WO2023102022A1 - 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

4-phenyl-2-(1h-1,2,3-triazol-4-yl)piperidin-4-ol derivatives as inhibitors of apol1 and methods of using same Download PDF

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Publication number
WO2023102022A1
WO2023102022A1 PCT/US2022/051364 US2022051364W WO2023102022A1 WO 2023102022 A1 WO2023102022 A1 WO 2023102022A1 US 2022051364 W US2022051364 W US 2022051364W WO 2023102022 A1 WO2023102022 A1 WO 2023102022A1
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alkyl
groups
compound
optionally substituted
independently chosen
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English (en)
French (fr)
Inventor
Leslie A. DAKIN
Michael A. Brodney
Elena DOLGIKH
Jessica H. OLSEN
Timothy J. SENTER
Akira J. SHIMIZU
Steven D. STONE
Kevin B. Daniel
Pedro M. GARCIA BARRANTES
Ales Medek
Charlene TSAY
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Priority to MX2024006473A priority Critical patent/MX2024006473A/es
Priority to CA3239394A priority patent/CA3239394A1/en
Priority to KR1020247021706A priority patent/KR20240131345A/ko
Priority to AU2022402839A priority patent/AU2022402839A1/en
Priority to CN202280089821.XA priority patent/CN118574809A/zh
Priority to CR20240261A priority patent/CR20240261A/es
Priority to PE2024001215A priority patent/PE20241628A1/es
Priority to JP2024531628A priority patent/JP2024543934A/ja
Priority to EP22843923.8A priority patent/EP4441032A1/en
Priority to IL312747A priority patent/IL312747A/en
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Publication of WO2023102022A1 publication Critical patent/WO2023102022A1/en
Priority to DO2024000104A priority patent/DOP2024000104A/es
Priority to CONC2024/0006736A priority patent/CO2024006736A2/es
Priority to JOJO/P/2024/0120A priority patent/JOP20240120A1/ar
Anticipated expiration legal-status Critical
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    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • This disclosure provides compounds that may inhibit apolipoprotein LI (APOL1) and methods of using those compounds to treat APOL1 -mediated diseases, such as, e.g., pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and/or non-diabetic kidney disease (NDKD).
  • APOL1 -mediated diseases such as, e.g., pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and/or non-diabetic kidney disease (NDKD).
  • the FSGS and/or NDKD is associated with at least one of the 2 common APOL1 genetic variants (Gl: S342G:I384M and G2: N388del:Y389del).
  • the pancreatic cancer is associated with elevated 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/y ear.
  • FSGS is a disease of the podocyte (glomerular visceral epithelial cells) responsible for proteinuria and progressive decline in kidney function.
  • NDKD is a kidney disease involving damage to the podocyte or glomerular vascular bed that is not attributable to diabetes.
  • NDKD is a disease characterized by hypertension and progressive decline in kidney function.
  • Human genetics support a causal role for the Gl and G2 APOL1 variants in inducing kidney disease.
  • EKD end-stage kidney disease
  • primary (idiopathic) FSGS primary (idiopathic) FSGS
  • human immunodeficiency virus (HlV)-associated FSGS NDKD
  • arterionephrosclerosis lupus nephritis
  • microalbuminuria and chronic kidney disease.
  • FSGS and NDKD can be divided into different subgroups based on the underlying etiology.
  • One homogeneous subgroup of FSGS is characterized by the presence of independent common sequence variants in the apolipoprotein LI (APOL1) gene termed Gl and G2, which are referred to as the “APOL1 risk alleles.”
  • Gl encodes a correlated pair of non-synonymous amino acid changes (S342G and I384M)
  • G2 encodes a 2 amino acid deletion (N388del:Y389del) near the C terminus of the protein, and GO is the ancestral (low risk) allele.
  • 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 secretion into the bloodstream, where it circulates bound to a subset of high-density lipoproteins.
  • APOL1 is responsible for protection against the invasive parasite, Trypanosoma brucei brucei (T. b. brucei).
