OA21973A - 4-Phenyl-2-(1H-1,2,3-Triazol-4-YL) Piperidin-4-OL derivatives as inhibitors Of APOL1 and methods of using same. - Google Patents

Abstract

The disclosure provides at least one compound, tautomer, deuterated derivative, or pharmaceutical acceptable salt chosen from compounds of Formula I, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, compositions comprising the same, and methods of using the same, including uses in treating APOL1 -mediated diseases, including pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and/or non-diabetic kidney disease (NDKD). <img file="OA21973A_A0001.tif"/>

Description

4-PHENYL-2-(lH-l,2,3-TRIAZOL-4-YL)PIPERIDIN-4-OL DERIVATIVES AS INHIBITORS OF APOL1 AND METHODS OF USING SAME

This application daims the benefit of priority of U.S. Provisional Application No. 63/284,166, filed Novembcr 30, 2021, U.S. Provisional Application No. 63/286,165, filed December 6, 2021, and U.S. Provisional Application No. 63/310,832, filed February 16, 2022, the contents of which are incorporated by reference herein in their entirety.

This disclosure provides compounds that may inhibit apolipoprotein L1 (APOL1) and methods of using those compounds to treat APOL1-mediated diseases, such as, e.g., pancreatîc cancer, focal segmentai glomerulosclerosis (FSGS), and/or non-diabetic kidney disease (NDKD). In some embodiments, the FSGS and/or NDKD is associated with at least one of the 2 common APOL1 genetic variants (Gl: S342G:1384M and G2: N388del:Y389del). In some embodiments, the pancreatic cancer is associated with devated levels of APOL1 (such as, e.g., elevated levels of APOL1 in pancreatic cancer tissues).

FSGS is a rare kidney disease with an estimated global incidence of 0.2 to 1.1/100,000/year. FSGS is a disease of the podocyte (glomerular viscéral épithélial cells) responsible for proteinuria and progressive décliné in kidney fonction. NDKD is a kidney disease involving damage to the podocyte or glomerular vascular bed that is not attributablc to diabètes. NDKD is a disease characterized by hypertension and progressive décliné in kidney fonction. Human genetics support a causal rôle for the Gl and G2 APOL1 variants in inducing kidney disease. Individuals with 2 APOL1 alleles are at increased risk of developing end-stage kidney disease (ESKD), including primary (idiopathic) FSGS, human immunodefîciency virus (HlV)-associated FSGS, NDKD, artenonephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. See, P. Dummer et al., Semin Nephrol. 35(3): 222-236 (2015).

FSGS and NDKD can be divided into different subgroups based on the underlying etiology. One homogeneous subgroup of FSGS is characterized by the presence of independent common sequence variants in the apolipoprotein L1 (APOL1) gene termed Gl and G2, which are referred to as the “APOL1 risk alleles.” Gl encodes a correlated pair of non-synonymous amino acid changes (S342G and I384M), G2 encodes a 2 amino acid délétion (N388del:Y389del) near the C terminus of the protein, and G0 is the ancestral (low risk) allele. A distinct phenotype of NDKD is found in patients with APOL1 genetic risk variants as well. In both APOL1-mediated FSGS and NDKD, higher levels of proteinuria and a more accelerated loss of kidney fonction occur in patients with two risk alleles compared to patients with the same disease who hâve no or just 1 APOL1 genetic risk variant. Alternatively in AMKD, higher levels of proteinuria and accelerated loss of kidney fonction can also occur in patients with one risk

I allele. See, G. Vajgel et al., J. RheumatoL, November 2019,jrheum. 190684.

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

While the ability to lyse T. b. brucei is shared by ail 3 APOL1 variants (GO, Gl, and G2), APOL1 Gl and G2 variants confcr additional protection against parasite species that hâve evolved a sérum résistant associated-protein (SRA) which inhibits APOL1 GO; APOL1 Gl and G2 variants confer additional protection against trypanosoma species that cause sleeping sickness. Gl and G2 variants évadé inhibition by SRA; Gl confers additional protection against T. b. ganibiense (which causes West Afrîcan sleeping sickness) while G2 confers additional protection against T. b. rhodesiense (which causes East African sleeping sickness).

In the kidney, APOL1 is expressed in podocytes, endothélial cells (including glomerular endothélial cells), and some tubular cells. Podocytc-specific expression of APOL1 Gl or G2 (but not GO) in transgenic mice induces structural and fanctional changes, including albuminuria, decreased kidney function, podocyte abnormalities, and glomerulosclerosis. Consistent with these data, Gl and G2 variants of APOL1 play a causative rôle in inducing FSGS and accelerating its progression in humans. Individuals with APOL1 risk alleles (i.e., homozygous or compound heterozygous for the APOL1 Gl or APOLI G2 alleles) hâve increased risk of developing FSGS and they are at risk for rapid décliné in kidney function if they develop FSGS. Thus, inhibition of APOLI could hâve a positive impact in individuals who harbor APOLI risk alleles.

Although normal plasma concentrations of APOLI are relatively high and can vary at least 20-fold in humans, circulating APOLI is not causally associated with kidney disease. However, APOLI in the kidney is thought to be responsible for the development of kidney diseases, including FSGS and NDKD. Under certain circumstances, APOLI protein synthesis can be increased by approximately 200-fold by pro-inflammatory cytokines such as interferons or tumor necrosis factor-α. In addition, several studies hâve shown that APOLI protein can form pH-gated NaVlC pores in the cell membrane, resulting in a net efflux of intracellular K', ultimately resulting in activation of local and systemic inflammatory responses, cell swelling, and death.

The risk ot ESKD is substantially higher in people of reccnt sub-Saharan African ancestry as comparée! to those of European ancestry. In the United States, ESKD is responsible for nearly as many lost years of life in women as from breast cancer and more lost years of life in men than from colorectal cancer.

FSGS and NDKD are caused by damage to podocytes, which are part ofthe glomerular filtration barrier, resulting in proteinuria. Patients with proteinuria are at a higher risk of developing end-stage kidney disease (ESKD) and developing proteinuria-related complications, such as infections or thromboembolie events. There is no standardized treatment regimen nor approved drugs for FSGS or NDKD. Currently, FSGS and NDKD are managed with symptomatic treatment (including blood pressure controi using blockers of the renin angiotensin system), and patients with FSGS and heavy proteinuria may be offered high dose steroids. Current therapeutic options for NDKD are anchored on blood pressure controi and blockade of the renin angiotensin system.

Corticostcroids, alone or in combination with other immunosuppressants, induce remission in a minority of patients {e.g., remission of proteinuria in a minority of patients) and are associated with numerous side effects. However, remission is frequently indurablc even in patients initially responsive to corticosteroid and/or îmmunosuppressant treatment. As a resuit, patients, in particular individuals of recent sub-Saharan African ancestry with 2 APOLl risk alleles, expérience rapid disease progression leading to end-stage rénal disease (ESRD). Thus, there is an unmet medical need for treatment for FSGS and NDKD. Illustratively, in view of evidence that APOLl plays a causaiive rôle in inducing and accelerating the progression of kidney disease, inhibition of APOLl should hâve a positive impact on patients with APOLl mediated kidney disease, particularly those who carry two APOLl risk alleles {i.e., are homozygous or compound heterozygous for the G1 or G2 alleles).

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

One aspect of the disclosure provides at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, lc-3, Ic-4, lc-5, Ic-6, 11, II-l, 11-2, II-3, 11-4, II-5, Π-6, ll-6a and II-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, which can be employed in the treatment of diseases mediated by APOLl, such as FSGS and NDKD.

In some embodiments, at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait of the disclosure is a compound represented by the following structural formula:

Formula I a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein:

X is a bond (i.e., X is absent) or is chosen from -(CH?)-, and -(CHijSO?-;

Ring A is chosen from C& cycloalkyl, Cô aryl and 5- and 6-membered heteroaryl groups;

R¹, for each occurrence, is independently chosen from halogen, -OR^e, =0, cyano, phenyl, Ci-Cô alkyl, Ci-Cô alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)N(R^C)2, -S-(cyclopropyl), and -SO?(R^C) groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C1-C4 alkyl groups;

the 4- to 6-membered heterocyclyl of R¹ comprises onc heteroatom chosen from nitrogen and oxygen;

the Ci-Cô alkyl of R¹ is optionally substituted with 1 to 6 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?, and C1-C4 alkoxy groups;

the Cj-Cô alkoxy of R¹ is optionally substituted with 1 to 3 groups independently chosen from -OH, cyano, and halogen groups;

the C3-C6 carbocyclyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -ΝΗ?, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C4 alkyl), and

-C(=O)N(Ci-C4 alkyl)? groups; and the phenyl of R’ is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(C|-C4 alkyl), -N(Cj-C4 alkyl)?, C1-C4 alkyl, C1-C4 alkoxy, -C(-O)NH?, -C(=O)NH(Ci-C4 alkyl), and -C(=O)N(Ci-C4 alkyl)? groups; or wherein two R¹ groups taken together with the Ring A atoms connecting them form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl,

5- to 6-membered aryl, 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and C|-C4 alkyl;

R² is choscn from cyano, Ci-Cô alkyl, -C(=O)O(Ci-C4 alkyl), C2-C6 alkynyl, and

the Ci-Cô alkyl of R²is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(C|-C4 alkyl)?, C1-C4 alkoxy, -C(=O)NH?, -C(=O)NH(Ci-C₄ alkyl), -C(=O)N(Ci-C₄ alkyl)?, Q-Cô carbocyclyl, 5- to 10-membered heterocyclyl, Cô aryl, and 5- to 10-membered heteroaryl groups;

Ring B is chosen from Cî-Ci₂ carbocyclyl, 3- to 12-membercd heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with 1, 2, 3, 4, or 5 R^a groups; wherein;

R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, C2-C6 alkenyl, Ci-Cô alkoxy, Ci-Cô haloalkyl, Ci-Cô haloalkenyl, C1-C0 haloalkoxy, -C(-O)NR^hR^!, -NR^hR^!, -NR^hC(=O)R\ -NR^hC(=O)OR^k, -NieCfrOJNRW, -NR^hS(=O)pR^k -OR^k, -OC(=O)R^k, -OC«))OR^k. -OC(=O)NR”Rⁱ, -[O(CH2)q]rO(Ci-C6 alkyl), -S(=O)PR^k, -S(=O)PNR^hR, -C(=O)OR^k, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Cô alkyl, C|-C& alkoxy, and the C₂-Cô alkenyl of R^a are each optionally substituted with 1 to 3 groups independently chosen from Cô to Cio aryl (optionally substituted with 1 to 3 R' groups), 5- to 10membered heterocyclyl (optionally substituted with 1 to 3 R^m groups), 55 ι

to l O-mcmbered heteroaryl (optionally substituted with l to 3 R'groups), cyano, -C(=O)R^k, -C(=O)OR\ -C(=O)NR^hRⁱ, -NR^hR', -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^hC(=O)NRⁱRL -NR^hS(~O)PR^k -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OCfoOW'R¹, -S(=O)PR^k,

-S(=O)_PNR^hR', -O(Cô aryl) (optionally substituted with 1 to 3 R^m groups), and C3-C6 earbocyclyl groups (optionally substituted with 1 to 3 R^m groups);

the C3-C12 earbocyclyl, the 3- to 12-mcmbered heterocyclyl, the

Cô and Cio aryl, and the 5- to 10-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C4 alkyl, -NR^hR‘, and -OR^k groups, wherein:

R^h, R‘, and R', for each occurrence, are each independently chosen from hydrogen, Cj-C4 alkyl, Cô-Cioaryl, and Cj-Côcycloalkyl groups, wherein:

the C1-C4 alkyl of any one of R^h, R', and Ri is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and 20 C3-C6 earbocyclyl groups, wherein:

the C1-C4 alkyl of any one of R^k is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^m, for each occurrence, is independently chosen from halogen, cyano, oxo, Ci-Cô alkyl, Ci-Ce alkoxy, -S(=O)_pR^k, and

-OR^k groups, wherein:

the Ci-Cô alkyl of R^m is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and -O(Ci-C4 alkyl) groups;

R³ is chosen from Ci-C& alkyl, -C(=O)O(Ci-C₄ alkyl), C3-C12 earbocyclyl, 3- to 12membered heterocyclyl, Cô and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein:

theCi-C₆ alkyl ofR³ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NHi, -NH(Ci-C₄ alkyl), -N(Cj-C4 alkyl)2, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(C|-C₄ alkyl)₂ groups;

the C3-C12 carbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cio aryl, and the 5- to l 0-membered heteroaryl of R³ are each optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl) (optionally substituted with -OH), -N(Ci-C4 alkyl)₂, C1-C5 alkyl (optionally substituted with -OH or -S(=O)₂(Ci-C₄ alkyl)), Ci-C4alkoxy, -C(-O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -NHC(=O)(Ci-C₄ alkyl), -C(=O)(Ci-C₄ alkoxy), and -C(-O)N(Ci-C₄ alkyl): groups;

R⁴ is chosen from hydrogen, halogen, cyano, Ci-Cô alkyl, Ci-Cft haloalkyl, (CH₂)„C(=O)NRR°,

-NR'R, -NR^ÜC(-O)RU -NRS(=O)pRp. -(CH2)hORp, -S(=O)pRp, -S(=O)pNRR⁰, -OS(=O)PNRⁿR°, and -(CH₂)nC(=O)ORP groups, wherein:

R and R°, for each occurrence, are each independently chosen from hydrogen and C1-C4 alkyl groups; and

R^p, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl groups;

R⁵ is chosen from hydrogen and Cj-Cô alkyl;

m is an integer chosen from 0, l, 2, 3, 4, and 5;

n is an integer chosen from 0, l, and 2;

p, for each occurrence, is an integer independently chosen from l and 2; and q and r, for each occurrence, are each an integer independently chosen from l, 2, 3, and 4,

In some embodiments, the variable X in the compounds of Formula I is a bond (i.e., X is absent). In some embodiments, Compound 1296 and Compound 43a are excluded from Formula I.

In some embodiments, the compound of Formula I is a compound represented by the following structural formula:

(R¹)m

R⁵

Formula la a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein:

Ring A is chosen from Cô aryl and 5- and 6-mcmbered heteroaryl groups;

R¹, for each occurrence, is independently chosen from halogen, -OH, =O, cyano, phenyl, Cj-Cô alkyl, Ci-Q alkoxy, Cj-Cô carbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)N(R^C)2, and -SO2(R^C) groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C1-C4 alkyl groups;

the 4- to 6-membered heterocyclyl of R¹ comprises one heteroatom chosen from nitrogen and oxygen;

the C1-C& alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C4 alkyl), -N(C|-C4 alkyl)2, and C1-C4 alkoxy groups;

the Ci-Cô alkoxy of R¹ is optionally substituted with 1 to 3 groups independently chosen from -OH, cyano, and halogen groups;

the C3-C6 carbocyclyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(C|-C4 alkyl), -N(Ct-C4 alkyl)₂, C1-C4 alkyl, C1-C4alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(Ci-C4 alkyl)? groups; and the phenyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C4 alkyl), -N(Cj-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(C|-C₄ alkyl)₂ groups; or wherein two R¹ groups taken together with the Ring A atoms connecting them form a 5- to 6-membered cycloalkyl, 5- to 8-mcmbered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and C1-C4 alkyl;

R² is chosen from cyano, Ci-Cô alkyl, -C(=O)O(Ci-C4 alkyl), C2-C6 alkynyl, and (R^a)_o.s

, wherein:

the Ci-Cô alkyl of R² is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Cj-C4 alkyl), -N(Ci-C4 alkyl)?, C1-C4 alkoxy, -C(=O)NH?, -C(=O)NH(Ci-C4 alkyl), -C(=O)N(C|-C4 alkyl)?, Cî-Cô earbocyclyl, 5- to 10-membercd heterocyclyl, Cô aryl, and 5- to lO-membercd heteroaryl groups;

Ring B is chosen from C3-C1? earbocyclyl, 3- to 12-mcmbered heterocyclyl, Cô and Cio aryl, and 5- to 10-mcmbered heteroaryl groups, wherein Ring B is optionally substituted with l, 2, 3, 4, or 5 R^a groups; wherein:

R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, C?-C<, alkenyl, Ci-Cô alkoxy, Ci-Cô haloalkyl, Ci-Cô haloalkenyl, C]-C6 haloalkoxy, -C(-O)NR^I|R', -NRbR¹, -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^,lC(=O)NRⁱR', -NR^hS(=O)pR^k-OR^k, -OC(~O)R^k, -OC(=O)OR^k, -OCiOjNR'·#, -[O(CH2)_q]rO(Ci-C₆ alkyl), -S(=O)_PR^k, -S^OjpNR¹^, -C(=O)OR^k, C3-C12 earbocyclyl, 3- to 12-membered heterocyclyl, Ce and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Cô alkyl, Ci-Cô alkoxy, and the C?-Cô alkenyl of R^a are each optionally substituted with 1 to 3 groups independently chosen from Cô to Cio aryl (optionally substituted with 1 to 3 R^m groups), 5- to 10membered heterocyclyl (optionally substituted with 1 to 3 R^m groups), 5to 10-membered heteroaryl (optionally substituted with 1 to 3 R^m groups), cyano, -C(=O)R^k, -C(=O)OR^k, -C(-O)NR^hRⁱ, -NR^hR', -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^OINR¹^, -NR^hS(=O)pR^k -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OC(=O)NR^hR', -S(=O)pR^k, -S(=O)pNR^llR^l, -O(Cô aryl) (optionally substituted with 1 to 3 R^m groups), and C₃-Cô earbocyclyl groups (optionally substituted with 1 to 3 R”¹ groups);

the C3-C12 earbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cioaryl, and the 5- to 10-membered heteroaryl of R^a are each optionally substituted with I to 3 groups independently chosen from halogen, cyano, Ci-C4 alkyl, -NR^hR', and -OR^k groups, wherein:

R^h, R¹, and Ri, for each occurrence, are each independently chosen from hydrogen, C1-C4 alkyl, Cô-Cioaryl, and Ci-Cô cycloalkyl groups, wherein:

the C1-C4 alkyl of any one of R¹¹, R', and R^j is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, Ci-Q alkyl, 5- to 10-membered heterocyclyl, and Cj-Cô carbocyclyl groups, wherein:

the C1-C4 alkyl of any one of R^k is optionally substituted with l to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^m, for each occurrence, is independently chosen from halogen, cyano, oxo, Ci-Cô alkyl, Ci-Cô alkoxy, -S(=O)_PR^k, and -OR^k groups, wherein:

the Ci-Cô alkyl of Rⁿⁱ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and -O(Ci-C4 alkyl) groups;

R³ is chosen from Ci-Cô alkyl, -C(=O)O(Cj-C4 alkyl), C3-C12 carbocyclyl, 3- to 12membered heterocyclyl, Cb and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Cô alkyl of R³ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C₄ alkyl), -N(Ci-C4 alkyl)₂, C1-C4 alkoxy, -C(=O)NH₂, -C(-O)NH(C_l-C₄ alkyl), and -C(=O)N(Ci-C₄ alkyl)₂ groups;

the C3-C12 carbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cioaryl, and the 5- to 10-membered heteroaryl of R³ are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C4 alkyl) (optionally substituted with -OH), -N(Ci-C4 alkyl)₂, C1-C5 alkyl (optionally substituted with -OH or-S(=O)₂(Ci-C₄ alkyl)), C,-C₄ alkoxy, -C(~O)NH₂. -C(=O)NH(Ci-C₄ alkyl), -NHC(=O)(Ci-C₄ alkyl), -C(=O)(Ci-C₄ alkoxy), and -C(=O)N(Cj-C₄ alkyl)₂ groups;

R⁴ is chosen from halogen, cyano, Ci-Cô alkyl, Ci-Cô haloalkyl, -(CH2)nC(=O)NRR°, -NRⁿR°, -NR°C(=O)R^P, -NRS(=O)PR^P. -(CH2)nOR^p, -S(=O)PR^P, -S(=O)PNRⁿR⁰, -OS(-O)PNRR⁰, and -(CH₂)nC(=O)OR^p groups, wherein:

R and R°, for each occurrence, are each independently chosen from hydrogen and C1-C4 alkyl groups; and

R^p, for each occurrence, is independently chosen from hydrogen, Ci-C₄ alkyl, and C1-C4 haloalkyl groups;

R⁵ is chosen from hydrogen and Ci-Cô alkyl;

m is an integer chosen from 0, 1,2, 3, 4, and 5;

n is an integer chosen from 0, 1, and 2;

p, for each occurrence, is an integer independently chosen from 1 and 2; and q and r, for each occurrence, are each an integer independently chosen from l, 2, 3, and 4.

In some embodiments, Compound I296 and Compound 43a are excluded from Formula la.

Formula I also encompasses compounds of Formula Ib having the following structure;

(R¹)m

Formula Ib, a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein:

Ring A is chosen from C& aryl and 5- and 6-membered heteroaryl groups;

R¹, for each occurrence, is independently chosen from halogen, -OH, =O, cyano, phenyl, Ci-C& alkyl, Ci-C(, alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)N(R^C)?, and -SO?(R^C) groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C1-C4 alkyl groups;

the 4- to 6-membered heterocyclyl of R¹ comprises one heteroatom chosen from nitrogen and oxygen;

the Ci-Cô alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?, and C1-C4 alkoxy groups;

the Ci-Cô alkoxy of R¹ is optionally substituted with 1 to 3 groups independently chosen from -OH, cyano, and halogen groups;

the C3-C6 carbocyclyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(C]-C4 alkyl), -N(Ci-C4 alkyl·)?, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(C|-C₄ alkyl), and -C(=O)N(Ci-C₄ alkyl)? groups; and the phenyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(C|-C4 alkyl), -N(C]-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(C]-C4 alkyl), and -C(=O)N(Ci-C4 alkylh groups; or wherein two R¹ groups taken together with the Ring A atoms connecting them fonn a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-mcmbered aryl, or 5- to 6-mcmbered heteroaryl ring, wherein the 5- to 6-membcred cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, 5- to 6-mcmbered heteroaryl are each optionally substituted with I to 4 groups selected from halogen, -OH, and C1-C4 alkyl;

R² is chosen from cyano, Cj-Cô alkyl, -C(=O)O(C|-C4 alkyl), C?-C₆ alkynyl, and

the Ci-Cô alkyl of R² is optionally substituted witli 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, C1-C4 alkoxy, -C(-O)NH2, -C(=O)NH(Ci-C4 alkyl), -C(=O)N(C|-C4 alkyl)?, Cî-Cô carbocyclyl, 5- to 10-membered heterocyclyl, C6 aryl, and 5- to 10-membered heteroaryl groups;

Ring B is chosen from C3-C12 carbocyclyl, 3- to 1 2-membered heterocyclyl, Ce and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with 1, 2, 3, 4, or 5 R^a groups; wherein:

R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, C?-Cô alkenyl, Ci-Cô alkoxy, Ci-Cô haloalkyl, Ci-Cô haloalkenyl, Ci-Cô haloalkoxy, -C(=O)NR^hRⁱ, -NRR', -NR^hC(-O)R\ -NR^llC(=O)OR^k, -ΝΗ*Ό(=Ο)ΝΗΉ\ -NR^hS(-O)pR^k -OR^k, -OC>O)R^k. -OC(=O)OR^k, -OC(-O)NR^llR', -[O(CH2)q]rO(Ci-C6 alkyl), -S(=O)PR^k, -S(=O)PNR^hR', -C(=O)OR^k, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce and Cio aryl, and 5- to 10-membercd heteroaryl groups, wherein:

the Ci-Cô alkyl, Ci-Cô alkoxy, and the C?-Cô alkenyl of R^a are each optionally substituted with 1 to 3 groups independently chosen from Cô to Cio aryl (optionally substituted with 1 to 3 R^m groups), 5- to 10membered heterocyclyl (optionally substituted with 1 to 3 R¹ groups), 5to 10-membered heteroaryl (optionally substituted with 1 to 3 R^,n groups), cyano, -C(=O)R^k, -C(=O)OR^k, -C(=O)NR^hR^!, -NR^hRⁱ,

-NR^hC(=O)R\ -NR^hC(=O)OR^k, -NR'OUOINRW, -NR^hS(=O)PR^k -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -00(=0)^^, -S(=O)PR^k, -S(=O)pNR^hR', -O(C6 aryl) (optionally substituted with l to 3 R^m groups), and C3-C6 carbocyclyl groups (optionally substituted with l to 3 R^m groups);

the C3-C12 carbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cioaryl, and the 5- to lO-membered hctcroaryl of R* are each optionally substituted with l to 3 groups independently chosen from halogen, cyano, C1-C4 alkyl, -NR^hR', and -OR^k groups, wherein:

R^h, R', and Ri, for each occurrence, are each independently chosen from hydrogen, C1-C4 alkyl, C&-Cioaryl, and C3-C6cycloalkyl groups, wherein:

the Ci-C4 alkyl of any one of R^h, R‘, and Ri is optionally substituted with l to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to lO-membercd heterocyclyl, and C3-C6 carbocyclyl groups, wherein:

the C1-C4 alkyl of any one of R^k is optionally substituted with l to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^m, for each occurrence, is independently chosen from halogen, cyano, oxo, Ci-Ce alkyl, Ci-Cô alkoxy, -S(=O)_PR^k, and -OR^k groups, wherein:

the Ci-Câ alkyl of R^m is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, and -O(Ci-C4 alkyl) groups;

R³ is chosen from Ci-C& alkyl, -C(=O)O(C|-C4 alkyl), C3-C12 carbocyclyl, 3- to 12membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein: the Cj-Cô alkyl of R³ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(CrC4 alkyl), and -C(=O)N(Ci-C₄ alkyl)₂ groups;

the C3-Ct2 carbocyclyl, the 3- to 12-membered heterocyclyl, the C& and Cioaryl, and the 5- to 10-membered heteroaryl of R³ are each optionally substituted with I to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C4 alkyl) (optionally substituted with -OH), -N(Ci-C₄ alkyl)?, C1-C5 alkyl (optionally substituted with -OH or -S(=O)₂(C|-C₄ alkyl)), C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -NHC(=O)(Ci-C₄ alkyl), -C(=O)(Ci-C₄ alkoxy), and -C(=O)N(Ci-C₄ alkyl)₂ groups;

R⁴ is chosen from halogen, cyano, Ct-Cô alkyl, Ci-Cô haloalkyl, -(CH2)nC(=O)NRⁿR⁰,

-NRR°, -NR°C(=O)Rp, -NRS(=O)_PR'’,-(CH₂).>ORp, -S(=O)_PRP, -S(=O)_pNRR°,

-OS(=O)_PNRⁿR°, and -(CH₂)riC(=O)OR^p groups, wherein:

Rⁿ and R°, for each occurrence, are each independently chosen from hydrogen and C1-C4 alkyl groups; and

Rp, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl groups;

m is an integer chosen from 0, l, 2, 3, 4, and 5;

n is an integer chosen from 0, l, and 2;

p, for each occurrence, is an integer independently chosen from l and 2; and q and r, for each occurrence, are each an integer independently chosen from l, 2, 3, and 4.

In some embodiments, Compound 1296 and Compound 43a are excluded from Formula Ib.

Formula I also encompasses compounds of Formula le having the following structure:

a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein:

Ring A is chosen from Ce aryl and 5- and 6-membered heteroaryl groups;

R¹, for each occurrence, is independently chosen from halogen, -OH, =O, cyano, phenyl, Ci-Câ alkyl, Ci-C& alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, and -C(=O)N(R^C)₂ groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C|-C₄ alkyl groups;

the 4- to 6-membered heterocyclyl of R¹ comprises one heteroatom chosen from nitrogen and oxygen;

the C[-Ct> alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C₄ alkyl), -N(Ci-C4 alkyl)?, and C|-C₄ alkoxy groups;

the Ci-Cô alkoxy of R¹ is optionally substituted with 1 to 3 groups independently chosen from -OH, cyano, and halogen groups;

the C3-C6 carbocyclyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C₄ alkyl)?, Ci-C₄ alkyl, C1-C4alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(Cj-C4 alkyl)₂ groups; and the phenyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(C|-C₄ alkyl), -N(C|-C₄ alkyl)₂, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(Ci-C₄ alkyl)? groups;

R²is chosen from cyano, Ci-Cô alkyl, -C(=O)O(Ci-C₄ alkyl), C?-Cô alkynyl, and

the Ci-Cô alkyl of R²is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C₄ alkyl), -N(Ci-C₄ alkyl)₂, C1-C4 alkoxy, -C(=O)NH?, -C(=O)NH(Ci-C₄ alkyl), -C(=O)N(C|-C₄ alkyl)?, C₃-C₆ carbocyclyl, 5- to 10-membered heterocyclyl, Cô aryl, and 5- to 10-membered heteroaryl groups;

Ring B is chosen from C3-C1? carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with 1, 2, 3, 4, or 5 R^a groups; wherein:

R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, C?-C& alkenyl, C1-C0 alkoxy, Cj-Cô haloalkyl, Cj-Cô haloalkenyl, Ci-Cô haloalkoxy, -C(=O)NR^hRⁱ, -NR¹*^, -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^hC(=O)NR'Rj, -NR^hS(=O)PR^k-OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OCtOJNR¹'^, -[O(CH?)q]rO(Ci-Cô alkyl), -S(=O)_PR^k, -S(=O)_PNR^l,Rⁱ,

-C(=O)OR^k, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, C_b and Cioaryl, and 5- to lO-membered heteroaryl groups, wherein:

the Ci-Cô alkyl, Ci-C& alkoxy, and the C2-C6 alkenyl of R^a are each optionally substituted with l to 3 groups independently chosen from Cô to Cio aryl (optionally substituted with l to 3 R^,tl groups), 5- to IOmembcred hetcrocyclyl (optionally substituted with l to 3 R^m groups), 5to 10-membered heteroaryl (optionally substituted with l to 3 R^m groups), cyano, -C(=O)R^k, -C(=O)OR^k, -C(=O)NR^hR', -NR^hR‘, -NR^hC(-O)R^k, -NR^hC(=O)OR^k, -NR^hC(=O)NR'Rj, -NR^hS(=O)PR^k -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OC(=O)NR^hRⁱ, -S(=O)PR^k, -S(=O)pNR^hR', -O(Cô aryl) (optionally substituted with l to 3 R^m groups), and Cj-Cô carbocyclyl groups (optionally substituted with l to 3 R^m groups);

the C3-C12 carbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cioaryl, and the 5- to 10-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C4 alkyl, -NR^hR', and -OR^k groups, wherein:

R^h, R¹, and R^j, for each occurrence, are each independently chosen from hydrogen, Cj-C4 alkyl, Cô-Cioaryl, and Ca-Côcycloalkyl groups, wherein:

the C1-C4 alkyl of any one of R¹¹, R', and R' is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl groups, wherein:

the C1-C4 alkyl of any one of R^k is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R¹, for each occurrence, is independently chosen from halogen, cyano, oxo, Ci-Cô alkyl, Ci-Cô alkoxy, -S(=O)_PR^k, and -OR^k groups, wherein:

the Ci-Cô alkyl of Rⁿⁱ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and -O(Ci-C4 alkyl) groups;

R³ is chosen from C|-C& alkyl, -C(=O)O(Ci-C₄ alkyl), Cj-Ci? carbocyclyl, 3- to I2membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Cô alkyl of R³ is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C₄ alkyl), -N(Ci-C₄ alkyl)?, Ci-C₄ alkoxy, -C(=O)NH?, -C(=O)NH(Cr-C₄ alkyl), and -C(=O)N(C|-C₄ alkyl)? groups;

the C3-C1? carbocyclyl, the 3- to 12-mcmbered heterocyclyl, the Cô and Cioaryl, and the 5- to 10-membered heteroaryl of R³ are each optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C₄ alkyl) (optionally substituted with -OH), -N(Ci-C₄ alkyl)?, C1-C5 alkyl (optionally substituted with -OH or-S(=O)?(Ci-C₄ alkyl)), C,-C₄ alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -NHC(=O)(Ci-C₄ alkyl), -C(=O)(C|-C₄ alkoxy), and -C(=O)N(Ci-C₄ alkyl)₂ groups;

R⁴ is chosen from halogen, cyano, Ci-Cô alkyl, Ci-Cô haloalkyl, -(CH2)nC(=O)NRR“, -NRⁿR°, -NR°C(=O)RP, -NRⁱ¹S(=O)pRp. -(CH2)nORP, -S(=O)_PRP, -S(=O)_PNRⁿR°, -OS(=O)_PNRR°, and -(CH?)„C(=O)ORP groups, wherein:

R and R°, for each occurrence, are each independently chosen from hydrogen and C1-C4 alkyl groups; and

R^p, for each occurrence, is independently chosen from hydrogen, C|-C₄ alkyl, and C1-C4 haloalkyl groups;

m is an integer chosen from 0, l, 2, 3, 4, and 5;

n is an integer chosen from 0, l, and 2;

p, for each occurrence, is an integer independently chosen from l and 2; and q and r, for each occurrence, are each an integer independently chosen from l, 2, 3, and 4.

In some embodiments, Compound I296 and Compound 43a are excluded from Formula le.

In some embodiments, in a compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait of Formula le, Ring A is chosen from Cô aryl and 5- and 6membered heteroaryl groups;

R‘, for each occurrence, is independently chosen from halogen, Ci-Cô alkyl, Ci-Cô alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, and -C(=O)N(R^C)₂ groups, wherein:

the 4- to 6-membered heterocyclyl of R¹ comprises one heteroatom chosen from nitrogen and oxygen;

the Ci-Cô alkyl and Ci-Cô alkoxy of R¹ are optionally substituted with 1-3 groups chosen from -OH, cyano, and halogen groups; and

R^c, for each occurrence, is independently chosen from hydrogen and Ci-C₄ alkyl groups;

R² and R³ are each independently chosen from Ci-C₄ alkyl, C3-C6 carbocyclic, and 5-membered heteroaryl groups, wherein:

the 5-membered heteroaryl groups are optionally substituted with l-2 C1-C4 alkyl groups optionally substituted with -S(=O)₂CH3; and the C1-C4 alkyl groups are optionally substituted with halogen and C3-C6 carbocyclic groups;

R⁴ is -OH and -O(C|-C₄ alkyl) groups; and m is an integer chosen from 0, l, 2, 3, 4, and 5.

In some embodiments, in a compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait of Formula le, Ring A is chosen from Cô aryl and 5- and 6membered heteroaryl groups;

R¹, for each occurrence, is independently chosen from halogen, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci cycloalkyl, and -C( O)N(R^C)? groups, wherein:

the C1-C4 alkyl and C1-C4 alkoxy of R¹ are optionally substituted with 1-3 groups chosen from halogens; and

R^c, for each occurrence, is independently chosen from hydrogen and Ci-C₄ alkyl groups;

R² and R³ are each independently chosen from C1-C4 alkyl and 5-membered heteroaryl groups, wherein the 5-membered heteroaryl groups are optionally substituted with 1-2 Cj-C₄ alkyl groups optionally substituted with -S(-O)₂CHi;

R⁴ is -OH; and ni is an integer chosen from 0, I, and 2.

In some embodiments, Compound 1296 and Compound 43a are excluded from Formula le.

In one aspect of the disclosure, the compounds of Formula I are chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, such that the at least one compound, pharmaceutically acceptable sait, solvaté, or deuterated dérivative is chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, pharmaceutically acceptable salts of any of those compounds, solvatés ofany of the foregoing, and deuterated dérivatives of any ofthc foregoing.

In some embodiments, the disclosure provides a pharmaceutical composition comprising at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, 11-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical composition may comprise at least one compound chosen from Compounds l to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, pharmaceutically acceptable salts of any of those compounds, solvatés ofany ofthe foregoing, and deuterated dérivatives of any ofthe foregoing. These compositions may further include at least one additional active pharmaceutical ingrédient and/or at least one carrier.

Another aspect ofthe disclosure provides methods of treating an APOL1-mediated disease comprising administering to a subject in need thereof, at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2, 11-3, 11-4, 11-5, II-6, II-6a and Il-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait. In some embodiments, the methods comprise administering at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

Another aspect of the disclosure provides methods of treating an APOLI-mediated cancer (such as, e.g., pancreatic cancer) comprising administering to a subject in need thereof, at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2,11-3, II-4, 11-5, II-6, II-6a and Il-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait. In some embodiments, the methods comprise administering at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

Another aspect of the disclosure provides methods of treating APOLI-mediated kidney disease (such as, e.g., ESKD, FSGS and/or NDKD) comprising administering to a subject in need thereof, at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from compounds of Formulae I, la, 1b, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic6, II, II-l, II-2, Π-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait. In some embodiments, the methods comprise administering at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds l to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from compounds of Fomiulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, lc-4, Ic-5, Ic6, II, II-l, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions. In some embodiments, the methods comprise administering at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any ofthe foregoing with at least one additional active agent, either in the same pharmaceutical composition or in a separate composition.

Also provided are methods of inhibiting APOL1, comprising administering to a subject in need thereof, at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic6, II, II-l, II-2, II-3, II-4, Π-5, II-6, II-6a and II-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait. In some embodiments, the methods of inhibiting APOL1 comprise administering at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait.

Brief Description of the Drawings

FIG. 1 depicts an XR.PD diffractogram of Compound 16 Form A.

FIG. 2 depicts a TGA of Compound 16 Form A.

FIG. 3 depicts a DSC of Compound 16 Form A.

FIG. 4 depicts a ^l3C SSNMR spectrum of Compound 16 Form A.

Detailed Description Définitions

The term “APOLl,” as used herein, means apolipoprotein Ll protein and the term “APOLl means apolipoprotein Ll gene.

The tenu “APOL l mediated disease” refers to a discase or condition associated with aberrant APOLl (e.g., certain APOLl genetic variants; elevated levels of APOLl). In some embodiments, an APOLl mediated disease is an APOLl mediated kidney disease. In some embodiments, an APOLl mediated disease is associated with patients having two APOLl risk alleles, e.g., patients who are homozygous or compound heterozygous for the Gl or G2 alleles. In some embodiments, an APOLl mediated disease is associated with patients having one APOLl risk allele.

The tenu “APOLl mediated kidney disease” refers to a disease or condition that impairs kidney fonction and can be attributed to APOLl. In some embodiments, APOLl mediated kidney disease is associated with patients having two APOLl risk alleles, e.g., patients who are homozygous or compound heterozygous for the Gl or G2 alleles. In some embodiments, the APOLl mediated kidney disease is choscn from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterîonephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease. In some embodiments, the APOLl mediated kidney disease is chronic kidney disease or proteinuria.

The term “FSGS,” as used herein, means focal segmentai glomerulosclerosis, which is a disease of the podocyte (glomerular viscéral épithélial cells) responsible for proteinuria and progressive décliné in kidney fonction, and associated with 2 common APOLl genetic variants (Gl: S342G:I384M and G2: N388del:Y389del).

The term “NDKD,” as used herein. means non-diabetic kidney disease, which is characterized by severe hypertension and progressive décliné in kidney fonction, and associated with 2 common APOLl genetic variants (Gl: S342G:I384M and G2: N388del:Y389del).

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

The term “compound,” when referring to a compound of this disclosure, refers to a collection of molécules having an identical Chemical structure unless otherwise indicated as a collection of stereoisomers (for example, a collection of racemates, a collection of cis/trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that there may be isotopic variation among the constituent atoms ofthe molécules. Thus, it will be clear to those of skill in the art that a compound represented by a particular Chemical structure containing indicated deuterium atoms will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this disclosure will dépend upon a number of factors including the isotopic purity of reagents used to make the compound and the efficiency of incorporation of isotopes in the various synthesis steps used to préparé the compound. However, as set forth above, the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

As used herein, “optionally substituted” is interchangeable with the phrase “substituted or unsubstituted.” In general, the term “substituted, whether prcccded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an “optionally substituted” group may hâve a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that resuit in the formation of stable or chemically feasible compounds.

The term “isotopologue” refers to a species in which the Chemical structure differs from a reference compound only in the isotopic composition thereof. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ^l3C or ^l4C, are within the scope of this disclosure.

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

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

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

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

The term “isotopic enrichment factor,” as used herein, means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

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

The tenus “cycloalkyl” and “cyclic alkyl, as used herein, refer to a monocyclic C3.8 hydrocarbon or a spirocyclic, fused, or bridged bicyclic or tricyclic Cs-14 hydrocarbon that is completely saturated, wherein any individual ring in said bicyclic ring System has 3 to 7 members. In some embodiments, the cycloalkyl is a C₃ to C12 cycloalkyl. In some embodiments, the cycloalkyl is a Cj to Cx cycloalkyl. In some embodiments, the cycloalkyl is a Cj to Cô cycloalkyl. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

The terms “earbocyclyl” or “cycloaliphatic,” as used herein, encompass the tenns “cycloalkyl” or “cyclic alkyl,” and refer to a monocyclic C3.8 hydrocarbon or a spirocyclic, fused, or bridged bicyclic or tricyclic Cs-u hydrocarbon that is completely saturated, or is partially saturated as in it contains one or more units of unsaturation but is not aromatic, wherein any individual ring in said bicyclic ring System has 3 to 7 members. Bicyclic carbocyclyls include combinations of a monocyclic carbocyclic ring fused to a phenyl. In some embodiments, the earbocyclyl is a Cj to C12 earbocyclyl. In some embodiments, the earbocyclyl is a C3 to Cio earbocyclyl. In some embodiments, the earbocyclyl is a C3 to Cs earbocyclyl.

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

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

The term “heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” or “heterocyclic,” as used herein, means non-aromatic (Le., completely saturated or partially saturated as in it contains one or more units of unsaturation but is not aromatic), monocyclic, or spirocyclic, fused, or bridged bicyclic or tricyclic ring Systems in which one or more ring members of the ring System is an independently chosen heteroatom. Bicyclic heterocyclyls include the following combinations of monocyclic rings; a monocyclic heteroaryl fused to a monocyclic heterocyclyl; a monocyclic heterocyclyl fused to another monocyclic heterocyclyl; a monocyclic heterocyclyl fused to phenyl; a monocyclic heterocyclyl fused to a monocyclic carbocyclyl/cycloalkyl; and a monocyclic heteroaryl fused to a monocyclic carbocyclyl/cycloalkyl.

In some embodiments, the heterocycle comprises a ring atom substituted with one or more oxo groups (such as, e.g., a C=O group, a S=O group, or a SO2 group).

In some embodiments, the “heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” or “heterocyclic” group has 3 to 14 ring members in which one or more ring members is a heteroatom independently chosen from oxygen, sulfur, nitrogen, and phosphores. In some embodiments, each ring in a bicyclic or tricyclic ring System contains 3 to 7 ring members. In some embodiments, the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has one heteroatom independently chosen from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocycle has one heteroatom that is a nitrogen atom. In some embodiments, the heterocycle has one heteroatom that is an oxygen atom. In some embodiments, the heterocycle has two heteroatoms that are each independently chosen from nitrogen and oxygen. In some embodiments, the heterocycle has three heteroatoms that are each independently chosen from nitrogen and oxygen. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl, tetrahydrothiophenyl 1,1-dioxide, etc.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or Silicon (including, e.g., any oxidized form of nitrogen, sulfur, phosphorus, or Silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), N H (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one or more units or degrees of unsaturation. Unsaturation is the State in which not ail of the available valence bonds in a compound are satisfied by substituents and thus the compound contains double or triple bonds.

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

The terms “haloalkyl,” “haloalkenyl,” and “haloalkoxy,” as used herein, mean a linear or branched alkyl, alkenyl, or alkoxy, respectively, which is substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF2, -CHiF, -CF3, -CF2-, and perhaloalkyls, such as -CF2CF3. Non-limiting examples of haloalkoxy groups include -OCHF2, -OCH?F, -OCF3, and -OCF?.

The term “halogen includes F, Cl, Br, and I, i.e., tluoro, chloro, bromo, and iodo, respectively.

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

As used herein, an “amino refers to a group which is a primary, secondary, or tertiary amine.

As used herein. a “carbonyl” group refers to C=O.

As used herein, a “cyano or “nitrile group refer to -C=N.

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

As used herein, a “thiol” group refers to -SH.

As used herein, “tert and “t-” each refer to tertiary.

As used herein, “aromatic groups” or “aromatic rings” refer to Chemical groups that contain conjugated, planar ring Systems with delocalized pi électron orbitals comprised of [4n+2] p orbital électrons, wherein n is an integer ranging from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

The term “aryl,” used alone or as part of a larger moiety as in “arylalkyl,” “arylalkoxy,” or “aryloxyalkyl,” refers to monocyclic or spirocyclic, fused, or bridged bicyclic or trîcyclic ring Systems having a total of five to fourteen ring members, wherein every ring in the System is an aromatic ring contaîning only carbon atoms and wherein each ring in a bicyclic or tricyclic ring System contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (Cô) and naphthyl (C io) rings.

