2, -C1-C6 alkyl, C1-C6 alkoxy, -OR k and C3-C6 cycloalkyl, wherein: R m The C1-C6 alkyl, the C1-C6 alkoxy and the 5- to 10-membered heterocyclyl of any one of the above are optionally substituted by 1 to 3 groups independently selected from the following: halogen, cyano, -OH and C1-C4 alkoxy groups; p is an integer independently selected from 1 and 2 at each occurrence.

58. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 44, 50 to 52 and 54 to 55, wherein each R a The groups are independently selected from -halogen; -Oxo; - cyano; -C1 haloalkoxy; -CH3; -CF2; By-OR k Substituted -C1 alkyl, wherein R k is -CH3; -C(=O)NR h R i Substituted -C1 alkyl, wherein R h and R i Both are CH3; -C(=O)NR h R i Substituted -C1 alkyl, wherein R h is hydrogen and R i It is CH3; -C(=O)NR h R i Substituted -C1 alkyl, wherein R h is hydrogen and R i is CH3 substituted by cyano which is optionally substituted by C3-C6 carbocyclyl; -C(=O)NR h R i Substituted -C1 alkyl, wherein R h is hydrogen and R i is CH3 substituted by a 5-membered heteroaryl; -C1 alkyl substituted by cyclopropyl, the cyclopropyl further being R m Substitution, where R m is selected from the group consisting of CH3, CH2OH and CH2C(=O)NH2; 4-membered heterocyclic ring Substituted -C1 alkyl, the 4-membered heterocyclic ring is further R m Substitution, where R m is C(=O)NH2; -C1 alkyl substituted by a 5-membered optionally substituted heterocycle; quilt Substituted -C1 alkyl, Optionally substituted with oxo and CH3; -C1 alkyl substituted by 5-membered optionally substituted heteroaryl; quilt Substituted -C1 alkyl, Optionally substituted with -OH or C(=O)NH2; quilt Substituted -C1 alkyl, Optionally substituted with -C1 to -C3 alkyl; quilt Substituted -C1 alkyl, Optionally substituted with N(CH3)2; quilt Substituted -C1 alkyl, Optionally, 1 to 3 R independently selected from the following m Group substitution: CH3, CH2OH and C(=O)NH2; -C1 alkyl substituted by 6-membered optionally substituted heteroaryl; quilt Substituted -C1 alkyl, Optionally, 1 to 3 R independently selected from the following m Group substitution: oxo, CH3 and CH2OH; quilt Substituted -C1 alkyl, Optionally, 1 to 3 R independently selected from the following m Group substitution: oxo, CH3, -C3 branched alkyl, cyclopropyl and NHCH3; quilt Substituted -C1 alkyl, Optionally, 1 to 3 R independently selected from the following m Group substitution: -OH, oxo and C1-C3 alkyl; quilt Substituted -C1 alkyl, Optionally, 1 to 2 R independently selected from the following m Group substitution: oxo and CH3; quilt Substituted -C1 alkyl, Optionally, 1 to 2 R independently selected from the following m Group substitution: oxo and CH3; quilt Substituted -C1 alkyl, Optionally 1 to 2 R m Group substitution; -C1-C3 alkoxy; -C2 alkyl; -C2 alkyl substituted by -OH and -C3-C6 carbocyclyl (optionally substituted by -OH); -C2 alkyl substituted by C1 alkoxy; -C2 alkyl substituted with -OH; NR h R i Substituted -C2 alkyl, wherein R h is hydrogen, and R i is R optionally selected from -C1-C3 alkyl m a 6-membered heteroaryl substituted with a radical; =NOR k Substituted -C2 alkyl, wherein R k is -C2 alkyl; NR h S(=O) p R k Substituted -C2 alkyl, wherein R h is hydrogen, p is 2 and R k is cyclopropyl; NR h C(=O)NR i R j Substituted -C2 alkyl, wherein R h and R i is hydrogen, and R j is -C2 alkyl; S(=O) p R k Substituted -C2 alkyl, wherein p is 2 and R k It is CH3; -S(=O) p NR h R i Substituted -C2 alkyl, wherein p is 2 and R h and R i Both are hydrogen; -S(=O) p NR h R i Substituted -C2 alkyl, wherein R h is hydrogen and R i It is CH3; -C2 alkyl substituted with -OH and a 6-membered heterocycle (optionally further substituted with -OH); 6-membered heterocyclic ring Substituted -C2 alkyl, the 6-membered heterocyclic ring is further R m Substitution, where R m Yes-OR k , where R k is -OH; -OH and optionally substituted Substituted-C2 alkyl, the optionally substituted further substituted by OH; -C2 alkyl substituted by 5-membered optionally substituted heteroaryl; 1 to 2 halogen groups and Substituted-C2 alkyl, Optionally substituted with C1-C3 alkyl; -C2 alkyl substituted by 6-membered optionally substituted heteroaryl; quilt Substituted-C2 alkyl, Optionally substituted with oxo; -C3 alkyl optionally substituted with 1 to 2 -OH groups; -C3 haloalkyl substituted with -OH; -C3 carbocyclic ring; -C3 alkyl substituted by 5-membered optionally substituted heteroaryl; quilt Substituted-C3 alkyl, Optionally substituted with oxo; -C3 alkyl substituted by a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group is optionally substituted by 1 to 2 oxo groups; quilt Substituted -C3 alkyl; -C4 alkyl substituted with two -OH groups; -C4 branched alkyl substituted with -OH; NR h S(=O) p R k Substituted -C4 branched alkyl, wherein R h is hydrogen, p is 2 and R k It is CH3; NR h R i Substituted -C4 branched alkoxy, wherein R h and R i Both are hydrogen; -C5 branched alkyl substituted with two -OH groups; -S(=O) p NR h R i Substituted -C5 branched alkyl, wherein p is 2 and R h and R i Both are hydrogen; -C6 aryl optionally substituted by CF3; -C(=O)OR k , where R k It is CH3; -C(=O)NR h R i , where R h is hydrogen and R i It is CH3; -C(=O)NR h R i , where R h and R i Both are hydrogen; -NR h R i , where R h and R i Both are hydrogen; -NR h R i , where R h is hydrogen and R i It is CH3; -NR h R i , where R h is hydrogen and R i It is a branched-C4 alkyl group substituted with -OH; -NR h C(=O)R k , where R h is hydrogen and R k It is CH3; -NR h C(=O)R k , where R h is hydrogen and R k is a 5-membered heteroaryl substituted by a group selected from Cl and cyclopropyl -NR h C(=O)R k , where R h is hydrogen and R k is not replaced Or it is replaced by CH3 -NR h S(=O) p R k , where R h is hydrogen, p is 2, and R k is -C2 alkyl; -NR h S(=O) p R k , where R h is hydrogen, p is 2, and R k is cyclopropyl; -NR h S(=O) p R k , where R h is hydrogen, p is 2, and R k is -cyano; -S(=O) p R k , where R k It is CH3; -S(=O) p NR h R i , where p is 2, and R h and R i Both are hydrogen; 4-membered heterocyclic ring, Optionally substituted with S(O)2CH3; 5-membered heterocyclic ring; Optionally substituted with CH3; Optionally substituted with oxo and CH3; 6-membered heterocyclic ring; Optional Substituted Optionally substituted with -OH 5-membered heteroaryl; 6-membered heteroaryl; Optionally substituted with -C1-C3 alkyl as well as Optionally substituted with -C1-C3 alkyl 59. A pharmaceutical composition comprising a compound according to any one of claims 1 to 56.