  • T. b. brucei Trypanosoma brucei brucei
  • APOL1 is endocytosed by T. b. brucei and transported to lysosomes, where it inserts into the lysosomal membrane and forms pores that lead to parasite swelling and death. [0006] While the ability to lyse T. b.
  • brucei is shared by all 3 APOL1 variants (G0, G1, and G2), APOL1 G1 and G2 variants confer additional protection against parasite species that have evolved a serum resistant associated-protein (SRA) which inhibits APOL1 G0; APOL1 G1 and G2 variants confer additional protection against trypanosoma species that cause sleeping sickness. G1 and G2 variants evade inhibition by SRA; G1 confers additional protection against T. b. gambiense (which causes West African sleeping sickness) while G2 confers additional protection against T. b. rhodesiense (which causes East African sleeping sickness).
  • SRA serum resistant associated-protein
  • APOL1 is expressed in podocytes, endothelial cells (including glomerular endothelial cells), and some tubular cells.
  • Podocyte-specific expression of APOL1 G1 or G2 (but not G0) in transgenic mice induces structural and functional changes, including albuminuria, decreased kidney function, podocyte abnormalities, and glomerulosclerosis. Consistent with these data, G1 and G2 variants of APOL1 play a causative role in inducing FSGS and accelerating its progression in humans.
  • APOL1 risk alleles i.e., homozygous or compound heterozygous for the APOL1 G1 or APOL1 G2 alleles
  • APOL1 risk alleles have increased risk of developing FSGS and they are at risk for rapid decline in kidney function if they develop FSGS.
  • inhibition of APOL1 could have a positive impact in individuals who harbor APOL1 risk alleles.
  • normal plasma concentrations of APOL1 are relatively high and can vary at least 20-fold in humans, circulating APOL1 is not causally associated with kidney disease.
  • APOL1 in the kidney is thought to be responsible for the development of kidney diseases, including FSGS and NDKD.
  • APOL1 protein synthesis can be increased by approximately 200-fold by pro-inflammatory cytokines such as interferons or tumor necrosis factor- ⁇ .
  • pro-inflammatory cytokines such as interferons or tumor necrosis factor- ⁇ .
  • APOL1 protein can form pH-gated Na + /K + pores in the cell membrane, resulting in a net efflux of intracellular K + , ultimately resulting in activation of local and systemic inflammatory responses, cell swelling, and death.
  • the risk of ESKD is substantially higher in people of recent sub-Saharan African ancestry as compared to those of European ancestry. In the United States, ESKD is responsible for nearly as many lost years of life in women as from breast cancer and more lost years of life in men than from colorectal cancer.
  • FSGS and NDKD are caused by damage to podocytes, which are part of the glomerular filtration barrier, resulting in proteinuria. Patients with proteinuria are at a higher risk of developing end-stage kidney disease (ESKD) and developing proteinuria-related complications, such as infections or thromboembolic events.
  • EKD end-stage kidney disease
  • FSGS and NDKD are managed with symptomatic treatment (including blood pressure control using blockers of the renin angiotensin system), and patients with FSGS and heavy proteinuria may be offered high dose steroids.
  • Current therapeutic options for NDKD are anchored on blood pressure control and blockade of the renin angiotensin system.
  • Corticosteroids alone or in combination with other immunosuppressants, induce remission in a minority of patients (e.g., remission of proteinuria in a minority of patients) and are associated with numerous side effects.
  • remission is frequently indurable even in patients initially responsive to corticosteroid and/or immunosuppressant treatment.
  • patients in particular individuals of recent sub-Saharan African ancestry with 2 APOL1 risk alleles, experience rapid disease progression leading to end-stage renal disease (ESRD).
  • ESRD end-stage renal disease
  • APOL1 plays a causative role in inducing and accelerating the progression of kidney disease
  • inhibition of APOL1 should have a positive impact on patients with APOL1 mediated kidney disease, particularly those who carry two APOL1 risk alleles (i.e., are homozygous or compound heterozygous for the G1 or G2 alleles).