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

In some embodiments, the heteroaryl comprises a ring atom substituted with one or more oxo groups (such as, e.g., a C=O group, a S=O group, or a SO? group). Illustratively, a nonlimiting example of a heteroaryl group is a benzo[d]oxazol-2(3H)-one group.

Non-limiting examplcs of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc) benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods of adding (a process generally referred to as “protecting”) and removing (process generally referred to as “dcprotecting”) such amine protecting groups are well-known in the art and available, for example, in P. J. Kocienski, Protecting Groups, Thieme, 1994, which is hereby incorporated by reference in its entirety and in Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Edition (John Wiley & Sons, New York, 1999) and 4^>h Edition (John Wiley & Sons, New Jersey, 2014),

Non-limiting examples of suitable solvents that may be used in this disclosure include, but are not limited to, water, methanol (MeOH), éthanol (EtOH), dichloromethane or “methylene chloride” (CH2CI2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethy 1 acetate (EtOAc), heptane, isopropyl acetate (IPAc), terf-butyl acetate (f-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), terf-butanol, diethyl ether (EtzO), methyl-rer/-butyl ether (MTBE), 1,4-dioxane, and jV-methyl pyrrolidone (NMP).

Non-limiting examples of suitable bases that may be used in this disclosure include, but are not limited to, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K?C0î), Wmethylmorpholine (NMM), triethylamine (EtjN; TEA), diisopropyl-ethyl amine (z-Pr?EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCHî).

This disclosure includes certain substantially crystalline solid forms of the compounds of the invention. As used herein, the tenus “crystalline form” and “Fonn” interchangeably refer to a crystal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice. Crystalline fonns can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, solid State nuclear magnetic résonance (SSNMR), differential scannîng calorimetry (DSC), infrared radiation (IR), and/or thermogravimetric analysis (TGA). Accordingly, as used herein, the tenu “crystalline Fonn [X] of Compound [Y]” refers to a unique crystalline fonn that can be identified and distinguîshed from other crystalline fonns of Compound [Y] by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, SSNMR, differential scanning calorimetry (DSC), infrared radiation (IR), and/or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline Fonn [X] of Compound [Y] is characterized by an X-ray powder diffractogram having one or more signais at one or more specified two-theta values (°20).

As used herein, the term “SSNMR refers to the analytical characterization method of solid state nuclear magnetic résonance. SSNMR spectra can be recorded at ambient or non-ambient (e.g., at 275 K) conditions on any magnetically active isotope présent in the sampie. Common examples of active isotopes for small molécule active phannaccutical ingrédients include'H, ²H, ^l3C, ^l9F, ^3IP, ^l5N, ^l4N,³⁵Cl, B, ⁷Li, ^l7O, ²³Na, ⁷⁹Br, and ^l95Pt.

As used herein, the tenn “XRPD refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded under ambient conditions in transmission or reflection geometry using a diffractometer.

As used herein, the tenus “X-ray powder diffractogram,” “X-ray powder diffraction pattern,” and “XRPD pattern” interchangeabty refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensifies (on the ordinate). For an amorphous material, an X-ray powder diffractogram may include one or more broad signais; and for a crystalline material, an X-ray powder diffractogram may include one or more signais, each identified by its angular value as measured in degrees 2Θ (° 20), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed as “a signal at ... degrees two-theta,” “a signal at [a] two-theta value(s) of...” and/or “a signal at at least ... two-theta value(s) chosen from ...”

A “signal” or “peak,” as used herein, refers to a point in an XRPD pattern or SSNMR spectrum where the intensity as measured in counts is at a local maximum. One of ordinary skill in the art would recognize that one or more signais (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognîzed methods are capable of and suitable for detennining whether a signal exists in a pattern, such as Rietveld refinement.

As used herein, “a signal at at ... degrees two-theta,” “a signal at [a] two-theta value[] of .and/or “a signal at at least ... two-theta value(s) chosen from ....” refer to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 20).

The repeatability ofthe angular values is in the range of ± 0.2° 2Θ, i.e., the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value - 0.2 degrees twotheta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta).

As used herein, the terms “signal intensities” and “peak intensifies” intcrchangeably refer to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).

The terms “X-ray powder diffractogram having a signal at ... two-theta values” and “Xray pow'der diffractogram comprising a signal at ... two-theta values” are used interchangeably herein and refer to an XRPD pattern that contains X-ray refiection positions as measured and observed in X-ray powder diffraction experiments (° 2Θ).

As used herein, an X-ray powder diffractogram is “substantiaily similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signais in the two diffractograms overlap. In determining “substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in XRPD diffractograms even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal positions in XRPD diffractograms (in degrees two-theta (” 2Θ) referred to herein) generally mean that value reported is ±0.2 degrees 20 of the reported value, an art-recognized variance.

As used hercin, an SSNMR spectrum is “substantiaily similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signais in the two spectra overlap. In determining “substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in SSNMR spectra even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal positions in SSNMR spectra (in ppm) referred to herein generally mean that value reported is ±0.2 ppm of the reported value, an art-recognized variance.

As used herein, the term “DSC” refers to the analytical method of Diffcrential Scanning Calorimetry. A DSC curve is “substantiaily similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the features in the two curves overlap. In determining “substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and/or peak (e.g., endotherm or exotherm) positions in DSC curves, even for the same solid form.

As used herein, the term “TGA” refers to the analytical method of Thermo Gravimétrie (or thermogravimetric) Analysis. A TGA thermogram is “substantiaily similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the features in the two thermograms overlap. In determining “substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensifies and/or peak (e.g., dégradation peak) positions in TGA thermograms even for the same solid form.

As used herein, the term substantially crystalline” refers to a solid material having few or no amorphous molécules. For example, substantially crystalline materials hâve less than 15% amorphous molécules (e.g., less than 10% amorphous molécules, less than 5% amorphous molécules, or less than 2% amorphous molécules). It is also noted that the term “substantially crystalline” includes the descriptor “crystalline,” which refers to materials that are 100% crystalline form.

As used herein, a crystalline form is “substantially pure” when it accounts for an amount by weight equal to or greater than 90% of the sum of ail solid form(s) in a sample as determined by a method in accordance with the art, such as, e.g., quantitative XRPD. In some embodiments, the solid form is “substantially pure” when it accounts for an amount by weight equal to or greater than 95% of the sum of ail solid form(s) in a sample. In some embodiments, the solid form is “substantially pure” when it accounts for an amount by weight equal to or greater than 99% of the sum of ail solid form(s) in a sample.

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

The term “pharmaceutically acceptable,” as used herein, refers to a component that is, within the scope of Sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergie response, and the like, and are commensurate with a reasonable benefît/risk ratio. A “pharmaceutically acceptable sait” means any non-toxic sait that, upon administration to a récipient, is capable of providing, either directly or indirectly, a compound of this disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1 to 19.

Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinîc acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propîonate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, βhydroxybutyratc, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalenel -sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with minerai acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

Pharmaceutically acceptable salts derived from appropriate bases include alkali métal, alkaline earth métal, ammonium, and N⁺(Ci-i alkyt)₄ salts. This disclosure also divisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth métal salts include sodium, lithium, potassium, calcium, and magnésium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quatemary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

The ternis “patient” and “subject” are used interchangeably herein and refer to an animal, including a human.

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

As used herein, the term “treatment” and its cognâtes refer to slowing or stopping disease progression. “Treatment” and its cognâtes as used herein, include, but are not limited to, the following: complété or partial rémission, lower risk of kidney failure (e.g., ESRD), and disease related complications (e.g., cdema, susceptibility to infections, or thrombo-embolic events). Improvements in or lessening the severity of any ofthese symptoms can be readily assessed according to methods and techniques known in the art or subsequently developcd.

The terms “about” and “approximately,” when used in connection with doses, amounts, or weight percent of ingrédients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary ski 11 in the art to pro vide a pharmacological effect équivalent to that obtained from the specified dose, amount, or weight percent. The tenus “about” and “approximately” may refer to an acceptable error for a particular value as detenuined by one of ski 11 in the art, which dépends in part on how the values is measured or detennined. In some embodiments, the ternis “about” and “approximately” mean within 20%, 15%, 10%, 5%, 4%, 3%, 2%, l %, or 0.5% of a given value or range. As used herein, the symbol appearing immediately before a numerical value has the same mcaning as the tenus “about” and “approximately.”

The at least one compound, tautomer, deuterated dérivative, or phanuaceutically acceptable sait chosen from compounds of Fonuulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic6, II, II-l, II-2, 11-3, II-4, II-5, Π-6, II-6a and II-6b, a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing may be administered once daily, twice daily, or three times daily, for example, for the treatment of FSGS. In some embodiments, the compounds of Fonuulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic5, Ic-6, II, II-l, II-2,II-3, 11-4, II-5, II-6, II-6a and II-6b, are chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a phanuaceutically acceptable sait of any of the foregoing. In some embodiments, at least one compound, tautomer, deuterated dérivative, or phanuaceutically acceptable sait chosen from compounds of Fonuulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2, 11-3,11-4, II-5,11-6, II-6a and II-6b, a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing is administered once daily. In some embodiments, at least one compound, tautomer, deuterated dérivative, or phanuaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a phanuaceutically acceptable sait of any of the foregoing is administered once daily. In some embodiments, at least one compound, tautomer, deuterated dérivative, or phanuaceutically acceptable sait chosen from compounds of Fonuulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, lc-6, II, II-l, II-2, II-3, Π-4, II5, II-6, Il-6a and Il-6b, a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait ofany ofthe foregoing is administcrcd twice daily. In some embodiments, at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds l to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any ofthe foregoing is administered twice daily. In some embodiments, at least one compound. tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2, II-3, 11-4, II-5, II-6, Il-6a and II-6b, a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing are administered three times daily. in some embodiments, at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing is administered three times daily.

In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, Ie-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2,11-3, II-4, II-5, II-6, II-6a and II-6b, a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait ofany ofthe foregoing are administered once daily, twice daily, or three times daily. In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing is administered once daily, twice daily, or three times daily.

One of ordinary skill in the art would recognîze that, when an amount of compound is disclosed, the relevant amount of a pharmaceutically acceptable sait form of the compound is an amount équivalent to the concentration of the free base of the compound. The amounts of the compounds, pharmaceutically acceptable salts, solvatés, and deuterated dérivatives disclosed herein are based upon the free base form of the reference compound. For example, “1000 mg of at least one compound or pharmaceutically acceptable sait chosen from compounds of Formula I and pharmaceutically acceptable salts thereof’ includes 1000 mg of a compound of Formula I and a concentration of a pharmaceutically acceptable sait of compounds of Formula I équivalent to 1000 mg of a compound of Formula I.

As used herein. the term “ambient conditions” means room température, open air condition, and uncontrolled humidity condition.

Compounds and Compositions

In some embodiments, at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait of the disclosure is a compound represented by the following structural formula:

R⁵

Formula la a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein:

Ring A is chosen from Cô aryl and 5- and 6-membered heteroaryl groups;

R', for each occurrence, is independently chosen from halogen, -OH, =O, cyano, phenyl, Ci-Cô alkyl, Ci-Cô alkoxy, Cj-Cô carbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)N(R^C)2, and -SO?R^C groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C1-C4 alkyl groups;

the 4- to 6-mcmbered heterocyclyl of R* comprises one heteroatom chosen from nitrogen and oxygen;

the Ci-Cô alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?, and C1-C4 alkoxy groups;

the Ci-Cô alkoxy of R¹ is optionally substituted with 1 to 3 groups independently chosen from -OH, cyano, and halogen groups;

the C3-C6 carbocyclyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl);. Ci-C; alkyl. C1-C4 alkoxy, -C(=O)NH;, -C(=O)NH(Ci-C₄ alkyl). and

-C(=O)N(Ci-C4 alkyl)? groups; and the phenyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C₄ alkyl), -N(C|-C₄ alkyl)?, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH₂, -C(-O)NH(Ci-Ci alkyl), and -C(=O)N(Ci-C₄ alkyl)? groups; or wherein two R^f groups taken together with the Ring A atoms connecting them form a 5- to 6-membered cycloaikyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered cycloaikyl, 5- to 8-membered heterocyclyl,

5- to 6-membered aryl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and C1-C4 alkyl;

R²is chosen from cyano, Ci-C& alkyl, -C(=O)O(C|-C₄ alkyl), C₂-C& alkynyl, and

the Ci-Cô alkyl of R²is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl), -N(Ci-C₄ alkyl)?, C1-C4 alkoxy, -C(=O)NH?, -C(=O)NH(C]-C₄ alkyl), -C(=O)N(Ct-C₄ alkyl)?, C₃-C₆ carbocyclyl, 5- to 10-membered heterocyclyl, Cô aryl, and 5- to 10-membered heteroaryl groups;

Ring B is chosen from C3-C1? carbocyclyl, 3- to 12-membered heterocyclyl, C& and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with 1,2, 3, 4, or 5 R^a groups; wherein:

R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, C2-Cô alkenyl, C|-C& alkoxy, Ci-C& haloalkyl, Ci-Cô haloalkenyl, Ci-C6 haloalkoxy, -C(=O)NRRⁱ, -NR^hR', -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NRbCfoOJNRW, -NR^hS(=O)pR^k-OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OCt-O W'RL -[O(CH?)_q]rO(Ci-C₆ alkyl), -S(=O)_PR^k, -S^OjpNR¹¹#, -C(-O)OR^k, C3-C1? carbocyclyl, 3- to 12-membcrcd heterocyclyl, C& and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Cô alkyl, Ci-Cô alkoxy, and the C?-C& alkenyl of R^a are each optionally substituted with I to 3 groups independently chosen from Cô to Cio aryl (optionally substituted with 1 to 3 R^m groups), 5- to 10membered heterocyclyl (optionally substituted with 1 to 3 R¹ groups), 5 to ΙΟ-membered heteroaryl (optionally substituted with l to 3 Rⁿⁱ groups), cyano, -C(=O)R^k, -C(=O)OR^k, -C(=O)NR^hR^!, -NR^hR\

-NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^hC(=O)NRⁱR^j, -NR^hS(=O)PR^k -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OC^OjNRW, -S(=O)PR^k, -S(=O)_PNR^liR^l, -O(Cô aryl) (optionally substituted with l to 3 R¹ groups), and C3-C6 carbocyclyl groups (optionally substituted with I to 3 R^m groups);

the C3-C12 carbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cm aryl, and the 5- to 10-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C4 alkyl, -NR^hR‘, and -OR^k groups, wherein:

R¹', R', and R', for each occurrence, are each independently chosen from hydrogen, C1-C4 alkyl, C&-Cioaryl, and C3-C6 cycloalkyl groups, wherein:

the C1-C4 alkyl of any one of R¹¹, R‘, and R^J is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 carbocyclyl groups, wherein:

the C_t-C₄ alkyl of any one of R^k is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R¹, for each occurrence, is independently chosen from halogen, cyano, oxo, C|-C& alkyl, Cj-Cô alkoxy, -S(=O)_PR^k, and -OR^k groups, wherein:

the Ci-Cô alkyl of R^m is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and -O(Ci-C4 alkyl) groups;

R³ is chosen from Ci-Cô alkyl, -C(=O)O(Ci-C4 alkyl), C3-C12 carbocyclyl, 3- to 12membered heterocyclyl, Cô and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Ce alkyl of R³ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkylh, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(Ci-C4 alkyl), and -C(=O)N(Ci-C₄ alkyl)? groups;

the C3-C12 carbocyclyl, the 3- to 12-membered heterocyclyl, the Cf, and Cioaryl, and the 5- to 10-membered heteroaryl of R³ are each optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(C|-C4 alkyl) (optionally substituted with -OH), -N(C|-C₄ alkyl)₂, C1-C5 alkyl (optionally substituted with -OH or -S(=O)₂(Ci-C₄ alkyl)), Ci-C₄alkoxy, -C(=O)NH₂, -C(=O)NH{Ci-C₄ alkyl), -NHC(=O)(Ci-C4 alkyl), -C(=O)(Cj-C4 alkoxy), and -C(=O)N(Ci-C4 alkyl)₂ groups;

R⁴ is chosen from halogen, cyano, Ci-C6 alkyl, Ci-Cô haloalkyl, -(CH2)nC(=O)NR^,lR°, -NRR°, -NR^ÜC(=O)R^ -NRⁿS(=O)PRP,-(CH₂)nOR^p, -S(=O)pRp, -S(=O)PNRⁿR°, -OS(^O)pNRⁿR^ü, and -(CH₂)nC(=O)OR^p groups, wherein:

R and R°, for each occurrence, are each independently chosen from hydrogen and C1-C4 alkyl groups; and

R^p, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl groups;

R¹¹ is chosen from hydrogen and Ci-Cô alkyl;

ni is an integer chosen from 0, 1,2, 3, 4, and 5;

n is an integer chosen from 0, 1, and 2;

p, for each occurrence, is an integer independently chosen from 1 and 2; and q and r, for each occurrence, are each an integer independently chosen from I, 2, 3, and 4.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ih, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R⁴ is -OH; and ail other variables not specifically defined herein are as defined in any one ofthe foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae 1, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof ni is an integer chosen from 0, I, and 2; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments. In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, tautomer, deuterated dérivative, or pharmaceutically acceptable sait of the disclosure, ni is 0; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments. In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, m is 1 ; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, Ring A is phenyl, thiophenyl, or pyridinyl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments. In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, Ring A is phenyl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments. In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, Ring A is thiophenyl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments. In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, Ring A is pyridinyl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable (R^a)₀-5 \ ^B / sait thereof, R² is chosen from C1-C4 alkyl and groups, wherein:

the C1-C4 alkyl of R²is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C₄ alkyl), -N(Ci-C₄ alkyl)₂, Ci-C₂alkoxy, Cî-Cû cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl groups; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable (R³)o-5 \ ^B / sait thereof, R² is chosen from C1-C2 alkyl and ---groups, wherein:

the C1-C2 alkyl of R² is optionally substituted with I to 3 groups independently chosen from halogen, cyano, -OH, and 5- to 6-membered heterocyclyl groups; and ail other variables not specifically defined herein are as defined in any one ofthe foregoing embodiments.

In some embodiments, in a compound ofthe disclosure (i.e., a compound of any one of Formulae I, la, 1b, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable

I B P sait thereof, R² is chosen from -CH3 and groups; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound ofthe disclosure (i.e., a compound ofany one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R²is chosen from -CH3, -CH₂OH, and (tetrahydro-2H-pyran-4-yl)methyl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, Ring B is chosen from cyclopropyl, 5- to 10-membered heterocyclyl, phenyl, and 5 to 9-membered heteroaryl groups, each of which is optionally substituted with l, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one ofthe foregoing embodiments.

In some embodiments, in a compound ofthe disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, Ring B is chosen from cyclopropyl, 5- to 10-membered heterocyclyl comprising l to 3 heteroatoms chosen from N and O, phenyl, and 5- to 9-membered heteroaryl comprising l to 3 heteroatoms chosen from N and O; each of which is optionally substituted with l, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, Ring B is chosen from cyclopropyl, 5-membered heterocyclyl comprising I to 3 heteroatoms chosen from N and O, 6-membered heterocyclyl comprising l to 3 heteroatoms chosen from N and O, 9-membercd heterocyclyl comprising l to 3 heteroatoms chosen from N and Ο, 10-membered heterocyclyl comprising I to 3 hcteroatoms chosen from N and O, phenyl, 5-membered heteroaryl comprising l to 3 heteroatoms chosen from N and O, 6-membercd heteroaryl comprising l to 3 heteroatoms chosen from N and O, and 9-membered heteroaryl comprising l to 3 heteroatoms chosen from N and O; each of which is optionally substituted with l, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable

1,2,3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound ofthe disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable

N

, each of which is optionally substituted with 1,2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of

Formulae 1, la, Ih, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable

sait thereof, R² is chosen from -CH3 and Ring B, wherein Ring B is chosen from

optionally substituted with 1, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments. In some embodiments,

Ring B is HN which is optionally substituted with 1 R^a group.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R³ is chosen from C1-C4 alkyl,

-C(=O)O(Ci-C2 alkyl), Cî-Cô cycloalkyl, and 5 to 10-membered heterocyclyl groups, wherein:

the C1-C4 alkyl of R³ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C2 alkoxy groups; and the C3-C6 cycloalkyl and the 5- to 10-membered heterocyclyl of R³ are each optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, C1-C2 alkyl, and C1-C2 alkoxy groups;

and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Fonnulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R³ is chosen from C1-C2 alkyl, -C(=O)O(C]-C2 alkyl), cyclopropyl, cyclobutyl, and 5- to 6-membered heterocyclyl groups, wherein:

the C1-C2 alkyl of R³ is optionally substituted with l to 3 groups independently chosen from F, Cl, Br, cyano, -OH, and C1-C2 alkoxy groups; and the cyclopropyl, the cyclobutyl, and the 5- to 6-membered heterocyclyl of R³ are each optionally substituted with l to 3 groups independently chosen from F, Cl, Br, cyano, -OH, C1-C2 alkyl, and C1-C2 alkoxy groups;

and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Fonnulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or phannaceutically acceptable sait thereof, R³ is chosen from -CH3, -CH^CHa, -CH2OH, -C(=O)OCH3, -CH2OCH3, -CH(CHa)2, cyclopropyl, difluorocyclopropyl, and tetrahydro-2H-pyranyl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R³ is -CH3; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Fonnulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or phannaceutically acceptable sait thereof, wherein R’, for each occurrence, is independently chosen from hydrogen, halogen, cyano, -OH, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)N(R^e)2, and -SO2(R^C), and C3-C6 cycloalkyl groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C1-C4 alkyl groups;

the C1-C4 alkyl of R' is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, and C1-C2 alkoxy groups;

the C1-C4 alkoxy of R¹ is optionally substituted with 1 to 3 independently chosen from halogen groups; and the Cî-Cô cycloalkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C2 alkoxy groups; or wherein two R¹ groups taken together with the Ring A atoms connecting them fonn a

5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or

5- to 6-membered heteroaryl ring, wherein thc 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6membered aryl, and 5- to 6-membcrcd heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and C1-C4 alkyl;

and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Fonnulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R¹, for each occurrence, is independently chosen from hydrogen, halogen, cyano, OH, Ct-C4 alkyl, C1-C4 alkoxy, -C(=O)N(R^C)2, and C3-C6 cycloalkyl groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C1-C2 alkyl groups;

theCi-C₄ alkyl ofR¹is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C2 alkoxy groups;

the C1-C4 alkoxy of R¹ is optionally substituted with 1 to 3 independently chosen from halogen groups; and the C3-C6 cycloalkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C2 alkoxy groups;

and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R¹, for each occurrence, is independently chosen from hydrogen, halogen, cyano, OH, C1-C4 alkyl, C1-C4 alkoxy, and C₃-Cô cycloalkyl; wherein:

the C1-C4 alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C2 alkoxy;

the C1-C4 alkoxy of R¹ is optionally substituted with I to 3 independently chosen halogen groups; and the C3-C6 cycloalkyl of R’ is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, and C1-C2 alkoxy;

and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of

Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R*, for each occurrence, is independently chosen from F, Cl, Br, Ci-C4 alkyl, and Cî-Cô cycloalkyl, wherein:

the C1-C4 alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH; and the C₃-C_ft cycloalkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH;

and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of

Formulae 1, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R¹, for each occurrence, is independently chosen from F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)N(R^C)2, and C₃-Cô cycloalkyl groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C1-C2 alkyl groups;

the C1-C4 alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH;

the C1-C4 alkoxy of R¹ is optionally substituted with 1 to 3 independently chosen from halogen groups; and the C₃-Cô cycloalkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH;

and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R¹, for each occurrence, is independently chosen from F, Cl, Br, Cj-C4 alkyl, and C₃-Cô cycloalkyl; wherein:

the C[-C4 alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH; and the C₃-Cô cycloalkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and-OH;

and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or phannaceutically acceptable sait thereof, R¹, for each occurrence, is independently chosen from F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)N(R^C)₂, and Cj-Cô cycloalkyl groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C|-C₂ alkyl groups;

the C1-C4 alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH; and the C1-C4 alkoxy of R¹ is optionally substituted with 1 to 3 independently chosen from halogen groups;

and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or phannaceutically acceptable sait thereof, R¹, for each occurrence, is independently chosen from Cl, Br, -CH3, -CF3, -CH2CH3, -CH(CH₃)2, -CH2CHF2, -CH₂CH(CH₃)₂, difluorocyclobutyl, and cyclohcxyl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Fonnulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or phannaceutically acceptable sait thereof, R¹, for each occurrence, is independently chosen from F, Cl, Br, -CH3, -CH(CH3)₂, CF3, -OCH3, -OCF3, -C(=O)N(CH3)₂, and cyclopropyl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait of the disclosure, R¹, for each occurrence, is Cl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait of the disclosure, R¹, for each occurrence, is independently chosen from halogen, -OH, and C1-C4 alkyl; wherein:

the C1-C4 alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH;

and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Fonnulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or phannaceutically acceptable sait thereof, R¹, for each occurrence, is independently chosen from F, Cl, Br, -OH, and C1-C2 alkyl; wherein:

the C1-C2 alkyl of R* is optionally substituted with 1 to 3 groups independently chosen from F, Cl, and -OH;

and ail other variables not specifically defined herein are as defined in any one ofthe foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R¹, for each occurrence, is independently chosen from F, -OH, -CH3, -CHF2, and -CH2OH; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R¹, for each occurrence, is independently chosen from -SO2(R^C), wherein R^c is chosen from hydrogen and C1-C2 alkyl groups; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments. In some embodiments, R^c is chosen from C1-C2 alkyl groups. In some embodiments, R^c is chosen from Ci alkyl groups. In some embodiments, R^c is -CH3.

In some embodiments, in a compound ofthe disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, two R¹ groups taken together with the Ring A atoms connecting them form a 5- to 6- membered cycloalkyl, 5- to 8- membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6membered heteroaryl ring, wherein the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and C1-C4 alkyl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, two R¹ groups taken together form a group chosen from

Ο , and F ; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait of the disclosure, two R¹ groups taken together with the Ring A atoms connecting them form a group chosen from and F ; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Fomiulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R^a, for each occurrence, is independcntly chosen from halogen, cyano, Ci-Cô alkyl, C1-C4 alkoxy, Ci-Cô haloalkyl, Ci-Cô haloalkoxy, -C(=O)NR^hRⁱ, -NR¹^, -NRC(=O)R^k, -OR^k, -[O(CH₂)_q]rO(Ci-C₆ alkyl), -S(=O)₂R^k, -S(=O)2NR^i,R‘, C3-C6 cycloalkyl, 5 to 10-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl; wherein:

the Ci-Cô alkyl of R^a is optionally substituted with 1 to 3 groups independcntly chosen from cyano, -C(=O)NR^hRⁱ, -ΝΗ'Έ', -NR^hC(-O)R^k, -NR^hC(=O)OR^k, -ΝΚ^ΙιΟ(=Ο)ΝΚΉ\ -NR^hS(=O)PR^k.-OR^k, -S(=O)2R^k, -S^O^R¹'^, and C₃-C₆ cycloalkyl;

the C₃-Cô cycloalkyl, the 5 to 10-membered heterocyclyl, the phenyl, and the 5- to 8membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independcntly chosen from halogen, C1-C2 alkyl, and -OR^k, wherein:

R¹', R¹, and R\ for each occurrence, are each independcntly chosen from hydrogen, C]-C₂ alkyl, cyclopropyl, and cyclobutyl, wherein:

the C|-C₂ alkyl of any one of R^h, R', and R^j is optionally substituted with to 3 groups independcntly chosen from halogen and -OH;

R^k, for each occurrence, is each independently chosen from hydrogen and C1-C4 alkyl, wherein:

the C1-C4 alkyl of R^k is optionally substituted with l to 3 groups independently chosen from halogen and -OH; and q and r are each an integer chosen from l, 2, and 3;

and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Ct, alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -C(=O)NR^hRⁱ, -NR' Rl -NR^hC(=O)R^k, -OR^k, -[O(CH₂)_q]rO(Ci-C₄ alkyl), -S(=O)₂R^k, -S(=O)2NR^hR¹, cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6membered heteroaryl, wherein:

the Ci-Cô alkyl of R^a is optionally substituted with 1 to 3 groups independently chosen from cyano, -C(=O)NR^l'Rⁱ, -NR^hR', -OR^k, cyclopropyl, and cyclobutyl;

the cyclopropyl, the cyclobutyl, the 5- to 6-membercd heterocyclyl, the phenyl, and the 5 to 6-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, -CH3, -OH, and -OCH3, wherein:

R¹¹ and R¹, for each occurrence, are each independently chosen from hydrogen, -CH3, cyclopropyl, and cyclobutyl, wherein:

the -CH3 of any one of R^h and R¹ is optionally substituted with 1 to 3 groups independently chosen from F, Cl, and -OH;

R^k, for each occurrence, is each independently chosen from hydrogen and

-CH3; wherein:

the -CH3ofR^k is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH;

and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound ofthe disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R^a, for each occurrence, is independently chosen from F, Cl, Br, cyano, Ci-Cô alkyl, C1-C2 alkoxy, CrC2 haloalkyl, -C^CONR¹'^, -NR^hRⁱ, -NR^hC(=O)R^k, -OR^k, -[O(CH2)_q]rO(Ci-C₂ alkyl), -S(=O)₂R^k, -S(=O)₂NR^hRⁱ, cyclopropyl, cyclobutyl, 5-membered heterocyclyl, phenyl, and 6-membered heteroaryl, wherein:

the Ci-Cô alkyl of R¹¹ is optionally substituted with 1 to 3 groups independently chosen from cyano, -C(=O)NR^l,Rⁱ, -OR^k, and cyclopropyl;

the cyclopropyl, the cyclobutyl, the 5 to 6-membered heterocyclyl, the phenyl, and the 5 to 6-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, -CH?, -OH, and -OCH₃, wherein:

R^!l and R¹, for each occurrence, are each independently chosen from hydrogen, -CH?, and cyclopropyl; wherein:

the -CH? of any one of R^h and R‘ is optionally substituted with I to 3 groups independently chosen from F, Cl, and -OH;

R^k, for each occurrence, is each independently chosen from hydrogen and

-CH?; and q and r are each an integer independently chosen from 1 and 2; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ih, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R^a, for each occurrence, is independently chosen from F, cyano, -OH, -CH?, -CF?, CH(CH₃)₂, -(CH₂)₂OH, -(CH₂)₂OCH?, -CH₂CH(OH)C₂H₅, -CH₂C(CH₃)(CH₂OH)₂, -OCH₃, -OCH₂CH₃, -[O(CH₂)₂]₂OCH₃, -CH₂C(=O)NHCH₃, -(CH₂)₂SO₂CH₃, -CH₂C(=O)N(CH₃)₂, -CH₂(cyclopropyl), -C(=O)NH₂, -C(=O)NH(cyclopropyl),-NH₂, -NHCH₃, -N(CH₃)₂, -NHC(CH₃)₂CH₂OH, -NHC(=O)CH₃, -SO₂CH₃, -SO₂NH₂, cyclopropyl, 2-methoxyphenyl, N-methylpiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl, and tetrahydrothiophenyl 1,1-dioxide; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R^a, for each occurrence, is independently chosen from -CH₃ and -(CH₂)₂SO₂CH₃; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R⁵ is chosen from hydrogen and Ci-C₄ alkyl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, of the disclosure (i.e., a compound of any one of Formulae I, la,

Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R⁵ is chosen from hydrogen, methyl, and propyl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R⁵ is hydrogen and R¹, for each occurrence, is independently chosen from -SO:(R^C), wherein R^c is chosen from hydrogen and C1-C2 alkyl groups; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments. In some embodiments, R^c is chosen from C1-C2 alkyl groups. In some embodiments, R^c is chosen from Ci alkyl groups. In some embodiments, R^c is -CH3.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R⁵ is hydrogen and two R¹ groups taken together with the Ring A atoms connecting them form a 5- to 6- membered cycloalkyl, 5- to 8- membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered cycloalkyl, 5- to 8membered heterocyclyl, 5- to 6-membercd aryl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and C1-C4 alkyl; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R⁵ is hydrogen and two R¹ groups taken together form a group chosen from

Ό , and F ; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, of the disclosure (i.e., a compound of any one of Formulae I, la, Ib, and le), or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R⁵ is hydrogen and two R¹ groups taken together with the Ring A atoms connecting them form a group chosen from and F and ail other variables not specifically defined herein are as defined in any one ofthe foregoing embodiments.

In some embodiments, a compound, tautomcr, deuterated dérivative, or pharmaceutically acceptable sait of the disclosure is represented by one of the following structural formutae:

Formula Ic-4

a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing; and ail other variables not specifically defined herein are as defined in any one ofthe foregoing embodiments. In some embodiments of Formula Ic-l through lc-6, Compound I296 and Compound 43a arc cxcluded.

In some embodiments, at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait ofthe disclosure is a compound represented by the following structural formula:

(R¹)m

Formula II a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait ofany ofthe foregoing, wherein:

Ring A is chosen from Ce aryl and 5- and 6-membered heteroaryl groups;

R¹, for each occurrence, is independently chosen from halogen, -OH, =O, cyano, phenyl, Cs-Cô alkyl, Ci-Cà alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, and -C(=O)N(R^c)2 groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C1-C4 alkyl groups;

the 4- to 6-membered heterocyclyl of R¹ comprises one heteroatom chosen from nitrogen and oxygen;

the Ci-Cô alkyl of R¹ is optionally substituted with I to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)₂, and C1-C4 alkoxy groups;

the Ci-Cô alkoxy of R' is optionally substituted with 1 to 3 groups independently chosen from -OH, cyano, and halogen groups;

the C3-C6 carbocyclyl of R¹ is optionally substituted with I to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C₄ alkyl), -N(Ci-C₄ alkyl)?, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH?, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(Ci-C₄ alkyl)? groups; and the phenyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C₄ alkyl), -N(Cj-C₄ alkyl)?, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH?, -C(=O)NH(Ci-C4 alkyl), and -C(=O)N(C|-C₄ alkyl)? groups;

R² is chosen from cyano, C|-C₆ alkyl, -C(=O)O(Ci-C4 alkyl), C₂-C₆ alkynyl, and

the Ci-Cô alkyl of R² is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C₄ alkyl), -N(Ci-C4 alkyl)?, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -C(=O)N(Ci-C₄ alkyl)?, C3-C0 carbocyclyl, 5- to 10-membered heterocyclyl, Cô aryl, and 5- to 10-membered heteroaryl groups;

Ring B is chosen from C3-C1? carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with 1, 2, 3, 4, or 5 R^a groups; wherein:

R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, C?-Cô alkenyl, Ci-Cô alkoxy, Ci-Cô haloalkyl, Ci-Cô haloalkenyl, Ci-Cô haloalkoxy, -C(=O)NR^hR^!, -NR^R', -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^hC(=O)NRⁱRî, -NR^hS(=O)pR^k-OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OCt-OlNRbRL -[O(CH₂)q]rO(Ci-Cô alkyl), -S(=O)_PR^k, -C(-O)OR^k, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Cô alkyl, Ci-Cô alkoxy, and the C₂-Cô alkenyl of R^a are each optionally substituted with 1 to 3 groups independently chosen from Cô to Cio aryl (optionally substituted with 1 to 3 R^m groups), 5- to 10membered heterocyclyl (optionally substituted with 1 to 3 R^nl groups), 5to 10-membered heteroaryl (optionally substituted with 1 to 3 R¹ groups), cyano, -C(-O)R^k, -C(=O)OR^k, -C(=O)NR^hRⁱ, -NR^hR', -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^hC(=O)NR'Rj, -NR^hS(-O)PR^k -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OC^OWR, -S(=O)PR^k, -S(=O)_PNR^hR^l, -O(Cô aryl) (optionally substituted with 1 to 3 R^m groups), and Cî-Cô carbocyclyl groups (optionally substituted with l to 3 R¹ groups);

the C3-C12 carbocyclyl, the 3- to 12-memhered heterocyclyl, the Ce and Cio aryl, and the 5- to 10-membered heteroaryl of R^u are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C4 alkyl, -NR^hR', and -OR^k groups, wherein:

R^h, R¹, and R^J, for each occurrence, are each independently chosen from hydrogen, C1-C4 alkyl, Cô-Cioaryl, and Cs-Côcycloalkyl groups, wherein:

the C1-C4 alkyl of any one of R^h, R', and R^J' is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and Cj-Cô carbocyclyl groups, wherein:

the C1-C4 alkyl of any one of R^k is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^m, for each occurrence, is independently chosen from halogen, cyano, oxo, Ci-Cô alkyl, C]-C& alkoxy, -S(=O)_PR^k, and -OR^k groups, wherein:

the Ci-Cô alkyl ofR^m is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and -O(Ci-C₄ alkyl) groups;

R³ is chosen from Ci-Cô alkyl, -C(=O)O(Ci-C4 alkyl), C3-C12 carbocyclyl, 3- to 12membered heterocyclyl, Cô and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein: the Ci-Cô alkyl of R³ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C₄ alkyl), -N(Ci-C₄ alkyl)₂, CrC₄ alkoxy, -C(=O)NH₂, -C(=O)NH(C|-C₄ alkyl), and -C(=O)N(Cj-C₄ alkyl)? groups;

the C3-C1? carbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cio aryl, and the 5- to 10-membered heteroaryl of R³ are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(C[-C₄ alkyl) (optionally substituted with -OH), -N(Ci-C₄ alkyl)?, C1-C5 alkyl (optionally substituted with -OH or -S(=O)₂(Ci-C₄ alkyl)), C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -NHC(=O)(Ci-C₄ alkyl). -C(=O)(Ci-C< alkoxy). and -C(-O)N(Ci-C₄ alkyl)₂ groups;

R⁴ is chosen from halogen, cyano, Ci-Cô alkyl, Ci-Cô haloalkyl, -(CH2)uC(=O)NRⁿR°, -NRR°, -NR°C(=O)Rp, -NRS(-O)pRP. -(CH2)i.ORp, -S(=O)pRp, -S(=O)pNRR°, -OS(-O)pNRR⁰, and -(CH2)nC(=O)OR^p groups, wherein:

R and R”, for each occurrence, are each independently chosen from hydrogen and C1-C4 alkyl groups; and

RP, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl groups;

m is an integer chosen from 0, l, 2, 3, 4, and 5;

n is an integer chosen from 0, l, and 2;

p, for each occurrence, is an integer independently chosen from l and 2; and q and r, for each occurrence, are each an integer independently chosen from l, 2, 3, and 4.

In some embodiments, Compound I296 and Compound 43a are excluded from Formula II.

In some embodiments, in a compound of Formula II or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R⁴ is -OH; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of Formula II or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, ni is an integer chosen from 0, l, and 2; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of Formula II or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, Ring A is phenyl, thiophenyl, or pyridinyl; and ali other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of Formula II or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R³is chosen from Cm alkyl groups; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of Formula II or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R³is chosen from -CH₃ and Ring B, wherein Ring B

or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of Formula II or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R³ is -CH3; and

R² is chosen from -CH3 and Ring B, wherein:

and

, each of which is optionally substituted with l, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments.

In some embodiments, in a compound of Formula II or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, R³ is -CH3; and

R² is chosen from -CH3 and Ring B, wherein:

Ring B is

, which is optionally substituted with l or 2

R^a groups; and ail other variables not specifically defined herein are as defined in any one ofthe foregoing embodiments.

In some embodiments, in a compound of Formula II or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof, Ring A is chosen from Cô aryl and 5- and 6membered heteroaryl groups;

R¹, for each occurrence, is independently chosen from halogen, Cm alkyl, Cm alkoxy, C3 cycloalkyl, and -C(=O)N(R^C)₂ groups, wherein:

the Ci-4 alkyl and Ci-4 alkoxy groups are optionally substituted with l-3 groups chosen from halogens; and

R\ for each occurrence, is independently chosen from hydrogen and Ci-4 alkyl groups;

R² is chosen from Ci-4 alkyl and 5-membered heteroaryl groups, wherein the

5-membered heteroaryl groups are optionally substituted with l-2 Cm alkyl groups optionally substituted with -S(=O)2CHî; and

R³ is chosen from Cm alkyl groups; and ni is an înteger chosen from 0, l, and 2.

IO In some embodiments, a compound of Formula II or a tautomer, deuterated dérivative, or pharmaceutically acceptable sait thereof is represented by one of the following structural formulae:

Formula II-1

Formula 11-3

Formula II-4 (R¹)m (R¹)m

Formula II-5

Formula II-6 a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any ofthe foregoing; and ail other variables not specifically defined herein are as defined in any one of the foregoing embodiments. In some embodiments of Formula II-1 through 116, Compound 1296 and Compound 43a are excluded.

In some embodiments, compounds of Formula II-6 are selected from Compounds of Formula II-6a and Formula II-6b:

wherein R^la and R^,b are independently chosen from halogen, H, C1-C4 alkyl, and C1-C4 haloalkyl groups;

R^k is chosen from halogen, H, CH3, -OH, and CH3OH; and wherein R2 in Formula H-6a is defined for Formula II.

In some embodiments, the at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait of the disclosure is chosen from Compounds 1 to 29 depicted in Table 1, Compounds 15 to 1295 depicted in Table 2, Compounds 30 to 44 and depicted in Table and Compounds 45 to 68 depicted in Table 4, tautomers thereof, deuterated dérivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any ofthe foregoing.

A wavy line in a compound depicted in any one of Tables l - 4 (i.e., ) represents a bond between two atoms and indicates a position of mixed stereochemistry for a collection of molécules, such as a racemic mixture, cis/trans isomers, or (E)/(Z) isomers. Similarly, a straight R^R^Y line (i.e., ) emanating from a chiral center (e.g., R^z and R² , where R^w, R^x, R^Y, and

R^z are different) in a compound depicted in Table 2 represents a position of mixed stereochemistry for a collection of molécules.

J

6I

Cl Cl Cf GoH °-ζ 0Ύ'' ^y γΉ n-^ / ! ! 17 18 Cl Cl ci O o c /\zoh rvH ri F ΓΊ N J H N J H N /N r r 21 22 F3C ,f CIx / Br, O O ' OH \z°H N' J H N' J H K' N N- N' ! ! ! 25 26 çy \.°H xyT· N-^ ! 29

CI 7 O \/oh /—\/oh Cj °x Cj h N. J H ! 19 20 0. ! ocF3 ci\ / x J O Az0H ^Ά/θπ H '' N-NJ'-V'' N-^ / 23 24 f3c P O c# —\OH ΓΒΛ- kYT'·'' / 27 28

118

I22

I28

7I

1158

1173

I202

I262

I270

I294

I295

Some embodiments of the disclosure include dérivatives of Compounds l to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2, Π-3, 11-4, 11-5, II-6, II-6a and I I-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the dérivatives are Silicon dérivatives in which at least one carbon atom in a compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, lc-3, Ic-4, Ic-5, Ic-6, II, II-l, Π-2, Π-3, II-4, II-5, 11-6, II-6a and II-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by Silicon. In some embodiments, the dérivatives are Silicon dérivatives in which at least one halogen atom (e.g., a fluorine) in a compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2, II-3, II-4, II5, II-6, II-6a and II-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by a Silicon dérivative (e.g., -Si(CH₃)₃). In some embodiments, the dérivatives are boron dérivatives, în which at least one carbon atom in a compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295,

Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, la, Ib, le, Ic-1, Ic2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2, II-3,11-4, II-5, 11-6, II-6a and II-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts ofany ofthe foregoing, has been replaced by boron. In other embodiments, the dérivatives are phosphorus dérivatives, in which at least one carbon atom in a compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by phosphorus.

In some embodiments, the dérivative is a Silicon dérivative in which one carbon atom in a compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2, II-3, II-4, II5, II-6, II-6a and II-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by Silicon or a Silicon dérivative (e.g., -SîfCHa)?- or -Si(OH)2-). The carbon replaced by Silicon may be a non-aromatic carbon. In other embodiments, a fluorine has been replaced by a Silicon dérivative (e.g., -SifCHafs). In some embodiments, the Silicon dérivatives of the disclosure may include one or more hydrogen atoms replaced by deuterium. In some embodiments, a Silicon dérivative of compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, la, Ib, le, Ic-1, lc-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2, Π-3, II-4, II-5, II-6, II-6a and II-6b, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, may hâve Silicon incorporated into a heterocycle ring.

In some embodiments, the derivative is a boron derivative in which one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, la, Ib, le, Ic-1, lc-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2, II-3, II-4, II5, II-6, II-6a and ll-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by boron or a boron derivative.

In some embodiments, the derivative is a phosphorus derivative in which one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable sait chosen from Compounds l to 29, Compounds 15 to I295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae 1, la, Ib, le, lc-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, Π, II-l, II-2, 11-3, I [-4, 11-5, 11-6, I I-6a and I I-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by phosphorus or a phosphorus dérivative.