60. A method of treating a disease mediated by ApoL1, the method comprising administering a compound according to any one of claims 1 to 56 or a pharmaceutical composition according to claim 57.

61. A method of treating focal segmental glomerulosclerosis (FSGS), the method comprising administering a compound according to any one of claims 1 to 56 or a pharmaceutical composition according to claim 57.

62. A method of treating non-diabetic kidney disease (NDKD) comprising administering a compound according to any one of claims 1 to 56 or a pharmaceutical composition according to claim 57.

63. A method of treating cancer mediated by ApoL1, the method comprising administering a compound according to any one of claims 1 to 56 or a pharmaceutical composition according to claim 57.

64. The method of treating cancer according to claim 61, wherein the cancer is pancreatic cancer.

65. A method of treatment according to any one of claims 58 to 62, wherein the patient to be treated has an APOL1 genetic variant.

66. The method of treatment of claim 63, wherein the genetic variant is selected from G1:S342G:I384M and G2:N388del:Y389del.

67. A method of inhibiting APOL1 activity, the method comprising contacting the APOL1 with at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of claims 1 to 56 or a pharmaceutical composition according to claim 57.

68. Use of a compound according to any one of claims 1 to 56 in the manufacture of a medicament for the treatment of an ApoL1 mediated disease.

69. Use of a compound according to any one of claims 1 to 56 in the manufacture of a medicament for the treatment of FSGS.

70. Use of a compound according to any one of claims 1 to 56 in the manufacture of a medicament for the treatment of NDKD.

71. Use of a compound according to any one of claims 1 to 56 in the manufacture of a medicament for treating cancer mediated by ApoL1.

72. Use of a compound according to any one of claims 1 to 56 in the manufacture of a medicament for treating pancreatic cancer mediated by ApoL1.

73. Use of a compound according to any one of claims 1 to 56 in the manufacture of a medicament for inhibiting ApoL1 activity in a patient in need thereof.

74. A compound according to any one of claims 1 to 56 or a pharmaceutical composition according to claim 57 for use in inhibiting ApoL1 activity in a patient in need thereof.

75. A compound according to any one of claims 1 to 56 or a pharmaceutical composition according to claim 57 for use in treating an ApoL1 mediated disorder.

76. A compound according to any one of claims 1 to 56 or a pharmaceutical composition according to claim 57 for use in the treatment of FSGS.

77. A compound according to any one of claims 1 to 56 or a pharmaceutical composition according to claim 57 for use in the treatment of NDKD.

78. A compound according to any one of claims 1 to 56 or a pharmaceutical composition according to claim 57 for use in the treatment of cancer mediated by ApoL1.

79. A compound according to any one of claims 1 to 56 or a pharmaceutical composition according to claim 57 for use in the treatment of pancreatic cancer mediated by ApoL1.

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