  • APOL1 is an aberrantly expressed gene in multiple cancers (Lin et al., Cell Death and Disease (2021), 12:760). Recently, APOL1 was found to be abnormally elevated in human pancreatic cancer tissues compared with adjacent tissues and was associated with poor prognosis in pancreatic cancer patients.
  • One aspect of the disclosure provides at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, which can be employed in the treatment of diseases mediated by APOL1, such as FSGS and NDKD.
  • variable X in the compounds of Formula I is a bond (i.e., X is absent).
  • Compound I296 and Compound 43a are excluded from Formula I.
  • the compound of Formula I is a compound represented by the following structural formula:
  • Ring A is chosen from C6 aryl and 5- and 6-membered heteroaryl groups
  • Ring A is chosen from C 6 aryl and 5- and 6- membered heteroaryl groups;
  • R c for each occurrence, is independently chosen from hydrogen and C 1 -C 4 alkyl groups;
  • R 2 and R 3 are each independently chosen from C 1 -C 4 alkyl and 5-membered heteroaryl groups, wherein the 5-membered heteroaryl groups are optionally substituted with 1-2 C1-C4 alkyl groups optionally substituted with -S
  • Compound I296 and Compound 43a are excluded from Formula Ic.
  • the compounds of Formula I are chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, such that the at least one compound, pharmaceutically acceptable salt, solvate, or deuterated derivative is chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic- 6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • the pharmaceutical composition may comprise at least one compound chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, pharmaceutically acceptable salts of any of those compounds, solvates of any of the foregoing, and deuterated derivatives of any of the foregoing.
  • These compositions may further include at least one additional active pharmaceutical ingredient and/or at least one carrier.
  • Another aspect of the disclosure provides methods of treating an APOL1-mediated disease comprising administering to a subject in need thereof, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.
  • the methods comprise administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • Another aspect of the disclosure provides methods of treating an APOL1-mediated cancer (such as, e.g., pancreatic cancer) comprising administering to a subject in need thereof, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.
  • an APOL1-mediated cancer such as, e.g., pancreatic cancer
  • the methods comprise administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • Another aspect of the disclosure provides methods of treating APOL1-mediated kidney disease (such as, e.g., ESKD, FSGS and/or NDKD) comprising administering to a subject in need thereof, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.
  • APOL1-mediated kidney disease such as, e.g., ESKD, FSGS and/or NDKD
  • the methods comprise administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic- 6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions.
  • the methods comprise administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing with at least one additional active agent, either in the same pharmaceutical composition or in a separate composition.
  • Also provided are methods of inhibiting APOL1, comprising administering to a subject in need thereof, at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.
  • the methods of inhibiting APOL1 comprise administering at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.
  • FIG. 1 depicts an XRPD diffractogram of Compound 16 Form A.
  • FIG. 2 depicts a TGA of Compound 16 Form A.
  • FIG. 1 depicts an XRPD diffractogram of Compound 16 Form A.
  • FIG. 2 depicts a TGA of Compound 16 Form A.
  • FIG. 1 depicts an XRPD 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 13 C SSNMR spectrum of Compound 16 Form A.
  • APOL1 means apolipoprotein L1 protein and the term “APOL1” means apolipoprotein L1 gene.
  • APOL1 mediated disease refers to a disease or condition associated with aberrant APOL1 (e.g., certain APOL1 genetic variants; elevated levels of APOL1).
  • an APOL1 mediated disease is an APOL1 mediated kidney disease.
  • an APOL1 mediated disease is associated with patients having two APOL1 risk alleles, e.g., patients who are homozygous or compound heterozygous for the G1 or G2 alleles. In some embodiments, an APOL1 mediated disease is associated with patients having one APOL1 risk allele.
  • APOL1 mediated kidney disease refers to a disease or condition that impairs kidney function and can be attributed to APOL1. In some embodiments, APOL1 mediated kidney disease is associated with patients having two APOL1 risk alleles, e.g., patients who are homozygous or compound heterozygous for the G1 or G2 alleles.
  • the APOL1 mediated kidney disease is chosen from ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.
  • the APOL1 mediated kidney disease is chronic kidney disease or proteinuria.