Another aspect of the disclosure provides pharmaceutical compositions comprising at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one formula chosen from Formulae I, la, Ib, le, lc-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic6, II, II-l,11-2, 11-3, II-4, 11-5, II-6, II-6a and II-6b, and Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical composition comprising at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Formulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2, II-3, II-4, II-5,11-6, II-6a and Il-6b, and Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered to a patient in need thereof.

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

It will also be appreciated that a pharmaceutical composition of this disclosure can be employed in combination thérapies; that is, the pharmaceutical compositions described herein can further include at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, lc-6, II, II-l, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subséquent to, a composition comprising at least one other active therapeutic agent. In some embodiments, a pharmaceutical composition comprising at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subséquent to, a composition comprising at least one other active therapeutic agent.

As described above, pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least onc pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The at least one pharmaceutically acceptable carrier, as used herein, includes any and ail solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonie agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21 st édition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, cds. J. Swarbrick and J. C. Boylan, 1988 to 1999, Marcel Dekker, New York discloses various carriers used in formulating pharmaceutical compositions and known techniques for the préparation thereof. Except insofar as any conventionai carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwîse interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stéarate, lecithin, sérum proteins (such as, e.g., human sérum albumin), buffer substances (such as, e.g., phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegctable fatty acids, water, salts, and electrolytes (such as, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloïdal silica, magnésium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as, e.g., lactose, glucose, and sucrosc), starches (such as, e.g., corn starch and potato starch), cellulose and its dérivatives (such as, e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as, e.g., cocoa butter and suppository waxes), oils (such as, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil, and soybean oil), glycols (such as, e.g., propylene glycol and polyethylene glycol), esters (such as, e.g., ethyl oleate and ethyl laurate), agar, buffering agents (such as, e.g., magnésium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonie saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as, e.g,, sodium lauryl sulfate and magnésium stéarate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.

In some embodiments of the disclosure, the compounds and the phannaceutical compositions described herein are used to treat FSGS and/or NDKD. In some embodiments, FSGS is mediated by APOLI. In some embodiments, NDKD is mediated by APOLI.

In some embodiments ofthe disclosure, the compounds and the phannaceutical compositions described herein are used to treat cancer. In some embodiments, the cancer is mediated by APOLI.

In some embodiments of the disclosure, the compounds and the phannaceutical compositions described herein arc used to treat pancreatic cancer. In some embodiments, the pancreatic cancer is mediated by APOLI.

In some embodiments, the methods ofthe disclosure comprise administering to a patient in need thereof at least one compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait chosen from compounds of Fonnulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic6, H, IM, II-2, II-3, II-4, II-5, ΪΙ-6, II-6a and II-6b, tautomers thereof, deuterated dérivatives of those compounds and tautomers, and phannaceutically acceptable salts of any of the foregoing. In some embodiments, the compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait is chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and phannaceutically acceptable salts of any of the foregoing. In some embodiments, said patient in need thereof possesses APOLI genetic variants, Le., Gl : S342G:I384M and G2: N388del:Y389del.

Another aspect of the disclosure provides methods of inhibiting APOLI activity comprising contacting said APOLI with at least one compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait chosen from compounds of Fonnulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-l, II-2, II-3, II-4, Π-5, Π-6, II-6a and ll-6b, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and phannaceutically acceptable salts of any of the foregoing. In some embodiments, the methods of inhibiting APOLI activity comprise contacting said APOLI with at least one compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait chosen from Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated dérivatives of those compounds or tautomers, and phannaceutically acceptable salts of any of the foregoing.

Solid Forms

Some embodiments ofthe disclosure provide a solid form of Compound 16. In some embodiments, the solid fonn of Compound 16 is Form A. In some embodiments of the disclosure, Compound 16 Form A is substantially pure. In some embodiments ofthe disclosure, Compound 16 Form A is substantially crystalline.

In some embodiments, Compound 16 Form A is characterized by an X-ray powder diffractogram comprising a signal at a degrees two-theta value selected from 19.9 ± 0.2 degrees two-theta, 20,0 ± 0.2 degrees two-theta, and 10.9 ± 0.2 degrees two-theta. In some embodiments, Compound 16 Form A is characterized by an X-ray powder diffractogram comprising two or more signais at 19.9 ± 0.2 degrees two-theta, 20.0 ± 0.2 degrees two-theta, and 10.9 ± 0.2 degrees two-theta. In some embodiments, the Compound 16 Form A is characterized by an X-ray powder diffractogram comprising signais at 19.9 ± 0.2 degrees twotheta, 20.0 ± 0.2 degrees two-theta, and 10.9 ± 0.2 degrees two-theta.

In some embodiments, Compound 16 Form A is characterized by an X-ray powder diffractogram comprising a signal at two or more degrees two-theta values selected from 10.9 ± 0.2 degrees two-theta, I4.l ± 0.2 degrees two-theta, I5.4 ± 0.2 degrees two-theta, I6.l ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 18.2 ± 0,2 degrees two-theta, 19.3 ± 0.2 degrees two-theta, 19.9 ± 0.2 degrees two-theta, 20.0 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees twotheta, 20.6 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.7 ± 0.2 degrees two-theta, 22,8 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, 26.1 ± 0.2 degrees two-theta, and 26.2 ± 0.2 degrees two-theta. In some embodiments, Compound 16 Form A is characterized by an X-ray powder diffractogram comprising a signal at three or more degrees two-theta values selected from 10.9 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees twotheta, 15.4 ± 0.2 degrees two-theta, 16.1 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 18.2 ± 0.2 degrees two-theta, 19.3 ± 0.2 degrees two-theta, 19.9 ± 0.2 degrees two-theta, 20.0 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees two-theta, 20.6 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.7 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, 26.1 ± 0.2 degrees two-theta, and 26.2 ± 0.2 degrees two-theta. In some embodiments, Compound 16 Form A is characterized by an X-ray powder diffractogram comprising a signal at four or more degrees two-theta values selected from 10.9 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 16.1 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 18.2 ± 0.2 degrees two-theta, 19.3 ± 0.2 degrees two-theta, 19.9 ± 0.2 degrees two-theta, 20.0 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees twotheta, 20.6 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.7 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, 26.1 ± 0.2 degrees two-theta, and 26.2 ± 0.2 degrees two-theta. In some embodiments, Compound 16 Form A is characterized by an X-ray powder diffractogram comprising a signal at five or more degrees two-theta values selected from 10.9 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees two thêta, 15.4 ± 0.2 degrees two-theta, I6.l ± 0.2 degrees two-theta. 17.5 ± 0.2 degrees two-theta, 18.2 ± 0.2 degrees two-theta, 19.3 ± 0.2 degrees two-theta, 19.9 ± 0.2 degrees two-theta, 20.0 ± 0.2 degrees two-theta, 20.5 ± 0,2 degrees two-theta, 20.6 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.7 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, 26.1 + 0.2 degrees two-theta, and 26.2 ± 0.2 degrees two-theta. In some embodiments, Compound 16 Form A is characterized by an X-ray powder diffractogram comprising a signal at six or more degrees two-theta values selected from 10.9 ± 0.2 degrees two-theta, I4.l ± 0.2 degrees two-theta, l 5.4 + 0.2 degrees two-theta, 16.1 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, l 8.2 ± 0.2 degrees two-theta, 19.3 ± 0.2 degrees two-theta, 19.9 ± 0.2 degrees two-theta, 20.0 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees twotheta. 20.6 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.7 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, 26.1 ± 0.2 degrees two-theta, and 26.2 ± 0.2 degrees two-theta. In some embodiments, Compound 16 Form A is characterized by an X-ray powder diffractogram comprising a signal at seven or more degrees two-theta values selected from 10.9 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees twotheta, 15.4 ± 0.2 degrees two-theta, 16.1 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 18.2 ± 0.2 degrees two-theta, 19.3 ± 0.2 degrees two-theta, 19.9 ± 0.2 degrees two-theta, 20.0 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees two-theta, 20.6 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.7 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, 26.1 ± 0.2 degrees two-theta, and 26.2 ± 0.2 degrees two-theta. In some embodiments, Compound 16 Form A is characterized by an X-ray powder diffractogram comprising a signal at eight or more degrees two-theta values selected from 10.9 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta, 16.1 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 18.2 ± 0.2 degrees two-theta, 19.3 ± 0.2 degrees two-theta, 19.9 ± 0.2 degrees two-theta. 20.0 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees twotheta, 20.6 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.7 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, 26.1 ± 0.2 degrees two-theta, and 26.2 ± 0.2 degrees two-theta. In some embodiments, Compound 16 Form A is characterized by an X-ray powder diffractogram comprising signais at 10.9 ± 0.2 degrees two-theta, 14.1 ± 0.2 degrees two-theta, 15.4 ± 0.2 degrees two-theta. 16.1 ± 0.2 degrees two-theta, 17.5 ± 0.2 degrees two-theta, 18.2 ± 0.2 degrees two-theta, 19.3 ± 0.2 degrees twotheta, 19.9 ± 0.2 degrees two-theta, 20.0 ± 0.2 degrees two-theta, 20.5 ± 0.2 degrees two-theta, 20.6 ± 0.2 degrees two-theta, 21.4 ± 0.2 degrees two-theta, 21.7 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, 23.3 ± 0.2 degrees two-theta, 23.8 ± 0.2 degrees two-theta, 26.1 ± 0.2 degrees two-theta, and 26.2 ± 0.2 degrees two-theta.

In some embodiments, Compound 16 Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 1.

In some embodiments, Compound 16 Fonn A is characterized by a thennogravimetric analysis that shows minimal weight loss from ambient température to 250 °C. In some embodiments, Compound 16 Form A is characterized by a TGA thennogram substantially similar to FIG. 2.

In some embodiments, Compound 16 Fonn A is characterized by a differential scanning calorimetry analysis showing one endothcnn peak at 147 °C. In some embodiments, Compound 16 Fonn A is characterized by a DSC thennogram substantially similar to FIG. 3.

In some embodiments, Compound 16 Fonn A is characterized by solid state NMR. In some embodiments, Compound 16 Fonn A is characterized by a ¹³C SSNMR spectrum comprising one or more signais selected from 153.5 ± 0.2 ppm, 151.5 ± 0.2 ppm, 126.9 ± 0.2 ppm, 125.1 ± 0.2 ppm, 123.9 ± 0.2 ppm, 122.1 ± 0.2 ppm, 73.6 ± 0.2 ppm, 49.9 ± 0.2 ppm, 47.2 ± 0.2 ppm, 37.2 ± 0.2 ppm, and 23.0 ± 0.2 ppm. In some embodiments, Compound 16 Fonn A is characterized by a ^l3C SSNMR spectrum comprising two or more signais selected from 153.5 ± 0.2 ppm, 151.5 ± 0.2 ppm, 126.9 ± 0.2 ppm, 125.1 ± 0.2 ppm, 123.9 ± 0.2 ppm, 122.1 ± 0.2 ppm, 73.6 ± 0.2 ppm, 49.9 ± 0.2 ppm, 47.2 ± 0.2 ppm, 37.2 ± 0.2 ppm, and 23.0 ± 0.2 ppm. In some embodiments, Compound 16 Fonn A is characterized by a ⁱ³C SSNMR spectrum comprising three or more signal selected from 153.5 ±0.2 ppm, 151.5 ±0.2 ppm, 126.9 ±0.2 ppm, 125.1 ± 0.2 ppm, 123.9 ± 0.2 ppm, 122.1 ± 0.2 ppm, 73.6 ± 0.2 ppm, 49.9 ± 0.2 ppm, 47.2 ± 0.2 ppm, 37.2 ± 0.2 ppm, and 23.0 ± 0.2 ppm. In some embodiments, Compound 16 Fonn A is characterized by a ^l3C SSNMR spectrum comprising four or more signais selected from 153.5 ± 0.2 ppm, 151.5 ± 0.2 ppm, 126.9 ± 0.2 ppm, 125.1 ± 0.2 ppm, 123.9 ± 0.2 ppm, 122.1 ± 0.2 ppm, 73.6 ± 0.2 ppm, 49.9 ± 0.2 ppm, 47.2 ± 0.2 ppm, 37.2 ± 0.2 ppm, and 23.0 ± 0.2 ppm. In some embodiments, Compound 16 Fonn A is characterized by a ^l3C SSNMR spectrum comprising five or more signais selected from 153.5 ± 0.2 ppm, 151.5 ± 0.2 ppm, 125.9 ± 0.2 ppm, 126.1 ± 0.2 ppm, 123.9 ± 0.2 ppm, 122.1 ± 0.2 ppm, 73.6 ± 0.2 ppm, 49.9 ± 0.2 ppm, 47.2 ± 0.2 ppm, 37.2 ± 0.2 ppm, and 23.0 ± 0.2 ppm. In some embodiments, Compound 16 Fonn A is characterized by a ¹³C SSNMR spectrum comprising six or more signais selected from 153.5 ± 0.2 ppm, 15 1.5 ± 0.2 ppm, 125.9 ± 0.2 ppm, 126.1 ± 0.2 ppm, 123.9 ± 0.2 ppm, 122.1 ± 0.2 ppm, 73.6 ± 0.2 ppm, 49.9 ± 0.2 ppm, 47.2 ± 0.2 ppm, 37.2 ± 0.2 ppm, and 23.0 ± 0.2 ppm.

In some embodiments, Compound 16 Fonn A is characterized by a ^l3C NMR spectrum substantially similar to FIG. 4.

In some embodiments, Compound 16 Form A is characterized by a ^l9F SSNMR spectrum comprising a signal at -58.0 ± 0.2 ppm.

In some embodiments Compound I6 Form A is characterized by an Orthorhombic crystal System, a P212121 space group, and a unit cell having dimensions measured at 100 K on Bruker diffractometer equipped with Cu K» radiation (λ=1.54178 Â) of:

a	5.0 ± 0.1 Â	a	90 0
b	9.0 ±0.1 Â	β	90°
c	34.5 ± 0.1 Â	γ	90 °

In some embodiments Compound 16 Form A is characterized by an Orthorhombic crystal

System, a P2|2|2i space group, and a unit cell having dimensions measured at 298 K on Bruker diffractometer equipped with Cu K_u radiation (λ=1.54178 Â), of:

a	5.1 ±0.1 Â	a	90
b	9.2 ±0.1 Â	β	90
c	34.5 ± 0.1 Â	Y	90

û

Another aspect ofthe disclosure provides a method of making crystalline Compound 16

Form A by crystallizing Compound 16 in MTBE, filtering the crystallized compound, and vacuum drying at 60 °C ovcmight to yield Compound 16 Form A.

Non-Limiting Example Embodiments

Without limitation, some embodiments ofthe présent disclosure include:

1. A compound represented by the formula:

a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein:

X is a bond (i.e., X is absent) or is chosen from -(CH2)-, and -(CH₂)SO₂-;

Ring A is chosen from C6 cycloalkyl, C& aryl and 5- and 6-membered heteroaryl groups; R¹, for each occurrence, is independently chosen from halogen, -OR^C, =0, cyano, phenyl, Ci-C& alkyl, Ci-Cô alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)N(R^C)₂, -S(cyclopropyl), and -SO₂(R^C) groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C1-C4 alkyl groups;

the 4- to 6-membered heterocyclyl of R¹ comprises one heteroatom chosen from nitrogen and oxygen;

the Ci-Cô alkyl of R¹ is optionally substituted with 1 to 6 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C₄ alkyl), -N(Ci-C4 alkyl)₂, and C1-C4 alkoxy groups;

the Ci-Cô alkoxy of R¹ is optionally substituted with 1 to 3 groups independently chosen from -OH, cyano, and halogen groups;

the C3-C6 carbocyclyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)₂, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(Ci-C4 alkyl)₂ groups; and the phenyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)₂, Ci-C₄ alkyl, C1-C4 alkoxy, C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(Ci-C₄ alkyl)₂ groups; or wherein two R¹ groups taken together with the Ring A atoms connecting them form a 5to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6membered heteroaryl ring, wherein the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6mcmbered aryl, 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen. -OH, and C1-C4 alkyl;

R² is chosen from cyano, Ci-Cô alkyl, -C(=O)O(C|-C₄ alkyl), C₂-Cô alkynyl, and

the Ci-Cô alkyl of R²is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(Ci-C₄ alkyl)?, C1-C4alkoxy, C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -C(=O)N(Ci-C₄ alkyl)₂, C₃-C₆ carbocyclyl, 5- to 10membered heterocyclyl, Cô aryl, and 5- to 10-membered heteroaryl groups;

Ring B is chosen from C₃-Ci₂ carbocyclyl, 3- to I2-membered heterocyclyl, Cô and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with 1, 2, 3, 4, or 5 R^a groups; wherein:

R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, C2-Cô alkenyl, C|-C& alkoxy, Cj-Cô haloalkyl, Ci-Cô haloalkenyl, Ci-Cô haloalkoxy, -CK^NR¹·^, -NR'Rf -NR^llC(=O)R^k, -NR^hC(=O)OR^k, -NR^hC(=O)NR'Rj, -NR^hS(-O)PR^k -OR^k, -OC(=O)R^k, -OC(-O)OR^k, -OC(=O)NR^hR', -[O(CH2)q]rO(Ci-Cô alkyl), -S(-O)PR^k, -S(=O)PNR^hRⁱ, -C(=O)OR^k, C₃-Ci₂ carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cioaryl, and 5- to 10membered heteroaryl groups, wherein:

the Ci-Cô alkyl, Ci-Cô alkoxy, and the C₂-C& alkenyl of R^a are each optionally substituted with 1 to 3 groups independently chosen from Cô to Cm aryl (optionally substituted with 1 to 3 R^r groups), 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 R^m groups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 Rⁿⁱ groups), cyano, -C(=O)R^k, C(=O)OR^k, -C(-O)NR^hR^j, -NR^hR‘, -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^hC(=O)NR'Rj, -NR^hS(=O)PR^k, -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OC(=O)NR^hRⁱ, -S(=O)PR\

-S(=O)_PNR^hR‘, -O(Cô aryl) (optionally substituted with 1 to 3 Rⁿⁱ groups), and C₃-Cô carbocyclyl groups (optionally substituted with 1 to 3 R^m groups);

the C3-C12 earbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cio aryl, and the 5- to 10-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C4 alkyl, -NR^hR', and -OR^k groups, wherein:

R^h, R¹, and R^j. for each occurrence, are each independently chosen from hydrogen, C1-C4 alkyl, Cô-Cioaryl, and Cj-Cô cycloalkyl groups, wherein:

the C1-C4 alkyl of any one of R¹’, R‘, and R' is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to 10membered heterocyclyl, and C3-C6 earbocyclyl groups, wherein:

the C1-C4 alkyl of any one of R^k is optionally substituted with l to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^m, for each occurrence, is independently chosen from halogen, cyano, oxo, Ci-Cô alkyl, Ci-Cô alkoxy, -S(=O)_pR^k, and -OR^k groups, wherein:

the Ci-Cô alkyl of R^m is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and -O(Ci-C4 alkyl) groups;

R³ is chosen from Ci-Cô alkyl, -C(=O)O(Ci-C4 alkyl), C3-C12 earbocyclyl, 3- to 12membered heterocyclyl, Cô and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Cô alkyl of R³ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?, C1-C4alkoxy, C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(Ci-C₄ alkyl)? groups;

the C3-C12 earbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cio aryl, and the 5- to 10-membered heteroaryl of R³ are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl) (optionally substituted with -OH), -N(Ci-C4 alkyl)?, C1-C5 alkyl (optionally substituted with -OH or-S(=O)₂(Ci-C4 alkyl)), C1-C4alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -NHC(=O)(Ci-C4 alkyl), C(=O)(Ci-C4 alkoxy), and -C(=O)N(Ci-C4 alkyl)₂ groups;

R⁴ is chosen from hydrogen, halogen, cyano, Ci-Cô alkyl, Ci-Cô haloalkyl, (CH₂)_nC(=O)NRR°,

-NRR°, -NR“C(=O)Rp, -NRⁿS(=O)_PRP, -(CH₂)„ORp, -S(-O)_PRP, -S(-O)_PNRR“. -OS(=O)_PNRR°, and -(CH₂)nC(=O)OR^p groups, wherein:

Rⁿ and R°, for each occurrence, are each independently chosen from hydrogen and C]-C4 alkyl groups; and

R^p, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl groups;

R⁵ is chosen from hydrogen and Ci-Cô alkyl;

m is an integer chosen from 0, l, 2, 3, 4, and 5;

n is an integer chosen from 0, I, and 2;

p, for each occurrence, is an integer independently chosen from l and 2; and q and r, for each occurrence, are each an integer independently chosen from l, 2, 3, and la.

A compound represented by the following structural formula:

Formula la a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein:

Ring A is chosen from Cô aryl and 5- and 6-membered heteroaryl groups;

R¹, for each occurrence, is independently chosen from halogen, -OH, =O, cyano, phenyl, Ci-Cô alkyl, Ci-Cô alkoxy, C3-C6 carbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)N(R^C)₂ and -SO2(R^C), groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C1-C4 alkyl groups;

the 4- to 6-membered heterocyclyl of R¹ comprises one heteroatom chosen from nitrogen and oxygen;

the C]-Cô alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C₄ alkyl), -N(Ci-C₄ alkyl)₂, and C1-C4 alkoxy groups;

the Ci-Cô alkoxy of R* is optionally substituted with 1 to 3 groups independently chosen from -OH, cyano, and halogen groups;

the C3-C6 carbocyclyl of R' is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)₂, C1-C4 alkyl, C1-C4alkoxy, -C(=O)NH₂, -C(=O)NH(C|-C₄ alkyl), and -C(-O)N(C|-C₄ alkyl)₂ groups; and the phenyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(C|-C4 alkyl), -N(Ci-C4 alkyl)?, G-C4 alkyl, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(Ci-C₄ alkyl)? groups; or wherein two R¹ groups taken togethcr with the Ring A atoms connecting them form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6membered aryl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and C1-C4 alkyl; R² is chosen from cyano, Ci-Cô (R^a)o-5 ( ^B alkyl, -C(=O)O(Ci-C4 alkyl), C2-C0 alkynyl, and , wherein:

the Ci-Cô alkyl of R² is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -C(=O)N(C_t-C₄ alkyl)₂, C₃-C₆ carbocyclyl, 5- to 10-membered heterocyclyl, Cô aryl, and 5- to 10-membered heteroaryl groups;

Ring B is chosen from C3-C12 carbocyclyl, 3- to 12-mcmbered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with 1, 2, 3, 4, or 5 R^a groups; wherein:

R^a, for each occurrence, is independently chosen from halogen, cyano, Cj-Cô alkyl, C2-C6 alkenyl, C1-C0 alkoxy, Ci-Cô haloalkyl, Ci-Cô haloalkenyl, Ci-Cô haloalkoxy, -C^CONR¹¹^, -NR¹'^, -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^hC(=O)NR'R^j, -NR^hS(=O)pR^k-OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OC(=O)NR^hR', -[O(CH2)_q]rO(Ci-C₆ alkyl), -S(=O)_PR^k, -S(=O)PNR^hRⁱ, -C(-ü)OR^k. C3-Ci2 carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein:

the Cj-Cô alkyl, Ci-Cô alkoxy, and the C₂-Cô alkenyl of R^a are each optionally substituted with I to 3 groups independently chosen from Cô to Cio aryl (optionally substituted with 1 to 3 R¹ groups), 5- to 10 membered heterocyclyl (optionally substituted with l to 3 R^m groups), 5to 10-membered heteroaryl (optionally substituted with l to 3 R^m groups), cyano, -C(=O)R^k, -C(=O)OR^k, -C(=O)NR^l'Rⁱ, -NR^hR‘, -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^OJNR’Rj, -NR^hS(=O)PR^k -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OC(=O)NR^hRⁱ, -S(=O)PR^k, -S(=O)_PNR^hR', -O(Cô aryl) (optionally substituted with l to 3 Rⁿⁱ groups), and C3-C6 earbocyclyl groups (optionally substituted with l to 3 R^m groups);

thc C3-C12 earbocyclyl, the 3- to 12-membered heterocyclyl, the Ce and Cio aryl, and the 5- to 10-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C4 alkyl, -NR^hR', and -OR^k groups, wherein:

R^h, R‘, and R', for each occurrence, are each independently chosen from hydrogen, C1-C4 alkyl, Cô-Cioaryl, and C3-C6 cycloalkyl groups, wherein:

the C1-C4 alkyl of any one of R^h, R', and Ri is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 earbocyclyl groups, wherein:

the C1-C4 alkyl of any one of R^k is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

Rⁿⁱ, for each occurrence, is independently chosen from halogen, cyano, oxo, Ci-Cô alkyl, Ci-Cô alkoxy, -S(=O)_pR^k, and -OR^k groups, wherein:

the Ci-Cô alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and -O(C|-C4 alkyl) groups;

R³ is chosen from Ci-Cô alkyl, -C(=O)O(Ci-C4 alkyl), C3-C12 earbocyclyl, 3- to 12membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein:

the Cι-Cô alkyl of R³ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(C|-C4 alkyl), -N(Ci-C4 alkyl)?, C1-C4 alkoxy, -C(=O)NH₂, -C(=0)NH(Ci-C₄ alkyl), and -C(=O)N(C|-C₄ alkyl)? groups;

100 the C3-C12 carbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cio aryl, and the 5- to 10-membered heteroaryl of R³ are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl) (optionally substituted with -OH), -N(Ci-C4 alkyl)?, Cj-Cs alkyl (optionally substituted with -OH or -S(=O)?(Ci-C₄ alkyl)), C1-C4 alkoxy, -C(=O)NH?, -C(=O)NH(Ci-C₄ alkyl), -NHC(=O)(Ci-C₄ alkyl), -C(=O)(Ci-C₄ alkoxy), and -C(=O)N(C|-C4 alkyl)? groups;

R⁴ is chosen from halogen, cyano, Ci-Cô alkyl, Ci-Cô haloalkyl, -(CH?)nC(=O)NRR⁰, -NRR°, -NR°C(=O)RP, -NRⁿS(=O)_PRP. -(CH₂)„ORP, -S(O)_pRP, -S(=O)_PNRR°, -OS(=O)_PNRR°, and -(CH₂)nC(=O)OR^p groups, wherein:

R and R°, for each occurrence, are each independently chosen from hydrogen and C1-C4 alkyl groups; and

Rp, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl groups;

R⁵ is chosen from hydrogen and Ci-Cô alkyl;

m is an integer chosen from 0, 1,2, 3, 4, and 5;

n is an integer chosen from 0, 1, and 2;

p, for cach occurrence, is an integer independently chosen from 1 and 2; and q and r, for each occurrence, are each an integer independently chosen from 1,2,3, and 4.

1b. A compound represented by the following structural formula:

(R¹)m

Formula Ib a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a phannaceutically acceptable sait of any of the foregoing, wherein:

Ring A is chosen from Cô aryl and 5- and 6-membered heteroaryl groups;

101

R¹, for each occurrence, is independently chosen from halogen, -OH, =0, cyano, phenyl, Ci-Cô alkyl, Ci-Cô alkoxy, Cj-CT carbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)N(R^C)2 and -SO₂(R^C), groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C1-C4 alkyl groups;

the 4- to 6-membered heterocyclyl of R¹ comprises one heteroatom chosen from nitrogen and oxygen;

the Ci-Cr, alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -ΝΗ?, -NH(Ci-C4 alkyl), -N(C|-C4 alkyl)?, and C1-C4 alkoxy groups;

the Cj-Cô alkoxy of R* is optionally substituted with 1 to 3 groups independently chosen from -OH, cyano, and halogen groups;

the C3-C6 carbocyclyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)₂, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(CrC4 alkyl)₂ groups; and the phenyl of R' is optionally substituted with I to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C₄ alkyl), -N(Ci-C₄ alkyl)?, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH?, -C(=O)NH(C|-C4 alkyl), and -C(=O)N(Ci-C4 alkyl)₂ groups; or wherein two R¹ groups taken together with the Ring A atoms connecting them form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6membered aryl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and C1-C4 alkyl;

R² is chosen from cyano, Cι-Ce alkyl, -C(=O)O(C]-C4 alkyl), C₂-Cô alkynyl, and A---/ wherein:

the Ci-Cô alkyl of R²is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)₂, C1-C4 alkoxy, -C(=0)NH?, -C(=O)NH(Ci-C₄ alkyl), -C(=O)N(Ci-C₄ alkyl)?, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl, Cô aryl, and 5- to 10-membered heteroaryl groups;

102

Ring B is chosen from C₃-C[₂ carbocyclyl, 3- to 12-membered heterocyclyl, C& and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with l, 2, 3, 4, or 5 R^agroups; wherein:

R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, C2-Cô alkenyl, Ci-Cô alkoxy, Ci-Co haloalkyl, Ci-Cô haloalkcnyl, Ci-Cô haloalkoxy, -0(=0)^^, -NR^hR', -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^hC(=O)NR'R·, -NR^hS(=O)PR^k -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OC(-O)NR^hR( -[O(CH2)q]rO(Ci-C6 alkyl), -S(=O)PR^k, -S(=O)PNR^hR', -C(=O)OR^k, C₃-Ci₂ carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Cô alkyl, Ci-Cô alkoxy, and the C₂-Cô alkenyl of R^a are each optionally substituted with 1 to 3 groups independently chosen from Cf, to Cio aryl (optionally substituted with 1 to 3 R^m groups), 5- to 10membered heterocyclyl (optionally substituted with 1 to 3 R^m groups), 5to 10-membered heteroaryl (optionally substituted with 1 to 3 R'ⁿ groups), cyano, -C«))R^k, -C(=O)OR^k, -Ci-OlNR¹®, -NR^hR', -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -ΝΚ^(=Ο)ΝΒΉξ -NR^hS(=O)PR^k -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OC(=O)NR^hR', -S(=O)PR^k, -S(=O)pNR^hR^l, -O(Cô aryl) (optionally substituted with 1 to 3 R^m groups), and C₃-Cô carbocyclyl groups (optionally substituted with 1 to 3 R^m groups);

the C₃-Ci₂ carbocyclyl, the 3- to 12-membered heterocyclyl, the Ce and Cioaryl, and the 5- to 10-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C4 alkyl, -NR^hR‘, and -OR^k groups, wherein:

R^h, R¹, and R^j, for each occurrence, are each independently chosen from hydrogen, C1-C4 alkyl, Cô-Cioaryl, and C₃-Cô cycloaikyl groups, wherein:

the C1-C4 alkyl of any one of R^h, R¹, and R' is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C₃-Cô carbocyclyl groups, wherein:

103 the C1-C4 alkyl of any one of R^k is optionally substituted with l to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^ra, for each occurrence, is independently chosen from halogen, cyano, oxo, Ci-Ce alkyl, Ci-Cô alkoxy, -S(=O)_PR^k, and -OR^k groups, wherein:

the Ci-Cf, alkyl of R^m is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, and -O(Cj-C4 alkyl) groups;

R³ is chosen from Ci-Cô alkyl, -C(=O)O(Ci-C₄ alkyl), C3-C12 carbocyclyl, 3- to 12membered heterocyclyl, Ce and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Cô alkyl of R³ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C₄ alkyl), -N(Ci-C₄ alkyl)?, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C4 alkyl), and -C(=O)N(Ci-C₄ alkyl)? groups;

the C3-C12 carbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cioaryl, and the 5- to 10-membered heteroaryl of R³ are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C₄ alkyl) (optionally substituted with -OH), -N(Cj-C₄ alkyl)?, C1-C5 alkyl (optionally substituted with -OH or -S(=O)₂(Ci-C₄ alkyl)), Cj-C₄ alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -NHC(=O)(Ci-C₄ alkyl), -C(=O)(C[-C₄ alkoxy), and -C(=O)N(CrC₄ alkyl)? groups;

R⁴ is chosen from halogen, cyano, Ci-Cô alkyl, Ci-Cô haloalkyl, -(CH?)i1C(=O)NR^,,R°, -NRⁿR°, -NR°C(=O)RP, -NRS(=O)PRP.-(CH₂)_nORP, -S(=O)_PRP, -S(=O)_PNRR°, -OS(=O)_PNRR°, and -(CH?)nC(=O)ORP groups, wherein:

R and R°, for each occurrence, are each independently chosen from hydrogen and C1-C4 alkyl groups; and

R^p, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl groups;

ni is an integer chosen from 0, 1,2, 3, 4, and 5;

n is an integer chosen from 0, 1, and 2;

p, for each occurrence, is an integer independently chosen from 1 and 2; and q and r, for each occurrence, are each an integer independently chosen from 1, 2, 3, and

104 le. A compound represented by the following structural formula:

(R¹)m

Formula le a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein:

Ring A is chosen from Cô aryl and 5- and 6-membered heteroaryl groups;

R¹, for each occurrence, is independently chosen from halogen, -OH, =O, cyano, phenyl, Ci-Ct, alkyl, Ci-Cô alkoxy, Ca-Cô carbocyclyl, 4- to 6-membcred heterocyclyl, and -C(=O)N(R^C)2 groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and Ci-C₄ alkyl groups;

the 4- to 6-membered heterocyclyl of R¹ comprises one heteroatom chosen from nitrogen and oxygen;

the Ci-Cô alkyl of R¹ is optionally substituted with I to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl), -N(Ci-C₄ alkyl)?, and C[-C₄ alkoxy groups;

the Ci-Cô alkoxy of R* is optionally substituted with 1 to 3 groups independently chosen from -OH, cyano, and halogen groups;

the Ca-Cô carbocyclyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C₄ alkyl), -N(Ci-C₄ alkyl)?, Ci-C₄ alkyl, C1-C4 alkoxy, -C(=O)NH?, -C(=O)NH(C]-C₄ alkyl), and -C(=O)N(C 1 -C₄ alkyl)? groups; and the phenyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C₄ alkyl), -N(Cj-C₄ alkyl)?, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH?, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(Ci-C₄ alkyl)? groups;

105

R² is chosen from cyano, Ci-Cô alkyl, -C(=O)O(Ci-C₄ alkyl), C₂-C& alkynyl, and

the Ci-Cô alkyl of R²is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C₄ alkyl), -N(C|-C₄ alkyl)₂, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -C(=O)N(Ci-C₄ alkyl)₂, C₃-C₆ carbocyclyl,

5- to 10-membered heterocyclyl, Cô aryl, and 5- to 10-membered heteroaryl groups;

Ring B is chosen from C₃-Ct₂ carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with l, 2, 3, 4, or 5 R^agroups; wherein:

IO R^a, for each occurrence, is independently chosen from halogen, cyano,

Ci-Cô alkyl, C₂-Cô alkenyl, Cj-Cô alkoxy, Ci-Cô haloalkyl, Ci-Cô haloalkenyl, Ci-Cô haloalkoxy, -C(=O)NR^hR', -NR^Rf -NR^hC(=O)R^k, -NR^llC(=O)OR^k, -NR^hC(=O)NR'Rj, -NR^hS(-O)PR^k -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OQOJNRbR¹, -[O(CH2)_q]rO(C]-Cô alkyl), -S(=O)_PR^k, -SlOjpNRbRf

-C(=O)OR^k, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Cô alkyl, Ci-Cô alkoxy, and the C2-C0 alkenyl of R^a are each optionally substituted with 1 to 3 groups independently chosen from Cô to Cio aryl (optionally substituted with 1 to 3 R^m groups), 5- to 1020 membered heterocyclyl (optionally substituted with 1 to 3 R^m groups), 5to 10-membered heteroaryl (optionally substituted with 1 to 3 R'groups), cyano, -C(=O)R^k, -C(=O)OR^k, -C(=O)NR^hR^!, -NR^hR', -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NRMOJNR’Rj, -NR^hS(=O)pR^k -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OCf-OINRbRf -S(=O)_PR^k,

-S^OjpNRbR¹, -O(C₆ aryl) (optionally substituted with 1 to 3 R^m groups), and C₃-Cô carbocyclyl groups (optionally substituted with 1 to 3 R^m groups);

the C₃-C_[2 carbocyclyl, the 3- to 12-membered heterocyclyl, the

Cô and Cioaryl, and the 5- to 10-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, Ci-C₄ alkyl, -NR^hR', and -OR^k groups, wherein:

106

R^h, R', and Rh for each occurrence, are each independently chosen from hydrogen, C1-C4 alkyl, Cô-Cmaryl, and C3-C6 cycloalkyl groups, wherein:

the C1-C4 alkyl of any one of R^h, R¹, and R' is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and Cj-Cô carbocyclyl groups, wherein:

the C1-C4 alkyl of any one of R^k is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R¹, for each occurrence, is independently chosen from halogen, cyano, oxo, Ci-Cô alkyl, Ci-Cô alkoxy, -S(-O)pR^k, and 15 -OR^k groups, wherein:

the Ci-Cô alkyl of R¹” is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and -O(Ci-C4 alkyl) groups;

R³ is chosen from Ci-Cô alkyl, -C(=O)O(Cj-C4 alkyl), C3-C12 carbocyclyl, 3- to 1220 membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-C₆ alkyl of R³ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(C|-C4 alkyl), -N(C|-C4 alkyl)₂, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), and -C(=O)N(Ci-C₄ alkyl)₂ groups;

the C3-C12 carbocyclyl, the 3- to 12-membered heterocyclyl, the Ce and Cio aryl, 25 and the 5- to 10-membered heteroaryl of R³ are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl) (optionally substituted with -OH), -N(Ci-C4 alkyl)2, C1-C5 alkyl (optionally substituted with -OH or -S(=O)₂(Ci-C4 alkyl)), C1-C4alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -NHC(=O)(Ci-C4 alkyl), -C(=O)(Ci-C4 alkoxy), and -C(=O)N(Ci-C4 alkyl)2 groups;

R⁴ is chosen from halogen, cyano, Ci-Cô alkyl, Ci-Cô haloalkyl, -(CH2)nC(=O)NR^,,R^o, -NRⁿR°, -NR°C(=O)RP, -NR^,’S(=O)pRp. -(CH₂)_nORP, -S(=O)_PRP, -S(=O)_pNRR°, -OS(=O)_PNRR°, and -(CH₂)_nC(=O)ORP groups, wherein:

R and R°, for each occurrence, are each independently chosen from hydrogen 35 and Q-C4 alkyl groups; and

107

R¹’, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl groups;

m is an integer chosen from 0, 1,2, 3, 4, and 5;

n is an integer chosen from 0, 1, and 2;

p, for each occurrence, is an integer independently chosen from 1 and 2; and q and r, for each occurrence, are each an integer independently chosen from 1,2, 3, and 4.

2. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments I to 1b, wherein the compound is represented by the following structural formula:

(R¹)m

Formula II a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein R¹, R², R³, R⁴, Ring A, and m are as defined in any one of Embodiments 1 to 1b.

3. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 2, wherein R⁴ is -OH; and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 2.

4. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 3, wherein R³ is chosen from C1-C4 alkyl groups; and ail other variables not specifically defined herein arc as defined in any one of Embodiments 1 to

3.

108

5. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 4, wherein R³ is -CH₃; and ail other variables not specifically defined herein are as defined in any one of Embodiments l to 4.

6. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 5, wherein R²is chosen from C1-C4 alkyl and (R^a)o-5 groups, wherein:

the C1-C4 alkyl of R² is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Cj-C4 alkyl), -N(C|-C4 alkyl)?, C1-C2 alkoxy, C₃-Cô cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl groups;

and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5.

7. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 6, wherein R² is chosen from -CH₃ and (R^a)0-5 groups;

and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 6.

109

8. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 7, wherein the compound is represented by one of the following structural formulae:

Formula Ic-4

Formula IID a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait ofany ofthe foregoing, wherein ail variables not specifically defined herein are as defined in any one of Embodiments l to 7.

9. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to Embodiment 8, wherein Ring B is chosen from cyclopropyl, 5- to 10-membered heterocyclyl, phcnyl, and 5- to 9-membered heteroaryl groups; each of which is optionally substituted with l, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of Embodiments l to 8.

10. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to Embodiment 8, wherein Ring B is chosen from cyclopropyl, 5- to 10-membered heterocyclyl comprising l to 3 heteroatoms chosen from N and O, phenyl, and 5- to 9-membered heteroaryl comprising l to 3 heteroatoms chosen from N and O; each of which is optionally substituted with l, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of Embodiments l to 8.

11. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to Embodiment 8, wherein Ring B is chosen from cyclopropyl, 5-membered heterocyclyl comprising l to 3 heteroatoms chosen from N and O, 6-membered heterocyclyl l 10 comprising l to 3 heteroatoms chosen from N and O, 9-membered heterocyclyl comprising 1 to 3 heteroatoms chosen from N and O, 10-membered heterocyclyl comprising 1 to 3 heteroatoms chosen from N and O, phenyl, 5-membered heteroaryl comprising 1 to 3 heteroatoms chosen from N and O, 6-membered heteroaryl comprising 1 to 3 heteroatoms chosen from N and O, and 5 9-membered heteroaryl comprising 1 to 3 heteroatoms chosen from N and O; each of which is optionally substituted with 1,2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 8.

12. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait

111 optionally substituted with I, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of Embodiments l to 8.

13. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait

112

with l, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of Embodiments l to 8.

14, The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to Embodiment 8, wherein Ring B is

which is optionally substituted with l R^a group; and ail other variables not specifically defined herein are as defined in any one of Embodiments l to 8.

15. The compound. tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 14, wherein R^], for each occurrence, is independently chosen from hydrogen, halogen, cyano, -OH, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)N(R^C)2, and Cî-Cô cycloalkyl groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and C1-C2 alkyl groups;

the C1-C4 alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C2 alkoxy groups;

the C1-C4 alkoxy of R¹ is optionally substituted with 1 to 3 independently chosen from halogen groups; and

113 the C₃-Cô cycloalkyl of R¹ is optionally substituted with I to 3 groups independently chosen from halogen, cyano, -OH, and C1-C2 alkoxy groups;

and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 14.

16. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 15, wherein R¹, for each occurrence, is independently chosen from F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)N( R^ch, and C₃-C₆ cycloalkyl groups, wherein;

R^c, for each occurrence, is independently chosen from hydrogen and C1-C2 alkyl groups;

the C1-C4 alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH;

the C1-C4 alkoxy of R* is optionally substituted with 1 to 3 independently chosen from halogen groups; and the C₃-Cô cycloalkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH;

and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 15.

17. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 16, wherein R¹, for each occurrence, is independently chosen from F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy, -C(-O)N(R^c)₂, and C₃-Cô cycloalkyl groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and Ci-C₂ alkyl groups;

the C1-C4 alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH; and the C1-C4 alkoxy of R¹ is optionally substituted with l to 3 independently chosen from halogen groups;

and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 16.

18. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 17, wherein R¹, for each occurrence, is independently chosen from F, Cl, Br, -CH₃, -CH(CH₃)₂, -CF₃, -OCH₃, -OCF₃, -C(=O)N(CH₃)₂, and cyclopropyl;

114 and ail other variables not specifically defined herein are as defined in any one of Embodiments l to 17.

18a. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 14, wherein R¹, for each occurrence, is independently chosen from -SO₂(R^C) groups, wherein R^c is independently chosen from C1-C4 alkyl groups;

and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 14.

18b. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 14, wherein R¹, for each occurrence, is independently chosen from -SO₂(R^C) groups, wherein R^c is independently chosen from Ci alkyl groups;

and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 14.

18c. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1, 1 a-1, la-2, and 2 to 14, wherein two R¹ groups taken together with the Ring A atoms connecting them form a 5- to 6-membered cycloalkyl, 5- to 8membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6membered aryl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OEI, and C1-C4 alkyl;

and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 14.

18d. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 14, wherein two R¹ groups taken together with the

115

and ail other variables not specifically defined herein are as defined in any one of Embodiments l to 14.

19. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 18, wherein m is l ; and ail other variables not specifically defined herein are as defined in any one of Embodiments l to 18.

20. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 18, wherein m is 2; and ail other variables not specifically defined herein are as defined in any one of Embodiments l to 18.

21. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 20, wherein R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, Ci-C4 alkoxy, C|-C6 haloalkyl, Ci-Cô haloalkoxy, -C(=O)NR^hR‘, -NR^hR', -NR^hC(=O)R^k, -OR^k, -[O(CH2)q]rO(Ci-C₆ alkyl), -S(=O)₂R^k, -S(=O)2NR^hR', C₃-Cû cycloalkyl, 5 to 10-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl groups, wherein:

the Ci-Cf, alkyl of R^a is optionally substituted with l to 3 groups independently chosen from cyano, £(=0)^, -NR^hR', -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^hC(=O)NRⁱRj, -NR^hS(=O)PR^k -OR^k, -S(=O)2R^k, -S^O^NR¹'^, and C₃-C₆ cycloalkyl groups;

the C₃-Cô cycloalkyl, the 5- to 10-membered heterocyclyl, the phenyl, and the 5- to 8membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, Ci-C₂ alkyl, and -OR^k groups, wherein;

R^h, R', and RÉ for each occurrence, are each independently chosen from hydrogen, C1-C2 alkyl, cyclopropyl, and cyclobutyl groups, wherein:

the Ci-C₂ alkyl of any one of R^h, R', and R^j is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH;

116

R^k, for each occurrence, is each independently chosen from hydrogen and C1-C4 alkyl groups, wherein:

the C1-C4 alkyl of R^k is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH; and q and r are each an integer chosen from 1, 2, and 3;

and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 20.