  • FSGS focal segmental glomerulosclerosis
  • podocyte glomerular visceral epithelial cells
  • N388del Y389del
  • NKD non-diabetic kidney disease, which is characterized by severe hypertension and progressive decline in kidney function, and associated with 2 common APOL1 genetic variants (G1: S342G:I384M and G2: N388del:Y389del).
  • ESKD end stage kidney disease or end stage renal disease.
  • ESKD/ESRD is the last stage of kidney disease, i.e., kidney failure, and means that the kidneys have stopped working well enough for the patient to survive without dialysis or a kidney transplant.
  • ESKD/ESRD is associated with two APOL1 risk alleles.
  • stereoisomers for example, a collection of racemates, a collection of cis/trans stereoisomers, or a collection of (E) and (Z) stereoisomers
  • the relative amount of such isotopologues in a compound of this disclosure will depend upon a number of factors including the isotopic purity of reagents used to make the compound and the efficiency of incorporation of isotopes in the various synthesis steps used to prepare the compound. However, as set forth above, the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.
  • substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.
  • 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 13 C or 14 C, are within the scope of this disclosure.
  • structures depicted herein are also meant to include all isomeric forms of the structures, e.g., racemic mixtures, cis/trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.
  • tautomer 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 molecule.
  • Stepoisomer refers to enantiomers and diastereomers.
  • deuterated derivative refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom (“D” or “ 2 H”). 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 deuterated derivatives of the disclosure have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • 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.
  • 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.
  • alkyl groups are linear or straight-chain or unbranched. In some embodiments, alkyl groups are branched.
  • cycloalkyl and cyclic alkyl refer to a monocyclic C3-8 hydrocarbon or a spirocyclic, fused, or bridged bicyclic or tricyclic C 8-14 hydrocarbon that is completely saturated, wherein any individual ring in said bicyclic ring system has 3 to 7 members.
  • the cycloalkyl is a C 3 to C 12 cycloalkyl. In some embodiments, the cycloalkyl is a C3 to C8 cycloalkyl. In some embodiments, the cycloalkyl is a C3 to C6 cycloalkyl.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.
  • carbocyclyl or “cycloaliphatic,” as used herein, encompass the terms “cycloalkyl” or “cyclic alkyl,” and refer to a monocyclic C3-8 hydrocarbon or a spirocyclic, fused, or bridged bicyclic or tricyclic C 8-14 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 carbocyclyl is a C 3 to C 12 carbocyclyl.
  • the carbocyclyl is a C 3 to C 10 carbocyclyl. In some embodiments, the carbocyclyl is a C3 to C8 carbocyclyl.
  • heteroalkyl or “heteroaliphatic,” as used herein, means an alkyl or aliphatic group as defined above, wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon.
  • 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.
  • alkenyl groups are branched.
  • heterocycle means non-aromatic (i.e., completely saturated or partially saturated as in it contains one or more units of unsaturation but is not aromatic), monocyclic, or spirocyclic, fused, or bridged bicyclic or tricyclic ring systems in which one or more ring members 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.
  • 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 phosphorus.
  • each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members.
  • the heterocycle has at least one unsaturated carbon-carbon bond.
  • 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 3- to 10-membered heterocyclyl.
  • 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.
  • monocyclic heterocyclyls include piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl, tetrahydrothiophenyl 1,1-dioxide, etc.
  • 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 quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units or degrees of unsaturation.
  • alkoxy or “thioalkyl,” as used herein, refers to an alkyl group, as previously defined, wherein one carbon of the alkyl group is replaced by an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom, respectively, provided that the oxygen and sulfur atoms are linked between two carbon atoms.
  • a “cyclic alkoxy” refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group, but is not aromatic.
  • Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl.
  • haloalkyl haloalkenyl
  • haloalkoxy as used herein, mean a linear or branched alkyl, alkenyl, or alkoxy, respectively, which is substituted with one or more halogen atoms.
  • Non-limiting examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CF2-, and perhaloalkyls, such as -CF 2 CF 3 .