22. The compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to any one of Embodiments 1 to 21, wherein R¹¹, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -C(=O)NR^hR‘, -NR^hR', -NR^hC(=O)R^k, -OR^k, -[O(CH₂)q]rO(Ci-C4 alkyl), -S(=O)₂R^k, -S(=O)2NRⁱ'Rⁱ, cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein:

the Ci-Cô alkyl of R^a is optionally substituted with 1 to 3 groups independently chosen from cyano, -C(=O)NR^hR‘, -S(=O)₂R^k, -NR^R', -OR^k, cyclopropyl, and cyclobutyl groups, wherein:

the cyclopropyl, the cyclobutyl, the 5- to 6-membered heterocyclyl, the phenyl, and the 5 to 6-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, -CH3, -OH, and -OCH3; wherein:

R^h and R', for each occurrence, are each independently chosen from hydrogen, -CH3, cyclopropyl, and cyclobutyl groups, wherein:

the -CH3 of any one of R^h and R¹ is optionally substituted with 1 to 3 groups independently chosen from F, Cl, and -OH;

R^k, for each occurrence, is each independently chosen from hydrogen and -CH3, wherein:

the -CH3ofR^kis optionally substituted with I to 3 groups independently chosen from halogen and -OH;

and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 21.

23. The compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to any one of Embodiments 1 to 22, wherein R^a, for each occurrence, is independently chosen from F, Cl, Br, cyano, Ci-Cô alkyl, C1-C2 alkoxy, C1-C2 haloalkyl,

-C(=O)NR^hR', -NR^hRⁱ, -NR^hC(=O)R^k, -OR^k, -[O(CH₂)q]rO(Ci-C₂ alkyl), -S(=O)₂R^k,

117

-S(=O)iNR^hR^l, cyclopropyl, cyclobutyl, 5-membered heterocyclyl, phenyl, and 6-membercd heteroaryl groups, wherein:

the Ci-C(, alkyl of R^a is optionally substituted with 1 to 3 groups independently chosen from cyano, -C(=O)NR^hR‘, -OR^k, -S(=O)?R^k, and cyclopropyl;

the cyclopropyl, the cyclobutyl, the 5- to 6-membcrcd heterocyclyl, the phenyl, and the 5- to 6-membercd heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, -CH3, -OH, and -OCH3, wherein:

R¹¹ and R¹, for each occurrence, are each independently chosen from hydrogen, -CH3, and cyclopropyl; wherein:

the -CH3 of any one of R^h and R‘ is optionally substituted with 1 to 3 groups independently chosen from F, Cl, and -OH;

R^k, for each occurrence, is each independently chosen from hydrogen and -CH3; and q and r are each an integer independently chosen from 1 and 2;

and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 22.

24. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 23, wherein R^a, for each occurrence, is independently chosen from F, cyano, -OH, -CH3, -CF3, -CH(CH3)2, -(CH₂)₂OH , -(CH₂)2OCH3,-CH2CH(OH)C₂H5, -CH₂C(CH3)(CH₂OH)2, -OCH3, -OCH2CH3, -[O(CH2)₂]₂OCH3, -CH₂C(=O)NHCH₃, -(CH2)₂SO₂CH3, -CH2C(=O)N(CH₃)₂, -CH₂(cyclopropyl), -C(=O)NH₂, -C(=O)NH(cyclopropyl),-NH₂, -NHCH3, -N(CH3)₂, -NHC(CH3)2CH₂OH, -NHC(=O)CH3, -SO2CH3, -SO2NH2, cyclopropyl, 2-methoxyphenyl, N-methylpiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl, and tetrahydrothiophenyl 1,1-dioxide; and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 23.

25. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 24, wherein R^a, for each occurrence, is independently chosen from -CH3 and -(CH₂)₂SO₂CH3; and ail other variables not specifically defined herein are as defined in any one of Embodiments 1 to 24.

26. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any onc of Embodiments 1 to 25, wherein Ring A is chosen from phenyl,

118 thiophenyl, and pyridinyl; and ail other variables not specifically defined herein are as defined in any one of Embodiments l to 25.

27. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 26, wherein Ring A is phenyl; and ail other variables not specifically defined herein are as defined in any one of Embodiments l to 26.

27a. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l and 2 to 27, wherein R⁵ is chosen from hydrogen, methyl, and propyl; and ail other variables not specifically defined herein are as defined in any one of Embodiments l and 2 to 27.

27b. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l and 2 to 27a, wherein R⁵ is hydrogen; and ail other variables not specifically defined herein are as defined in any one of Embodiments l and 2 to 27a.

28. A compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from the compounds of Table l, tautomers thereof, deuterated dérivative of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

28a. A compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from the compounds of Table 2, tautomers thereof, deuterated dérivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

28b. A compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait chosen from the compounds of Table 3, tautomers thereof, deuterated dérivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

29. A pharmaceutical composition comprising at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 28b and a pharmaceutically acceptable carrier.

30. A method of treating focal segmentai glomerulosclerosis and/or non-diabetic kîdney disease comprising administering to a patient in need thereof at least one compound according to

119 any one of Embodiments l to 28b or the phannaceutical composition according to Embodiment 29.

31. Use of at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 28b or a pharmaceuticai composition according to Embodiment 29 for the manufacture of the médicament for treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease.

32. At least one compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to any one of Embodiments l to 28b or the phannaceutical composition according to Embodiment 29 for use in treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease.

33. A method of inhibiting APOLl activity comprising contacting said APOLl with at least one compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to any one of Embodiments l to 28b or the phannaceutical composition according to Embodiment 29.

34. Use of at least one compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to any one of Embodiments l to 28b or the phannaceutical composition according to Embodiment 29 for the manufacture of a médicament for inhibiting APOLl activity.

35. At least one compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to any one of Embodiments l to 28b or a phannaceutical composition according to Embodiment 29 for use in inhibiting APOLl activity.

36. A method of treating an APOLl-mediated disease comprising administering to a patient in need thereof at least one compound according to any one of Embodiments l to 28b or the phannaceutical composition according to Embodiment 29.

37. The method according to Embodiment 36, wherein the APOLl-mediated disease is cancer.

120

38. The method according to Embodiment 36 or Embodiment 37, wherein the APOL1-mediated disease is pancreatic cancer.

39. Use of at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 28b or the pharmaceutical composition according to Embodiment 29 for the manufacture of a médicament for treating an APOL1-mediated disease.

40. The use according to Embodiment 39, wherein the APOL1-mediated disease is cancer.

41. The use according to Embodiment 39 or Embodiment 40, wherein the APOL1 -mediated disease is pancreatic cancer.

42. At least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 28b or the pharmaceutical composition according to Embodiment 29 for use in treating an APOL1-mediated disease.

43. The at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait for use according to Embodiment 42, wherein the APOL1-mediated disease is cancer.

44. The at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait for use according to Embodiment 42 or Embodiment 43, wherein the APOL1-mediated disease is pancreatic cancer.

45. A method of inhibiting APOL1 activity comprising contacting said APOL1 with at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 28b or a pharmaceutical composition according to Embodiment 29.

46. Use of at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments 1 to 28b or a pharmaceutical composition according to Embodiment 29 for the manufacture of a médicament for inhibiting APOL1 activity.

121

47. At least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 28b or a pharmaceutical composition according to Embodiment 29 for use in inhibiting APOLI activity.

48. A Silicon dérivative ofthe at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 28b.

49. A pharmaceutical composition comprising a Silicon dérivative of Embodiment 48.

50. A method of treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof the Silicon dérivative according to Embodiment 48 or the pharmaceutical composition according to Embodiment 49.

51. Use of the Silicon dérivative according to Embodiment 48 or the pharmaceutical composition according to Embodiment 49 for the manufacture of a médicament for treating focal segmentai glomerulosclerosis and/or non-diabetic kidney discase.

52. The Silicon dérivative according to Embodiment 48 or the pharmaceutical composition according to Embodiment 49 for use in treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease.

53. A method of treating an APOLI -mediated disease comprising administering to a patient in need thereof the Silicon dérivative according to Embodiment 48 or the pharmaceutical composition according to Embodiment 49.

54. The method according to Embodiment 53, wherein the APOLI-mediated disease is cancer.

55. The method according to Embodiment 53 or Embodiment 54, wherein the APOLI-mediated disease is pancreatic cancer.

56. Use of the Silicon dérivative according to Embodiment 48 or the pharmaceutical composition according to Embodiment 49 for the manufacture of a médicament for treating an APOLI-mediated disease.

122

57. The use according to Embodiment 56, wherein the APOLl-mediated disease is cancer.

58. The use according to Embodiment 56 or Embodiment 57, wherein the APOLl-mediated disease is pancreatic cancer.

59. The Silicon dérivative according to Embodiment 48 or the pharmaceutical composition according to Embodiment 49 for use in treating an APOLl-mediated disease.

60. The Silicon dérivative or pharmaceutical composition for use according to Embodiment 59, wherein the APOLl-mediated disease is cancer.

61. The Silicon dérivative or pharmaceutical composition for use according to Embodiment 59 or Embodiment 60, wherein the APOLl-mediated disease is pancreatic cancer.

62. A boron dérivative of the at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of Embodiments l to 28b.

63. A pharmaceutical composition comprising a boron dérivative of Embodiment 62.

64. A method of treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof a boron dérivative according to Embodiment 62 or a pharmaceutical composition according to Embodiment 63.

65. Use of the boron dérivative according to Embodiment 62 or a pharmaceutical composition according to Embodiment 63 for the manufacture of a médicament for treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease.

66. The boron dérivative according to Embodiment 62 or a pharmaceutical composition according to Embodiment 63 for use in treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease.

67. A method of treating an APOLl-mediated disease comprising administering to a patient in need thereof a boron dérivative according to Embodiment 62 or a pharmaceutical composition according to Embodiment 63.

123

68. The method according to Embodiment 67, wherein the APOLl-mediated disease is cancer.

69. The method according to Embodiment 67 or Embodiment 68, wherein the APOLl-mediated disease is pancreatic cancer.

70. Use ofthe boron dérivative according to Embodiment 62 or the pharmaceutical composition according to Embodiment 63 for the manufacture of a médicament for treating an APOLl-mediated disease.

71. The use according to Embodiment 70, wherein the APOLI -mediated disease is cancer.

72. The use according to Embodiment 70 or Embodiment 71, wherein the APOLl-mediated disease is pancreatic cancer.

73. The boron dérivative according to Embodiment 62 or the pharmaceutical composition according to Embodiment 63 for use in treating an APOLl-mediated discase.

74. The boron dérivative or pharmaceutical composition for use according to Embodiment

73, wherein the APOLl-mediated disease is cancer.

75. The boron dérivative or pharmaceutical composition for use according to Embodiment 73 or Embodiment 74, wherein the APOLl-mediated disease is pancreatic cancer.

76. A phosphorus dérivative of at least one compound, tautomer, deuterated dérivative or pharmaceutically acceptable sait according to any one of Embodiments l to 28b.

77. A pharmaceutical composition comprising a phosphorus dérivative of Embodiment 76.

78. A method of treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof a phosphorus dérivative according to Embodiment 76 or a pharmaceutical composition according to Embodiment 77.

124

79. Use of the phosphorus dérivative according to Embodiment 76 or the pharmaceutical composition according to Embodiment 77 for the manufacture of a médicament for treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease.

80. The phosphorus dérivative according to Embodiment 76 or the pharmaceutical composition according to Embodiment 77 for use in treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease.

81. A method of treating an APOLl-mediated disease comprising administering to a patient in need thereof a phosphorus dérivative according to Embodiment 76 or the pharmaceutical composition according to Embodiment 77.

82. Themethod according to Embodiment 81, wherein the APOLl-mediated disease is cancer.

83. The method according to Embodiment 81 or Embodiment 82, wherein the APOLl-mediated disease is pancrcatic cancer.

84. Use of the phosphorus dérivative according to Embodiment 76 or the pharmaceutical composition according to Embodiment 77 for the manufacture of a médicament for treating an APOLl-mediated disease.

85. The use according to Embodiment 84, wherein the APOLl-mediated disease is cancer.

86. The use according to Embodiment 84 or Embodiment 85, wherein the APOLl-mediated disease is pancreatic cancer.

87. The phosphorus dérivative according to Embodiment 76 or a pharmaceutical composition according to Embodiment 77 for use in treating an APOLl-mediated disease.

88. The phosphorus dérivative or pharmaceutical composition for use according to Embodiment 87, wherein the APOLl-mediated disease is cancer.

89. The phosphorus dérivative or pharmaceutical composition for use according to Embodiment 87 or Embodiment 88, wherein the APOLl-mediated disease is pancreatic cancer.

I25

90. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to Embodiment l, wherein the variable X is a bond (i.e., X is not présent).

91. A compound represented by the formula:

Formula I I-6a a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein:

R^la and R^lb are independently chosen from halogen, H, C1-C4 alkyl, and C1-C4 haloalkyl groups;

R^lc is chosen from halogen, H, CH3, -OH, and CH3OH; and

R2 is chosen from cyano, Ci-Cô alkyl, -C(=O)O(C|-C4 alkyl), C2-C6 alkynyl, and (R^a)o-5 , wherein:

the Ci-Cô alkyl of R²is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -C(=O)N(Ci-C₄ alkyl)?, C₃-Cô carbocyclyl, 5- to 10-membered heterocyclyl, Cô aryl, and 5- to 10-membered heteroaryl groups;

Ring B is chosen from C₃-Ci₂ carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with l, 2, 3, 4, or 5 R^a groups; wherein:

R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, C?-Cô alkenyl, Ci-Cô alkoxy, Ci-Cô haloalkyl, Ci-Cô haloalkenyl, Cj-Cô haloalkoxy, -C(=O)NR^hR^!, -NR^hR', -NR^hC(=O)R^k, -NR^hC(-ü)OR^k, -NR'Oi^OJNWRj, -NRS(=O)_PR^k-OR^k, -OC(=O)R^k, -OC(=O)OR^k,

126

-OC^OJNRbR¹, -[O(CH2)q]rO(C]-C6 alkyl), -S(=O)PR^k, -S(-O)PNR^hRⁱ, -C(-O)OR^k, C3-C12 earbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cto aryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Cô alkyl, C1-C0 alkoxy, and the C₂-Cô alkenyl of R^a are each optionally substituted with 1 to 3 groups independently chosen from Cô to Cio aryl (optionally substituted with 1 to 3 R^m groups), 5- to 10membered heterocyclyl (optionally substituted with 1 to 3 R^m groups), 5to 10-membered heteroaryl (optionally substituted with 1 to 3 R^m groups), cyano, -C(=O)R^k, -C(=O)OR^k, -CfoOW'R¹, -NR^hR‘, -NR^hC(=O)R^k, -NR^llC(=O)OR^k, -NR^hC(=O)NRⁱRj, -NR^hS(=O)PR^k -OR^k, -OC(=O)R\ -OC(=O)OR^k, -OCrOjNR'W, -S(=O)PR^k, -S(=O)pNR^hR', -O(Cô aryl) (optionally substituted with 1 to 3 R^m groups), and C3-C0 earbocyclyl groups (optionally substituted with 1 to 3 R¹¹¹ groups);

the C3-C12 earbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cio aryl, and the 5- to 10-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C4 alkyl, -NR^hR^l, and -OR^k groups, wherein:

R^h, R', and RL for each occurrence, are each independently chosen from hydrogen, C1-C4 alkyl, Cô-Cioaryl, and C3-C6 cycloalkyl groups, wherein:

the C1-C4 alkyl of any one of R^h, R', and R^j is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-C6 earbocyclyl groups, wherein:

the C1-C4 alkyl of any one of R^k is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R¹, for each occurrence, is independently chosen from halogen, cyano, oxo, C1-C0 alkyl, Ci-Cô alkoxy, -S(=O)_PR^k, and -OR^k groups, wherein:

127 the Ci-Cô alkyl of R^m is optionally substituted with l to 3 groups independently chosen from halogen, cyano, OH, and -O(Ci-C₄ alkyl) groups.

92. A compound represented by the formula:

/ II-6b a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein:

R¹'¹ and R^lb are independently chosen from halogen, H, Cj-C₄ alkyl, and Ci-C₄ haloalkyl groups; and

R^lc is chosen from halogen, H, CH3, -OH, and CH3OH.

93. A pharmaceutical composition comprising the compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to Embodiment 91 or Embodiment 92.

94. A method of treating an APOLl-mediated disease comprising administering to a patient in need thereof the compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to Embodiment 91 or Embodiment 92, or the pharmaceutical composition according to Embodiment 93.

95. The method according to Embodiment 94, wherein the APOLl-mediated disease is cancer.

96. The method according to Embodiment 94 or Embodiment 95, wherein the APOLl-mediated disease is pancreatic cancer.

97. A method of treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof the compound, tautomer,

128 deuterated dérivative, or phannaceutically acceptable sait according to Embodiment 91 or Embodiment 92, or the phannaceutical composition according to Embodiment 93.

98. Use of the compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to Embodiment 91 or Embodiment 92, or the phannaceutical composition according to Embodiment 93 for the manufacture of a médicament for treating an APOLI mediated disease.

99. The use according to Embodiment 98, wherein the APOLI-mediated disease is cancer.

100. The use according to Embodiment 98 or Embodiment 99, wherein the APOLI-mediated disease is pancreatic cancer.

101. Use of the compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to Embodiment 91 or Embodiment 92, or the phannaceutical composition according to Embodiment 93 for the manufacture of the médicament for treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease.

102. The compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to Embodiment 91 or Embodiment 92 or the phannaceutical composition according to Embodiment 93 for use in treating an APOLI-mediated disease.

103. The compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to Embodiment 91 or Embodiment 92 or the phannaceutical composition according to Embodiment 93, for use in treating an APOLI-mediated cancer.

104. The compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to Embodiment 91 or Embodiment 92 or the phannaceutical composition according to Embodiment 93, for use in treating APOLI-mediated pancreatic cancer.

105. The compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to Embodiment 91 or Embodiment 92 or the phannaceutical composition according to Embodiment 93, for use in treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease.

129

EXAMPLES

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

The compounds of the disclosure may be made according to standard Chemical practices or as described herein. Throughout the following synthetic schemes and in the descriptions for preparing compounds of Formulae I, la, Ib, le, Ic-1, Ic-2, Ic-3, Ic-4, lc-5, Ic-6, II, Ιί-1, 11-2, II3,11-4, Π-5, II-6, II-6a and II-6b, Compounds 1 to 29, Compounds 15 to 1295, Compounds 30 to 44, and Compounds 45 to 68, a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, the following abbreviations are used:

Abbreviations

AIBN = azobisisobutyronitrile

ARP = assay ready plate

BBBPY = 4,4'-Di-/i?r/-butyl-2,2'-dipyridyl

BFs= boron trifluoride

BF₃.OEt2 = boro trifluoride diethyl etherate

BOC2O = di-tert-butyl dicarbonate

CBzCl = benzyl chloroformate

CDMT = 2-chloro-4,6-dimethoxy-I,3,5-triazine

DAST = diethylaminosulfur trifluoride

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

DCM = dichloromethane

DIBAL-H = diisobutylaluminum hydride

DIPEA = Ν,Ν-Diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine

DMAP = dimethylamino pyridine

DMA = dimethyl acetamide

DME = dimethoxyethane

DMEM = Dulbecco’s modified Eagle’s medium

DMF = dimethyl form ami de

DMPU = N,N’-dimethylpropyleneurea

DMSO = dimethyl sulfoxide

DPPA = diphenylphosphoryl azide dppb = l-4-bis[P(Ph)2]-butane

130

EtOAc = ethyl acetate

EtOH = éthanol

Et?O = diethyl ether

FBS = fêtai bovine sérum

FLU = fluorescent values

HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyIammonium (Phosphorus Hexafluoride Ion)

HDMC = A-[(5-Chloro-3-oxido-l/7-benzotriazol-l -yl)-4-morpholinylmethylene]- Nmethylmethanaminium hexafluorophosphate

HEPES = 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid

HBSS = Hank’s balanced sait solution

IPA = isopropyl alcohol

Ir[df(CF3)ppy]2(dtbbpy)PF6 = phosphorus hexafluoride

LDA = lithium diisopropyl amide

LED = light emitting diode

MeCN = acetonitrile

Mel = methyl iodide

MeOH = methanol

MsOH = methanesulfonic acid

MTBE or TBME = Methyl /ert-butyl ether n-BuLi = n-butyllithium

NBS = N-bromosuccinimide

NMM = N-methyl morpholine

NMP = N-methyl pyrrolidine

PBS = phosphate-buffered saline

PdfdppfhCh = [ l ,r-Bis(diphenylphosphino)fenOcene]dichloropalladium(II)

PdChf PPh?)? = Bis(triphenylphosphine)palladium(H) dîchloride

Pd^dba? = Tris(dibenzylideneacetone)dipalladium

PP = polypropylene psig = pounds per square inch gauge

PTS A =/?-Toluenesulfonic acid monohydrate rt = room température

I3l

SFC = supercritical fluid chromatography

T3P = 2,4,6-Tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide

TB A F = tctra-n-butylammonium fluoride

TBSCI = tert-butyldimethylsilyl chloride

TBME = methyl tert-butyl ether

TEA = triethylamine

Tet = tétracycline

TFA or TFAA = trifluoroacetic acid

TfOH = triflic acid

THF = tetrahydrofuran

2-Me-THF = 2=methyl tetrahydrofuran

THP = tetrahydropyran

TMSCl = trimethylsilyl chloride

TMSS = Trîs(trimethylsilyl)silane

Example 1. Synthesis of Compounds

Ali the spécifie and generic compounds, and the intermediates disclosed for making those compounds, are considered to be part of the disclosure disclosed herein.

Synthesis of Starting Materials

Préparations describe synthetic routes to intermediates used in the synthesis of Compounds 1 to 29, Compounds 15 to 1295, Compound 1296, Compounds 30 to 44, and Compounds 45-68.

General Schemes

In some embodiments, processes for preparing compounds of Formula I comprise the reactions described in Schemes 1-10. In the schemes below, A is CH or N and R¹, R², and R³ are as defined above.

Scheme 1 shows a process for the préparation of a compound of formula 1-2 from piperidinone SI. The piperidinone SI can be optionally substituted with a protecting group reagent such as allyl bromide to provide the protected piperidinone depicted by S2. Suitable aryl halides are treated with hexyl lithium in a solvent such as THF, which are then combined with S2 to form compounds depicted by formula 1-1. This is followed by deprotection of the allyl group to provide compounds depicted by formula 1-2.

132

Scheme 1

Représentative scheme using n-hexyllithium to form aryl lithium nucleophiles for 1,2-addition

SI allyl bromide (1.4 equiv)

K₂CO₃ (1.1 equiv)

MeCN, 40 °C, 18 h

hexyl lithium (2.0 equiv) Aryl halide (2.0 equiv)

THF, -78 °C, 30 min

S2

73%

THF, 23 °C, 10 min

Pd₂(dba)₃ (2.5 mol%) dppb (5 mol%) 2-sulfanylbenzoic acid (1.1 equiv)

Scheme 2 shows an alternative process for the préparation of a compound of formula 2-2 5 from the protected piperidinone S2. Suitable aryl halides are treated with i-butyllithium in a solvent such as THF, which are then combined with S2 to form compounds depicted by formula 2-1. This is followed by deprotection of the allyl group to provide compounds depicted by formula 2-2.

133

Scheme 2

Représentative scheme using tert-butyllithium to form aryl lithium nucleophiles for 1,2-addition

THF, -78 °C, 30 min

Aryl halide (1.5 equiv

Tbutyllithium (3.0 equiv)

S2

Pd₂(dba)₃ (2.5 mol%) dppb (5 mol%) 2-sulfanylbenzoic acid (1.1 equiv)

THF, 23 °C, 10 min

Scheme 3 shows an alternative process for the préparation of a compound of formula 3-2 5 from the protected piperidinone S2. Suitable aryl halides are treated with w-butylithium in a solvent such as THF, which are then combined with S2 to form compounds depicted by formula 3-1. This is followed by deprotection of the allyl group to provide compounds depicted by formula 3-2.

134

Scheme 3

Représentative scheme using n-butyllithium to form aryl lithium nucleophiles for 1,2-addition

THF, -78 °C, 30 min

Aryl halide (2.0 equiv

n-butyllithium (2.0 equiv)

S2

Pd₂(dba)₃ (2.5 mol%) dppb (5 mol%) 2-sulfanylbenzoic acid (1.1 equiv)

THF, 23 °C, 10 min

Scheme 4 shows an alternative process for the préparation of a compound of formula 4-2 from the protected piperidinone S2. Suitable aryl halides are treated with s-butyllithium in a solvent such as THF, which are then combined with S2 to form compounds depicted by formula 4-1. This is followed by deprotection of the allyl group to provide compounds depicted by formula 4-2.

135

Schemc 4

Représentative scheme using sec-butyllithium to form aryl lithium micleophiles for 1,2-addition

THF, -78 °C, 30 min

Ary! halide (2.0 equiv

s-butyllithium (2.0 equiv)

S2

Pd₂(dba)₃ (2.5 mol%) dppb (5 mol%) 2-sulfanylbenzoic acid (1.1 equiv)

THF, 23 °C, 10 min

Scheme 5 shows an alternative process for the préparation of a compound of formula 5-2 5 from the protected piperidinone S2. Suitable aryl lithiate reagents in a solvent such as THF are combined with S2 to form compounds depicted by formula 5-1. This is followed by deprotection of the allyl group to provide compounds depicted by formula 5-2.

136

Scheme 5

Représentative scheme of 1,2-addition using phenyl lithium to aryl lithium micleophiles

THF, -78 °C phenyl lithium

2.2 equiv

6:5 trans:cis

Pd₂(dba)₃ (2.5 mol%) dppb (5 mol%) 2-sulfanylbenzoic acid (1.05 equiv)

THF, 23 °C, 10 min

Scheme 6 shows an alternative process for the préparation of a compound of formula 6-2 5 from the protected piperidinone S2. Suitable aryl Grignard reagents (ArMgX), which in some embodiments are prepared by treatment of appropriate aryl halides with magnésium in a solvent such as THF, are then combined with S2 to fonn compounds depicted by fonnula 6-1. This is followed by deprotection of the allyl group to provide compounds depicted by fonnula 6-2.

137

Scheme 6

Représentative scheme of 1,2-addition using arylmagnesium bromide nucleophiles

ArMgBr 2 equiv

THF, 0 °C h

S2

Pd₂(dba)₃ (2.5 mol%) dppb (5 mol%) 2-sulfanylbenzoic acid (1.05 equiv)

THF, 23 °C, 10 min

Scheme 7 shows an alternative process for the préparation of a compound of formula 7-2 5 from the protected piperidinone S2. Suitable aryl halides may be treated with ÎPrMgCI-LiCl in a solvent such as THF, then combined with S2 to form compounds depicted by formula 7-1, followed by deprotection of the allyl group to provide compounds depicted by formula 7-2.

138

Scheme 7

Représentative scheme to generate arylmagnesinm halide micleophiles and their addition

ArX (2 equiv) iPcMgChLiCI (2 equiv) DME (1 equiv)

THF, 0 °C 3 h

S2

THF, 23 ’C, 10 min

Pd₂(dba)₃ (2.5 mol%) dppb (5 mol%) 2-sulfanylbenzoic acid (1.05 equiv)

Scheme 8 shows an alternative process for the préparation of a compound of formula 8-2 5 from the protected piperidinone S2. Suitable aryl Grignard reagents (ArMgX), which in some embodiments are prepared by treatment of appropriate aryl halides with magnésium in a solvent such as THF, are then combined with LaCl3-2LiCl and S2 to form compounds depicted by formula 8-1. This is followed by deprotection of the allyl group to provide compounds depicted by formula 8-2.

139

Schenie 8

Représentative scheme using arylmagnesium halide Grignard reagents with LaCh-2LiCl as nudeophiles

S2

THF, 23 “C, 10 min

LaCI₃*LiCI (x mol%)

ArX (2 equiv)

Mg (2 equiv)

THF 60 - 0 °C x h

Pd₂(dba)₃ (2.5 mol%) dppb (5 mol%) 2-sulfanylbenzoic acid (1.05 equiv)

Scheme 8a shows an alternative process for the préparation of a compound of formula 16 from pîperidinones of formula SI. Note that this chemistry can proceed in the absence of a Nprotecting group. Suitabie aryl Grignard reagents (ArMgX), which in some embodiments are prepared by treatment of appropriate aryl halides with magnésium in a solvent such as THF or 2-

MeTHF, are then combined with SI to form compounds depicted by formula 16.

Scheme 8a

Représentative scheme to generale arylmagnesium halide mtcleophiies and their addition

Mg turnings /-PrMgBr i-PrMgCI

- 60 °C 2-MeTHF

S1

-15 - 0 °C

140

CF,

Br

Mg turnings /-PrMgBr /-PrMgCI

- 60 °C 2-MeTHF

S1

-15 - 0 °C

Scheme 9 shows an alternative process for the préparation of a compound of formula 9-6 from N-protected beta-amino acids of formula 9-1. PG⁴ may be Boc or any suitable nitrogen protecting group. Compound 9-2 dimagnesium sait may be coupled to compounds of formula

9-1 using a reagent such as GDI in a solvent such as THF. Condensation of compounds of formula 9-3 with aldéhydes of formula 9-4 affords compounds of formula 9-5. In some embodiments, the reaction may be performed by treatment of a compound of formula 9-3 with an acid such as TFA in a solvent such as dichloromethane, followed by the addition of aldéhyde of formula 9-4. A compound of formula 9-6 may be prepared from a compound of formula 9-5 by treatment with an acid such as methanesulfonic acid in a solvent such as dichloromethane. The reaction may be performed in the presence of added heat (e.g., reflux conditions).

Scheme 9

Représentative scheme to synthesize 2,6-disubstituted piperidinones

Scheme 10 shows a process for the préparation of a compound of formula 10-3 from piperidinone 9-6. The piperidinone 9-6 can be optionally substituted with a protecting group reagent such as allyl bromide to provide the protected piperidinone depicted by formula 10-1.

141

Suitable aryl halides such as l-iodo-4-(trifluoromethyl)benzene are treated with hexyl lithium in a solvent such as THF, which are then combined with formula 10-1 to form compounds depicted by formula 10-2. This is followed by deprotection of the allyl group to provide compounds depicted by formula 10-3.

Scheme 10

General scheme of allyl protection, l,2-addition, and deprotection

hexyl ithium, THF, -70 °C allyl bromide, K₂CO₃

MeCN

10-2

Pd₂dba₃, dppb,

2-sulfanylbenzoic acid, THF

H

10-3

142

Préparation SI (2S,6S)-l-allyl-2-methyl-6-(l-melhyl-lH-l,2,3-triazol-4-yl)piperidin-4-one (SI)

MsOH (4 eq.)

DCM, reflux

allyt bromide K₂CO₃

MeCN, 40 °C

Step î. Synthesis of bis[(3-iert-butoxy-3-oxo-propanoyl)oxy]magnésium (C2)

A solution of 3-tert-butoxy-3-oxo-propanoic acid (Cl) (321.51 g, l.907 mol) in THF (2 L) was cooled to 5 °C in an ice-bath, and Mg(OEt)₂ (l 11.33 g, 953.5 mmol) was added. The reaction was stirred for 30 minutes at 0 °C, removed from the cooling bath, and stirred at room température overnight. The reaction was fïltered over a plug of Celite®, and the plug was washed with additional THF. The clear, colorless filtrate was evaporated in vacuo to afford a wet solid. The solid was triturated with l L of diethyl ether and fïltered. The filter-cake was washed with Et₂O and dried in vacuo. The filtrate was evaporated in vacuo again and was then triturated with a small volume of Et₂O and fïltered to afford a second crop of the product. The crops were combined and dried in vacuo to afford the title compound C2 (294.49 g, 90%) as a white solid. ^lH NMR (300 MHz, Methanol-Λ) δ 4.92 (s, 4Η), l .48 (s, 18Η).

Step 2. Synthesis of tert-butyl (5S)-5-(tert-butoxycarbonylamino)-3-oxo-hexanoate (C4)

To a solution of (35)-3-(tert-butoxycarbonylamino)butanoic acid (C3) (170.15 g, 837.2 mmol) in THF (1.5 L) was added CDI (149.8 g, 923.8 mmol). The milky suspension cleared over the next few minutes. Gas évolution was observed. The reaction was stirred at room température for 3 hours. /?(s[(3-tert-butoxy-3-oxo-propanoyl)oxy]magnesium (C2) (172.19 g, 502.6 mmol) was added. Another milky suspension was formed that cleared after stirring for 30 minutes. The

143 reaction was stirred for 48 hours. The reaction was poured into l .5 L of l M HCl and extracted with MTBE (l L). The pH was confirmed to be approximately 3. The extract was washed with saturated NaHCOi, dried over MgSÛ4, filtered, and concentrated in vacuo to afford the title compound C4 (248.5 g, 99%) as a clear oil. 'H NMR (300 MHz, Chloroform-i7) δ 4.90 (d, J = I8.l Hz, 1H), 4.04 (dt, J = 13.8, 6.6 Hz, IH), 3.47 - 3.22 (m, 2H), 2.76 (qd, J - 17.0, 5.7 Hz, 2H), l.48(s, 9H), l .44 (s, 9H), l .23 (d, J = 6.8 Hz, 3H).

Step 3. Synthesis pftert-butyl (2S,3R,6S)-6-methyi-2-(l-methyltria~ol-4-yl)-4-oxo-piperidine-3carboxylate (C6)

To a solution of ier/-butyl (55)-5-(tert-butoxycarbonylamino)-3-oxo-hexanoate (C4) (248.5 g, 824.5 mmol) in DCM (1.5 L) was added TFA (240 mL, 3.115 mol), and the reaction was stirred ovemight. The reaction was evaporated in vacuo at 25 °C. The solid that remained was triturated with 500 mL of pentane and filtered. The filter cake was washed with pentane, and most ofthe solvent was pulled off of the filter-cake. The cake was transferred back to the reaction flask and dissolved in l L of DCM. l-Methyltriazole-4-carbaldehyde ( 120.7 g, l .086 mol) was added. The reaction was stirred at room température ovemight. Brine (100 mL) was added, and then 6 M NaOH was added until the aqueous layer remained alkaline when the funnel was shaken. The organic layer was isolated, and the aqueous layer was extracted with DCM ( l L). The organic layers were combined, dried over MgSÛ4, and filtered over a plug of silica gel. The plug was eluted with 10% MeOH/EtOAc. The filtrate was evaporated in vacuo to afford a solid that was triturated with MTBE (500 mL) and filtered. The filter cake was washed with MTBE and dried in vacuo to give a crop of product. The mother liquor from the trituration was concentrated. The solid that precipitated was filtered to provide a second crop ofthe product. The crops were combined to give the title compound C6 (l05.45 g, 43%) as a white solid. ’H NMR (300 MHz, Chloroform-J) δ 7.48 (s, IH), 4.52 (d, J = l l.O Hz, IH), 4.09 (s, 3H), 3.61 (dd, J = ll.O, l.O Hz, IH), 3.21 (ddd, J = 11.7,6.1, 2.9 Hz, IH), 2.55 (dd, J = 13.7, 2.9 Hz, IH), 2.37 -2.13 (m, IH), 1.98 (s, IH), 1.39 (s, 9H), 1.29 (d, J = 6.3 Hz, 3H).

Step 4. Synthesis of (2S,6S)-2-methyl-6-( 1 -methyhriazol-4-yl)piperidin-4-one (SI)

To a solution of tert-butyl (2S',37?,65)-6-methyl-2-(l-methyltriazol-4-yl)-4-oxopiperidine-3-carboxylate (C6) (70.59 g, 239.8 mmol) in DCM (750 mL) was added MsOH (62 mL, 955.4 mmol) and the reaction was heated to reflux for 6 hours. The reaction was cooled down to room température and then poured into a separatory funnel. Brine (100 mL) was added, and then 6 M NaOH was added until the aqueous layer remained alkaline after shaking. The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 500 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound SI (43.74 g, 94%) as an off-white solid. ’H NMR (300 MHz, Chloroform-<7)

144

Ô 7.46 (s, IH), 4.20 (dd, J = 10.1,5.1 Hz, IH), 4.06 (s, 311), 3.11 (dqd, J = 12.3, 6.2, 3.0 Hz, IH), 2.73 -2.48 (m, 2H), 2.40 (ddd, J = 14.1,3.0, 1.5 Hz, 1 H), 2.25 - 2.00 (m, 2H), 1.23 (d, J = 6.2 Hz, 3H).

Step 5. (2S,6S)-Î-allyl-2-methyl-6-( 1-methyl-l H-l ,2,3-triazol-4-yl)piperidin-4-one (S2)

To a suspension of (25',6.S')-2-methyl-6-( l-mcthyltnazol-4-yl)piperidin-4-onc (SI) ( 10.0 g, 50.5 mmol) and K2CO3 (8.0 g, 57.9 mmol) in MeCN ( 100 mL) was added allyl bromide (5.5 mL, 63,6 mmol), and the mixture was heated to 40 °C and stirred for 1 8 hours. The suspension was then filtered, rinscd with MeCN, and concentrated to about 3 volumes. The mixture was diluted with TBME/EtOAe/DCM 1:1:1 (300 mL) and water (250 mL). The aqueous layer was extracted with DCM (2 x 150 mL). The combined organic layer was washed with saturated brine (250 mL), dried with MgSCL, filtered, and concentrated. The mixture was suspended in TBME (180 mL) and refluxed. Upon reflux, full dissolution to a yellow solution was observed. The mixture was rcmoved from the bath and stirred. After about 5 minutes, significant précipitation was observed. At this time, the mixture was cooled with an ice bath for 10 minutes, filtered, and rinsed with TBME (2x15 mL). Dissolution was observed, so subséquent rinses were carried out using heptane (3 x 20 mL). The addition of heptane caused a significant amount of précipitation in the mother liquor, which was filtered and rinsed with heptane (3x10 mL) to yield the second crop. The crops were combined to yield the title compound S2 (2S,6S)-1 -allyl-2-methyl-6-( 1 methyltriazol-4-yl)pîperidin-4-one (8.42 g, 71%) as an off-white solid. ^lH NMR (300 MHz, Chloroform-i/) δ 7.48 (s, 1H), 5.91 (ddt, J = 16.9, 11.1, 6.4 Hz, 1H), 5.13 (t, J = 14.6 Hz, 2H), 4.23 (dd, J = 10.9,3.8 Hz, 1H), 4.12 (d, J = 1.3 Hz, 3H), 3.44 (dd, J = 16.0, 6.8 Hz, 1H), 3.17 (dd, J= 16.0,6.3 Hz, 1H), 3.06 (dt, J = 10.5,5.4 Hz, 1H), 2.88 (dd, J = 14.6, 10.9 Hz, IH), 2.59 (dd,J = 14.8,3.7 Hz, IH), 2.53 - 2.34 (m, 2H), 1.27 (d, J = 6.2 Hz, 3H).

Préparation S3 2-methyl-6flf2fmethylsidfonyl)ethyl)-lH-pyrazol-4-yl)piperidin-4-one (S3)

145

NH₂ O

Boc2O

Boc

C7

OH

NaOH

C8

O

HN

I HCl

OH T3P, DIPEA

Boc..

NH O MeMgl

N'⁰-----

C9

/ °

Step 1. Synthesis of (3S)-3ftert-biitoxycarbonylamino)biUanoic acid (C8)

To a solution of (35)-3-aminobutanoic acid (C7) (100 g, 969.7 mmol) in dioxane (600 mL) was added aqueous NaOH solution (950 mL of 1 M, 950.0 mmol) over 15 minutes, followed by Boc₂O (300 g, 1.375 mol). The reaction mixture was stirred at room température for 12 hours. The reaction was partitioned with MTBE (1 L) and water (300 mL). The layers were separatcd, and the aqueous layer was extracted again with MTBE (500 mL). The aqueous layer was then acidificd with 1 M HCl until pH = 2 and extracted with DCM (3 x 600 mL). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated in vaciio to yield the title compound C8 ( 176 g, 89%) as a white solid. ’H NMR (300 MHz, Chloroform-J) δ 4.92 (s, 1H), 4.04 (s, 1 H), 2.56 (dd, J = 5.5, 2.9 Hz, 2H), 1.44 (s, 9H), 1.25 (d,J = 6.8 Hz, 3H).

Step 2. Synthesis of tert-butyl N-[(lS)-3fmethoxy(methyl)amino]-l-methyl-3-oxopropyl] carbamate (€9)

To a solution of (3*S)-3-(tert-butoxycarbonylamino)butanoic acid (C8) (160 g, 787.3 mmol) in DCM (1.5 L) was added N-methoxymethanamine (Hydrochloride sait) (81 g, 830.4 mmol), followed by the addition of DIPEA (560 mL, 3.215 mol) over 10 minutes. The reaction mixture was cooled to 0 °C, and T3P (600 g of 50 %w/w in EtOAc, 942.9 mmol) was added over 45 minutes. After the addition, the cooling bath was removed, and the reaction was stirred at room température for 1 hour. The reaction mixture was cooled to 10 °C, and aqueous 1 M NaOH solution (700 mL) was added. The solution was stirred for 15 minutes. The organic phase was separated, washed with aqueous saturated ammonium chloride solution (200 mL) and brine (200 mL), dried, filtered through a silica gel plug, and concentrated in vacuo to afford the title compound C9 (180 g, 93%) as a clear, colorless viscous oil. ’H NMR (300 MHz, Chloroform-t/ ) 146 δ 5.30 (s, IH), 4.06 (ddd, J = 14.3, 9.7, 6.0 Hz, l H), 3.68 (s, 3H), 3.17 (s, 3H), 2.71 (dd, J = 15.6, 5.2 Hz, IH), 2.54 (dd, J= 15.7,5.7 Hz, 1H), 1.43 (s, 9H), 1.24 (d, J = 6.8 Hz, 3H).

Step 3. Svnthesis of tert-butvl N-[( 1 S)-1 -meihyl-3-oxo-butylf carbamate (CIO)

To a solution of /er/-butyl N-[(l.S')-3-[i'nethoxy(methyl)arnino]-l-rnethyl-3-oxopropyl]carbamate (C9) (220 g, 893.2 mmol) in THF (4 L) at 0 °C was added iodo(methyl)magnesium (900 mL of 3M, 2.7 mol) over 40 minutes. The resulting reaction mixture was stirred at 0 °C for 4 hours. The reaction was quenched with saturated ammonium chloride solution (2 L), followed by MTBE (1 L) and water (2 L). The mixture was stirred for 30 minutes, and the organic layer was separated. The aqueous phase was extracted with MTBE (I L), and the combined organic layers were washed with saturated ammonium chloride solution ( 1 L), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-70% EtOAc in heptane) yielded the title compound CIO (115 g, 64%) as a white solid. Ή NMR (300 MHz, Chloroform-t/) δ 4.83 (s, IH), 4.12 - 3.87 (m, IH), 2.69 (dd, J = 16.5, 5.2 Hz, 1 H), 2.63 - 2.47 (m, 1 H), 2.15 (d, J = 2.3 Hz, 3H), 1.43 (d, J = 2.4 Hz, 9H), 1.20 (dd, J = 6.8, 2.4 Hz, 3H).

Step 4. Synthesis of (4S)-4-aminopentan-2-one (Hydrochloride Sait) (Cil)

To a solution of Ze/7-butyl N-[(15)-l-methyl-3-oxo-butyl]carbamate (CIO) (16.3 g, 80.2 mmol) in MeOH (30 mL) was added hydrogen chloride (50 mL of 4 M in dioxane, 200.0 mmol) over 3 minutes. The reaction was stirred at rooin température for 5 hours and then concentrated under reduced pressure. The residue was co-cvaporated with EtOH (2 x 30 mL) and dried under vacuum to afford the title compound Cl 1 (12 g, 98%) as a pink viscous oil. ‘H NMR (300 MHz, Chloroform-r/) δ 8.06 (s, 3H), 3.48 (d, J = 6.8 Hz, IH), 2.88 (dd, J = 18.0, 5.8 Hz, 1 H), 2.75 (dd, J = 18.0, 7.2 Hz, IH), 2.13 (s, 3H), 1.17 (d, J=6.6 Hz, 3H).

Step 5. Svnthesis of 2-methyl-6-( 1 -(2-(methylsulfonyl)ethyl)-1 H-pyrazol-4-yl)piperidin-4~one (S3)

To a mixture of (4Sj-4-aminopentan-2-one (hydrochloride sait) Cil (580 mg, 4.088 mmol) in EtOH (13 mL) was added 1-(2-methylsulfonylethyl)pyrazole-4-carbaldehyde (760 mg, 3.758 mmol), L-proline (94 mg, 0.8165 mmol), magnésium sulfate (600 mg, 4.985 mmol), and TEA (600 pL, 4.305 mmol). The reaction mixture was stirred at room température ovemight. TLC indicated incomplète reaction, so additional l-(2-methylsulfonylethyl)pyrazole-4carbaldehyde (C12) (150 mg, 0.74 mmol) was added and the reaction was stirred ovemight. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was quenched with saturated sodium bicarbonate solution and extracted with DCM (x 3). The combined organic extracts were washed with brine, dried over magnésium sulfate, filtered, and concentrated in vacuo. The crude was purified via silica gel chromatography (0-60% of 20%

147

MeOH/DCM in DCM) to yield the title compound S3 (500 mg, 38%) in 7: l cis to trans ratio as an orange oil. Additionally, the enantiomeric ratio at the stereocenter from Cil was eroded to -85%. Ή NMR (300 MHz, Chloroform-d) δ 7.58 (s, IH), 7.53 (s, IH), 4.60 (t. J = 6.3 Hz, 2H), 4.00 (dd, J = H.6, 3.3 Hz, lH), 3.65 (t, J = 6.2 Hz, 2H), 3,l0(dqd, J = 12.1,6.0, 2.9 Hz, IH), 2.58-2.51 (m, 4H), 2.48 - 2.37 (m, 2H), 2.17 (dd, J = 14.1, 11.6 Hz, IH), 1.26 (d, J = 6.1 Hz, 3H) (cA isomer).

Compound 1 (2S,6R)-4-(3-chlorophenyl)-2,6-dimethyl-piperidin-4-ol) (1)

C13 1

A THF solution of bromo-(3-chlorophenyl)magnesium (3.2 mL of 0.5 Μ, T60 mmol) was diluted with THF (4.8 mL) and then cooled to 0 °C. To this solution was added (25,6/()-2,6dimethylpiperidin-4-one (C13) (100 mg, 0.786 mmol) as a solution in THF (2 mL), and the reaction was stirred at 0 °C for 1 hour and then warmed to room température and stirred for 3 hours. At this time, the mixture was quenched with water (5 mL) and diluted with DCM (5 mL). The aqueous layer was extracted with additional DCM (3x5 mL). The combined organic layer was passed over a phase separator and concentrated in vacuo. The crude residue was purified by silica gel chromatography (Gradient: 0-20 % MeOH in DCM) to yield the title compound 1 as a -3:1 mixture of diastereomers. The oil was then repurified by silica gel chromatography (Gradient: 0-20 % MeOH in DCM) to yield the purified title Compound 1 (60.5 mg, 30%) as a yellow solid. 'H NMR (300 MHz, Chloroform-t7) δ 7.70 - 7.14 (m, 4H), 3.22 (ddd, J = 11.2, 6.1, 2.3 Hz, 2H), 1.80 - 1.68 (m, 2H), 1.64 - 1.48 (m, 2H), 1.13 (d, J = 6.4 Hz, 6H). ESl-MS m/z cale. 239.1077, found 240.09 (M+H)⁺.

148

Compound 2 4-(3-chlorophenyl)-2-methyl-6-[l-(2~methylsulfonylethyl)pyrazol-4-yl]piperidin-4-oî (2)

O

bromo-(3-chlorophenyl)magnesium

THF, 0 °C

Compound 2 was prepared from compound S3 following the method described for

Compound 1. The reaction was purified by silica gel chromatography (Gradient: 0-20 % MeOH in DCM) and then reversed-phase HPLC (Method: Waters XSelect CSH C18 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: Acetonitrile in Water with 0.1% Trifluoroacetic Acid) to afford the title Compound 2 (2.0 mg, 2%) as a yellow solid. 'H NMR (300 MHz, Methanol-i/4) Ô 7.74 (s, 1 H), 7.62 (s, ! H), 7.56 (t, J = 2.0 Hz, 1 H), 7.33 (t, J = 7.8 Hz, 1 H), 7.50 10 7.13 (m, 2H), 4.60 (t, J = 6.5 Hz, 2H), 4.32 (dd, J = 11.4, 3.4 Hz, 1H), 3.67 (t, J = 6.5 Hz, 2H),

3.47 - 3.34 (m, 1 H), 2.73 (s, 3H), 2.07 - 1.86 (m,2H), 1.84- 1.59 (m, 2H), 1.19 (d, J = 6.4 Hz, 3H). ESI-MS m/z cale. 397.12268, found 398.26 (M+H)⁺.

Compound 3 (2S,4R,6S)-4-(3-chlorophenyl)-2-methyl-6-(l~methyItriazol-4-yl)piperidiri-4-ol) (3)

bromo-(3-chlorophenyl)magnesium

THF, 0 °C

Compound 3 was prepared from compound SI following the method described for

Compound 1. The reaction mixture was purified by reversed-phase HPLC (Method: Waters

149

XSelect CSH Cl8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: Acetonitrile in Water with 10 mM Ammonium Hydroxide) to afford the title Compound 3 (2 mg, l%) as a yellow solid. 'H NMR (300 MHz, Methanol-iW) ô 7.85 (s, IH), 7.62 - 7.50 (m, 2H), 7.46 - 7.28 (m, 2H), 4.10 (s, 3H), 3.84 (dd, J = 12.3, 2.4 Hz, l H), 2.85 - 2.73 (m, 2H), 2.55 (dt, J = 13.4, 2.5 Hz, l H), 1.98 - 1.84 (m, IH), 1.60 (dd, J = 13.4, 11.8 Hz, 1 H), 1.19 (d, J = 6.3 Hz, 3H). ESI-MS m/z cale. 306.12473, found 307.32 (M+H)⁺.

Compound 4 (2S,4S,6S)-4d4-chlorophenyl)-2-inethyl-6-(l-meihyltria-ol-4-yl)pipetïdin-4-ol (4)

i. bromo-(4-chlorophenyl)magnesium THF, -20 °C ii. Pd₂(dba)₃ 4-diphenylphosphanylbutyl(diphenyl)phosphane (dppb) 2-sulfanylbenzoic acid THF

To a mixture of compound S2(100 mg, 0.4268 mmol) in THF (2 mL) was added a diethyl ether solution of bromo-(4-chlorophenyl)magnesium (1 mL of 1 Μ, 1.000 mmol) at -20 °C (1:15). After addition, UPLC was obtained, which indicated complété conversion. The mixture was quenched with saturated aqueous ammonium chloride and then warmed to room température. The suspension was diluted with water (1 mL) and ethyl acetate (4 mL). The aqueous layer was washed with additional ethyl acetate (2x2 mL), and the combined organic layer was passed over a phase separator, concentrated, and minimally diluted in DCM and loaded onto a silica gel column for purification (Gradient: 0-10% MeOH in DCM) to afford the intermediate.

In an inert glovebox, to a mixture of Pd2(dba)3 (4 mg, 0.004368 mmol) and dppb (5 mg, 0.01172 mmol) in THF (0.5 mL) was added 2-sulfanylbenzoic acid (30 mg, 0.1946 mmol). The mixture was stirred under argon for 10 minutes (9:30). At this time, to the mixture was added the intermediate (60 mg, 0.1730 mmol) in THF ( 1 mL), and the reaction was stirred at room température for 20 minutes. At this time, the reaction was diluted with TBME (6 mL) and 1 M HCl (5 mL). The layers were mixed, and the organic layer was removed and extracted with 1 M HCl (5 mL). The organic layer was removed, and the combined aqueous layer was filtered through a 0.45 micron filter, washed with additional TBME (5 mL), pH adjusted with a combination of saturated aqueous sodium bicarbonate and 6 M NaOH until pH -11. The hazy

150 mixture was then extracted with DCM (3 x 5 mL), and the combined organic layer was passed over a phase separator and concentrated to yield the title Compound 4 (37.5 mg, 65%) as a pale yellow oil. 'H NMR (300 MHz, Chloroformé) δ 7.50 - 7.43 (m, 2H), 7.41 (s, l H), 7.32 - 7.26 (m, 2H), 4.51 (dd, J = 9.6, 4.8 Hz, l H), 4.03 (s, 3H), 3.79 - 3.68 (m, l H), 3.38 (dtd, J = 12.6, 6.3, 2.7 Hz, IH), 2.07- 1.92 (m, 2H), 1.88 - I.75 (m, 2H), I.59 (dd, J = 13.6, 11.2 Hz, IH), l.l4(d, J = 6.3 Hz, 3H). ESI-MS m/z cale. 306.12473, found 307.15 (M+Hf.

Compound 5 (2S,4S,6S)-2-methyl-6-( l-methyllriazol-4-yl)-4-(p-tolyl)piperidin-4-ol (5)

i. bromo(p-tolyl)magnesium LaCI₃*LiCI THF, 0 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Compound S2 (20 mg, 0.08536 mmol) was diluted with a THF solution of chlorolithium;trichlorolanthanum (145 pL of 0.6 M, 0.0870 mmol) and cooled to -20 °C. At this time, bromo(p-tolyl)magnesium (200 pL of 1 M, 0.200 mmol was added at -20 °C (1:15). After addition, LJPLC was obtained, which indicated complété conversion. The mixture was quenched with saturated aqueous ammonium chloride (2 mL) and ethyl acetate (2 mL) and then warmed to room température. The aqueous layer was extracted with additional ethyl acetate (2x2 mL), and the combined organic layer was dried with magnésium sulfate, filtered, and concentrated in vacuo. The crude residue was used in the next step without further purification.

The crude mixture was diluted with THF (0.2 mL), and 2-sulfanylbenzoic acid (14 mg, 0.09080 mmol) was added. In an inert glovebox, a solution of dppb (2 mg, 0.004690 mmol) and Pd2(dba)₃ (2 mg, 0.002184 mmol) in THF (0.2 mL) was prepared and, after 5 minutes of mixing, the light brown mixture was added to the intermediate mixture and the formed solution was stirred for 5 minutes. At this time, the reaction was diluted with ethyl acetate ( 1 mL) and 1 M TFA (2 x 0.75 mL). The aqueous layer was combined and purified by reversed-phase HPLC (Method: Waters XSelect CSH Cl8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 0.1% Trifluoroacetic Acid). The title Compound 5 (8.3 mg, 24%) was isolated as a clear amorphous solid 'H NMR (400 MHz, DMSO-r/6) 5 9.27 (s, IH),

151

8.89 (s, IH), 8.24 (s, IH), 7.38 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 5.65 (s, IH), 4.79 (d, J = 10.9 Hz, l H), 4.09 (s, 3H), 3.72 (s, l H), 2.40 (t, J = 13.3 Hz. I H), 2.29 (s, 3H), 2.07 (d, J = 13.9 Hz, l H), 2.03 - l .85 (ni, 2H), l.28(d, J =6.5 Hz, 3H).

ESI-MS m/z cale. 286.17935, found 287.36 (M+Hf.

Compound 6 (2S, 4S. 6S)-2-methyl-6-(/ -mediyltriazoî-4-yl)-4-(m-tolyl)piperidin-4-ol (6)

i. bromo(m-tolyl)magnesium LaCI₃*LiCI THF, 0°C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Compound 6 was synthesized from compound S2 following the method described for Compound 5, with purification by reversed-phase HPLC (Method: Waters XSelect CSH Cl8

OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 0.1% Trifluoroacetic Acid) to afford the title Compound 6 (8.3 mg, 24%) as a white solid. 'H NMR (400 MHz, DMSO-ί/ό) δ 9.28 (s, IH), 8.88 (s, 1 H), 8.24 (s, IH), 7.30 (d, J = 10.4 Hz, 3H), 7.10 (t. J = 4.1 Hz, IH), 5.67 (s, IH), 4.81 (d, J = 11.7 Hz, 1 H), 4.09 (s, 3H), 3.72 (s, IH), 2.42 (t, J = 13.4 Hz, IH), 2.33 (s, 3H), 2.13-2.00(m, IH), 1.93 (dd, J = 27.8, 13.0 Hz, 2H), 1.29 (d, J = 6.5

Hz, 3H). ESI-MS m/z cale. 286.17935, found 287.32 (M+H)\

Compound 7 (2S, 4S, 6S)-2-methy!-6-(1 -methyltriazol-4-yl)-4-(phenyl)piperÎdm-4-ol (7)

i. bromo(phenyl)magnesium LaCI₃*LiCI THF, 0 °C

ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid

THF

Compound 7 was synthesized from compound S2 following the method described for

152

Compound 5, with purification by reversed-phase HPLC (Method: Watcrs XSelect CSH Cl 8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 0.1% Trifluoroacetic Acid) to afford the title Compound 7 (8.9 mg, 25%) as a white solid. 'H NMR (400 MHz, DMSO-î/6) δ 9.29 (s, 1H), 8.91 (s, 1H), 8.25 (s, III), 7.50 (d, J = 7.7 Hz, 2H), 7.40 (t, J - 7.6 Hz, 2H), 7.30 (d, J = 7.3 Hz, 1 H), 5.72 (s, 1 H), 4.82 (s, 1 H), 4.09 (s, 3H), 3.74 (s, 1 H), 2.43 (t, J = 13.3 Hz, 1 H), 2.09 (d, J = 14.1 Hz, I H), 2.05 - 1.95 (m, 1H), 1.91 (d, J = 14.0 Hz, 1H), 1.29 (d, J = 6.5 Hz, 3H). ESI-MS m/z cale. 272.1637, found 273.32 (M+H)’.

Compound 8 (2S. 4S, 6S)-4-(4-isopropylphenyl)-2-methyl-6-( 1 -niethyltriazol~4-vl)piperidin-4-ol (8)

i. To a solution of compound S2 (80 mg, 0.3414 mmol) in THF (0.4 mL) was added a THF solution of chlorolithium;trichlorolanthanum (580 pL of 0.6 M, 0.3480 mmol), and the mixture was cooled to -20 °C. At this time, bromo-(4-isopropylphenyl)magnesium ( 1.2 mL of 0.5 M, 0.6000 mmol) was added at -20 °C. After 10 minutes, the mixture was quenched with saturated aqueous ammonium chloride (0.1 mL) and then warmed to room température. The suspension was diluted with water (2 mL) and EtOAc (2 mL), extracted with EtOAc (2x2 mL), dried over Na?SO4, filtered, and concentrated in vacuo to yield a crude residue.

ii. The crude mixture was diluted with THF (0.4 mL), and 2-sulfanylbenzoic acid (56 mg, 0.3632 mmol) was added. In a glovebox, a solution of dppb (4 mg, 0.009379 mmol) and Pd?(dba)3 (4 mg, 0.004368 mmol) was prepared and, after 30 minutes of mixing, the light brown mixture was added to the in ter médiate solution. The mixtures were stirred. After 30 minutes, full conversion was observed. The mixture was diluted with TBME (5 mL), followed by 1 M HCl (2 x 5 mL). The aqueous layer was removed and combined and then pH adjusted with aqueous NaOH (6 Μ, 1.7 mL) followed by saturated aqueous ammonium chloride to achieve pH ~9. The mixture was diluted and extracted with TBME (3x10 mL), and the combined organic layer was filtered through a phase separator and concentrated to a crude residue, which was purified by

153 reversed-phase HPLC (Method: Waters XBridge Prcp C8 Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 10 mM Ammonium Hydroxide) to afford the title Compound 8 (23 mg, 21%) as a white solid. 'H NMR (400 MHz, Chlorofomi-J) δ 7.49 - 7.38 (m, 3H), 7.23 (d, J = 8.3 Hz, 2H), 4.53 (p, J = 7.0 Hz, IH), 4.05 (s, 3H), 3.47 - 3.34 (m, l H), 2.90 (hept, J = 6.9 Hz, IH), 2.H -2.05 (m, 2H), 1.89- l.63(m,3H), 1.25 (d, J = 7.0 Hz, 6H), Ll6(d, J = 6.3 Hz, 3H). ESI-MS m/z cale. 314.21066, found3l5.32 (M+Hf.

Compound 9 (2S,4S,6S)-4-(3-chloro-4-fhioro-phenyb-2-methyl-6-(l-methyltriazol-4-yl)piperidin-4-ol (9)

i. 4-bromo-2-chloro-1-fluoro-benzene iPrMgChLiCl, THF, -20 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

S2

i. A mixture of 4-bromo-2-chloro-l-fluoro-benzene (54 mg, 0.258 mmol) was diluted in THF (0.25 mL). To the mixture coolcd to -20 °C was added Turbo Grignard (200 pL of 1.3 M, 0.260 mmol). The mixtures were stirred for 30 minutes (11:00), at which time a THF (0.25 mL) solution of compound S2 (20 mg, 0.0854 mmol) was added and the réactions were stirred for 45 minutes. At this time, saturated aqueous ammonium chloride was added, and the mixture was diluted with ethyl acetate (2 mL) and separated. The aqueous layer was extracted with additional ethyl acetate (2 mL), and the combined organic layer was passed over a phase separator, concentrated, and used in the next step directly.

ii. A mixture of Pdzfdba)} (2 mg, 0.00218 mmol) and 4-diphenylphosphanylbutyl (diphenyl)phosphane (2 mg, 0.00469 mmol) in THF (0.25 mL) was stirred at room température under argon for 15 minutes. At this time, the intermediate from step i, (2S,4S,6S)-l-allyl-4-(3chloro-4-fluorophenyl)-2-methyl-6-( 1 -methyl-1 H-1,2,3-triazol-4-yl)piperidin-4-ol, and 2sulfanylbenzoic acid (15 mg, 0.0973 mmol) in THF (0.25 mL) was added and the mixture was stirred for 10 minutes. The reaction was extracted with 1 M HCl (2 x 750 pL) and directly purified by reversed-phase HPLC. (Method: Waters XSelect CSH Cl8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 5 mM Hydrochloric Acid.) The title Compound 9 was isolated as a white solid. (7.6 mg, 23%) 'H NMR (300 MHz, Methanold4) Ô 8.08 (s, 1 H), 7.68 (dd, J = 7.1, 2.4 Hz, 1 H), 7.50 (ddd, J = 8.7, 4.5, 2.4 Hz, 1 H), 7.27 (t, J =

154

8.9 Hz, IH), 4.96 (dd, J = 12.5, 3.I Hz, IH), 4.13 (s, 3H), 3.98 - 3.81 (m, IH), 2.51 (dd, J = I4.5, 12.5 Hz, IH), 2.23 (d, J = 14.3 Hz, l H), 2.08- 1.97 (m, 2H), 1.42 (d, J = 6.6 Hz, 3H). ESI-MS m/z cale. 324.11533, found 325.34 (M+H)*.

Compound 10 (2S,4S,6S)-4-(3-chloro-4-fluoro-phenyl)-2-niethyl-6-(l-methyltria~ol-4-yl)piperidin-4-ol (10)

i. 3-bromo-5-chloro-1 -fluoro-benzene iPrMgCFLiCI, THF, -20 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

i. A mixture of l-bromo-3-chloro-5-fluoro-benzene (67 mg, 0.320 mmol) was diluted in THF (0.25 mL). To the mixture cooled to -20 °C was added Turbo Grignard (250 pL of l .3 M, 0.325 mmol) followed by diglyme (50 pL, 0.349 mmol). The mixtures were stirred for 30 minutes, at which time a THF (0.25 mL) solution of compound S2 (25 mg, 0.107 mmol) was added and the reactions were stirred for 45 minutes. At this time, saturated aqueous ammonium chloride was added, and the mixture was diluted with ethyl acetate (2 mL) and separated. The aqueous layer was extracted with additional ethyl acetate (2 mL), and the combined organic layer was passed over a phase separator, concentrated, and used in the next step directly.

ii. A mixture of Pd₂(dba)3 (2.5 mg, 0.00273 mmol) and 4-diphenylphosphanylbutyl (diphenyl)phosphane (2.5 mg, 0.00586 mmol) in THF (0.25 mL) was stirred at room température under argon for 15 minutes. At this time, the intennedîate and 2-sulfanylbenzoic acid ( 18 mg, 0.117 mmol) in THF (0.25 mL) were added, and the mixture was stirred for 10 minutes. The reaction was extracted with 1 M HCl (2 x 750 pL) and directly purified by reversed-phase HPLC. (Method: Waters XSelect CSH Cl8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: Acetonitrile in Water with 5 mM Hydrochloric Acid.) The title Compound 10 was isolated as a white solid (17 mg, 43%). 'H NMR (300 MHz, Methanol-t/4) δ 8.08 (s, IH), 7.68 (dd, J = 7.1,2.4 Hz, IH), 7.50 (ddd, J = 8.7, 4.5, 2.4 Hz, IH), 7.27 (t, J = 8.9 Hz, IH), 4.96 (dd, J = 12.5,3.1 Hz, IH), 4.13 (s, 3H), 3.98 - 3.81 (m, IH), 2.51 (dd, J = 14.5, 12.5 Hz, IH), 2.23 (d, J = 14.3 Hz, I H), 2.08 - 1.97 (m, 2H), 1.42 (d, J = 6.6 Hz, 3H). ESI-MS m/z cale. 324.781, found 325.29 (M+H)⁺.

Compound 11

155 (2S,4S,6S)-4-(3-fhioro-4-methyl-phenyl)-2-methyl-6-(l-melhyltriazol-4-yl)piperidin-4-ol (11)

i. 2-fluoro-4-iodo-1 -methyl-benzene iP^gOI-LiCI, diglyme, THF, -20 °C ---------------------------------------------------------->.

ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Compound 11 was synthesized from compound S2 following the method described for Compound lü. Purification by reversed-phase HPLC (Method: Waters XSelect CSH C18 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 5 mM Hydrochloric Acid) afforded the titlc Compound 11 (18.3 mg, 50%) as a white solid. 'H NMR (400 MHz, DMSO-i/6) δ 9.46 -9.18 (m, 2H), 8.32 (s, 1 H), 7.30 (t, J = 8.0 Hz, 1 H), 7.27 -7.14 (m, 2H), 5.80 (s, 1 H), 4.77 (t, J = 11.2 Hz, 1 H), 4.09 (s, 3H), 3.70 (s, 1 H), 2.46 (s, 1 H), 2.22 (d, J - 1.7 Hz, 3H), 2.08 (t, J= 13.3 Hz, 2H), 1.88 (d, J = 14.1 Hz, 1H), 1.31 (d, J = 6.4 Hz, 3H). ESIMS m/z cale. 304.363, found 305.34 (M+H)⁴.

Compound 12 (2S.4S, 6S)-4-(4-Jhioro-3-methyl-phenyl)-2-methyl-6-(l-meihyltriazol-4-yl)piperidin-4-ol (12)

i. 1 -fluoro-4-iodo-2-methyl-benzene iPrMgCI-LiCI, diglyme, THF, -20 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid

THF

Compound 12 was synthesized from compound S2 following the method described for Compound 10. Purification by reversed-phase HPLC (Method: Waters XSelect CSH CI8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: Acetonitrile in Water with 5 mM Hydrochloric Acid) afforded the title Compound 12 (4.6 mg, 12%) as a white solid. ’H NMR (400 MHz, DMSO-î/6) δ 9.37 (s, 2H), 8.34 (s, IH), 7.43-7.31 (m, 2H), 7.31 -7.05 (m, 2H), 5.71 (s, 1H), 4.76 (t, J = 11.2 Hz, 1 H), 4.09 (s, 3H), 3.69 (s, 1 H), 2.25 (d, J = 1.9 Hz, 3H), 2.08 (t, J = 15.7 Hz,

156

2H), 1.88 (d, J = 13.9 Hz, IH), 1.31 (d, J = 6.4 Hz, 3H). ESI-MS m/z cale. 304.363, found 305.34 (M+Hf.

Compound 13 (2S, 4S, 6S)-4-(4-fhioro-3-methyl-phenyl)-2-methyl-6-(l-methyltriazol-4-yl)piperidin-4-ol ( 13)

i. 4-bromo-1-chloro-2-fluoro-benzene iPriyigCI-LiCI, diglyme, THF, -20 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Compound 13 was synthesized from compound S2 following the method described for Compound 10. Purification by reversed-phase HPLC (Method: Waters XSelect CSH Cl8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 5 mM Hydrochloric Acid) afforded the title Compound 13 (23 mg, 59%) as a white solid. 'H NMR (300 MHz, Methanol-rW) ô 8.12 (s, 1H), 7.54 - 7.41 (m, 2H), 7.36 (dd, J = 8.5, 2.2 Hz, 1H), 4.97 (dd,J= 12.5,3.1 Hz, 1H), 4.13 (s, 3H), 3.97 - 3.82 (m, 1H), 2.55 (dd, J = 14.5, 12.6 Hz, 1H), 2.22 (d, J = 13.8 Hz, 1 H), 2.11 -2.01 (m, 2H), 1.43 (d, J = 6.6 Hz, 3H). ESI-MS m/z cale. 324.781, found 325.29 (M+H)⁺.

Compound 14 (2S,6S)-2-methyl-6-( 1 -methyltriazol-4-yl)-4-[5-(trifluoromethyl)-3-thienyl]piperidin-4-ol (14)

i. 4-bromo-2-(trifluoromethyl)thiophene iPrMgCI’LiCI, diglyme, THF, -20 °C - ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Compound 14 was synthesized from compound S2 following the method described for Compound 10. Purification by reversed-phase HPLC (Method: Waters XSelect CSH C18 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: Acetonitrile in Water with 5 mM Hydrochloric Acid) afforded the title Compound 14 (21 mg, 51%) as a white solid. ESI-MS m/z cale. 346.371,

157 found 347.28 (M+H)’.

Compound 15 (2S,4S,6S)-4-(4-fhiorophenyl)-2-methyl-6-(l-niethylbïazol-4-yl)piperidin-4-ol (15)

i. 1-fluoro-4-iodo-benzene iPrMgCI-LiCI, diglyme, THF, -20 °C ti. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Compound 15 was synthesized from compound S2 following the method described for

Compound 10. Purification by reversed-phase HPLC (Method: Waters XSelect CSH Cl 8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 5 mM Hydrochloric Acid) afforded the title Compound 15(17 mg, 46%) as a white solid. 'H NMR (400 MHz, DMSO-ί/ά) δ 9.47 (d, J = 10.1 Hz, IH), 9.18 (d, J = 10.2 Hz, IH), 8.28 (s, IH), 7.79 10 7.61 (m, IH), 7.36 (dt. J= 11.0, 5.4 Hz, 1 H), 7.30 - 7.08 (m, 2H), 6.02 (s, 1 H), 4.82 (t, J = 11.4

Hz, IH), 4.09 (s, 3H), 3.75 (s, 1 H), 2.70 (t, J = 13.3 Hz, IH), 2.24 (t, J = 13.1 Hz, IH), 2.10 (d, J = 14.0 Hz, IH), 1.91 (d, J = 13.9 Hz, IH), 1.30 (d, J = 6.5 Hz, 3H). ESI-MS m/z cale. 290.336, found 291.34 (M+H)⁺.

Compound 16 (2S,4S,6S)-2-melhyl-6-(l-methyltriazoî-4-yl)-4-l4-(trifluoromethyl)phenyl]pipendm-4-ol (16)

i. 1-bromo-4-(trifluoromethyl)benzene tBuLi, THF, -78 °C ii, Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Step z. A THF (10 mL) solution of l-bromo-4-(trifluoromethyl)benzene (600 pL, 4.285 mmol) was cooled to -78 °C. At this time, a pentane solution of tBuLi (5 mL of 1.7 M, 8.500 mmol) was added dropwise over 20 minutes, and the yellow suspension was stirred at this

158 température for 30 minutes. At this time, a THF solution of compound S2 (5 mL of 0.427 M, 2.135 mmol) was added dropwise over 20 minutes. After 30 minutes, the reaction was quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL) and water (10 mL). The aqueous layer was extracted with additional ether (20 mL), and the combined organic layer was washed with brine (20 mL), dried with magnésium sulfate, filtered, and concentrated. The crude material was minimally dissolved in DCM and loaded onto a silica gel column for purification (Gradient: 0 - 10% MeOH in DCM). The product-containing fractions were pooled and concentrated. The sequence was repeated twice more and combined for the next step, about 60% yicld per reaction.

Alternative Préparation oj Step i:

O

N

i. 1 -bromo-4-(tnfluoromethyl)benzene Mg, diglyme. THF ii. Pd₂(dba)₃ dppb, 2-sulfanylbenzoic acid, THF

To a suspension of magnésium ( l .712 g, 70.44 mmol) in THF ( 100 mL) under nitrogen atmosphère was added one drop of L2-dibiOmocthanc followed by l-bromo-4(trifluoromethyl)benzene (14.88 g, 66.13 mmol). The mixture was sonicated for 5 minutes and allowed to stir at ambient température for l hour. The solution was cooled to -10 °C to - 15 °C via sait ice bath, and diglyme (3.123 mL, 2l.8l mmol) was added, followed by a THF solution of (2S,6S)-l-allyl-2-methyl-6-(]-methyltriazol-4-yl)piperidin-4-one (49.98 mL of 0.427 M, 21.34 mmol), dropwise. Stirring was continued for 45 minutes. The mixture was quenched with water (50 mL) and pH adjusted to pH -9 with ammonium chloride (50 mL), extracted with ether (2 x 100 mL), and the organic layer was washed with brine (50 mL) and dried with magnésium sulfate, filtered, and concentrated. The concentrate was minimally diluted in DCM and loaded onto a silica gel column for purification (Gradient: 0 - 10% MeOH in DCM). The productcontaining fractions were pooled and concentrated to yield (2S,4S,6S)-l-allyl-2-methyl-6-( lmethyltriazol-4-yl)-4-[4-(trifluoromethyl)phenyl]piperidin-4-ol (4.350 g, 51%) ESI-MS m/z cale. 380.1824, found 381.2 (M+H)* as an off-white solid, which was used in the next step.

Step ii: To the intermediate ( 1.756 g, 4.496 mmol) diluted with THF (5 mL) was added 2-sulfanylbenzoic acid (740 mg, 4.607 mmol). In an inert glovebox, a solution of dppb (20 mg, 0.04690 mmol) and Pd₂(dba)₃ (20 mg, 0.02184 mmol) in THF (5 mL) was prepared and, after 10

159 minutes of mixing, the light brown solution was added to the previous mixture. The newly formed brown solution was stirred for 35 minutes. At this time, the mixture was diluted with TBME (30 mL), followed by l M HCl (2 x 20 mL). The aqueous layer was removed and combined and then pH adjusted with aqueous NaOH (7.4 mL of 6 M, 44.40 mmol), followed by -l mL saturated aqueous ammonium chloridc to achicvc pH -9. The mixture was diluted and extracted with TBME (3 x 20 mL), and the combined organic layer was dried with brine (20 mL) that was pH adjusted with saturated aqueous ammonium chloride to pH -9. The organic layer was dried with magnésium sulfate, and to the suspension was added MP-TMT resin (350 mg, 0.66 mmol/g) and the suspension was stirred for 2 hours, and then fïltered and concentrated. The foam was diluted in 30 mL TBME and to the yellow solution was added a dioxane solution of HCl ( l .2 mL of 4 M, 4.800 mmol) dropwise, which immediately resulted in a loss of color in the mixture and a white precipitate. The suspension was stirred for 3 minutes and then fïltered, rinsed with additional TBME, and dried for 3 days at 70 °C to yield the title Compound 16 (1.463 g, 84%) as an off-white solid. 'H NMR (300 MHz, MethanoI-i/4) Ô 7.85 (s, IH), 7.72 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 4.49 (dd, J = 9.1, 5.5 Hz, 1 H), 4.08 (s, 3H), 3.40 (dtd, J = 12.9,6.5,2.9 Hz, 1 H), 2.14 - 2.02 (m, 2H), 1.86 - 1.76 (m, IH), 1.67 (dd, J = 13.6, 11.2 Hz, IH), 1.19 (d, J = 6.4 Hz, 3H). ESI-MS m/z cale. 340.1511, found 341.14(M+H)\

Préparation and Characterization of Compound 16 Form A:

To (25,45,65)-1-allyl-2-methyl-6-( I-methyltriazol-4-yl)-4-[4-(trifluoiOmethyl) phenyl]piperidin-4-ol (1.534 g, 3.928 mmol) diluted with THF (4.365 mL) was added 2sulfanylbenzoic acid (646.0 mg, 4.022 mmol). In an inert glovebox, a solution of dppb (17.47 mg, 0.04096 mmol) and Pd^dbaj (17.47 mg, 0.01908 mmol) in THF (4.365 mL) was prepared and after 10 min of mixing the light brown solution was added to the previous mixture. The newly formed brown solution was stirred for 35 min. At this time, the mixture was diluted with TBME (30 mL) followed by 1 N HCl (2 x 20 mL). The aqueous layer was removed and combined and then pH adjusted with aqueous NaOH (6.463 mL of 6 M, 38.78 mmol) followed by — 1 mL sat. aq. ammonium chloride to achieve pH ~9. The mixture was diluted and extracted with TBME (3 x 20 mL), and the combined organic layer was dried with brine (10 mL) that was pH adjusted with sat. aq. ammonium chloride to pH -9. The organic layer was dried with magnésium sulfate, and fïltered through a pad of Florisil and slowly rotovated while allowing for crystallization to a dense white solid.

Material was diluted in MTBE to homogenize, and then slowly concentrated while observîng a dense white solid precipitating out of solution. The resulting white solid was dried in vacuum oven ovemight at 60 °C.

160

X-Ray Powder Diffraction

The X-ray powder diffraction (XRPD) diffractogram of Compound 16 Form A was acquired at room température in transmission mode using a PANaiytical Empyrean System equipped with a sealed tube source and a PIXcel 3D Medipix-3 detector (Malvern PANaiytical Inc, Westborough, Massachusetts). The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation ( l .54060 Â). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 40°2θ with a step size of 0.0131303° and 49s per step. The results arc depicted in FIG. I and the table below:

XRPD Pcaks	Angle (°20 ±0.2)	Intensity %	XRPD Peaks	Angle (°20 ±0.2)	Intensity %
1	19.9	100.0	10	26.1	15.8
2	20.0	60.3	11	23.8	15.0
3	10.9	28.5	12	21.7	14.4
4	20.6	26.6	13	18.2	14.4
5	20.5	24.0	14	23.3	13.3
6	16.1	20.4	15	26.2	12.9
7	17.5	19.6	16	14.1	12.9
8	19.3	19.6	17	21.4	10.9
9	22.8	16.9	18	15.4	10.1

Thermogravimetric analysis (TGA):

Thermal gravimétrie analysis of Compound 16 Form A was measured using the TA5500 Discovery TGA. A sample with a weight of approximately 1-10 mg in a open platinum pan. The program was set to heat from ambient at a heating rate of 10° C per min to 350 °C with nitrogen purge. The TGA thermogram shows minimal weight loss from ambient until 250 °C. The TGA thermogram is shown as FIG. 2.

Differential Scanning Calorimetry Analysis (DSC):

DSC analysis of Compound 16 Form A was measured using the TA Instruments TA2500 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the référencé position. The calorimeter cell was closed, and a flow of nitrogen was passed through the cell. The program was set with a heat rate at 10 °C per min to a température of 250 °C. The thermogram (FIG. 3) shows one endotherm peak at 147 °C.

161

Solid State NMR

A Bruker-Biospin 400 MHz wide-bore spectrometer equipped with Bruker-Biospin 4mm HFX probe was used. Samples were packed into 4mm ZrO? rotors and spun under Magic Angle Spinning (MAS) condition with spinning speed typically set to 12.5 kHz. The proton relaxation time was measured using 'H MAS Tj saturation recovery relaxation experiment in order to set up proper recycle delay of the ^l3C cross-polarization (CP) MAS experiment. The fluorine relaxation time was measured using ^l9F MAS Ti saturation recovery relaxation experiment in order to set up proper recycle delay of the ^l9F MAS experiment. The CP contact time of carbon CPMAS expcrimcnts was set to 2 ms. A CP proton puise with linear ramp (from 50% to 100%) was employed. The carbon Hartmann-Hahn match was optimized on extcmal reference sample (glycine). Carbon and fluorine spectra were recorded with proton decoupling using TPPM15 decoupling sequence with the field strength of approximately 100 kHz. The results are shown in FIG. 4 (¹³C CPMAS) and in the tables below:

^l3C CPMAS SSNMR

Peak #	Chem Shift [ppm]	Intensity [rel]
1	153.5	3.57
2	151.5	5.83
3	126.9	3.7
4	125.1	1.05
5	123.9	0.95
6	122.1	5.34
7	73.6	6.95
8	49.9	10
9	47.2	3.72
10	37.2	9.7
11	23.0	7.77

19F SSNMR

Peak #	Chem Shift [PPm]	Intensity [rel]
1	-58.0	10

162

Single Crystal Elucidation:

Single crystals having the Compound 16 Form A structure were grown from DVS cyclîng experiment at room température (25 ± 2 °C) from 0%-95%-0% Relative Humidity. X-ray diffraction data were acquired at 100 K on a Broker diffractometer equipped with Cu K_u radiation (λ=1.54178 Â) and a CMOS detector. The structure was solved and refined using SHELX programs (Sheldrick, G.M., Acta Cryst., (2008) A64, 112-122) and results are summanzed below.

Single crystal élucidation of Compound 16 Form A at 100 K

Crystal System	Orthorhombic
Space Group	P212121
a(Â)	5.02810(10)
b(Â)	9.0057(2)
c (Â)	34.4600(8)
a(°)	90
β(°)	90
γ(°)	90
V(Â3)	1560.40(6)
Z/Z'	4/1
Température	100K

Single crystal élucidation of Compound 16 Form A at 298 K

Crystal System	Orthorhombic
Space Group	P212121
a(Â)	5.11990(10)
b (Â)	9.1779(2)
c (Â)	34.4956(8)
a(°)	90
β (°)	90
γ(°)	90

163

v (A3)	1620.95(6)
Z/Z'	4/1
Température	298K

Compound 17 (2S.4S,6S)-4 -(6-chloro-3-pyridyl)-2-methy 1-6-(1 -methyltriazol-4-yl)piperidin-4-ol (17)

Cl

i. 5-bromo-2-chloro-pyridine II hexyllithium, THF, -78 °C

JS' '' Pd₂(dba)_3N ^N J L *P^b N fl N '

N \ 2-sulfanylbenzoic acid ¹ II THF/

S217

Step i: A mixture of 5-bromo-2-chloro-pyridine (38 mg, 0.198 mmol) in THF (0.2 mL) was cooled to -78 °C. At this time, hexyllithium (85 pL of 2.3 M, 0.196 mmol) was added, and the mixture was stirred at this température for 15 minutes. The reaction turned blue within 5 minutes. At this time, a THF solution of compound S2 (0.2 mL of 0.5 M, 0.100 mmol) was added over 30 seconds. After 5 minutes, the mixture was diluted with saturated aqueous ammonium chloride (2 mL) and ethyl acetate (2 mL). The aqueous layer was extracted with additional ethyl acetate (2x2 mL), and the combined organic layer was dried with magnésium sulfate, filtered, concentrated, and minimally diluted in DCM and loaded onto a silica gel column for purification (0 - 10% MeOH in DCM). Two spots were isolated, correlating to the major and minor diastereomers. The product containing fractions were pooled and concentrated.

Step ii: The intermediate was diluted with THF (250 pL), and 2-sulfanylbenzoic acid (17 mg, 0.110 mmol) was added. In a glovebox, a solution of dppb (2 mg, 0.00469 mmol) and Pd?(dba)3 (2 mg, 0.00218 mmol) in THF (250 pL) was prepared and, after 5 minutes of mixing, the light brown mixture was added to the intermediate solutions. The mixtures were stirred (8:20). After 5 minutes, full conversion was observcd. The mixture was diluted and split with 1 M HCl (2 x 750 pL). The combined aqueous layer was pH adjusted with saturated aqueous sodium bicarbonate ( 1 mL), followed by extraction with DCM (3x5 mL). The organic layer was passed over a phase separator and concentrated to yield the title compound afford the title Compound 17 (7.6 mg, 16%) as a white solid. 41 NMR (300 MHz, Methanol-i/4) δ 8.55 (d, J = 2.6 Hz, 1H), 8.06 (s, 1H), 7.98 (dd, J = 8.4, 2.7 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.99 (d, J =

164

12.5 Hz, IH), 4.13 (s, 3H), 3.94 (s, l H), 2.58 - 2.45 (m, IH), 2.29 (d, J = 14.9 Hz. IH), 2.20 -

1.97 (m, 2H), 1.43 (d. J = 6.6 Hz, 3H). ESI-MS m/z cale. 307.12, found 308.32 (M+H)\

Compound 18 (2S,4S,6S)-4-(5-chloro-2-pyridvl)-2-methyl-6-(l-methyltriazol-4-yl)piperidin-4-ol (18)

i. 2-bromo-5-chloro-pyridine hexyllithium, THF, -78 °C it. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Compound 18 was synthesized from compound S2 following the method described for Compound 17. Purification by reversed-phase HPLC (Method: Waters XSelect CSH Cl8 OBD Prcp Column; 30 x 150 mm, 5 micron. Gradient: Acetonitrile in Water with 0.1 % trifluoroacetic acid) afforded the title Compound 18 (3.1 mg, 5%) as a clear oil. ’H NMR (300 MHz, Methanol10 d4) δ 8.54 (s, III), 8.04 (s, IH), 7.89 (d, J = 8.9 Hz, III), 7.75 (d, J = 8.7 Hz, III), 4.95 (d, J =

15.1 Hz, IH), 4.12 (s, 3H), 3.89 (s, IH), 2.79 - 2.66 (m, I H), 2.35 - 2.22 (m, IH), 2.17 (d, J = 14.9 Hz, IH), 1.99 (d, J = 13.7 Hz, IH), 1.41 (d, J = 6.5 Hz, 3H). ESI-MS m/z cale. 307.12, found 308.36 (M+H)'.

Compound 19 (2S,4S,6S)-4-(4~cidoro-3-methoxv-plienyl)-2-inetli\l-6-(l-methyltriaz()Î-4-yl)piperidin-4-ol (19)

O

S2

i. 4-bromo-1 -chloro-2-methoxy-benzene hexyllithium, THF, -78 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Compound 19 was synthesized from compound S2 following the method described for

Compound 17. Purification by reversed-phase HPLC (Method: Waters XSelect CSH Cl8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 0.1 %

165 trifluoroacetic acid) afforded the title Compound 19 (3.8 mg. 8%) as a clear oil. *H NMR (300 MHz, Methanol-ώ?) δ 8.06 (s, 1 H), 7.37 (d, J = 8.2 Hz, 111), 7.26 (s, 111), 7.05 (d, J = 8.5 Hz, 1 H), 4.97 (d, J = 12.3 Hz, 1 H), 4.13 (s, 3H), 3.92 (s, 4H), 2.57 - 2.45 (m, 1 H), 2.24 (d, J = 14.5 Hz, 1H), 2.05 (d, J = 10.6 Hz, 2H), 1.42 (d, J = 6.6 Hz, 3H). ESI-MS m/z cale. 336.135, found

337.30 (M+H)\

Compound 20 (2S,4S,6S)-4-(4-chloro-2-methoxy-phenyI)-2-methyl-6-(l-methyltriazol-4-yl)piperidin-4-ol (20)

i. 1 -bromo-4-chloro-2-methoxy-benzene hexyllithium, THF, -78 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

S2

Compound 20 was synthesized from compound S2 following the method described for

Compound 17. Purification by reversed-phase HPLC (Method: Waters XSelect CSH Cl8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: Acctonitrile in Water with 0.1 % trifiuoroacetic acid) afforded the title Compound 20 (7.3 mg, 16%) as a clear oil. 'H NMR (300 MHz, Methanol-i/4) δ 8.03 (s, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.07 (d, J = 1.8 Hz, 1H), 7.04 - 6.94 (m, 1 H), 4.96 (d, J = 12.7 Hz, 1H), 4.12 (s, 3H), 3.90 (s, 4H), 3.03 (s, 1 H), 2.65 - 2.52 (m, 1H),2.O3 (s, 1H), 1.88 (d, J = 14.4 Hz, 1H), 1.39 (d, J = 6.8 Hz, 3H). ESI-MS m/z cale. 336.135, found

337.35 (M+H)⁺.