  • Non-limiting examples of haloalkoxy groups include -OCHF2, -OCH2F, -OCF3, and -OCF2.
  • halogen includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.
  • aminoalkyl means an alkyl group which is substituted with or contains an amino group.
  • an “amino” refers to a group which is a primary, secondary, or tertiary amine.
  • a “cyano” or “nitrile” group refer to -C ⁇ N.
  • a “hydroxy” group refers to -OH.
  • a “thiol” group refers to -SH.
  • tert and t- each refer to tertiary.
  • aromatic groups or “aromatic rings” refer to chemical groups that contain conjugated, planar ring systems with delocalized pi electron orbitals comprised of [4n+2] p orbital electrons, wherein n is an integer ranging from 0 to 6.
  • aromatic groups include aryl and heteroaryl groups.
  • aryl used alone or as part of a larger moiety as in “arylalkyl,” “arylalkoxy,” or “aryloxyalkyl,” refers to monocyclic or spirocyclic, fused, or bridged bicyclic or tricyclic ring systems having a total of five to fourteen ring members, wherein every ring in the system is an aromatic ring containing only carbon atoms and wherein each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members.
  • aryl groups include phenyl (C6) and naphthyl (C10) rings.
  • 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.
  • heteroaryl groups have one or more heteroatoms chosen from nitrogen, oxygen, and sulfur.
  • heteroaryl groups have one heteroatom.
  • heteroaryl groups have two heteroatoms.
  • heteroaryl groups are monocyclic ring systems having five ring members.
  • heteroaryl groups are monocyclic ring systems having six ring members.
  • the heteroaryl is a 3- to 12-membered heteroaryl.
  • the heteroaryl is a 3- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl.
  • monocyclic heteroaryls are pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, etc.
  • a non-limiting example of a heteroaryl group is a benzo[d]oxazol-2(3H)-one group.
  • Non-limiting examples of useful protecting groups for nitrogen-containing groups, such as amine groups include, for example, t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc) benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide.
  • Methods of adding (a process generally referred to as “protecting”) and removing (process generally referred to as “deprotecting”) such amine protecting groups are well-known in the art and available, for example, in P. J.
  • Non-limiting examples of suitable solvents include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or “methylene chloride” (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl-tert-butyl ether (MTBE), 1,4-dioxan
  • Non-limiting examples of suitable bases include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K 2 CO 3 ), N-methylmorpholine (NMM), triethylamine (Et 3 N; TEA), diisopropyl-ethyl amine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCH3).
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • KtBu potassium tert-butoxide
  • K 2 CO 3 N-methylmorpholine
  • NMM N-methylmorpholine
  • Et 3 N triethylamine
  • i-Pr2EtN diisopropyl-ethy
  • crystalline form and “Form” interchangeably refer to a crystal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice.
  • Crystalline forms 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 resonance (SSNMR), differential scanning calorimetry (DSC), infrared radiation (IR), and/or thermogravimetric analysis (TGA).
  • XRPD X-ray powder diffraction
  • SSNMR solid state nuclear magnetic resonance
  • DSC differential scanning calorimetry
  • IR infrared radiation
  • TGA thermogravimetric analysis
  • the term “crystalline Form [X] of Compound [Y]” refers to a unique crystalline form that can be identified and distinguished from other crystalline forms 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).
  • XRPD X-ray powder diffraction
  • SSNMR single crystal X-ray diffraction
  • DSC differential scanning calorimetry
  • IR infrared radiation
  • TGA thermogravimetric analysis
  • the novel crystalline Form [X] of Compound [Y] is characterized by an X-ray powder diffractogram having one or more signals at one or more specified two-theta values (°2 ⁇ ).
  • SSNMR refers to the analytical characterization method of solid state nuclear magnetic resonance. SSNMR spectra can be recorded at ambient or non-ambient (e.g., at 275 K) conditions on any magnetically active isotope present in the sample. Common examples of active isotopes for small molecule active pharmaceutical ingredients include 1 H, 2 H, 13 C, 19 F, 31 P, 15 N, 14 N, 35 Cl, 11 B, 7 Li, 17 O, 23 Na, 79 Br, and 195 Pt.
  • 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.
  • the terms “X-ray powder diffractogram,” “X-ray powder diffraction pattern,” and “XRPD pattern” interchangeably refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities (on the ordinate).
  • an X-ray powder diffractogram may include one or more broad signals; and for a crystalline material, an X-ray powder diffractogram may include one or more signals, each identified by its angular value as measured in degrees 2 ⁇ (° 2 ⁇ ), 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 ....” [0081] 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.
  • a signal at at ... degrees two-theta refers to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (o 2 ⁇ ).
  • the repeatability of the angular values is in the range of ⁇ 0.2° 2 ⁇ , i.e., the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value - 0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta).
  • the terms “signal intensities” and “peak intensities” interchangeably 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).
  • X-ray powder diffractogram having a signal at ... two-theta values and “X-ray powder diffractogram comprising a signal at ... two-theta values” are used interchangeably herein and refer to an XRPD pattern that contains X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (o 2 ⁇ ).
  • an X-ray powder diffractogram is “substantially 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 signals in the two diffractograms overlap.
  • an SSNMR spectrum is “substantially 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 signals in the two spectra overlap.
  • DSC refers to the analytical method of Differential Scanning Calorimetry. A DSC curve is “substantially 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.
  • TGA refers to the analytical method of Thermo Gravimetric (or thermogravimetric) Analysis.
  • a TGA thermogram is “substantially 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.
  • substantially crystalline refers to a solid material having few or no amorphous molecules.
  • substantially crystalline materials have less than 15% amorphous molecules (e.g., less than 10% amorphous molecules, less than 5% amorphous molecules, or less than 2% amorphous molecules).
  • substantially crystalline includes the descriptor “crystalline,” which refers to materials that are 100% crystalline form.
  • a crystalline form is “substantially pure” when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by a method in accordance with the art, such as, e.g., quantitative XRPD.
  • the solid form is “substantially pure” when it accounts for an amount by weight equal to or greater than 95% of the sum of all solid form(s) in a sample.
  • the solid form is “substantially pure” when it accounts for an amount by weight equal to or greater than 99% of the sum of all solid form(s) in a sample.
  • the disclosure includes pharmaceutically acceptable salts of the disclosed compounds.
  • a salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M.
  • 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, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids.
  • inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne- l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylprop
  • pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C1-4 alkyl)4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.
  • compositions include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.
  • an effective dose and “effective amount” are used interchangeably herein and refer to that amount of compound that produces a desired effect for which it is administered (e.g., improvement in a symptom of FSGS and/or NDKD, lessening the severity of FSGS and/NDKD or a symptom of FSGS and/or NDKD, and/or reducing progression of FSGS and/or NDKD or a symptom of FSGS and/or NDKD).
  • the exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).
  • treatment and its cognates refer to slowing or stopping disease progression.
  • Treatment and its cognates as used herein, include, but are not limited to, the following: complete or partial remission, lower risk of kidney failure (e.g., ESRD), and disease-related complications (e.g., edema, susceptibility to infections, or thrombo-embolic events). Improvements in or lessening the severity of any of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed.
  • the terms “about” and “approximately,” when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent.
  • the terms “about” and “approximately” may refer to an acceptable error for a particular value as determined by one of skill in the art, which depends in part on how the values is measured or determined.
  • the terms “about” and “approximately” mean within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.
  • the symbol “ ⁇ ” appearing immediately before a numerical value has the same meaning as the terms “about” and “approximately.”
  • the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic- 6, II, II-1, II-2, II-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 salt of any of the foregoing may be administered once daily, twice daily, or three times daily, for example, for the treatment of FSGS.
  • the compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic- 5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b are chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
  • At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-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 salt of any of the foregoing is administered once daily.
  • At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing is administered once daily.
  • At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-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 salt of any of the foregoing is administered twice daily.
  • At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing is administered twice daily.
  • At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-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 salt of any of the foregoing are administered three times daily.
  • At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing is administered three times daily.