Compound 21 (2S, 4S, 6S)-4f4-chloro-2-methyl-phenylE2~methyl-6-(l-methyltriazol-4-yl)piperidin-4-ol (21)

S2

i. 1 -bromo-4-chloro-2-methyl-benzene hexyllithium, THF, -78 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

166

Compound 21 was synthesized from compound S2 foliowing the method described for Compound 17. Purification by reversed-phase HPLC (Method: Waters XSelect CSH C18 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 0.1 % trifluoroacetic acid) afforded the title Compound 21 (3.8 mg, 9%) as a clear oil. 'H NMR (300

MHz, Methanol-^) δ 8.08 (s, 111), 7.42 (d, J = 8.5 Hz, 111), 7.23 (s, IH), 7.19 (d, J = 8.6 Hz, IH), 5.05 - 4.97 (m, 1 H), 4.14 (s, 3H), 3.96 (s, 1 H), 2.63 (s, 3H), 2.48 (dd, J = 21.7, 13.0 Hz, 2H), 2.29 (d, J = 14.3 Hz, l H), 2.10- 1.97 (m, IH), 1.42 (d, J = 6.6 Hz, 3H). ESI-MS m/z cale. 320.140, found 321.32 (M+H)\

Compound 22 (2S,4S,6S)-4-(4-chloro-2-fluoro-phenyl)-2-methyl-6-(l-methyltriazol-4-yl)piperidin-4-ol (22)

i. 1-bromo-4-chloro-2-f!uoro-benzene hexyltithîum, THF, -78 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Compound 22 was synthesized from compound S2 foliowing the method described for Compound 17. Purification by reversed-phase HPLC (Method: Waters XSelect CSH Cl8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 0.1 % trifluoroacetic acid) afforded the title Compound 22 (5.7 mg, 12%) as a clear oil. ^lH NMR (300 MHz, Methanol-i/4) δ 8.04 (s, 1 H), 7.69 (t, J = 8.6 Hz, 1 H), 7.34 (s, 2H), 4.99 (d, J = 12.2 Hz, IH), 4.12 (s, 3H), 3.92 (s, IH), 2.84 -2.72 (m, IH), 2.38 - 2.26 (m, IH), 2.20 (d, J = 14.5 Hz, 1 H), 2.03 (d, J = 14.6 Hz, I H), 1.40 (d, J = 6.6 Hz, 3H). ESI-MS m/z cale. 324.115, found 325.29 (M+H)⁺.

167

Compound 23 (2S,4S,6S)-4-(4-chloro-3-(trifhioromethoxy)pheHyl]-2-methyl6-(l-tnethyltriazol-4-yl)pipeiïdin-4-ol (23)

O

i. 4-bromo-1 -chloro-2-(trifluoromethoxy)benzene hexyllithium, THF, -78 °C ii. Pd₂(dba)₃ dppb 2-sulfany!benzoic acid THF

S2

Compound 23 was synthesized from compound S2 following the method described for Compound 17. Purification by reversed-phase HPLC (Method: Waters XSelect CSH C18 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 0.1 % trifluoroacetic acid) afforded the title Compound 23 (22.3 mg, 44%) as a white solid. ^lH NMR (300 MHz, Methanol-r/4) δ 8.06 (s, 1 H), 7.64 (s, 111), 7.62 (d, J = 8.7 Hz, 1 H), 7.52 (dd, J = 8.6,

2.1 Hz, 1 H), 4.98 (dd, J = 12.4,3.1 Hz, IH), 4.13 (s, 3H), 3.90 (p, J = 7.0, 6.5 Hz, IH), 2.52(dd,

J = 14.4, 12.6 Hz, 1 H), 2.23 (d, J = 14.6 Hz, 1 H), 2.11 - 1.94 (m,2H), 1.42 (d, J = 6.6 Hz, 3H). ESI-MS m/z cale. 390.107, found 391.22 (M+H)'.

Compound 24

2-chloro-5-[ (2S, 4S, 6S)-4-hydroxy-2-methyl-6-( 1 -methyltriazol-4-yl)-4-piperidyl] -N,N-dimethyl15 benzamide (24)

i. 5-bromo-2-chloro-N,N-dimethyl-benzamide hexyllithium, THF, -78 °C

S2 ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid

THF /”

Compound 24 was synthesized from compound S2 following the method described for

Compound 17. Purification by reversed-phase HPLC (Method: Waters XSelect CSH Cl 8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 0.1 %

168 trifluoroacetic acid) afforded the title Compound 24 (3 mg, 6%) as a clear oil. 'H NMR (300 MHz, Methanol-r/4) Ô 8.05 (s, 1H), 7.59 (s, 1H), 7.52 (d, J = 8.3 Hz, 2H),4.97 (d, J = 15.8 Hz, 1H), 4.13 (s, 3H), 3.95 - 3.89 (m, 1 H), 3.13 (s, 3H), 2.89 (s, 3H), 2.50 (s, 1H), 2.21 (s, 1H), 2.06 (d, J = 5.7 Hz, 2H), 1.41 (d, J = 6.6 Hz, 3H). ESI-MS m/z cale. 377.162, found 378.3 (M+H)⁺.

Compound 25 (2S,4S,6S)-4-[3-fhioro~4-(trifliioromethyl)phenyl]-2-methyl-6( 1 -methyhriazol-4-yl)piperidin-4-ol (25)

S2

i. 4-bromo-2-fluoro-1-(trifluoromethyl)benzene hexyllithium, THF, -78 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Compound 25 was synthesized from compound S2 following the method described for Compound 17. Purification by reversed-phase HPLC (Method: Waters XSelect CSH Cl8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 0.1 % trifluoroacetic acid) afforded the title Compound 25 (8.4 mg, 17%) as a white solid. 'H NMR (300 MHz, Methanol-//4) δ 8.06 (s, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.58 - 7.49 (m, 2H), 5.03 - 4.95 (m, 1H), 4.13 (s, 3H), 3.92 (dd, J = 10.9, 5.9 Hz, 1H), 2.58 - 2.47 (m, 1H), 2.24 (d, J = 14.2 Hz, 1H), 2.06 (d, J = 10.4 Hz, 2H), 1.42 (d, J = 6.6 Hz, 3H). ESI-MS m/z cale. 358.142, found 359.29 (M+H)⁺.

Compound 26 (2S,4S,6S)-4-(4-chloro-3-methyl-phenyl)-2-methyl-6-(l-methyltriazol-4-yl)piperidin-4-ol (26)

S2

i. 4-bromo-1 -chloro-2-methyl-benzene hexyllithium, THF, -78 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Compound 26 was synthesized from compound S2 following the method described for

169

Compound 17. Purification by reversed-phase HPLC (Method: Waters XSelect CSH C18 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 0.1 % trifluoroacetic acid) afforded the title Compound 26 ( 12.6 mg, 28%) as a white solid. 'H NMR (300 MHz, Methanol-i/4) δ 8.06 (s, 1 H), 7.47 (d, J = 1.8 Hz, 1 H), 7.35 (d, J = 4.2 Hz, 2H), 4.96 (dd, J = 12.4,3.1 Hz, IH), 4.13 (s, 3H), 3.91 (dt, J = 11.3,5.6 Hz, IH), 2.55-2.41 (m, IH), 2.40 (s, 3H), 2.22 (d, J = 14.6 Hz, 1 H), 2.03 (d, J = 10.8 Hz, 2H), 1.41 (d, J = 6.6 Hz, 3H). ESI-MS m/zcalc. 320.140, found 321.28 (M+Hf.

Compound 27 (2S. 4 R, 6S)-4-(4-bromophenyl)-2-methyl-6-(l-methyltriazol~4-yl)piperidin-4-ol (2 7)

i. 1,4-dibromobenzene butyllithium, THF, -78 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Step i: A mixture of 1,4-dibromobenzene (1 20.8 mg, 0.512 mmol) in THF (800 pL) was cooled to -78 °C. At this time, butyllithium (260 pL of 1.6 M, 0.416 mmol) was added dropwise, and the mixture was stirred at -78 °C for 15 minutes. At this time, a THF (800 pL) solution of compound S2 (80 mg, 0.3414 mmol) was added dropwise, and the reaction was stirred for 15 minutes. The mixture was diluted with saturated aqueous ammonium chloride (10 mL), water (10 mL), and ethyl acetate (10 mL). The aqueous layer was extracted with additional ethyl acetate (2x10 mL), and the combined organic layer was dried with sodium sulfate, filtered, and concentrated to a crude residue.

Step ii: The intermediate was diluted with THF (400 pL) and 2-sulfanylbenzoic acid (56 mg, 0.363 mmol) was added. In an inert glovebox, a solution of dppb (4 mg, 0.00938 mmol) and Pd₂(dba)3 (4 mg, 0.00437 mmol) in THF (400 pL) was prepared and, after 30 minutes of mixing, the light brown mixture was added to the intermediate solution. The mixtures were stirred. After 30 minutes, UPLC indicated complété conversion. The mixture was diluted with TBME (5 mL), followed by 1 M HCl (2x5 mL). The aqueous layer was removed and combined and then pH adjusted with aqueous NaOH (6 M, 1.7 mL) followed by saturated aqueous ammonium chloride to achieve pH ~9. The mixture was diluted and extracted with TBME (3x10 mL), and the combined organic layer was filtered through a phase separator and concentrated to a crude

170 residue, which was purified via reverse phase chromatography Purification by reversed-phase HPLC (Method: Waters XBridge Prep C8 Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 10 mM Ammonium Hydroxide) yielded the title Compound 27 (16.6 mg, 14%) as a white solid. 'H NMR. (400 MHz, Chloroformé) δ 7.55 - 7.41 (m, 5H), 4.07 (s, 3H), 3.98 (dd, J = 12.0,2.6 Hz, 1 H), 2.90 - 2.80 (m, IH), 2.79 - 2.72 (m, IH), 2.51 -2.43 (m, IH), 2,01 (t, J = 12.4 Hz, IH), 1.73 - 1.57 (m, IH), 1.17 (d, J = 6.1 Hz, 3H). ESI-MS m/z cale. 350.0742, found 351.17 (M+H)⁺.

Compound 28 (2S, 4R, 6S)-4-(4-bromophenvl)-2-methvl-6-(l-methyltriazol-4-yl)piperidin-4-ol (28)

i. 4-bromo-2-methoxy-1-(trifluoromethy[)benzene butyllithium, THF, -78 °C ii. Pd₂(dba)₃ dppb 2-sulfanylbenzoic acid THF

Step i: A mixture of 4-biOmo-2-methoxy-l-(tnfluoromethyl)benzene (220 mg, 0.863 mmol) in THF (1000 pL) was cooled to -78 °C. At this time, sec-butyllithium (600 pL of 1.4 M, 0.840 mmol) was added, and the mixture was stirred at this température for 40 minutes. At this time, a THF (1,000 pL) solution of compound S2 (100 mg, 0.427 mmol) was added over 30 seconds. The mixture was then stirred for 2 minutes, and then quenched with 2 mL saturated aqueous ammonium chloride and ethyl acetate (4 mL). The aqueous layer was extracted with additional ethyl acetate (2x4 mL), and the combined organic layer was washed with brine (5 mL), dried with magnésium sulfate, filtered, and concentrated. The mixture was minimally diluted with DCM and loaded onto a silica gel column for purification (Gradient: 0 - 8% MeOH in DCM). The product-containing fractions were pooled and concentrated and found to be only about 80% purity, with the remainder being the starting material. The mixture was redissolved in DCM and loaded onto another silica gel column for purification (0 - 6% MeOH in DCM). The product-containing fractions were pooled and concentrated.

Step ii: In an inert glovebox, a solution of dppb (2 mg, 0.004690 mmol) and Pd₂(dba)₃ (2 mg, 0.002184 mmol) in THF (0.5 mL) was prepared and, after 5 minutes of mixing, the light brown mixture was added to a solution of the intermediate and 2-sulfanylbenzoic acid (15 mg, 0.09729 mmol) in THF (0.5 mL). The mixture was stirred for 5 minutes. At this time, the mixtures were diluted with TBME (2 mL) and extracted with 1 M HCl (2 x I mL), which was

171 then pH adjusted to pH >10 and then extracted with DCM (2 mL). The organic layer was passed over a phase separator, concentrated to a minimal volume, and then diluted in DCM for silica gel purification (Gradient: 0-10% MeOH in DCM). The product-containing fractions were pooled and concentrated to yield the titlc Compound 28 (26 mg, 14%) as a white solid. ^lH NMR (300 MHz, Methanol-J4) δ 7.87 (s, 1H), 7.53 (d, J = 8.1 Hz, IH), 7.35 (s, 1H), 7.18 (d, J = 8.2 Hz, IH), 4.51 (dd, J = 10.9, 3.8 Hz, 1H), 4.08 (d, J = 1.5 Hz, 3H), 3.93 (d, J = 1.5 Hz, 3H), 3.43 (ddd, J= 12.5, 6.5,3.3 Hz, 1 H), 2.19 - 2.01 (m, 2H), 1.81 (dd, J = 13.6,2.4 Hz, 1H), 1.70 (dd, J = 13.4, 11.4 Hz, 1H), 1.23 - 1.15 (m,3H). ESI-MS m/z cale. 370.162, found 371.14 (M+H)7

Compound 29 (2S.4S,6S)-4-(4-cyclopropylphenyl)-2-methyl-6-(l-methyltriazol-4-yl)piperidin-4-ol (29)

Step i: A mixture of 1-bromo-4-cyclopropyl-benzene (120 mg, 0.609 mmol) in THF (800 pL) was cooled to -78 °C. At this time, butyllithium (260 pL of 1.6 M, 0.416 mmol) was added dropwîse, and the mixture was stirred at -78 °C for 10 minutes. To the reaction was added LaCh-LiCl (580 pL of 0.6 M, 0.348 mmol), and the reaction was stirred for 5 minutes. At this time, a THF (800 pL) solution of compound S2 (80 mg, 0.341 mmol) was added dropwise. The mixture was diluted with saturated aqueous ammonium chloride (10 mL), water (10 mL), and ethyl acetate (10 mL). The aqueous layer was extracted with additional ethyl acetate (2x10 mL), and the combined organic layer was dried with sodium sulfate, fïltered, and concentrated.

Step H: The intermediate was diluted with THF (400 pL) and 2-sulfanylbenzoic acid (55 mg, 0.357 mmol) was added. In a glovebox, a solution of dppb (4 mg, 0.00938 mmol) and Pd?(dba)3 (4 mg, 0.00437 mmol) in THF (400 pL) was prepared and, after 30 minutes of mixing, the hght brown mixture was added to the intermediate solution. The mixture was stirred for 30 minutes. The mixture was diluted with TBME (5 mL) followed by 1 M HCl (2x5 mL). The aqueous layer was removed and combined and then pH adjusted with aqueous NaOH (6N, 1.7 mL) followed by saturated aqueous ammonium chloride to achieve pH ~9. The mixture was diluted and extracted with TBME (3x10 mL), and the combined organic layer was fïltered

172 through a phase separator and concentrated to a crude residue, which was purified via reverse phase chromatography (Purification by reversed-phase HPLC. Method: Waters XBridge Prep C8 Column; 30 x 150 mm, 5 micron. Gradient: 5-98% Acetonitrile in Water with 10 mM Ammonium Hydroxide) to yield the title Compound 29 (19.4 mg, 18%) as a whitc solid. 'H NMR (400 MHz, Chloroform-d) δ 7.47 (s, IH), 7.45 - 7.38 (m, 2H), 7.07 (d, J = 8.0 Hz, 2H), 4.54 (dd, J = 10.7,3.8 Hz, 1 H), 4.06 (d, J =1.1 Hz, 3H), 3.43 (s, 1 H), 2.19- 1.99 (m,2H), 1.971.68 (m, 4H), 1.18 (d, J = 6.3 Hz, 3H), 1.01 -0.92 (m, 2H), 0.75-0.61 (m, 2H). ESI-MS m/z cale. 312.195, found 313.33 (M+H)⁺.

Compound 30

4-[(2S,4S,6S)-4-hydroxy-2-methy 1-6-( 1 -methyltriazol-4-yl)-4-piperidvl]benzonitrile (30)

N.

i. 4-bromobenzonitrile Mg, LiCI, 1,2-dibromoethane THF, -20 °C ii. Pd₂dba₃, dppb 2-sulfanylbenzoic acid, THF

To a mixture of Mg (17 mg, 699 pmol) in THF (500 pL), LiCI (430 uL of 0.5 M in THF) a drop of 1,2-dibromoethane was added, followed by 4-bromobenzonitrile (117 mg, 643 pmol). The mixture was stirred for 1 h at rt and then heated to 40 °C. After 1 h, the formed solution was cooled to -20 °C in a dry ice/acctone bath and a solution of (2S,65')-l-allyl-2-methyl-6-(lmethyl-lH-l,2,3-triazol-4-yl)piperidin-4-one S2 (50 mg, 213 pmol) in THF (500 pL) was added. After 5 min, the reactions were quenched with sat. aq. ammonium chloride (2 mL), diluted with TBME (5 mL) and water (3 mL). The organic layer was passed over a phase separator and concentrated and diluted in DMSO (1 mL). Purification by reversed-phase HPLC. Method: C18 Waters Sunfïre column (30 x 150 mm, 5 micron). Gradient: MeCN in H?O with 0.2 % fonnic acid. The pure product-containing fractions were pooled, concentrated, and diluted with THF (500 pL), at which time 2-sulfanylbenzoic acid (32.9 mg, 0.213 mmol) was added and the mixture was evacuated and back-filled with nitrogen (3x). In an inert glove box, a solution of Pd^dbaHl mg, 107 pmol) and DPPB (I mg, 213 pmol) in THF (500 pL) was prepared and the mixture was stirred until mostly homogeneous and yellow-brown, about 5 min. At this time, a THF (500 pL) solution ofthe tertiary alcohol and 2-sulfanylbenzoic acid was evacuated and back-filled with nitrogen 3 times and then stirred at rt. At this time, the catalyst solution was added and the mixture was allowed to continue stirring under nitrogen. After 1 h, the mixture

173 was diluted with TBME ( l mL) and extracted with l M HCl (2 x l mL) and the aqueous layer was washed with TBME (2 x l mL). The combined aqueous layers were pH adjusted to pH 9 with 6 M NaOH and sat. aq. ammonium chloride if necessary. The cloudy aqueous layer was extracted with TBME (2 x l mL), and the combined organic layer was washed with brinc ( l mL), dried with magnésium sulfate, passed over a florisil cartridge and washed with methanol (2 x l mL). The combined organics were concentrated to yield the title compound 30 (2.9 mg, 4%) as a white solid. 'H NMR (300 MHz, Methanol-^i) δ 7.84 (s, IH), 7.72 (s, 4H), 4.47 (dd, J = 9.2,

5.3 Hz, IH), 4.08 (s, 3H), 3.45 - 3.35 (m, IH), 2.10 - l.96(m, 2H), l.8l - L72 (m, IH), L64 (dd, J = 13.6, l L2 Hz, IH), l. 17 (d, 6.4 Hz, 3H). LCMS m/z 298.08 [M+H]⁺.

Compound 31 (2S,4S,6S)-4-(2,2-dimethyl-3H-benzofuran-6-yl)-2-methyl-6( 1 -methyltriazoI-4-yl)piperidin-4~ol (31)

S2

i. 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran Mg, LiCI, 1 2-dibromoethane THF, -20 °C ii. Pd₂dba₃, dppb 2-sulfanylbenzoic acid, THF

Compound 31 was synthesized from compound S2 following the method described for compound 30 with the appropriate aryl halide. The title compound 31 (8.7 mg, 11%) was isolated as a white solid. 'H NMR (300 MHz, Methanol-i/4) δ 7.83 (s, IH), 7.13 - 7.05 (m, IH), 6.95 (dd, 7=7.8, 1.7 Hz, IH), 6.85 (d,J = 1.6 Hz, 1 H), 4.45 (dd,J=8.5, 6.1 Hz, 1 H), 4.08 (s, 3H), 3.41 - 3.36 (m, IH), 3.34 (s, 1 H), 2.98 (d,y = L1 Hz, 2H), 2.06 - 1.98 (m, 2H), 1.78 (dd, J = 13.4, 2.5 Hz, IH), 1.61 (dd, J = 13.7, 11.3 Hz, IH), 1.42 (s, 6H), 1.16 (d, J= 6.4 Hz, 3H). LCMS m/z 343.13 [M+H]⁺.

174

Compound 32 (2S, 4S, 6S)-2-methyl-6-( 1 -methyltriazol-4-yl)-4-spiro

[chromane-4,1 '-cyclopropane]-7-yl-piperidin-4-ol (32)

O

S2

i. 6-bromospiro[chromane-4, 1 '-cyclopropane]

Mg, LiCI, 1,2-dibromoethane

THF, -20 °C

n. Pd₂dba₃, dppb 2-sulfanylbenzoic acid, THF

Compound 32 was synthesized from compound S2 following the method described for compound 30 with the appropriate aryl halide. The title compound 32 (14.5 mg, 19%) was isolated as a white solid. ^lH NMR (300 MHz, Methanol-i/4) δ 7.82 (s, 1 H), 6.94 (dd, J- 8.1, 2.0 Hz, IH), 6.91 (d, J = 1.9 Hz, 1 H), 6.66 (d, J = 8.1 Hz, 1 H), 4.44 (dd, J= 9.4, 5.3 Hz, 1 H), 4.284.15 (m, 2H), 4.07 (s, 3H), 3.41 - 3.35 (m, IH), 2.06 - 1.90 (m, 2H), 1.87 - 1.80 (m, 2H), 1.77 (dt, J= 13.8,2.3 Hz, IH), 1.58(dd,J = 13.7, 11.3 Hz, IH), 1.16 (d, y = 6.4 Hz, 3H), 1.05-0.98 (m, 2H), 0.88 - 0.77 (m, 2H). LCMS m/z 355.14 [M+H]’.

Compound 33 (2S,4S,6S)-4-[4-chloro-3-(triJliioromethyl)phenyl]-2-metlivl-6( 1 -meîhyltriazol-4-yl)piperidin-4-ol (33)

S2

i. 4-bromo-1 -chloro-2-(trifluoromethyl)benzene Mg, LiCI, 1,2-dibromoethane THF, -20 °C ii. Pd₂dba₃, dppb 2-sulfanylbenzoic acid, THF

Compound 33 was synthesized from compound S2 following the method described for compound 30 with the appropriate aryl halide, with a modified work up and isolation for the final step as follows: The reaction mixture was diluted with TBME (500 pL) and extracted with 1 M HCl (3 x 500 pL). The combined aqueous layer was submitted for reversed phase purification to isolate the final product (Method: Cl8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H?O with 0.2 % formic acid.). Fractions were concentrated to yield 175 the title compound 33 (formic acid sait) (2.9 mg, 4%) as a white solid 'H NMR (300 MHz, Methanol-Λ) δ 8.06 (s, IH), 7.99 (d, J = 2.3 Hz, lH), 7.78 (dd,7=8.5, 2.3 Hz, l H), 7.67 (d,7 = 8.5 Hz, 1H),4.95 (d,.7=3.1 Hz, 1 H), 4.15 (s, 3H), 3.87 (dt, J = 11.2,5.8 Hz, IH), 2.48 (fJ = 13.4 Hz, IH), 2.23 (d,7 = 14.0 Hz, IH), 2.14- 1.95 (m, 2H), 1.41 (d,7=6.6 Hz, 3H). LCMS m/z 375.25 [M+H]L

Compound 34 (2S,4S.6S)-2-methyl-6-(l-methyltriazol-4-yl)-4-[3-methvl-4(trifhioromeihyl)phenyl]piperidin-4-ol (34)

S2

i. 1 -bromo-3-methyl-4-(trifluoromethyl)benzene

Mg, LiCI, 1,2-dibromoethane

THF, -20 °C ii. Pd2dba3, dppb 2-sulfanylbenzoic acid, THF

Compound 34 was synthesized from compound S2 following the method described for compound 30 with the appropriate aryl halide with the modification from compound 33. Fractions were concentrated to yield the title compound 34 (formic acid sait) (19.7 mg, 23%) as a white solid Ή NMR (300 MHz, Methanol-ck) δ 8.06 (s, IH), 7.68 (d,7= 8.3 Hz, IH), 7.58 (s, IH), 7.53 (d,7=8.1 Hz, IH), 4.95 (dd,7= 12.3,3.1 Hz, IH), 4.15 (s, 3H), 3.90 (dd,7= 10.3, 5.8 Hz, 1 H), 2.56-2.51 (m, 3H), 2.51 -2.42 (m, 1 H), 2.23 (d,7= 14.0 Hz, 1 H), 2.04 (d, 7 = 10.0 Hz, 2H), 1.42 (d, 7= 6.6 Hz, 3H). LCMS m/z 355.28 [M+H]'.

Compound 35 (2S,4S,6S)-2-methyl-6-( 1 -methyltriazol-4~yl)-4-f2ftrifluoromethyl)-4-pyridyl]piperidin-4-ol (35)

S2

i. 4-bromo-2-(trifluoromethyl)pyridine

Mg, LiCI, 1,2-dibromoethane

THF, -20 °C ii. Pd₂dba3, dppb 2-sulfanylbenzoic acid, THF

Compound 35 was synthesized from compound S2 following the method described for compound 30 with the appropriate aryl halide with the modification from compound 33.

176

Fractions were concentrated to yield the title compound 35 ( 16.9 mg, 23%) as a white solid 'H NMR (300 MHz, Methanol-rf₄) δ 8.77 (d, J= 5.2 Hz, IH), 8.17 (s, IH), 8.03 (dd, J = 1.8, 0.8 Hz, IH), 7.84 (dd, J = 5.1, l.8Hz, IH), 5.04 (dd, J = 12.6,3.1 Hz, IH), 4.16 (s, 3H), 3.98 (ddd, J = 11.0, 6.5,4.1 Hz, IH), 2.66 (dd,J= 14.5, 12.5 Hz, IH), 2.31 -2.22 (m, 1 H), 2.22 - 2.02 (m, 2H), 1.47 (d, 6.6 Hz, 3H). LCMS m/z 342.31 [M+H]*.

Compound 36 (2S, 4S, 6S)-4-[ 3-chloro-4-(trifhioromethyl)phenyl]-2-methyl-6-( 1 ~niethyltrÎa~ol-4-yl)piperidin-4ol (36)

S2

i. 1 -bromo-3-chloro-4-(trîfluoromethyl)benzene

Mg, LiCI, 1,2-dibromoethane

THF, -20 °C ii. Pd₂dba₃₁ dppb 2-sulfanylbenzoic acid, THF

Compound 35 was synthesized from compound S2 following the method described for compound 30 with the appropriate aryl halide with the modification from compound 33. Fractions were concentrated to yield the title compound 36 (19.7 mg, 24%) as a white solid. ’H NMR (300 MHz, Methanol-</₄) δ 8.11 (s, IH), 7.88 - 7.80 (m, 2H), 7.67 (d, J= 8.3 Hz, 1 H), 5.02 (dd, J= 12.4,3.1 Hz, IH), 4.16 (s, 3H), 4.02 - 3.83 (m, IH), 2.65 - 2.48 (m, IH), 2.27 (d, J = 14.0 Hz, IH), 2.10 (d, J= 8.3 Hz, 2H), 1.45 (d,J = 6.6 Hz, 3H). LCMS m/z 375.29 [M+H]⁺.

Compound 37 (2S,4S,6S)-2-methyl-6-(l-methyltriazol-4-yl)-4-[4-(trifhioromethyl)-3-pyridyl]piperidîn-4-ol (37)

S2

i. 5-bromo-2-(trifluoromethyl)pyridine

Mg, LiCI, 1,2-dibromoethane

THF, -20 °C ii. Pd₂dba₃, dppb 2-sulfanylbenzoic acid, THF

Compound 37 was synthesized from compound S2 following the method described for compound 30 with the appropriate aryl halide with the modification from compound 33. Fractions were concentrated to yield the title compound 35 (26.5 mg, 24%) as a white solid ‘H

177

NMR (300 MHz, Methanol-rf₄) ô 8.93 (s, 1H), 8.23 (d,7= 8.2 Hz, 1H), 8.11 (s, 1H), 7.89 (d, J = 8.4 Hz. 1H), 5.05 (dd, J = 12.6, 3.2 Hz, 1H), 4.16 (s, 3H), 3.99 (s, 1H), 2.61 (t, J = 13.5 Hz, 1H), 2.34(d,7 = 14.2 Hz, 1 H), 2.14 (d, J = 11.0 Hz, 2H), 1.47 (d,7=6.6 Hz, 3H). LCMS m/z 342.31 [M+H]⁺.

Compound 38 (2S,4S,6S)-4-(4-(diJhioromethyl)phenyl)-2-methyl-6-(l-methyl-lH-l,2,3-triazol-4-yl)piperidin-4ol (38)

S2

i. 1 -bromo-4(difluoromethyl)benzene Mg, LiCI, 1,2-dibromoethane THF, -20 °C ii. Pd₂dba₃, dppb 2-sulfanylbenzoic acid, THF

Compound 38 was synthesized from compound S2 following the method described for compound 30 with the appropriate aryl halide with the modification from compound 33, in addition the ailyl intermediate was not purified. Fractions were concentrated to yield the title compound 38 (formic acid) (60 mg. 37%) as a white solid. ’H NMR (400 MHz, DMSO-Jô) δ 8.20 (s, 1H), 7.97 (s, 1H), 7.64 (d, 7= 8.1 Hz, 2H), 7.54 (d, 7= 8.1 Hz, 2H), 7.02 (t, 7 =56.0 Hz, 1 H), 5.28 (s, 1H), 4.40 (dd, 7= 9.3, 5.1 Hz, 1 H), 4.02 (s, 3H),2.00- 1.90 (m,2H), 1.69 (d, 7 = 13.0 Hz, 1 H), 1.61 - 1.51 (m, 1H), 1.09 (d,7=6.3 Hz, 3H). LCMS m/z 323.25 [M+H]⁺.

Compound 39 (2S,4S,6S)~2~methvI-6-(l-methyltriazol-4-yl)-4-[4-(trifluoromethyl)-3-pyridyl]piperidin-4-ol (39)

S2

i. 1 -bromo-4(1,1 -difluoroethyl)benzene iPrMgChLiCI THF, -10 °C ii. Pd₂dba₃, dppb 2-sulfanylbenzoic acid, THF

To an oven dried vial containing l-bromo-4(l,l-difluoroethyl)benzene (566 m, 2.56 mmol) was added 2-methyltetrahydrofuran (2.3 mL) followed by isopropylmagnesium chloride

178 lithium chloride complex (2.3 mL of l .3 M, 2.99 mmol) and stirred at rt for 4 h. At this time, the reaction mixture was cooled to - 10 °C and solid S2 was added in one portion and stirred for l h. The reaction mixture was quenched with water and sat. aq. ammonium chloride and then extracted with ethyl acetate (2 x). The organic layer was passed over a phase separator and concentrated. The residual oil was brought into an inert glovc box and the vial was chargcd with 2-sulfanylbenzoic acid (53 mg, 0.344 mmol) and dissolved in THF (300 pL). A separate vial was charged with Pd₂dba3 (3 mg, 3.28 pmol), dppb (3 mg, 7.04 pmol), and THF (300 pL) and then stirred for 10 min. This solution was added to the other mixture and the reaction was stirred for 3 h. At this time, the mixture was diluted with TBME followed by extraction with l M HCl (2 x). The aqueous layer was removed and combined and then pH adjusted with aqueous 6 M NaOH followed by sat. aq. ammonium chloride to achievc pH -9. The mixture was diluted and extracted with TBME (3 x 10 mL), and the combined organic layer was filtered through a phase separator, and concentrated to a crude residue. Purification by reversed-phase HPLC. (Method: Waters XSelect CSH Cl8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: Aceonitrile in Water with 0.2 Formic Acid.) afforded the title compound 39 (31.7 mg, 3 l %) as a white solid. ’H NMR (400 MHz, DMSO-î/₆) δ 8.29 (d, J = l .2 Hz, 2H), 7.94 (s, l H), 7.62 - 7.49 (m, 4H), 4.35 (dd, J =9.0, 5.2 Hz, lH),4.0l (s, 3H),3.28 (t,7=8.6 Hz, IH), l.96(t,7 = 18.8 Hz, 3H), 1.88 (d, 7 = 4.0 Hz, IH), l.7l - 1.45 (m, 2H), l .06 (d, 7 =6.3 Hz, 3H). LCMS m/z 337.30 [M+Hf.

Compound 40 (2S,4S,6S)-2-methyl-6fl-methyltriazol-4-yl)-4-[4-(trijhioromethyÎ)-3-pyridyljpiperidin-4-ol (40)

Compound 40 was synthesized from compound S2 foliowing the method described for compound 29 with the appropriate aryl halide to yield the title compound 40 (l6 mg, 19%) as a white solid. Ή NMR (400 MHz, DMSO-7₆) δ 8.19 (s, IH), 7.94 (s, IH), 7.91 -7.84(m, IH), 7.54 (dd, 7=8.1, 1.4 Hz, IH), 7.48 (s, IH), 5.46 (s, IH), 4.34 (dd, 7= 8.6, 5.6 Hz, IH),4.0l (s, 3H), 1.97 - 1.87 (m, 2H), 1.66 (d,7= 12.9 Hz, IH), 1.53 (dd.7= I3.l, l l.O Hz, IH), 1.06 (d,7 =

179

6.3 Hz, 3H). LCMS m/z 387.3 [M+H]'.

Compound 41 (25, 45, 65)-4-(lJ-difhioro-2,3-dihydro-lH-inden-5-yl)-2-methyI-6-(l -methyl-1H-1,2,3-triazol-4yl)piperidin-4-ol (41)

S2

i. 6-bromo-2,2_r3,3-tetrafluoro-2,3-dihydrobenzofuran butyllithium THF, -78 °C ii Pd₂dba₃, dppb 2-sulfanylbenzoic acid, THF

Compound 41 was synthesized from compound S2 following the method described for compound 29 with the appropriate aryl halide to yield the title compound 41 (33.2 mg, 31%) as a white solid. 'H NMR (400 MHz, DMSO-î/₆) δ 8.23 (s, III), 8.01 (s, 111), 7.51 (s, 3H), 4.45 (dd, J = 11.6, 2.9 Hz, 1 H), 4.02 (s, 3H), 3.38 (ddd, J = 9.9, 6.3, 3.2 Hz, 1 H), 3.03 (tt, J= 6.7, 3.1 Hz, 2H), 2.67-2.52 (m, 2H), 2.13 - 1.99 (m, IH), 1.93 (dt, J = 13.4,2.6 Hz, IH), 1.75 - 1.58 (m, 2H), 1.11 (d, J = 6.3 Hz, 3H). LCMS m/z 349.31 [M+H]⁺.

Compound 42 (2S,4S,6S)-4-[3-methoxy-4-(triJhioromethyl)phenyl]-l,2-dimethyl-6-(l-methyltriazol-4yl)piperidin-4-ol (42)

S2

i. 1 -bromo-3-methoxy-4(trifluoromethyl)benzene Mg, LiCI, 1,2-dibromoethane

THF, rt, ii .Mel, rt^ 40 °C iii . Pd₂dba3, dppb 2-sulfanylbenzoic acid, THF

To a mixture of Mg ( 17 mg, 699 pmol) in THF (500 pL), LiCI (430 uL of 0.5 M in THF was added 1,2-dibromoethane, followed by l-bromo-3-methoxy-4(trifluoromethyl)benzene (165 mg, 647 pmol). The mixture was stirred for 1 h at rt and then heated to 40 °C. After 1 h, compound S2 (50 mg, 209 pmol) was added as a solution in THF (500 pL) at rt. At this time, Mel (60 pL, 964 pmol) was added and the reaction was stirred. After 25 min, the reaction was heated to

180 °C. The reaction was stirred for I 8 h. At this time, the reaction mixture was diluted with sat. aq. ammonium chloride ( l mL) and DCM (3 mL). The layers were phase separated and the aqueous layer was washed with additional DCM (3 mL). The combined organic layer was concentrated and minimally diluted in DCM for column chromatography (silica gel, 0-10% MeOH.DCM). The product-containing fractions were pooled and concentrated. To the crude oil and 2-sulfanylbenzoic acid (10 mg, 65 pmol) in an inert glove box was charged THF (125 pL) followed by a THF ( 125 pL) solution of Pd2dba₃ (0.25 mg, 0.261 pmol)/DPPB (approximately 0.25 mg, 0.523 pmol). The mixture was sealed and removed from the glove box and stirred for l h. At this time, the mixture was diluted with TBME (500 pL) and l M HCl (500 pL). The organic layer was extracted with 2 additional portions of l M HCl (2 x 500 mL). The combined aqueous layer was pH adjusted with at. NaOH and sat. aq. ammonium chloride to a pH of ~9. The aqueous layer was extracted with TBME (3 x 500 pL), and the combined organic layer was washed with brine, dried with magnésium sulfate, filtered, and concentrated to yield the title compound 42(l2.2mg, 15%). ¹H NMR (300 MHz, Chloroform-J) δ 7.48 (s, 1 H), 7.44 (d, J = 8.2 Hz, 1H), 7.23 (s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 4.01 (d,J=8.3 Hz, 1H), 3.98 (s, 3H), 3.86 (s, 3H), 3.14 (s, IH), 2.80 (s, 1H), 2.28 (t, J= 12.9 Hz, 1H), 2.13 (s, 3H), 2.03 - 1.91 (m, 1H), 1.88 (dt, J = 13.8,3.2 Hz, IH), 1.76 (dt, J = 13.8,2.9 Hz, IH), 1.16 (d, J= 6.3 Hz,3H). LC MS m/z 385.16 [M+H]⁺.

Compound 43 (2S,4S,6S)-4-[3-hydroxy-4-(trifluoromethyl)phcnyl|-2-methyl-6(l-methyltriazol-4-yl)piperidin-4-ol (43) f₃c j^0H ο λΧ

Ôi.4-bromo-2-((4-methoxybenzyl)oxy)-1-(trifluoromethyl)benzene \\ H Mg. LiCI. 1,2-dibromoethane '— _N ...___________________. PS

V ».Pd/C,H_a,M.0H N./ fl ''' / S2

To a mixture of LiCI (28 mg, 661 pmol) and Mg (15 mg, 61 7 pmol) tumings was added 1,2dibromoethane (1 pL, 11.6 pmol) followed by THF (1000 pL). The reaction mixture was heated to 50 °C and stirred for 1 h. At this time, ail solid magnésium was consumed. The solution was cooled to -20 °C and to the solution was added a solution of piperidone S2 (50 mg, 209 pmol) in THF (500 pL) After 5 min, the mixture was diluted with sat. aq. ammonium chloride (10 mL) and TBME (10 mL). The layers were phase separated and the organic layer was washed with brine (10 mL). The organic layer was dried with magnésium sulfate, filtered, and concentrated.

181

The crude oil was dissolved in DCM ( l mL) and loaded on to a silica gel column for purification (0-10 % MeOH:DCM), The product containing fractions were pooled and concentrated. To the purified oil was added Pd/C (50 mg of 2.5 %w/w, 11.8 pmol) followed by MeOH ( l mL), and the mixture was stirred under 40 psig hydrogen for 21 h. At this time, the mixture was passed through a 0.45 micron membrane filter, rinsed with methanol (0.5 mL) and concentrated. The crude concentrate was dissolved in DMSO (l mL) and purified by reversed-phase HPLC (Method: Cl8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H?O with 0.2 % fonnic acid). The title compound 43 (5.5 mg, 7 %) was isolated as a white solid. 'H NMR(300MHz, Methanol^) δ 8.08 (s, IH), 7.53 (d, J = 8.2 Hz, 1H), 7.23 (s, IH), 7.07 (d, J = 8.2 Hz, IH), 4.99 (dd, J = 12.4, 3.1 Hz, IH), 4.15 (s, 3H), 4.05 - 3.80 (m, 1 H), 2.58 - 2.48 (m, IH), 2.24 (d, J = 13.9 Hz, IH), 2.06 (d, J = 8.5 Hz, 2H), 1.44 (d,7= 6.6 Hz, 3H). LCMS m/z 357.31 [M+H]⁺.

The process of producing Compound 33 also produces Compound 33a

43a

In some embodiments, Compound 33a is specifically excluded from the formulae of this disclosure by proviso.

Compound 44 (2S,4S,6S)-4-[2-hydroxy~4-(trijluoromethyl)phenyl]-2-methyl-6( 1 -methyltriazol-4-yl)piperidin-4-ol (44)

S2

i. 1 -bromo-2-(methoxynnethoxy)-4-(trifluoromethyl)benzene Mg. LiCI, 1,2-dibromoethane THF, -20 °C ii. Pd₂dba₃, dppb 2-sulfanylbenzoic acid, THF

To a mixture of LiCI (28 mg, 661 pmol) and Mg (15 mg, 617 pmol) tumings was added 1,2dibromoethane (1 pL, 11.6 pmol) followed by THF (1000 pL). The reaction mixture was heated

182 to 50 °C and stirred for l h. At this time, ail solid magnésium was consumed. The solution was cooled to -20 °C and to the solution was added a solution of S2 (50 mg, 209 pmol) in THF (500 pL). After 5 min, the reaction mixture w^ras diluted with sat. aq. ammonium chloride (10 mL) and TBME ( 10 mL). The layers were phase separated and the organic layer was washed with brine ( 10 mL). The organic layer was dried with magnésium sulfate, filtcrcd, and concentrated. At this time, the crude oil was taken up in aqueous HCl (1000 pL of 37 %w/w, 12.18 mmol)/MeOH (l mL), which was then heated to 50 °C (3:15). After 45 min, the mixture was diluted with water ( 10 mL) and TBME ( 10 mL). The organic layer was extracted with l M HCl (3x5 mL). The combined aqueous layer was pH adjusted with 6 M aq. NaOH to a pH ~8 and extracted with DCM (3 x 15 mL). The combined organic layer was dried with magnésium sulfate, filtered, and concentrated. To the residual oil was added 2-sulfanylbenzoic acid (16 mg, 104 pmol) and in an inert glove box was charged THF (250 pL) followed by a THF (250 pL) solution of Pd₂dba₃ (0.5 mg, 0.546 pmol)/DPPB (0.5 mg, l. 17 pmol). The mixture was stirred for I h, at which time the mixture was diluted with TBME (500 pL) and extracted with l M HCl (3 x 500 pL). The aqueous layer was then directly purified by reversed-phase HPLC. Method: Cl8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H₂O with 0.2 % formic acid. The title compound 44 formic acid sait (15.7 mg, 18%) was isolated as a white solid. 'H NMR (300 MHz, Methanolé₄) δ 8.05 (s, IH), 7.72 (d, y = 8.2 Hz, IH), 7.l9(d, J=8.l Hz, IH), 7.H (d, J= 1.8 Hz, l H), 5.03 -4.95 (m, IH), 4.14 (s, 3H), 3.90 (dd, J = 7.5, 4.1 Hz, IH), 3.17 - 3.03 (m, IH), 2.68 (dd, J = 14.5, 12.2 Hz, l H), 2.24 - 2.09 (m, lH), 2.02 - 1.93 (m, IH), l .42 (d,J=6.6 Hz, 3H). LCMSm/z 357.31 [M+H]'.

Compound 45 (2S,4S,6S)-4-(((4-bromophenyl)sulfonyl)methyl)-2-methyl-6-(l-melhyl-lH-l,2,3-triazol-4yl)piperidin-4-ol (45)

Br .P hexyllithiumO~Sîq

THF, -78 °C(

ii. Pd₂dba₃, dppbf

2-sulfanylbenzoic acid, THFn Q n-T H /

S245

To a mixture of l-bromo-4-methylsulfonyl-benzene ( 150 mg, 638 pmol) in THF (l mL) cooled to -78 °C was added a hexane solution of hexyllithium (280 pL of 2.3 M, 644 pmol).

183

After 5 min, a solution of piperidone S2 (50 mg, 2 13 pmol) in THF (500 pL) was added and the mixture was allowed to warm to rt. At this time, the mixture was quenched with sat. aq. ammonium chloride ( l mL). The crude mixture was warmed to rt, diluted with TBME (5 mL) and water (2 mL). The organic layer was removed and washed with brinc (5 mL), dried with magnésium sulfate, filtered and concentrâted. To this crude mixture was added 2-sulfanylbenzoic acid (33 mg, 214 pmol), at which time the reaction was transferred to an inert glove box, when THF (0.5 mL) and a THF (0.5 mL) solution of Pdidbaj ( l mg, l .09 pmol)/dppb ( l mg, 2.35 pmol) was added. The reaction stirred for l h, at which time the mixture was diluted with TBME (500 pL) and extracted with l N HCl (3 x 500 pL). The aqueous layers were combined and were purified by reversed-phase HPLC (Method: Cl8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H₂O with 0.2 % formic acid). The title compound 45 (4.9 mg, 5 %) was isolated as a clear oil. 'H NMR (300 MHz, Methanol-i/4) δ 8.05 (s, IH), 7.96 - 7.80 (m, 4H), 4.16 (s, 3H), 3.77 (s, l H), 3.59 (s, 2H), 3.29 (d, J = 1.6 Hz, l H), 2.43 (d, J = 11.3 Hz, 2H), 2.27 (d,J = 14.2 Hz, IH), L96(dd, J= 14.5, 12.2 Hz, IH), l.40(d,J = 6.6 Hz, 3H). LCMS m/z 428.95 [M+H] ^h

Compound 46 (2S,4S,6S)-2-methyl-6-(l-methyltriazol-4-yl)-4-[4-(trifhioromethyl)phenyl] piperidine-4-carbomtrile (46)

Step I. Synthesis of (2S,6S)-l-allyl-2-methyl-6-(l-methyl-lH-l,2,3-triazol-4-yl)piperidine-4carbonitrile (C12)

To a solution of piperidone S2 (150 mg, 0.608 mmol) in DME (5 mL)/tBuOH (O.l mL) was added dropwîse t-BuOK in THF (1.25 mL of l M, 1.2500 mmol). The reaction was stirred at room température for 3 hours. Water (10 mL) was added, the phases were separated, and the aqueous phase extracted with EtOAc (3 x 15 mL). The organic phases were combined, washed

184 with brine (40 mL), dried over sodium sulfate and the solvent removed under reduced pressure. Purification by silica gel chromatography (0-l 5 % MeOH in DCM) yielded the title compound C12 ( 111 mg, 59 %) as a light orange solid. Ή NMR (400 MHz, CDC13) δ 7.48 (s, IH), 7.44 (s, IH), 6.02 - 5.77 (m, 2H), 5.19 - 4.98 (m, 3H), 4.19 - 4.02 (m, 5H), 3.85 (dd, J = 11.6, 2.7 Hz, IH), 3.39 - 3.25 (m, 2H), 3.10 - 2.94 (m, 2H), 2.67 - 2.54 (m, 2H), 2.20 (br dd, J = 13.0, 3.0 Hz, IH), 2.15 - 1.99 (m, 2H), 1.93 (q, J = 12.4 Hz, IH), 1.78 - 1.65 (m, 2H), 1.26 (d, J = 5.0 Hz, 2H), 1.21 (d, 7=6.1 Hz, 4H). LCMS m/z 246.2 [M+H]⁺

Step 2. Synthesis of(2S,4S,6S)-I-allyl-2-methyl-6-(I-methyl-IH-l,2,3-triazol-4-yl)-4-(4(trifhtoromethyl)phenyl)piperidine-4-carbonitfile (Cl3)

To a solution of piperidine C12 (85 mg, 0.3461 mmol) and l-fluoro-4(trifluoromethyl)benzene (78 mg, 0.06 mL, 0.473 mmol) in freshly distilled THF (2 mL) at room température was added dropwise KHMDS in THF (0.5 mL of l M, 0.500 mmol). The reaction was stirred for 3 hours before addition of water (5 mL) and few drops of saturated solution of NH4CI until pH 8-9 was reached. The aqueous phase was extracted with EtOAc (3 x 10 mL), the combined organic phase was dried over anhydrous sodium sulfate, fïltered then concentrated in vacuo. Purification by silica gel chromatography (Column 40 g Combiflash Isco, gradient: ΟΙ 5 % MeOH in DCM) yielded (25,45,65)-l-allyi-2-methyl-6-(l-methyltriazol-4-yl)-4-[4(trifluoromethyl)phenyl]piperidine-4-carbonitrile (94 mg, 70 %) as a tacky yellow solid. LCMS m/z 390.2 [M+H] ⁺

Step 3. Synthesis of (2S_f4S_f6S)-2-methyl-6-(l-methyltriazol-4-yl)-4-[4(trifhιoromethyl)phenyl]piperidine-4-carbonitrile (46)

To a solution of (25,45,65)-! -allyl-2-methyl-6-( l-methyltriazol-4-yl)-4-[4(trifluoromethyl)phenyl]piperidine-4-carbonitrile (73 mg, 0.1873 mmol) and N,Ndimethylbarbituric acid (40 mg, 0.2408 mmol) in DCM (2 mL) was added Pd(PPhj)4 (20 mg, 0.0171 mmol). The reaction was stirred for 2 hours. The solvent was removed under vacuum then the residue dissolved with a IM aqueous solution of hydrochloric acid (10 mL). The aqueous phase was washed with MTBE (3x10 mL) then the pH was adjusted to 8-9 by addition of a IM aqueous solution of sodium hydroxide. The aqueous solution was then extracted with MeTHF (3 x 20 mL), dried over sodium sulfate and the solvent removed under vacuum. Purification by reversed-phase chromatography (column: C18; gradient: 5 % of MeCN in basic buffer (NH4CO3/NH4OH 0. IM) followed by 5-100 % MeCN in water) yielded. after overnight freeze-drying, the title compound 46 (48 mg, 73 %) as a white solid. '11 NMR (400 MHz, DMSO-î/ô) δ 8.01 (s, I H), 7.86 - 7.79 (m, 4H), 4.25 (brd, 7 = 10.9 Hz, 1 H), 4.03 (s, 3H), 3.23 3.13 (m, IH), 2.98 - 2.70 (m, IH), 2.40 (brd, J = 13.2 Hz, IH), 2.19 (brd, J = 12.6 Hz, IH), 1.99

185 (brt, J = 12.2 Hz, IH), 1.65 (brt, 7 = 11.9 Hz, lH), l. 15 (d, 7 = 6.1 Hz, 3H).I9FNMR (377

MHz, DMSO-t/ô) δ -61.12 (s, 3F). LCMS mh 350.2 [M+H]*

Compound 47 (2S,4S,6S)-2-methyl-6-( l-niethyltriazol-4-yl)-4-[4-(l ,1,2,2,2-pentcifhioroethyi) phenyl]piperidin-4-ol (4 7)

S2

i. 1 -bromo-4-(1,1,2,2,2-pentafluoroethyl)benzene Mg, LiCI, THF ii. Pd₂dba₃, dppb 2-sulfanylbenzoic acid. THF

To an oven dried vial containing magnésium (12 mg, 0.4559 mmol) was added l-bromo-4(1,1,2,2,2-pentaf!uoroethyl)benzene ( 106 mg, 0.3854 mmol) as a solution with LiCI ( 1.4 mL of 0.285 M, 0.3990 mmol) in THF. The reaction was stirred at room température ovemight. At this time, the mixture was cooled to -15 °C and piperidone S2 (46 mg, 0.196 mmol) was added as a solution in THF (300 pL) and stirred for 30 min. The mixture was diluted with sat. aq. ammonium chloride, water, and DCM. The aqueous layer was extracted with additional DCM, and the combined organic layer was fdtered through a phase separator and concentrated, to which was added 2-sulfanylbenzoic acid (32 mg, 0.208 mmol). In an inert glovebox, a solution of Pd?(dba)3 ( 1.9 mg, 0.00208 mmol) and dppb ( 1.9 mg, 0.00446 mmol) in THF (950 pL) was added to the mixture. The resulting brown solution was stirred for 3 h. The mixture was diluted with TBME followed by extraction with 1 N HCl (2x10 mL). The aqueous layer was removed and combined and then pH adjusted with aqueous 6N NaOH followed by sat. aq. ammonium chloride to achieve pH -9. The mixture was diluted and extracted with TBME (3x10, mL), and the combined organic layer was filtered through a phase separator and concentrated to a crude residue. The residue was diluted with DMSO and purified by reversed-phase HPLC. (Method: Waters XSelect CSH C18 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: Acetonitrile in Water with 0.2 % Fonnic Acid.) to yield the title compound 47 (29.8 mg, 39 %) as a white solid. Ή NMR (300 MHz, DMSO-7₆) δ 8.24 (s, 1H), 8.05 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.68 (d,7=8.4 Hz, 2H), 4.48 (dd,7= 11.7,3.0 Hz, 1H), 4.02 (s,3H),3.51 - 3.32 (m. 1H), 2.10 (dd, J = 13.4, 11.7Hz, 1H), 1.96(d,J = 13.0 Hz, 1H), 1.83- l.60(m,2H), 1.13(d,7 = 6.4 Hz, 3H). 19F NMR (282 MHz, DMSO-4) ô-84.07 (t, 7 = 2.3 Hz),-113.29 (d, 7= 2.4 Hz). LCMS m/~ 391.28 [M+H]⁺

186

Compounds 48- 59

Compounds 48-59 were prepared from piperidone S2 and the relevant halide as described for compound 47. Halides were obtained from commercial sources.

Method of préparation, structure and physicochemical data for Compounds 48- 59.

Product	Piperidone and halide	Ή NMR; LC MS m/z [M+H]+
Compound 48 cf3 O A-k 0H Ν^Χ,.Α N'J H hr /	S2; l-bromo-3(trifluoromethyl)benz ene	'H NMR (300 MHz, MethanoU/4) δ 8.05 (s, 1 H), 7.89 (s, 1 H), 7.84 - 7.67 (m, 1 H), 7.68 - 7.53 (m, 2H), 4.95 (d, J = 12.1 Hz, 1H), 4.12 (s, 3H), 3.89 (q, J = 7.3 Hz, 1H), 2.51 (t, J- 13.7 Hz, 1H), 2.22 (d, J = 14.5 Hz, 1H), 2.15-2.01 (m, 2H), 1.40 (d,J = 6.5 Hz, 3H); LCMS m/z 391.280 (M+H)+
Compound 49 O Oh N J H /	S2; 1 -bromo-4cyclopropylsulfanylbenzene	Ή NMR (300 MHz, Methanol-</4) δ 8.03 (s, 1 H), 7.47 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 4.94 (s, 1H), 4.13 (s, 3H), 3.86 (s, 1 H), 2.44 (s, 1H), 2.31 - 2.16 (m, 2H), 2.00 (d, J= 14.8 Hz, 2H), 1.39 (d, J = 6.6 Hz, 3H), 1.14-1.02 (m, 2H), 0.60 (dt, J = 6.5, 4.4 Hz, 2H); LCMS m/z 345.29 [M+Hf
Compound 50 O'CF3 f3c / O Ay N J H N !	S2; 4-bromo-2(trifluoromethoxy)-l (trifluoromethyl)benz ene	lH NMR (300 MHz, Methanol-t/4) δ 8.44 (s, 1H), 8.01 (s, 1H), 7.84 (d,J=8.3 Hz, 1 H), 7.76 (s, 1 H), 7.67 (d, J= 8.3 Hz, 1H), 4.88 (s, 1H), 4.12 (s, 3H), 3.88 - 3.67 (m, 1H), 2.50 -2.35 (m, 1 H), 2.19 (d, J = 14.2 Hz, IH), 1.98 (d, J = 10.5 Hz, 2H), 1.37 (d, J -6.6 Hz, 3H) ; LCMS m/z 425.29 [M+H]+
Compound 51 cf3 F3C\J O A+k OH N? J H N' !	S2; 4-bromo-l,2bis(trifluoromethyl)be nzene	lH NMR (300 MHz, Methanol-i/4) δ 8.37 (s, 1H), 8.15 (s, 1H), 8.08-7.93 (m, 3H), 4.95 (d,J= 12.8 Hz, 1 H), 4.12 (s, 3H), 3.98 -3.80 (m, 1 H), 2.61 -2.41 (m, 1 H), 2.23 (d, J = 14.5 Hz, 1H), 2.08 - 2.00 (m, 2H), 1.40 (dd, J= 6.6, 2.8 Hz, 3H) ; LCMS m/z 409.30 [M+H]*
Compound 52	S2;	'H NMR (300 MHz, Methanol-t/4) δ 8.04 7.97 (m, 1H), 7.94 (s, IH), 7.79 - 7.73 (m,

187

Product	Piperîdone and halide	lH NMR; LCMS tn/z [M+Hf
HN-Â 7 N. ,Α..Λ N'J H N' !	6-bromo-l (tetrahydro-2H-pyran2-yl)-l H-indazole	2H), 7.34 (dd,7=8.8, 1.4 Hz, IH), 4.70 (dd, 7= 11.9, 3.0 Hz, 1 H), 4.10 (s, 3H), 3.72 - 3.53 (m, IH), 2.43 - 1.76 (m, 4H), 1.29 (d, 7 = 6.5 Hz, 3H); LCMS m/z 313.31 [M+Hf

188

Compound 53 + J H N' !	S2; 6-bromo-2,3dihydrobenzofuran	‘H NMR (300 MHz, Methanol-A) δ 8.39 (s, IH), 8.09 (s, IH), 7.21 (dd, J = Ί.Ί, 1.2 Hz, IH), 7.01 (dd, 7=7.8, 1.7 Hz, IH), 6.94 (d,7 = 1.7 Hz, IH), 4.95 (dd, J = 12.5, 3.1 Hz, IH), 4.54 (t,7 = 8.7 Hz, 2H), 4.13 (s, 3H), 3.89 (dp, 7= 9.4, 6.6 Hz, 1 H), 3.18 (td, y = 8.7, 1.1 Hz, 2H), 2.51 (dd. J = 14.5, 12.5 Hz, IH), 2.26 - 1.95 (m, 3H), 1.41 (d, J = 6.6 Hz. 3H); LCMS m/z 3 15.34 [M+H]
Compound 54 ^N^V'A N^\ + V'-A.qh A H /	S2; 6-bromo-2-methyl2H-indazole	LCMS m/z 327.36 [M+H]'
Compound 55 ,N. n a\ HJ X-\.OH X..-LA, + } H ιΆ !	S2; 5-bromo-l-methylIH- benzo[d][l,2,3]triazol e	LCMS m/z 328.39 [M+H]*
Compound 56 N A\ H j ^-A^oh N? J H N' !	S2; 5-bromo-1 -methylIH-indazole	Ή NMR (300 MHz, Methanol-A) δ 8.42 (d, J = 27.0 Hz, 1 H), 8.14 (s, 1 H), 8.04 7.92 (m, 2H), 7.68 (dd, J = 8.9, 1.7 Hz, IH), 7.59 (dt,7= 9.0, 0.9 Hz, IH), 5.02 (dd, J= 12.5,3.1 Hz, IH), 4.14 (s, 3H), 4.07 (s, 3H), 4.01 - 3.89 (m, IH), 2.66 (dd, J= 14.4, 12.6 Hz, IH), 2.31 (ddd, J= 14.5, 3.2, 1.9 Hz, IH), 2.24 - 2.09 (m, 2H), 1.45 (d, J = 6.6 Hz, 3H) ; LCMS m/z 327.36 [M+H]’

189

Compound 57 N' n-A J) / χ-^γΟΗ x J h /	S2; 6-bromo-1 -methyl1Hbenzo[d] [ 1,2,3]triazol e	LCMS m/z 328.31 |M+H]'
Compound 58 N-À J / OH N^· X J·.,, 'O H /	S2; 6-bromo-1 -methyl- 1 H-indazole	'H NMR (300 MHz, Methanol-^) δ 8.15 (s, IH), 7.98 (d, J=0.9 Hz, IH), 7.83 7.73 (m, 2H), 7.37 (dd, J = 8.6, 1.5 Hz, 1 H), 5.03 (dd, J= 12.5, 3.1 Hz, 1 H), 4.14 (s, 3H), 4.09 (s, 3H), 4.06 - 3.89 (m, IH), 2.71 (dd, J = 14.5, 12.6 Hz, IH), 2.372.07 (m, 3H), 1.46 (d, J= 6.6 Hz, 3H); LCMS m/z 327.36 [M+H]+
Compound 59 ,N. — N 7^\ / - .^OH h^,AmA„ N. J H N' /	S2; 5-bromo-l,3dimcthyl-1 H-indazole	LCMS m/z 341.36 [M+H]+

Compound 60 (2S, 4S, 6S)-4-cyclohexyl-2-methyl-6-( 1 -methyltriazoI-4-yl)piperidin-4-ol (60)

Step l : Synthèses of (2S,4S,6S)-l-allyl-4-cyclohexyl-2-methyl-6-(i-methyltriazol-4yl)piperidin-4-ol (C14)

In a flame dried, nitrogen-flushed flask equipped with a septum and a magnetic stirring bar was placed lanthanum(III) chloride bis(lithium chloride) complex solution (0.8 mL οί'0.6 M, 0.480 mmol). in another flame dried, nitrogen-flushed flask was placed piperidone S2 (102.3

190 mg, 0.437 mmol). The solid was transferred to the lanthanum-containing flask using anhydrous THF (3 mL) as solvent. The mixture was stirred at ambient température for l hour. The réaction was cooled to 0 °C and cyclohexylmagnesium chloride (0.5 mL of l M, 0.500 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for l hour. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated under vacuum. The crude residue was purified by reversedphase chromatography (Column: Cl8. Gradient: 0-100 % MeCN in basic buffer (NH4HCO3/NH4OH O.l M)) to afford, after ovemight freeze-drying the title compound C14 (53.3 mg, 36 %) as a white solid. LCMS m/z 319.3 [M+H]’

Step 2: Svnthesis of (2S,4S,6S)-4-cvclohexyl-2-methvl-6-( l-meth\dtriazol-4-vl)pipendin-4-ol (60)

Piperidine C14 (53.3 mg, 0.159 mmol), methyl Meldrum’s acid (44.2 mg, 0.2711 mmol) and Pd(PPh?)4 (22.5 mg, 0.0191 mmol) were placed under nitrogen, followed by addition of DCM (8 mL). The yellow solution was then stirred at ambient température for 2 hours. Then the mixture was dried under vacuum and purified by reversed phase chromatography (Column: Cl8, 30g. Gradient: 0-100 % MeCN in basic buffer (NH4HCO3/NH4OH O.l M)) afforded, after freezedrying, the title compound 60 (31.9 mg, 70 %) as a white solid. 'H NMR (400 MHz, DMSO-î/&) δ 7.84 (s, l H), 4.11 (br d, J = 9.4 Hz, l H), 3.97 (s, 3H), 3.92 - 3.89 (m, l H), 3.11 - 3.01 (m, l H), 1.95 (brs, IH), 1.82- L57 (m, 6H), l .45 - 1.38 (m, IH), 1.29 (t, J = 12.2 Hz, IH), 1.21 -0.90 (m, 10H). LCMS m/z 279.2 [M+H]⁺

Compound 61 (2S, 4S, 6S)-2-methyl-6-( I -methyltriazol-4-yl)-4-[[3ftrifhioromethyl)phenylJ methyl]piperidin-4-ol (61)

S2 C15

191 methyl Meldrum's acid Pd(PPh₃)₄

DCM

Step 1: Synthesis qf(2S,4S,6S)-l-allyl-2-methyl-6-(l-methyltriazol-4-yl)-4-[[3(trifhioromethyl)phenyl] methyl]piperidin-4-ol (C15)

In a flame dried, nitrogen-flushed flask equipped with a septum and a magnetic stirring bar was placed magnésium (147 mg, 6.065 mmol) and a small amount of iodine in diethyl ether (8 mL). The solution was stirred for 15 minutes. Then was added 3-(trifluoromethyl)benzyl bromide (1.064 g, 0.68 mL, 4.45 mmol) dropwise. The solution was heated at 40 °C until the boiling observed. Then the mixture was stirred at room température for 1 hour. A green Grignard solution was obtained (8 mL, 0.56 M). In a flame dried, nitrogen-flushed flask equipped with a septum and a magnetic stirring bar was placed piperidone S2 ( 125 mg, 0.535 mmol) in THF (3 mL). Then lanthanum(IH) chloride bis(lithium chloride) complex solution (0.8 mL of 0.6 M, 0.480 mmol) was added and the mixture was stirred at room température for 1 hour. The reaction was cooled to 0 °C and the previously prepared Grignard (2 mL, 1.12 mmol, 2 eq) was added dropwise, and the reaction mixture was stirred at 0 °C for 1 hour. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated under vacuum. The crude residue was purified by reversed-phase chromatography (Column: Cl8. Gradient: 0-100 % MeCN in basic buffer (NH4HCO3/NH4OH 0.1 M)) to afford, after ovemight freeze-drying, the title compound C15 (37.3 mg, 17 %) as a white solid. 'HNMR (400 MHz, CDC13) δ 7.54 - 7.50 (m, 2H), 7.47 - 7.39 (m, 3H), 6.06 - 5.95 (m. 1 H), 5.21 -5.l6(m, 1 H), 5.15 - 5.09 (m, IH), 4.16 (dd, J = 11.3,3.5 Hz, lH),4.09(s, 3H), 3.35 (dd, J = 16.0, 7.1 Hz, IH), 3.10 - 2.96 (m, 3H), 2.89 (dqd, J = 11.7,6.1, 2.8 Hz, IH), 1.94 - 1.79 (m, 2H), 1.68 (s, IH), 1.59 - 1.50 (m, IH overlapped with water), 1.17 (d, J = 6.1 Hz, 3H); ^l9F NMR (377 MHz, CDCI3) δ -62.53 (s, 3F). LCMS m/z 395.2 [M+H] ⁺

Step 2: Svnthesis of (2S,4S,6S)-2-methyl-6-( 1 -methyltriazol-4-yl)-4-[[3(trifluoromethyl)phenyl]methyl] pipendin-4-ol (61)

Piperidine C15 (37.3 mg, 0.0898 mmol), methyl Meldrum's acid (54.5 mg, 0.334 mmol) and Pd(PPh3>4 ( 17.3 mg, 0.0147 mmol) were placed under nitrogen, then was added CH2CI2 (6 mL). The yellow solution was then stirred at rt for 2 hours. Then the mixture was dried under vacuum

192 and purified by reversed phase chromatography (Column: Cl 8, 30g. Gradient: 0-100 % MeCN in basic buffer (NH4HCO3/NH4OH 0.1 M)) followed by another purification by reversed phase chromatography (Column: Cl 8, 15.5g. Gradient: 0-100 % MeCN in water) followed by another purification in reversed-phase préparative chromatography (Column: Cl8. Gradient 0-95 % acetonitrile in acidic water (formic acid 0.1 M)) to afford the product as a sait. At this time, the product was obtained as a free base by purification in reversed phase chromatography (Column: Cl 8, 15.5g. Gradient: 0-100 % MeCN in basic buffer (NH4HCO3/NH4OH 0.1 M)), to afford, after freeze-drying the title compound 61(10 mg, 31 %) as a white solid. 'H NMR (400 MHz, DMSO-rfô) δ 7.80 (s, 1 H), 7.57 - 7.46 (m, 4H), 4.43 (s, I H), 4.08 (br d, J = 9.8 Hz, 1 H), 3.97 (s, 3H), 3.05 - 2.96 (m, 1H), 2.76 (s, 2H), 2.04 (br s, 1H), 1.62 (br d, J = 12.8 Hz, 1H), 1.40- 1.30 (m, 2H), 1.05 (t, J = 12.0 Hz, 1 H), 0.94 (d, J = 6.2 Hz, 3H). ¹⁹F NMR (377 MHz, DMSO-î/₆) Ô 60.81 (s, 3F); LCMS m/z 355.2 [M+H]~

Préparation of Cl 7 2-(tetrahydro-2H-pyran-2-yl)-2H-l,2,3-triazole-4-carbaldehyde (Cl 7) dihydropyran pTsOH HNJ^ ⁰ —— f\j⁼N DCM

C16

C17 l H-l,2,3-triazole-4-carbaldehyde (Cl6) was obtained from commercial sources. To a mixture of C16 (l g, 10.30 mmol) and 3,4-dihydro-2H-pyran (1000 pL, 10.96 mmol) in DCM (20 mL) cooled to 0 °C was added p-TsOH. HzO (100 mg, 0.526 mmol). The mixture was warmed to rt and stirred ( 1:30). After 10 min, a bright purple color appeared and solids began to dissolve. The mixture was stirred for 3 h. At this time, the mixture was diluted with sat. aq. sodium bicarbonate (5 mL), shaken, and phase separated. The aqueous layer was washed with DCM (2x5 mL). The combined organic layer was concentrated and diluted in minimal DCM for silica gel purification (0-50 % EtOAc:heptane). Two regioisomers were isolated, only the major was kept. The title compound C17 (1094 mg, 57 %) was isolatcd as a clear oil. 'H NMR (300 MHz, Chlorotbrm-7) δ 10.17 (s, IH), 8.15 (s, 1 H), 5.83 (dd, J = 8.6, 2.7 Hz, 1H), 4.18 4.02 (m, 1H), 3.89 - 3.73 (m, 1H), 2.56- 2.35 (m, 1H), 2.25 - 2.07 (m, 2H), 1.94- 1.63 (m, 3H). LCMS m/z 181.73 [M+H]

193

Compound 62 2-methyl-6-(lH~triazol-4-yl)-4-[4-(trijluoromethyl)phenyllpiperidin-4-ol (62)

(2S)- pyrrolidine-2-carboxylic acid Et₃N

C18

C17

DCM

i. Mg, LiCI, 1-bromo-4-trifluoromethylbenzene THF ii. HCl MeOH

Step 1: Synthesis of 2-methyl-6-( I-tetrahydropyran-2-yltriazol-4-yl)piperidin-4-one (C19)

Intermediate C18 (4-aminopentane-2-one hydrochloride sait) was obtained from commercial sources. Ketone C18 (hydrochloride sait) (250 mg, 1.817 mmol) was dissolved in éthanol (10 mL) and the mixture was cooled to 0 °C. To the mixture was added compound S9 (346 mg, 1.910 mmol), EtjN (270 pL, 1.937 mmol) followed by (2y)-pyrrolidine-2-carboxylic acid (45 mg, 0.391 mmol). The mixture was stirred at 0 °C. After 1.5 h. the reaction was warmed to rt and 10 stirred. After 20 h, the mixture was concentrated, dissolved in DCM (10 mL) and sat. aq. sodium bicarbonate (5 mL). The aqueous layer was extracted with additional DCM (2x10 mL), and the combined organic layer was dried, minimally dissolved in DCM, and loaded onto a silica gel column for purification (0-10 % MeOH:DCM). The product containing fractions (visualized by KMnO4) were pooled and concentrated to yield the title compound C19 (313 mg, 65 %) as a yellow oil. ‘H NMR (300 MHz, Chloroform-7) δ 7.64 (s, 1 H), 5.69 (dd, J = 9.3, 2.6 Hz, IH), 4.25 (ddd, J = 11.3,3.9, 1.2 Hz, IH), 4.13 - 4.00 (m, IH), 3.76 (ddd, J = 11.6, 9.7,3.1 Hz, IH), 3.15 (dqd, J = 12.3,6.2,2.9 Hz, IH), 2.75 -2.66 (m, 1 H), 2.66 - 2.54 (m, 1 H), 2.52 - 2.35 (m, 2H), 2.30-2.17 (m, IH), 2.17- 1.98 (m, 3H), 1.82 - 1.64 (m, 3H), 1.29 (dd, J = 6.2, 0.6 Hz, 3H),

194

î. Mg, LiCI, 1-bromo-4-trifluoromethylbenzene THF

ii. HCl MeOH

Step 3: Synthesis of 2-methyl-6-( 1 H-triazol-4-yl)-4-[4-(ti ifliiorometliyl)phenyllpiperidin-4ol(62)

To a mixture of I-bromo-4-(trifluoromethyl)benzene (200 mg, 0.8889 mmol), LiCI (37 mg, 0.8728 mmol), and Mg (21 mg, 0.8640 mmol) was added THF ( 1 mL) and the mixture was sonicated until Grignard initiation was observed. At this time, the dark brown solution was cooled to -10 °C, at which time a THF (1 mL) solution of piperidone C19 (100 mg, 0.329 mmol) was added. The mixture was stirred for 5 min and then quenched with water (4 mL) and TBME (4 mL). The organic layer was removed, concentrated, and diluted in minimal DCM for silica gel purification (0-10 % MeOH:DCM, 1 wt% ammonia modifier). The product-containing fractions were pooled and concentrated. To the residue was added MeOH (0.2 mL) and HCl (25 pL of 4 M, 0.1000 mmol) in dioxane was added. The reaction mixture was stirred at rt. After 1 h, the mixture was concentrated and rediluted in TBME and water ( 1 mL each). The organic layer was washed with 1 N HCl (1 mL) and the combined aqueous layer was purified by reversed-phase HPLC (Method: Cl8 Waters Sunfire column (30 x 150 mm, 5 micron). Gradient: MeCN in H2O with 0.2 % formic acid). The title compound 62 formic acid sait (13.7 mg, 10 %) was isolated as a white solid. Ή NMR (300 MHz, Methanol-d4) δ 7.96 (s, 111), 7.76 (d, J = 9.2 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 5.04 (dd, J = 12.5, 3.1 Hz, IH), 3.93 (h, J = 7.0 Hz, IH), 2.54 (dd, J = 14.4, 12.5 Hz, IH), 2.28 (dd, J = 14.6, 3.2 Hz, 1 H), 2.14-2.01 (m, 2H), 1.42 (d, J = 6.6 Hz, 3H). LCMS m/z 327.27 [M+H]⁺

195

Compound 63 (2S,4S,6S)-4-(5-chloropyridin-2-yl)-2-methyl-6-(l-methyl-lII-I,2.3-triazol-4-yl) piperidine-4-carbonitnle

Step 1 : Synthesis of (2S,6S)-2-methyl-6-( 1 -methyl-/11-1,2,3-triazol-4-yl)piperidine-4carbonitrile (C20)

To a solution of piperidone SI (5 g, 24.97 mmol) and TOSMic (5.12 g, 26.22 mmol) in DME (150 mL)/tBuOH (5 mL) cooled to 0 °C was added KO'Bu (6 g, 53.47 mmol) in four portions. The reaction was then allowed to warm to rt and stirred, at which time a brown-yellow solid began to precipitate heavily. Aftcr 15 min, the reaction was filtered and rinsed with additional DME (3x5 mL). The filtrate was concentrated and partitioned between water (100 mL) and DCM (100 mL). Sat. aq. ammonium chloride (25 mL) was added to lower the pH to about 9, resulting in a milky organic layer. The organic layer was removed and the aqueous layer was extracted with additional DCM (2 x 150 mL). The aqueous layer was then diluted with brine (100 mL) followed by sodium chloride (~3 g) to re-saturate the mixture. This salted layer was further extracted with DCM (3 x 150 mL). The pooled organic layer was dried with magnésium sulfate, filtered, and concentrated. The orange solid was diluted with DCM (30 ml) and about 75 mL of TBME, which caused an immédiate précipitation. The suspension was sonicated for 5 minutes and then filtered and rinsed with additional TBME to yield the title compound C20 (2.82 g, 55 %) as a yellow solid, 4:1 mixture of nitrile diastereomers. 'H NMR (300 MHz, DMSO-7₆) Ô 7.92 (s, 1 H), 4.01 (d,J = 1.1 Hz, 3H), 3.80 (dd, J = 11.3,2.6 Hz, 1 H), 2.99 (tt, J = 12.4, 3.8 Hz, IH), 2.72 (ddd, J = 11.0, 6.3, 2.5 Hz, IH), 2.39 (s, IH), 2.23 - 1.98 (m, IH), 1.98 1.74 (m, IH), 1.66 - 1.37 (m, 1 H), 1.34 - 1.11 (m, IH), 1.04 (dd, 7= 6.3, 5.1 Hz, 3H).

Step 2: Synthesis of (2S,4S,65)-4-(5-chloropyridin-2-yl)-2-methy 1-6-( 1 -methyl-1 H-1,2,3triazol-4-yl)piperidine-4-carbonitrile (63)

To a mixture of 5-chloro-2-fluoro-pyridine (863 mg, 6.561 mmol) and piperidine C20 ( 1 g, 4.87 mmol) in THF ( 15 mL) cooled to 0 °C was added KHMDS (9.8 mL of 1 M in THF, 9.80 mmol) over 3 min. Upon completion of addition, water and sat. aq. sodium bicarbonate (10 mL

196 each) were added followed by TBME (30 mL). The organic layer was removed and the aqueous layer was extracted with additional TBME (30 mL). The combined organic layer was dried with magnésium sulfate, filtered and concentrâted. The crude oil was minimally dissolved in DCM and loaded on to a silica gel column for purification (0-10 % MeOH:DCM). The productcontaining fractions were pooled and concentrated to yield the title compound 63 ( l .3 l g, 80 %) as a brown glass. 'H NMR (300 MHz, Chloroform-J) δ 8.40 (dd, J = 2.5, 0.8 Hz, IH), 7.57 (dd, 7=8.5, 2.5 Hz, IH), 7.42 (dd, 7= 8.5, 0.8 Hz, l H), 7.34 (s, IH), 4.4] -4.29 (m, l H), 3.92 (s, 3H), 3.24 (dqd, 7= 12.5, 6.2, 2.4 Hz, lH), 2.30 - 2.19 (m, l H), 2.12 (dd, 7 = 13.2, H.6 Hz, IH), 1.98 (dt, 7 = 13.2,2.3 Hz, IH), l,70(dd,7= 13.2, 11.4 Hz,2H), 1.07 (d,7=6.2 Hz,3H). LCMS m/z 317.02 [M+H]⁺

Compound 64 (2S,4S,6S)-4-(5-chloropyriclin-2-yl)-2-methyl-6-(l-methyl-lH-l ,2,3-triazol-4-yl)piperidme4-carboxamide

To a pressure vessel was added compound 63 (50 mg, 0.158 mmol) and aqueous NaOH (1 mL of 2 M, 2.00 mmol). The biphasic mixture was heated to 140 °C and stirred for 90 min. At this time, the mixture was pH adjusted with ~500 uL 2 N HCl to a pH of about 10, at which time the mixture was extracted with DCM (2 x 1 mL). The combined organic layer was concentrated to yield the title compound 64 (23 mg, 43 %) as an off-white solid. 'H NMR (300 MHz, Chloroform-J) δ 8.48 (d, J = 2.5 Hz, 1 H), 7.62 (dd, 7=8.5, 2.6 Hz, 1 H), 7.49 (s, 1 H), 7.32 (d, J = 8.6 Hz, IH), 6.46 (s, 1 H), 5.68 (s, IH), 4.32 (dd,7= 11.8, 2.4 Hz, 1 H), 4.05 (s,3H),3.273.09 (m, IH), 2.94 (dt,7= 13.3, 2.5 Hz, 1 H), 2.69 (dt, 7 = 13.4,2.4 Hz, 1 H), 2.03 (s, IH), 1.85 (dd, 7= 13.4, 11.8 Hz, IH), 1.42 (dd, 7= 13.3, 11.3 Hz, IH), 1.18 (d, 7= 6.2 Hz, 3H). LCMS m/z 335.07 [M+H]⁺

Compound 65 ((2S,4S,6S)-2-methyl-6-(l-methyl-lH-l,2,3-}riazol-4-yl)-4-(4(trifhioromethyl)phenyl)piperidin-4-yl)methanol

197

Step 1: Synthesis of(2S,4S, 6S)-2-methyl-6-( 1 -methyl-lH-l,2,3-triazol-4-yl)-4-(4(trifluoromethyl)phenyl)piperidine-4-carbaldehyde (C21)

To a THF (1 mL) solution of piperidine 46 (50 mg, 0.1431 mmol) cooled to -78 °C was added diisobutylalumane (290 pL of 1 M, 0.290 mmol) dropwise and the mixture was stirred at 78 °C. After 90 min, the reaction mixture was warmcd to -35 °C. After 40 min at this température, the mixture was cooled to -78 °C once again and additional diisobutylalumane (290 pL of 1 M, 0.290 mmol) was added dropwise and the mixture continued to stir at this température, and then allowed to wann up to rt for 18 h. At this time, the mixture was cooled back to - 78 °C and quenched with 15 % citric acid (1 mL). TBME (3 mL) was added and the resulting suspension was filtered. The aqueous layer was extracted with TBME (2 x 1 mL). The combined organic layer was dried with magnésium sulfate, filtered and concentrated to yield the title compound C21 (45 mg, 86 %) as a clear oil. 'H NMR (300 MHz, Chloroform-t/) δ 9.50 (d, J = 1.0 Hz, IH), 7.71 -7.60 (m, 2H), 7.48 (s, IH), 7.47 - 7.36 (m, 2H), 4.18 (dd, J= 11.9, 2.7 Hz, 1H),4.O8 (s,3H),3.02 (dtd, J = 12.3,6.2,2.4 Hz, IH), 2.87 (dt, J = 13.2, 2.5 Hz, 1H),2.57 (dt, J = 13.2, 2.4 Hz, IH), 1.93 (ddd,7= 13.1, 12.0, 1.1 Hz, IH), 1.57 (d, J= 12.4 Hz, IH), 1.22 (d, J = 6.2 Hz, 3H). 19F NMR (282 MHz, CDCI3) δ -62.71. LCMS m/z 353.12 [M+H]⁺

Step 2: Synthesis of((2S, 4S, 6S)-2-methyl-6-( 1 -methyl-lH-l,2,3-triazol-4-yl)-4-(4(trifluoromethyl)phenyl)piperidin-4-yl)methanol (65)

To a mixture of aldéhyde C21 (22 mg, 0.0624 mmol) in THF ( 1 mL) was added NaBHa (10 mg, 0.264 mmol) After 1 h. the reaction was diluted with sat. aq. ammonium chloride (1 mL) and TBME ( 1 mL) and the mixture was stirred ovemight. At this time, the organic layer was

198 removed and the aqueous layer was extracted with additional TBME (1 mL). The combined organic layer was concentrated and diluted in MeOH for reversed-phase purification (Method: Waters XSelect CSH Cl8 OBD Prep Column; 30 x 150 mm, 5 micron. Gradient: Acetonitrile in Water with 10 mM Ammonium Hydroxide). The product containing fraction was concentrated to 5 yield the title compound 65 ( 11.5 mg, 48 %) was isolated as a whitc solid. ¹H NMR (300 MHz,

Methanol-d4) δ 7.86 (s, IH), 7.61 (s, 4H), 4.29 (dd, J = 12.2, 2.7 Hz, 1 H), 4.09 (s, 311), 4.01 -

3.89 (m, 2H), 3.22 (dqd, J = 12.4, 6.3, 2.7 Hz, 1 H), 2.56 (dt, J = 13.4,2.5 Hz, 1 H), 2.30 (dt, J = 13.5, 2.5 Hz, IH), 1.73 (dd, J = 13.4, 12.3 Hz, IH), 1.38 (dd, J = 13.5, I 1.7 Hz, IH), 1.21 (d, J = 6.2 Hz, 3H). 19F NMR (282 MHz, Methanol-d4) δ-63.91. LCMS m/z 355.37 [M+H]⁺

Compound 66 (2S,4R,6S)-2-methyl-6-( l -methyl-1 H-1,2.3-triazol-4-yl)-4-(4(trifluoromethyl)phenyl)piperidine

C23 66

Step I: Synthesis of (2S,4R,6S)-2-methyl-6-(l-methyl-lH-I,2,3-triazol-4-yl)-4-(415 (trijhioromethyl)phenyl)piperidin-4-ol (C22)

To a suspension of Mg (4.8 g, 197.5 mmol) in 2-MeTHF (400 mL) under nitrogen was added I-bromo-4-(trifluoromethyl)benzene (27,9 mL, 199.3 mmol) followed by iodine (180 mg, 0.709 mmol). The mixture was then heated to 45 °C until no evidence of solid magnésium was observed. The reaction mixture was cooled to rt and stirred ovemîght. At this time, the mixture

199 was sonicated in a 30 °C sonicator bath for a brief time and then the mixture was cooled to 10 °C. Piperidone SI (15 g, 77.23 mmol) was added in portions over 20 min, maintaining an internai température below -5 °C. Upon completion of addition, additional 2-MeTHF (50 mL) was added. After l 5 min. the mixture was diluted with water (100 mL), sat. aq. ammonium chloride (100 mL), and the formed biphasic was diluted with EtOAc (250 mL). The formed layers were split and the aqueous layer was extracted with additional EtOAc (100 mL). The combined organic layer was dried with sodium sulfate, filtered and concentrated. The crude mixture was diluted with DCM and loaded on to a silica gel column for purification (100 % EtOAc - 2 % Et?N:8 % MeOH:90 % EtOAc). The product-containing fractions were pooled and concentrated and submitted for SFC purification (DAICEL CHIRALPAK ® AD-H 20x250 mm column, 40 % MeOH:CO₂, 75 mL/min flow rate). The product containing fractions were pooled and concentrated to yield the title compound C22 ( l .53 g, 6%) as an orange glass. LCMS m/z 340.10 [M+H]⁺

Step 2: Synthesis of (2S,6S)-6-methyl-2-(l-methyl-lH-L2,3-triazol-4-vl)-4~(4(trifluoromethyl)phenyl)-1.2,3,6-tetrahydropyridine (C23)

To a mixture of piperidine C22 (100 mg, 0.294 mmol) in DCM (2 mL) was added MsOH (60 pL, 0.925 mmol), which immediately eaused précipitation. The suspension was heated to reflux for 10 min, at which time MeOH (0.5 mL) was added. The thin suspension was stirred at reflux for 4 h. At this time, MsOH (500 pL, 7.71 mmol) was added, which resulted in a clear solution. After stirring ovemight, the reaction was heated to 70 °C open to the air. After stirring ovemight, the reaction mixture was cooled to rt, diluted with DCM (8 mL) and the oiled-out mixture was added dropwise to sat. aq. sodium bicarbonate (10 mL). The layers were split and the organic layer was passed over a phase separator, concentrated to a minimal volume and loaded on to a silica gel column for purification (0-10 % MeOH:DCM). The product-containing fraction was concentrated to yield the title compound C23 (55 mg, 58 %) as a clear oil. LCMS m/z 323.19 [M+H]⁺

Step 3: Synthesis of (2S,4R,6S)-2-methyl-6-(l-methyltriazol-4-yl)-4~[4(trifluoromethyl)phenvi(piperidine (66)

To a solution of alkene C23 (55 mg, 0.171 mmol) from the first step was added Pd/C (30 mg, 0.0141 mmol) followed by éthanol (2 mL). The mixture was pressure purged with 60 psig nitrogen (5x) and 50 psig hydrogen (3x) and stirred under 50 psig hydrogen (5:00). After stirring ovemight, the mixture was once again purged with 60 psig nitrogen (5x), filtered over Celite®, rinsed with additional éthanol (~3 mL) and concentrated. The crude mixture was dissolved in minimal DCM and loaded on to a silica gel column for purification (0-25 % MeOH:DCM, l %

200

NHî modifier). Two product containing fractions were kept separated and evaluated by ‘H NMR. The first fraction was found to contain the title compound 66 ( 12.6 mg, 13 %) as a white solid. 'H NMR (300 MHz, MeOD) δ 7.84 (s, lU), 7.65 - 7.54 (m, 2H), 7.47 (d, J= 7.9 Hz, 2H), 4.08 (s, 4H), 3.11 -3.01 (m, IH), 3.01 - 2.90 (m, l H), 2.22 - 2.10 (m. IH), l.9l (ddt,7 = 12.9,4.2, 2.2 Hz, IH), 1.71 (td,7 = 12.6, 11.5 Hz, IH), 1.39 (td, 7 = 12.6, 11.0 Hz, IH), 1.21 (d,7=6.3 Hz, 3H). LCMS m/z 325.26 [M+H]’

Compound 67 (2S,4S,6S)-2-methyl-6-( 1-methyl-1 H-J , 2,3-triazol-4-y 1)-4-(4(trifluoromethyl)phenyl)piperidine-4-carboxamide (67)

C13 024 67

Step l : Préparation of (2S.4S.6S)-1-allyl-2-melhyl-6-(l- methyltriazol-4-yl)-4-[4 (trifhioromethyl)phenyI]piperidine-4-carboxamide (C24)

To a solution of (2S,4S,6S)-1-allyl-2-methyl-6-(l-methyl-lH-l,2,3-triazol-4-yl)-4-(4(trifluoromethyl)phenyl)piperidine-4-carbonitrile C13 (120 mg, 0.3041 mmol) in ethylene glycol (3 mL)/water (0.3 mL) was added KOH (400 mg, 7.1294 mmol). The reaction was warmed-up to 120 °C and stirred at this température for 6 hours. The reaction was coolcd down to room température and directly loaded onto the Cl8 column. Purification by reversed-phase chromatography (column: Cl8; gradient: 0-100 % MeCN in water) affordcd, after ovemight freeze-drying, (25,45,65)-1 -allyl-2-methyl-6-(l- methyltriazol-4-yl)-4-[4 (trifluoromethyl)phenyl]piperidine-4-carboxamide (105 mg, 84%) as a white powder. 'H NMR (400 MHz, DMSO-d6) δ 7.99 (s, I H), 7.68 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.2 Hz, 211), 7.34 (s, IH), 7.11 (s, IH), 5.89 (ddt, J = 17.1, 10.4, 6.5 Hz, IH), 5.13 - 5.01 (m, 2H), 4.01 (s, 3H), 3.93 (brd, J = 10.8 Hz, IH), 3.19 (br dd, J = 15.8,7.3 Hz, 1H),2.83 (br dd, J = 15.8,5.7 Hz, IH), 2.78 - 2.70 (m, 1 H), 2.70 - 2.59 (m, 2H), 1.80 (t, J = 12.3 Hz, IH), 1.50 (brt, J = 12.1 Hz, IH), 1.12 (d, J = 6.0 Hz, 3H). ¹⁴F NMR (377 MHz, DMSO-d6) δ -60.87 (s, 3F). ESI-MS m/z cale. 407.1933, found 408.2 (M+l)⁺

201

Step 2: Synthesis of (2S,4S,6S)-2-methyl-6-(l-methyl-1 H-1,2.3-triazol-4-yl)-4-(4(trifhioromethyl)phenyl)piperidine-4-carboxamide (67)

To a solution of (2S,4S,65>i-allyl-2-methyl-6-( 1-methyltriazol-4-yl)-4-[4(trifluoromethyl)phenyl]piperidine-4-carboxamide C24 (103 mg, 0.2515 mmol) and N,Ndimethylbarbituric acid (54 mg, 0.3251 mmol) in DCM (2 mL) was added Pd(PPhî)₄ (30 mg, 0.0257 mmol). The réaction was stirred for 1.5 hours. The solvent was removed under vacuum then the residue dissolved with a IM aqueous solution of hydrochloric acid ( 10 mL). The aqueous phase was washed with MTBE (3x10 mL) then the pH was adjusted to 8-9 by addition of a 1M aqueous solution of sodium hydroxide. The aqueous solution was then extracted with MeTHF (3 x 20 mL), dried over sodium sulfate and the solvent removed under vacuum. Purification by reversed-phase chromatography (column: Cl 8; gradient: 5-100 % MeCN in water) yielded, after ovemight freeze-drying, (2S,4S,6S)-2-methyl-6-(l- methyltriazol-4-yl)-4[4-(trifluoromethyl)phenyl]piperidine-4-carboxamide 67 (50 mg, 54%) as a white solid. 'H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1 H), 7.70 (br d, J = 8.3 Hz, 2H), 7.60 (br d, J = 8.3 Hz, 2H), 7.33 (s, IH), 7.12 (s, IH), 4.05 - 3.92 (m, 4H), 2.96 - 2.88 (m, IH), 2.85 (d, J = 13.0 Hz, IH), 2.59 (brd, J = 13.0 Hz, 1 H), 2.28 - 2.10 (m, IH), 1.50 (br t, J = 12.2 Hz, IH), 1.22 (br t, J = 12.0 Hz, IH), 1.07 (d, J = 6.1 Hz, 3H); ^,9F NMR (377 MHz, DMSO-d6) δ-60.84 (s, 3F). ESI-MS m/z cale. 367.162, found 368.2 (M+l)7

Compound 68 (2S, 4S, 6S)-2-methyl-6-( 1 -methyl-1 H-1,2,3-triazol-4-yl)-4-(4-(trifhioromethyl)phenyl2,3,5,6-d4)pipeiïdin-4-ol (68)

To a round bottom flask was added magnésium tumings (1.7 g, 65.24 mmol). The flask was charged with 2-MeTHF (98.6 mL) with N? flowing through the reactor headspace. At this time, isopropylmagnesium chloride (0.21 g, 1.01 mL, 2M in THF) was added with stirring. The solution was heated to 50 °C for 20 min, at which time l-bromo-4-(trifluoromethyl)benzene2,3,5,6-d4 was added slowly via syringe pump. The formed dark solution was then cooled to -10 °C. (25^,,6S)-2-methyl-6-(l-methyI-l//-l,2,3-triazol-4-yl)piperidin-4-one SI {4.93g, 25.4

202 mmol) was added, after which the reaction was stirred at room température for 1.5 hours, and then quenched with NH4CI ( 100 mL), and H?O ( 100 mL). The mixture was extracted four times with 2-MeTHF, and the combined fractions dried over sodium sulfate, fïltered, and concentrated. Purification by chiral SFC chromatography provided, after drying, (25,45,65j-2-methyl-6-(lmethyl-l//-l,2,3-triazol-4-yl)-4-(4-(trifluoromethyl)phenyl-2,3,5,6-d4)piperidin-4-ol 68 (3.11 g).