  • 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-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 salt of any of the foregoing are administered once daily, twice daily, or three times daily.
  • 2 mg to 1500 mg or 5 mg to 1000 mg of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing is administered once daily, twice daily, or three times daily.
  • the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound.
  • “1000 mg of at least one compound or pharmaceutically acceptable salt chosen from compounds of Formula I and pharmaceutically acceptable salts thereof” includes 1000 mg of a compound of Formula I and a concentration of a pharmaceutically acceptable salt of compounds of Formula I equivalent to 1000 mg of a compound of Formula I.
  • the term “ambient conditions” means room temperature, open air condition, and uncontrolled humidity condition.
  • R 4 is -OH; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • m is an integer chosen from 0, 1, and 2; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • a compound of the disclosure i.e., a compound of any one of Formulae I, Ia, Ib, and Ic
  • a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure
  • m is 0; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • m is 1; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • Ring A is phenyl, thiophenyl, or pyridinyl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • Ring A in a compound of the disclosure (i.e., a compound of any one of Formulae I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, Ring A is phenyl; and all 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, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, Ring A is thiophenyl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • Ring A is pyridinyl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 2 is chosen from groups, wherein: the C1-C4 alkyl of R 2 is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , C 1 -C 2 alkoxy, C3-C6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl groups; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 2 is chosen from groups, wherein: the C1-C2 alkyl of R 2 is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and 5- to 6-membered heterocyclyl groups; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 2 is chosen from - groups; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 2 is chosen from -CH 3 , -CH 2 OH, and (tetrahydro-2H-pyran-4- yl)methyl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • 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 1, 2, 3, 4, or 5 R a groups; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • Ring B is chosen from cyclopropyl, 5- to 10-membered heterocyclyl comprising 1 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 all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • Ring B is chosen from cyclopropyl, 5-membered heterocyclyl comprising 1 to 3 heteroatoms chosen from N and O, 6-membered 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
  • Ring B is chosen from , ,
  • Ring B is chosen from , , , ,
  • R 2 is chosen from -CH3 and Ring B, wherein Ring B is chosen from , each of which is optionally substituted with 1, 2, 3, 4, or 5 R a groups; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • Ring which is optionally substituted with 1 R a group in some embodiments, Ring which is optionally substituted with 1 R a group.
  • R 3 is -CH3; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • a compound of the disclosure i.e., a compound of any one of Formulae I, Ia, Ib, and Ic
  • R c for each occurrence, is independently chosen from hydrogen and C1-C4 alkyl groups
  • the C 1 -C 4 alkyl of R 1 is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C1-C2 alkoxy groups
  • the C 1 -C 4 alkoxy of R 1 is optionally substituted with 1 to 3 independently chosen from
  • R 1 in a compound of the disclosure (i.e., a compound of any one of Formulae I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, R 1 , for each occurrence, is independently chosen from hydrogen, halogen, cyano, -OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and C 3 -C 6 cycloalkyl; wherein: the C1-C4 alkyl of R 1 is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C 1 -C 2 alkoxy; the C1-C4 alkoxy of R 1 is optionally substituted with 1 to 3 independently chosen halogen groups; and the C3-C6 cycloalkyl of R 1 is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, and C 1 -C 2 alkoxy;
  • R 1 in a compound of the disclosure (i.e., a compound of any one of Formulae I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, R 1 , for each occurrence, is independently chosen from F, Cl, Br, C1-C4 alkyl, and C 3 -C 6 cycloalkyl, wherein: the C1-C4 alkyl of R 1 is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH; and the C 3 -C 6 cycloalkyl of R 1 is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 1 in a compound of the disclosure (i.e., a compound of any one of Formulae I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, R 1 , for each occurrence, is independently chosen from F, Cl, Br, C 1 -C 4 alkyl, and C3-C6 cycloalkyl; wherein: the C 1 -C 4 alkyl of R 1 is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH; and the C 3 -C 6 cycloalkyl of R 1 is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 1 in a compound of the disclosure (i.e., a compound of any one of Formulae I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, R 1 , for each occurrence, is independently chosen from Cl, Br, -CH 3 , - CF3, -CH2CH3, -CH(CH3)2, -CH2CHF2, -CH2CH(CH3)2, difluorocyclobutyl, and cyclohexyl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 1 for each occurrence, is Cl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 1 for each occurrence, is independently chosen from halogen, -OH, and C1-C4 alkyl; wherein: the C 1 -C 4 alkyl of R 1 is optionally substituted with 1 to 3 groups independently chosen from halogen and -OH; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 1 in a compound of the disclosure (i.e., a compound of any one of Formulae I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, R 1 , for each occurrence, is independently chosen from F, Cl, Br, -OH, and C1-C2 alkyl; wherein: the C 1 -C 2 alkyl of R 1 is optionally substituted with 1 to 3 groups independently chosen from F, Cl, and -OH; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 1 in a compound of the disclosure (i.e., a compound of any one of Formulae I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, R 1 , for each occurrence, is independently chosen from F, -OH, -CH3, - CHF 2 , and -CH 2 OH; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 1 for each occurrence, is independently chosen from -SO 2 (R c ), wherein R c is chosen from hydrogen and C1-C2 alkyl groups; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R c is chosen from C1-C2 alkyl groups.