Compounds I5-I296

Compounds I5-I296 can be prepared in manners analogous to those described for Compounds l -30, Compounds 31-44, and Compounds 45-68 disclosed above.

Example 2. MultiTox-Fluor Multiplex Cytotoxicity Assay for Detecting and Measuring APOL1 Inhibitor Properties

The MultiTox-Fluor Multiplex Cytotoxicity Assay is a single-rcagent-addition, homogeneous, fluorescence assay that measures the number of live and dead cells simultaneously in culture wells. The assay measures cell viability and cytotoxicity by detecting two distinct protease activities. The live-cell protease activity is restricted to intact viable cells and is measured using a fluorogenic, cell-permeant peptide glycyl-phenylalanylamino fluorocoumarin (GF-AFC) substrate. The substrate enters intact cells, where it is cleaved to generate a fluorescent signal proportional to the number of living cells. This live-cell protease activity marker becomes inactive upon loss of membrane integrity and leakage into the surrounding culture medium. A second, cell-impermeant, fluorogenic peptide substrate (bisAAF-Rl 10 Substrate) is used to measure dead-cell protease that has been released from cells that hâve lost membrane integrity. A ratio of dead to live cells is used to normalize data.

Briefly, the tet-inducible transgenic APOLl T-REx-HEK293 cell lines were incubated with 50 ng/mL tet to induce APOLl in the presence of 3-(2-(4-fluorophcnyl)-IH-indol-3-yl)-N((3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl)propenamide at 10.03, 3.24, l. 13, 0.356, 0.129, 0.042, O.l29, 0.0045, 0.0015, 0.0005 μΜ in duplicate for 24 hours in a humidified 37 °C incubator. The MultiTox reagent was added to each well and placed back in the incubator for an additional 30 minutes. The plate was read on the EnVision plate reader. A ratio of dead to live cells was used to normalize, and data was imported, analyzed, and fit using Genedata Screener (Basel, Switzerland) software. Data was normalized using percent of control, no tet (100% viability), and 50 ng/mL tet treated (0% viability), and fit using Smart Fit. The reagents, methods, and complété protocol for the MultiTox assay are described below.

203

Reagent	Catalog Number	Vendor
384 well, transparent, fiat bottom tissue culture treated, Poly-D lysine coated	356663	Corning (Corning, NY)
384 well round bottom polypropylene plates	3656	CoStar (Corning, NY)
Universal plate lids	250002	Thermo Fisher (Waltham)
Axygen 30 μ L tips for Bravo 384 well	VT-384-3 1UL-R-S	Corning (Corning, NY)
MultiTox-Fluor Multiplex Cytotoxicity Assay	G9202	Promega (Madison, WI)
225 cm2 flask, angled neck, treated, vented cap	431082	Corning (Corning, NY)
Dulbecco's PhosphateBuffered Saline (DPBS), calcium and magnesiumfree	14190-136	Thermo Fisher (Waltham)
Dulbecco's Modified Eagle Medium (DMEM), high glucose, no glutamine, no sodium pyruvate	11960-077	Thermo Fisher (Waltham)
Fêtai Bovine Sérum (FBS), tetracycline-free, USSourced	631368	Takara (Kusatsu, Japan)
L-Glutamine, 200 mM	25030-081	Thermo Fisher (Waltham)
Penicillin-Streptomycin, 10,000 Units/mL	15140-122	Thermo Fisher (Waltham)
Blasticidin S HCl, 10 mg/mL	Al 1139-03	Thermo Fisher (Waltham)
Tétracycline hydrochloride	T7660 -5G	Sigma (St. Louis, MO)
Puromycin dihydrochloride, 10 mg/mL	Al 1138-03	Thermo Fisher (Waltham)
Trypsin-EDTA	25300-054	Thermo Fisher (Waltham)

Instrument	Model	Supplier	Location
Bravo	16050-101	Agilent Technologies	Santa Clara, CA
Multidrop	N/A	Thermo	Waltham, MA
Combi		Scientific
EnVision	N/A	PerkinElmer	Waltham, MA

Multi-Tox Assay Protocol

Human embryonic kidney (HEK293) cell lines containing a tet-inducible expression

System (T-REx™; Invitrogen, Carlsbad, CA) and Adeno-associated virus site l pAAVS 1-Puro-APOLl GO or pAAVS l-Puro-APOLl Gl or pAAVS l-Pure-APOLl G2 Clones

204

GO DC2.13, Gl DC3.25, and G2 DC4.44 were grown in a T-225 flask at -90% confluency in cell growth media (DMEM, 10% Tet-free FBS, 2 mM L-glutamine, 100 Units/mL penicillinstreptomycin, 5 pg/mL blasticidin S HCl, l pg/mL puromycin dihydrochloride). Cells were washed with DPBS and then trypsinized to dissociate from the flask. Media was used to quench the trypsin, cells were then pelleted at 200g and resuspended in fresh cell assay media (DMEM, 2% Tet-free FBS, 2 mM L-glutamine, 100 Units/mL penicillin-streptomycin). Cells were counted and diluted to l.17 x 10⁶ cells/mL. 20 pL of cells (23,400/well) were dispensed in every well of a 384-well Poly-D-Lysine coated plate using the Multidrop dispenser. The plates were then incubated at room température for one hour.

Tétracycline is needed to induce APOLl expression. I mg/mL tet stock in water was diluted to 250 ng/mL (5X) in cell assay media. 60 pL of cell assay media (no tet control) was dispensed in columns l and 24, and 60 pL of 5X tet in 384-PP-round botfom plate was dispensed in columns 2 to 23 with the Multidrop dispenser.

100011 Assay ready plates from the Global Compound Archive were ordered using template 384_APOLlCell_DR10n2_50uM_v3. Compounds were dispensed at 200 nL in DMSO. The final top concentration was 10 pM with a 10 point 3-fold dilution in duplicate in the MultiTox assay.

pL was transferred from the 5X tet plate to the ARP and mixed, then 5 pL of 5X tet and the compounds were transferred to the cell plate and mixed using the Bravo. The cell plate was placed in the humidified 37 °C 5% CO? incubator for 24 hours.

The MultiTox-Fluor Multiplex Cytotoxicity Assay was performed in accordance with the manufacturées protocol. After cells were incubated with tet and compound for 24 hours, 25 pL of Ix MultiTox reagent was added to each well using the Multidrop dispenser; the plates were placed on a plate shaker (600 rpm) for 2 minutes, then centrifuged briefly and placed back in the 37 °C incubator for 30 minutes. The cell viability (excitation: 400 nm, émission: 486 nm) and cytotoxicity (excitation: 485 nm, émission: 535 mu) were read using the EnVision plate reader. A ratio of dead (cytotoxicity) to live (viability) cells was reported. Data was exported and analyzed in Genedata. Data was normalized using percent of control, no tet (100% viability), and 50 ng/mL tet treated (0% viability), and fit using Smart Fit settings in Genedata.

Potency Data for Compounds 1 to 29

The compounds of Formula I are useful as inhibitors of APOLl activity. Table 6 below illustrâtes the ICsü of Compounds 1 to 68 using procedures described above. The procedures above may also be used to détermine the potency of Compounds 15 to 1295, and Compound 1296. In the table below, the foliowing meanings apply. For IP50 (f e., IC50 for cell

205 prolifération), “+++” means < 50 nM; “++” means between 50 nM and 500 nM; “+” means > 500 nM. RND = 100% inhibition at 10 pm. ND = Not determined.

206

Potency Data for Compounds 1 to 68

Compound No.	IP5e (nM)	Compound No.	IPso(nM)	Compound No.	IPsu (nM)
1	4-	24	++	47	-|-ψ4-
2		25	+++	48	-H-
3	++	26	+++	49	-H-
4	+++	27	+++	50	+++
5		28	+-Hh	51	+-H-
6	++	29		52	-HH-
7	+	30	++	53	+
8	+++	31	+	54	+
9	++	32	-H-	55	+
10	++	33	-H-+	56	+
11	II·	34	-HH-	57	+
12	++	35	+	58
13	+++	36	-HH-	59	-H-
14	++	37	-H-	60	+
15	+	38	-HH-	61	+
16	+++	39	-H-l·	62	H—H-
17	++	40	-HH-	63	+
18	++	41	RND	64	+
19	+++	42	-H-	65	-H-
20	+	43	-HH-	66	-H-
21	-H-	44	-H-	67	-H-
22	I· 1	45	+	68	ND
23	rj. |	46	-H-

207

Other Embodiments

This disclosure provides merely non-limiting example embodiments of the disclosed subject matter. One skilled in the art will readily recognize from the disclosure and claims, that various changes, modifications and variations can be made therein without departing from the 5 spirit and scope of the disclosure as defined in the following claims.

Claims (5)

I. A compound represented by the formula: (R1)m R5 Formula la a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait ofany ofthe foregoing, wherein: Ring A is chosen from Cô aryl and 5- and 6-membered heteroaryl groups; R1, for each occurrence, is independently chosen from halogen, -OH, =O, cyano, phenyl, Ci-C& alkyl, Ci-Cô alkoxy, Cj-Cô earbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)N(RC)2, and -SO2(RC) groups, wherein: Rc, for each occurrence, is independently chosen from hydrogen and C1-C4 alkyl groups; the 4- to 6-membered heterocyclyl of R1 comprises one heteroatom chosen from nitrogen and oxygen; the Cj-Cô alkyl of R1 is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(C|-C4 alkyl), -N(C|-C4 alkyl)2, and C1-C4 alkoxy groups; the Ci-Cô alkoxy of R1 is optionally substituted with 1 to 3 groups independently chosen from -OH, cyano, and halogen groups; the Cî-Cô earbocyclyl of R1 is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(Ci-C4 alkyl), and -C(=O)N(Ci-C4 alkyl)2 groups; and 209 the phenyl of R1 is optionally substituted with I to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl), -N(C]-C4 alkyl)?, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH?, -C(=O)NH(Ci-C4 alkyl), and -C(=O)N(Ci-C4 alkyl)? groups; or wherein two R1 groups taken together with the Ring A atoms connecting them form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and C1-C4 alkyl; R2is chosen from cyano, Ci-Cô alkyl, -C(=O)O(Ci-C4 alkyl), C2-Cô alkynyl, and the Ci-Cô alkyl of R2is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH2, -NH(Cj-C4 alkyl), -N(C|-C4 alkyl)?, C1-C4 alkoxy, -C(=O)NH2, -C(=O)NH(Ci-C4 alkyl), -C(=O)N(Cj-C4 alkyl)?, C3-C6 carbocyclyl, 5- to 10-membered heterocyclyl, Cô aryl, and 5- to 10-membered heteroaryl groups; Ring B is chosen from C3-C|2 carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with 1, 2, 3, 4, or 5 Ra groups; wherein: Ra, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, C2-Cô alkenyl, Cj-Cô alkoxy, Ci-Cô haloalkyl, Ci-Cô haloalkenyl, Ci-Cô haloalkoxy, -C(=O)NRhR!, -NR1*^, -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NR'Rj, -NR,,S(=O)PRk -ORk, -OC(=O)Rk, -OC(=O)ORk, -OC(=O)NRhR', -[O(CH2)M]rO(Ci-C6 alkyl), -S(=O)PRk, -S(=O)PNRhRi, -C(=O)ORk, C3-C|2 carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein: the Ci-Cô alkyl, Ci-Cô alkoxy, and the C2-Cô alkenyl of Ra are each optionally substituted with 1 to 3 groups independently chosen from Cô to Cio aryl (optionally substituted with 1 to 3 Rm groups), 5- to 10membered heterocyclyl (optionally substituted with 1 to 3 Rm groups), 5to 10-membered heteroaryl (optionally substituted with 1 to 3 Rm groups), cyano, -C(=O)Rk, -C(=O)ORk, -C(=O)NRhRi, -NRhR‘, 210 -NRhC(=O)Rk, -NRhC(=O)ORk, -NRhC(=O)NRiRj, -NRhS(=O)PRk -ORk, -OC(-O)Rk, -OC(=O)ORk, -OC(=O)NRhRi, -S(-O)PRk. -S(=O)PNRhR', -O(Cô aryl) (optionally substituted with l to 3 Rm groups), and Ci-Cô carbocyclyl groups (optionally substituted with l to 3 R’ groups); the C3-C12 carbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cio aryl, and the 5- to 10-membered heteroaryl of Ra are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C4 alkyl, -NRhR‘, and -ORk groups, wherein: R11, R1, and Ri, for each occurrence, are each independently chosen from hydrogen, C1-C4 alkyl, Cô-Cioaryl, and C3-Cô cycloalkyl groups, wherein: the C1-C4 alkyl of any one of Rh, R1, and R' is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups; Rk, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to 10-membered heterocyclyl, and C3-Cô carbocyclyl groups, wherein: the C1-C4 alkyl of any one of Rk is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups; Rm, for each occurrence, is independently chosen from halogen, cyano, oxo, Ci-Cô alkyl, Ci-Cô alkoxy, -S(=O)PRk, and -ORk groups, wherein: the Ci-Cô alkyl of R,n is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and -O(Ci-C4 alkyl) groups; R3 is chosen from Ci-Cô alkyl, -C(=O)O(Ci-C4 alkyl), C3-Ci2 carbocyclyl, 3- to 12membered heterocyclyl, Cô and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein: the Ci-Cô alkyl of R3 is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?, C1-C4 alkoxy, -C(=O)NH?, -C(=O)NH(Ci-C4 alkyl), and -C(=O)N(Ci-C4 alkyl)? groups; the C3-Ci? carbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cio aryl, and the 5- to 10-membered heteroaryl of R3 are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl) 211 (optionally substituted with -OH), -N(Ci-C4 alkyl)?, C1-C5 alkyl (optionally substituted with -OH or -S(=O)?(Ci-C4 alkyl)), Ci-C4alkoxy, -C(=O)NH?, -C(=O)NH(C|-C4 alkyl), -NHC(=O)(Ci-C4 alkyl), -C(=O)(Ci-C4 alkoxy), and -C(=O)N(C|-C4 alkyl)? groups; R4 is chosen from halogen, cyano, Ci-Cô alkyl, Ci-Cô haloalkyl, -(CH?)nC(=0)NRR, -NRnR°, -NR“C(=O)RP, -NRnS(=O)PRp-(CH2)nORp, -S(=O)PRP, -S(=O)PNRnR°, -OS(=O)PNRR°, and -(CH2)nC(=O)ORp groups, wherein: R'1 and R°, for each occurrence, are each independently chosen from hydrogen and C1-C4 alkyl groups; and Rp, for each occurrence, is independently chosen from hydrogen, Ci-C4 alkyl, and C1-C4 haloalkyl groups; R5 is chosen from hydrogen and C1-C0 alkyl; m is an integer chosen from 0, 1,2, 3, 4, and 5; n is an integer chosen from 0, 1, and 2; p, for each occurrence, is an integer independently chosen from 1 and 2; and q and r, for each occurrence, are each an integer independently chosen from 1,2, 3, and 4.

1 to 3 groups independently chosen from halogen, cyano, OH, and -O(Ci-C4 alkyl) groups.

40. A compound represented by the formula:

a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein:

R^,a and R^lb are independently chosen from halogen, H, C1-C4 alkyl, and C1-C4 haloalkyl groups; and

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R^lc is chosen From halogen, H, CH3, -OH, and CH3OH.

41. Compound 16 Form A.

42. A pharmaceutical composition comprising at least one compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of claims l to 40 and a pharmaceutically acceptable carrier.

43. A pharmaceutical composition comprising Compound 16 Form A and a pharmaceutically acceptable carrier.

44. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of claims l to 40 or the pharmaceutical composition according to claim 42 for use in treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease.

45. Compound 16 or Compound 16 Form A or the pharmaceutical composition according to claim 43 for use in treating focal segmentai glomerulosclerosis and/or non-diabetic kidney disease.

46. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of claims l to 40 or the pharmaceutical composition according to claim 42 for use in treating an APOLl-mediated disease.

47. Compound 16 or Compound 16 Form A or the pharmaceutical composition according to claim 43 for use in treating an APOLl-mediated disease.

48. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of claims l to 40 or the pharmaceutical composition according to claim 42, for use in treating an APOLl-mediated cancer.

49. Compound 16 or Compound 16 Form A or the pharmaceutical composition according to claim 43 for use in treating an APOLl-mediated cancer.

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50. The compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to any one of claims l to 40 or the phannaceutical composition according to claim 42 for use in treating APOLI-mediated pancreatic cancer.

2. A compound represented by the formula:

a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a phannaceutically acceptable sait of any of the foregoing, wherein:

X is a bond (i.e., X is absent) or is chosen from -(CH?)-, and -(CH?)SO?-;

212

Ring A is chosen from C6 cycloalkyl, Cô aryl and 5- and 6-membered heteroaryl groups; R¹, for each occurrence, is independently chosen from halogen, -OR^C, =O, cyano, phenyl, Ci-Cô alkyl, Cj-Cô alkoxy, C?-Cô carbocyclyl, 4- to 6-membered heterocyclyl, -C(=O)N(R^C)₂, -S(cyclopropyl), and -SO₂(R^C) groups, wherein:

R^c, for cach occurrence, is independently chosen from hydrogen and C1-C4 alkyl groups;

the 4- to 6-membered heterocyclyl of R¹ comprises one heteroatom chosen from nitrogen and oxygen;

the Ci-Cô alkyl of R’ is optionally substituted with 1 to 6 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?, and C1-C4 alkoxy groups;

the Cj-Cô alkoxy of R¹ is optionally substituted with 1 to 3 groups independently chosen from -OH, cyano, and halogen groups;

the Cî-Cô carbocyclyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), and

-C(=O)N(C 1-C4 alkyl)? groups; and the phenyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)₂, C1-C4 alkyl, C]-C4 alkoxy, C(=O)NH₂, -C(=O)NH(Ct-C4 alkyl), and -C{=O)N(Ci-C₄ alkyl)? groups; or wherein two R¹ groups taken together with the Ring A atoms connecting them form a 5to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, or 5- to 6membered heteroaryl ring, wherein the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6membered aryl, 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and C1-C4 alkyl;

R² is chosen from cyano, Ci-Cô alkyl, -C(=O)O(Cj-C4 alkyl), C₂-Cô alkynyl, and

the Ci-Cô alkyl of R² is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C4 alkyl), -N(C|-C4 alkyl )₂, C1-C4 alkoxy, C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -C(=O)N(C|-C₄ alkyl)?, C₃-C₆ carbocyclyl, 5- to 10membered heterocyclyl, Cô aryl, and 5- to 10-membered heteroaryl groups;

213

Ring B is chosen from C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with l, 2, 3, 4, or 5 R^a groups; wherein:

R^a, for each occurrence, is independently chosen from halogen, cyano, Cj-Cô alkyl, Ci-Cô alkenyl, Ci-Cô alkoxy, Ci-Cô haloalkyl, Ci-C& haloalkenyl, Cj-Cô haloalkoxy, -C(=O)NR^hR', -NR^hR', -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -^0(=0)^^, -NR^!,S(=O)PR^k-OR^k. -OC(=O)R^k, -OC(=O)OR^k, -OC(=O)NR^hR', -[O(CH2)q]rO(Ci-C₆ alkyl), -S(=O)_PR\ -S(=O)_PNR^llRⁱ, -C(^_O)OR^k, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cio aryl, and 5- to IOmembered heteroaryl groups, wherein:

the Ci-Cô alkyl, Ci-Cô alkoxy, and the C2-C6 alkenyl of R^a are each optionally substituted with l to 3 groups independently chosen from Cô to Cio aryl (optionally substituted with l to 3 R¹ groups), 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 R^m groups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 R¹ groups), cyano, -C(=O)R^k, C(=O)OR^k, -C(=O)NR^I1R‘, MTR'.

-NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^l’C(=O)NRⁱRⁱ, -NR^hS(=O)PR^k -OR^k, -OC(=O)R^k, -OC(O)OR^k, -00(=0)^^, -S(=O)PR^k,

-S(=O)_pNR^hR', -O(Cô aryl) (optionally substituted with 1 to 3 R^m groups), and Cj-Cô carbocyclyl groups (optionally substituted with 1 to 3 R¹ groups);

the C3-C12 carbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cio aryl, and the 5- to 10-membered heteroaryl of R^a are each optionally substituted with I to 3 groups independently chosen from halogen, cyano, C1-C4 alkyl, -NR^hR', and -OR^k groups, wherein:

R^h, R¹, and R\ for each occurrence, are each independently chosen from hydrogen, C1-C4 alkyl, Cô-Cioaryl, and Cj-Cô cycloalkyl groups, wherein:

the C1-C4 alkyl of any one of R¹¹, R‘, and R^j is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to 10membered heterocyclyl, and

Cj-Cô carbocyclyl groups, wherein:

the C1-C4 alkyl of any one of R^k is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^m, for each occurrence, is independently chosen from halogen, cyano, oxo, Cj-Cô alkyl, Cj-Cô alkoxy, -S(=O)_PR^k, and -OR^k groups, wherein:

the Ci-Cô alkyl of R^m is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and -0(Cj-C4 alkyl) groups;

214

R³ is chosen from Ci-Cô alkyl, -C(=O)O(Ct-C4 alkyl), C3-C12 carbocyclyl, 3- to 12membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein:

the C1-C0 alkyl of R³ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C₄ alkyl), -N(Ci-C₄ alkyl)?, C]-C4alkoxy, C(=O)NH?, -C(=O)NH(Ci-C4 alkyl), and -C(=O)N(Ci-C4 alkyl)? groups;

the C3-C1? carbocyclyl, the 3- to 12-membcrcd heterocyclyl, the Cô and Cioaryl, and the 5- to 10-membered heteroaryl of R³ are each optionally substituted with I to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl) (optionally substituted with -OH), -N(Ci-C4 alkyl)2, C1-C5 alkyl (optionally substituted with -OH or -S(=O)?(Ci-C4 alkyl)), C1-C4alkoxy, -C(=O)NH₂, -C(=O)NH(Ci-C₄ alkyl), -NHC(=O)(Ci-C₄ alkyl), C(=O)(Ci-C₄ alkoxy), and -C(=O)N(Ci-C₄ alkyl)? groups;

R⁴ is chosen from hydrogen, halogen, cyano, Ci-Cô alkyl, Ci-Cô haloalkyl, (CH?)nC(=O)NRⁿR°,

-NRⁿR°, -NR°C(=O)RP, -NRS(=O)_PRP -(CH₂)»ORp, -S(=O)_pR”, -S(=O)_pNRR°, -OS(=O)_PNR^I1R°, and -(CH?)nC(=O)OR^p groups, wherein:

R and R”, for each occurrence, are each independently chosen from hydrogen and C1-C4 alkyl groups; and

R^p, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, and Q-C4 haloalkyl groups;

R⁵ is chosen from hydrogen and Ci-Cô alkyl;

m is an integer chosen from 0, 1,2, 3, 4, and 5;

n is an integer chosen from 0, 1, and 2;

p, for each occurrence, is an integer independently chosen from 1 and 2; and q and r, for each occurrence, are each an integer independently chosen from 1,2, 3, and 4.

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3. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to claim 1, wherein the compound is represented by the following structural formula:

a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein R¹, R^z, R³, R⁴, Ring A, and m are as defined in claim I or claim 2.

4. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of daims 1 to 3, wherein R⁴ is -OH; and ail other variables not specifically defined herein are as defined in any one of daims 1 to 3.

5. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of daims 1 to 4, wherein R³ is chosen from C1-C4 alkyl groups; and ail other variables not specifically defined herein are as defined in any one of daims 1 to 4.

6. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of daims 1 to 5, wherein R³ is -CH3; and ail other variables not specifically defined herein are as defined in any one of daims 1 to 5.

7. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of daims 1 to 6, wherein R² is chosen from C1-C4 alkyl and

groups, wherein:

216 the C1-C4 alkyl of R² is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, -NH?, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?, C1-C2alkoxy, C₃-C₆ cycloalkyl, 5- to 6-membered heterocyclyl, phcnyl, and 5- to 6-membered heteroaryl groups;

and ail other variables not specifically defined herein are as defined in any one of claims l to 6.

8. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait (R^a)0-5 according to any one of claims l to 7, wherein R² is chosen from -CH3 and groups;

and ail other variables not specifically defined herein are as defined in any one of claims I to 7.

9. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of claims l to 8, wherein the compound is represented by one of the following structural formulae:

(R¹)m(R ( A )( A ) <2/ OH VV ,OH (B) ^HH (R^a)o-5 (R^a)o-5

Formula Ic-4 Formula Π-4 a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a pharmaceutically acceptable sait of any of the foregoing, wherein ail variables not specifically defined herein are as defined in any one of claims 1 to 8.

217

ΙΟ. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of claims l to 9, wherein Ring B is chosen from cyclopropyl, 5- to 10membered heterocyclyl, phenyl, and 5- to 9-membered heteroaryl groups; each of which is optionally substituted with l, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of claims l to 9.

11. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of claims 1 to 9, wherein Ring B is chosen from cyclopropyl, 5- to 10membered heterocyclyl comprising I to 3 heteroatoms chosen from N and O, phenyl, and 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms chosen from N and O; each of which is optionally substituted with 1, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of claims 1 to 9.

12. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of claims 1 to 9, wherein Ring B is chosen from cyclopropyl, 5-membered heterocyclyl comprising 1 to 3 heteroatoms chosen from N and O, 6-mcmbered heterocyclyl comprising 1 to 3 heteroatoms chosen from N and O, 9-membered heterocyclyl comprising 1 to 3 heteroatoms chosen from N and O, 10-membered heterocyclyl comprising 1 to 3 heteroatoms chosen from N and O, phenyl, 5-membered heteroaryl comprising 1 to 3 heteroatoms chosen from N and O, 6-membered heteroaryl comprising 1 to 3 heteroatoms chosen from N and O, and 9-membered heteroaryl comprising 1 to 3 heteroatoms chosen from N and O; each of which is optionally substituted with 1,2,3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of claims 1 to 9.

13. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait

218

optionally substituted with l, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of daims l to 9.

14. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait

2I9

with l, 2, 3, 4, or 5 R^a groups; and ail other variables not specifically defined herein are as defined in any one of claims l to 9.

220

15. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait

according to any one of daims l to 9, wherein Ring B is HN which is optionally substituted with l R^a group; and ail other variables not specifically defined herein are as defined in any one of daims l to 9.

16. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of daims l to 15, wherein R¹, for each occurrence, is independently chosen from hydrogen, halogen, cyano, -OH, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)N(R^C)2, and C3-C6 cycloalkyl groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and Ct-C? alkyl groups;

the C1-C4 alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C2 alkoxy groups;

the C1-C4 alkoxy of R¹ is optionally substituted with 1 to 3 independently chosen from halogen groups; and the C3-C6 cycloalkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C2 alkoxy groups;

and ail other variables not specifically defined herein are as defined in any one of daims l to 15.

17. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of daims 1 to 15, wherein R¹, for each occurrence, is independently chosen from F, Cl, Br, C1-C4 alkyl, Ci-C₄ alkoxy, -C(=O)N(R^C)2, and C3-C6 cycloalkyl groups, wherein:

R^c, for each occurrence, is independently chosen from hydrogen and Ci-C2 alkyl groups;

the C1-C4 alkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH;

the C1-C4 alkoxy of R¹ is optionally substituted with 1 to 3 independently chosen from halogen groups; and the C3-C6 cycloalkyl of R¹ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH;

and ail other variables not specifically defined herein are as defined in any one of daims 1 to 15.

18. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of daims 1 to 15, wherein R¹, for each occurrence, is independently chosen from F, Cl, Br, C1-C4 alkyl, Ci-C4 alkoxy, -C(=O)N(R^C)2, and C3-C6 cycloalkyl groups, wherein:

221

R^c, for each occurrence, is independently chosen from hydrogen and C1-C2 alkyl groups; the C1-C4 alkyl of R* is optionally substituted with l to 3 groups independently chosen from halogen and -OH; and the C1-C4 alkoxy of R' is optionally substituted with l to 3 independently chosen from halogen groups;

and ail other variables not specifically defined herein are as defined in any one of claims l to 15.

19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable sait according to any one of claims l to 15, wherein R', for each occurrence, is independently chosen from F, Cl, Br, -CH3, -CHfCHsh, -CFj, -OCH3, -OCF3, -C(=O)N(CH3)2, and cyclopropyl;

and ail other variables not specifically defined herein are as defined in any one of claims I to 15.

20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable sait according to any one of claims l to 15, wherein R¹, for each occurrence, is independently chosen from -SO₂(R^C) groups, wherein R' is independently chosen from Ct-C4 alkyl groups; and ail other variables not specifically defined herein are as defined in any one of claims 1 to 15.

21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable sait according to any one of claims 1 to 15, wherein R¹, for each occurrence, is independently chosen from -SO2(R^C) groups, wherein R^c is independently chosen from Ci alkyl groups; and ail other variables not specifically defined herein are as defined in any one of claims 1 to 1 5.

22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable sait according to any one of claims 1 to 15, wherein two R¹ groups taken together with the Ring A atoms connecting them form a 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, διό 6-membered aryl, or 5- to 6-membered heteroaryl ring, wherein the 5- to 6-membered cycloalkyl, 5- to 8-membered heterocyclyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and CiC4 alkyl;

and ail other variables not specifically defined herein are as defined in any one of claims 1 to 15.

23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable sait according to any one of claims 1 to 15, wherein two R¹ groups taken together with the Ring A

222

and ' F ;

and ail other variables not specifically defined herein are as defined in any one of claims l to 15.

24. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of claims I to 23, wherein m is I; and ail other variables not specifically defined herein are as defined in any one of claims l to 23.

25. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of claims l to 23, wherein m is 2; and ail other variables not specifically defined herein are as defined in any one of claims l to 23.

26. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of claims l to 25, wherein R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, Ci-C4 alkoxy, Ci-Cô haloalkyl, Ci-Cô haloalkoxy, -C(=O)NR^hR', -NR^hR‘, -NR^hC(=O)R^k, -OR^k, -[O(CH2)q]rO(Ci-C6 alkyl),

-S(=O)2R^k, -S(=O)2NR^hR', C3-C₆ cycloalkyl, 5 to 10-membered heterocyclyl, phenyl, and 5- to 8-membered heteroaryl groups, wherein:

the Ci-Cô alkyl of R^a is optionally substituted with 1 to 3 groups independently chosen from cyano, -C(=O)NR^hRⁱ, -NR¹*^, -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -ΝΚ^(=Ο)ΝΗΉξ -NR^hS(=O)PR^k-OR^k, -S(-O)2R^k, -S(=O)PNR^hRⁱ, and C3-C₆ cycloalkyl groups;

the C₃-Cô cycloalkyl, the 5- to 10-membered heterocyclyl, the phenyl, and the 5- to 8membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, C|-C₂ alkyl, and -OR^k groups, wherein:

R^h, R¹, and R\ for each occurrence, are each independently chosen from hydrogen,

Ci-C₂ alkyl, cyclopropyl, andcyclobuty! groups, wherein:

the C r-C₂ alkyl of any one of R^h, R¹, and RJ is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH;

R^k, for each occurrence, is each independently chosen from hydrogen and Ci-C₄ alkyl groups, wherein:

223 the C1-C4 alkyl of R^k is optionally substituted with l to 3 groups independently chosen from halogen and -OH; and q and r are each an integer chosen from l, 2, and 3;

and ail other variables not specifically defined herein are as defined in any one of claims l to 25.

27. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of claims l to 25, wherein R^a, for each occurrence, is independently chosen from halogen. cyano, Ci-Cô alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,

C1-C4 haloalkoxy, -Ο(=Ο)ΝΗ^Η^, -NR¹¹^, -NR^hC(=O)R^k, -OR^k, -[O(CH2)q]rO(Ci-C4 alkyl), -S(=O)2R^k, -S(=O)2NR^hR', cyclopropyl, cyclobutyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein:

the Ci-Cô alkyl of R^a is optionally substituted with 1 to 3 groups independently chosen from cyano, -C(=O)NR^1,Rⁱ, -S(=O)₂R^k, -NR^hR', -OR^k, cyclopropyl, and cyclobutyl groups, wherein:

the cyclopropyl, the cyclobutyl, the 5- to 6-membered heterocyclyl, the phenyl, and the 5 to 6-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, -CH3, -OH, and -OCH3; wherein:

R^h and R¹, for each occurrence, are each independently chosen from hydrogen,

-CHs, cyclopropyl, and cyclobutyl groups, wherein:

the -CH3 of any one of R¹' and R¹ is optionally substituted with 1 to 3 groups independently chosen from F, Cl, and -OH;

R^k, for each occurrence, is each independently chosen from hydrogen and -CH3, wherein:

the -CH₃ofR^k is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH;

and ail other variables not specifically defined herein are as defined in any one of claims 1 to 25.

28. The compound, tautomer, deuterated dérivative, or phanuaceutically acceptable sait according to any one of claims 1 to 25, wherein R^a, for each occurrence, is independently chosen from F, Cl, Br, cyano, Ci-Cô alkyl, Ci-C₂ alkoxy, C1-C2 haloalkyl,

-C^OjNR'·^, -NR^hR', -NR^hC(=O)R^k, -OR^k, -[O(CH2)q]rO(Ci-C2 alkyl), -S(=O)2R^k, -S(=O)2NR^hR^l, cyclopropyl, cyclobutyl, 5-membered heterocyclyl, phenyl, and 6-membered heteroaryl groups, wherein:

the C1-C0 alkyl of R^a is optionally substituted with 1 to 3 groups independently chosen from cyano, -C(=O)NR^hR', -OR^k, -S(=O)₂R^k, and cyclopropyl;

224 the cyclopropyl, the cyclobutyl, the 5- to 6-membered heterocyclyl, the phenyl, and the 5- to 6-membered heteroaryl of R^a are each optionally substituted with l to 3 groups independently chosen from halogen, -CH?, -OH, and -OCH₃, wherein:

R^h and R', for each occurrence, are each independently chosen from hydrogen, -CH?, and cyclopropyl; wherein:

the -CH? of any one of R^h and R¹ is optionally substituted with 1 to 3 groups independently chosen from F, Cl, and -OH;

R^k, for each occurrence, is each independently chosen from hydrogen and -CH?; and q and r are each an integer independently chosen from 1 and 2;

and ail other variables not specifically defined herein are as defined in any one of daims 1 to 25.

29. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of daims 1 to 25, wherein R^a, for each occurrence, is independently chosen from F, cyano, -OH, -CH?, -CF?, -CH(CH?)2, -(CHzhOH , -(CH₂)₂OCH₃,-CH₂CH(OH)C₂H₅, -CH₂C(CH3)(CH₂OH)₂, -OCH₃, -OCH₂CH₃, -[O(CH₂)₂]₂OCH₃, -CH₂C(=O)NHCH?, -(CH₂)₂SO2CH?, -CH₂C(=O)N(CH₃)₂, -CH₂(cyclopropyl), -C(=O)NH₂, -C(=O)NH(cyclopropyl), -NH?, -NHCH₃, -N(CH₃)₂, -NHC(CH?)₂CH₂OH, -NHC(=O)CH₃, -SO₂CH₃, -SO₂NH₂, cyclopropyl, 2-methoxyphenyl, N-methylpiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl, and tetrahydrothiophenyl 1,1-dioxide; and ail other variables not specifically defined herein are as defined in any one of daims 1 to 25.

30. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of daims 1 to 25, wherein R^a, for each occurrence, is independently chosen from -CH₃ and -(CH₂)₂SO2CH?; and ail other variables not specifically defined herein are as defined in any one of daims 1 to 25.

31. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of daims 1 to 30, wherein Ring A is chosen from phenyl, thiophenyl, and pyridinyl; and ail other variables not specifically defined herein are as defined in any one of daims 1 to 30.

32. The compound, tautomer, deuterated dérivative, or pharmaceutically acceptable sait according to any one of daims 1 to 30, wherein Ring A is phenyl; and ail other variables not specifically defined herein are as defined in any one of daims 1 to 30.

225

33. The compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to claim 2, wherein X is a bond.

34. A compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait chosen from the compounds of Table l, tautomers thereof, deuterated dérivatives of those compounds and tautomers, and phannaceutically acceptable salts of any ofthe foregoing.

35. A compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait chosen from the compounds of Table 2, tautomers thereof, deuterated dérivatives of those compounds and tautomers, and phannaceutically acceptable salts of any of the foregoing.

36. A compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait chosen from the compounds of Table 3, tautomers thereof, deuterated dérivatives of those compounds and tautomers, and phannaceutically acceptable salts of any of the foregoing, with the proviso that the compound is not Compound I296.

37. A compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait chosen from the compounds of Table 4, tautomers thereof, deuterated dérivatives of those compounds and tautomers, and phannaceutically acceptable salts of any of the foregoing.

38. The compound, tautomer, deuterated dérivative, or phannaceutically acceptable sait according to any one of claims l to 33, wherein compound is not Compound I296 or Compound 43 a.

39. A compound represented by the fonnula:

Fonnula II-6a a tautomer thereof, a deuterated dérivative of that compound or tautomer, or a phannaceutically acceptable sait of any of the foregoing, wherein:

226

R^la and R^lh are independently chosen from halogen. H, C|-C₄ alkyl, and C1-C4 haloalkyl groups;

R^lc is chosen from halogen. H, CH3, -OH, and CH3OH; and

R2 is chosen from cyano, Ci-C(> alkyl, -C(=O)O(Ci-C4 alkyl), C₂-Cô alkynyl, and

the Ci-Cô alkyl of R²is optionally substituted with l to 3 groups independently chosen from halogen, cyano, -OH, -NH₂, -NH(Ci-C₄ alkyl), -N(Ci-C₄ alkyl)₂, Ci-C₄ alkoxy, -C(=O)NH₂, -C(=O)NH(C|-C₄ alkyl), -C(=O)N(Ci-C₄ alkyl)₂, C₃-C₆ carbocyclyl, 5- to 10-membered heterocyclyl, Cô aryl, and 5- to 10-membered heteroaryl groups;

Ring B is chosen from C₃-C|₂ carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cio aryl, and 5- to 10-membered heteroaryl groups, wherein Ring B is optionally substituted with l, 2, 3, 4, or 5 R^agroups; wherein:

R^a, for each occurrence, is independently chosen from halogen, cyano, Ci-Cô alkyl, C2-Cô alkenyl, Ci-Cô alkoxy, Ci-Cô haloalkyl, Ci-Cô haloalkcnyl, Ci-Cô haloalkoxy, -C(=O)NR^hRⁱ, -NR¹¹^, -NR^hC>O)R^k. -NR^hC(=O)OR^k, -NR^hC(=O)NR'Rj, -NR^llS(=O)PR^k-OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OC(=O)NR^hR', -[O(CH2)q]rO(Ci-Cô alkyl), -S(=O)PR^k, -S(=O)PNR¹'Rⁱ, -C(=O)OR^k, C₃-C[₂ carbocyclyl, 3- to 12-membered heterocyclyl, Cô and Cioaryl, and 5- to 10-membered heteroaryl groups, wherein:

the Ci-Cô alkyl, Ci-Cô alkoxy, and the C₂-Cô alkenyl of R^a are each optionally substituted with 1 to 3 groups independently chosen from Cô to Cio aryl (optionally substituted with 1 to 3 R' groups), 5- to 10membered heterocyclyl (optionally substituted with 1 to 3 R^m groups), 5to 10-membered heteroaryl (optionally substituted with 1 to 3 R”’groups), cyano, -C(=O)R^k, -C(=O)OR^k, -C(-O)NR^hRⁱ, -NR^hR', -NR^hC(=O)R^k, -NR^hC(=O)OR^k, -NR^hC(=O)NR'R^J, -NR^hS(=O)PR^k -OR^k, -OC(=O)R^k, -OC(=O)OR^k, -OC(=O)NR^hRⁱ, -S(=O)PR^k, -S(=O)PNR^!,R', -O(Cô aryl) (optionally substituted with 1 to 3 R^m groups), and C3-Cô carbocyclyl groups (optionally substituted with 1 to 3 R^m groups);

227 the Cs-Ci? earbocyclyl, the 3- to 12-membered heterocyclyl, the Cô and Cio aryl, and the 5- to 10-membered heteroaryl of R^a are each optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, C1-C4 alkyl, -NR^hR', and -OR^k groups, wherein:

R^h, R¹, and R^j, for each occurrence, are each independently chosen from hydrogen, C1-C4 alkyl, Cô-Cioaryl, and C3-C6 cycloalkyl groups, wherein:

the C1 -C₄ alkyl of any one of R^h, R', and R^j is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, and -OH groups;

R^k, for each occurrence, is independently chosen from hydrogen, C1-C4 alkyl, 5- to 10-membercd heterocyclyl, and Ci-Cô earbocyclyl groups, wherein:

the C1-C4 alkyl of any one of R^k is optionally substituted with I to 3 groups independently chosen from halogen, cyano, and -OH groups;

R”¹, for each occurrence, is independently chosen from halogen, cyano, oxo, Ci-Cô alkyl, C1-C0 alkoxy, -S(=O)_PR^k, and -OR^k groups, wherein:

the Ci-Cô alkyl of R^m is optionally substituted with

5 51. Compound 16 or Compound 16 Fonn A or the phannaceutical composition according to claim 43 for use in treating an APOLI-mediated pancreatic cancer.