  • R c is chosen from C1 alkyl groups.
  • R c is -CH 3 .
  • a compound of the disclosure i.e., a compound of any one of Formulae I, Ia, Ib, and Ic
  • two R 1 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, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and C 1 -C 4 alkyl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • a compound of the disclosure i.e., a compound of any one of Formulae I, Ia, Ib, and Ic
  • two R 1 groups taken together form a group chosen from , all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • two R 1 groups taken together with the Ring A atoms connecting them form a group chosen from , , all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R a in a compound of the disclosure (i.e., a compound of any one of Formulae I, Ia, Ib, and Ic), or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, R a , for each occurrence, is independently chosen from -CH3 and - (CH 2 ) 2 SO 2 CH 3 ; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 5 is chosen from hydrogen and C 1 -C 4 alkyl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 5 is chosen from hydrogen, methyl, and propyl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 5 is hydrogen and R 1 , for each occurrence, is independently chosen from -SO 2 (R c ), wherein R c is chosen from hydrogen and C 1 -C 2 alkyl groups; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R c is chosen from C 1 -C 2 alkyl groups.
  • R c is chosen from C1 alkyl groups.
  • R c is -CH3.
  • R 5 is hydrogen and two R 1 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, and 5- to 6-membered heteroaryl are each optionally substituted with 1 to 4 groups selected from halogen, -OH, and C 1 -C 4 alkyl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 5 is hydrogen and two R 1 groups taken together form a group chosen f defined herein are as defined in any one of the foregoing embodiments.
  • R 5 is hydrogen and two R 1 groups taken together with the Ring A atoms connecting them form a group chosen from all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by one of the following structural formulae: a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • Compound I296 and Compound 43a are excluded.
  • Compound I296 and Compound 43a are excluded from Formula II.
  • R 4 is -OH; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • m is an integer chosen from 0, 1, and 2; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • Ring A is phenyl, thiophenyl, or pyridinyl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 3 is chosen from C1-4 alkyl groups; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 3 is chosen from -CH 3 and Ring B, wherein Ring B is chosen from , each of which is optionally substituted with 1, 2, 3, 4, or 5 R a groups; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 3 is -CH 3 ; and R 2 is chosen from -CH3 and Ring B, wherein: Ring B is chosen from , , , , each of which is optionally substituted with 1, 2, 3, 4, or 5 R a groups; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • R 3 is -CH 3 ; and R 2 is chosen from -CH3 and Ring B, wherein: Ring , which is optionally substituted with 1 or 2 R a groups; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
  • Ring A is chosen from C 6 aryl and 5- and 6-membered heteroaryl groups;
  • R c for each occurrence, is independently chosen from hydrogen and C 1-4 alkyl groups;
  • R 3 is chosen from C1-4 alkyl groups; and
  • m is
  • compounds of Formula II-6 are selected from Compounds of Formula II-6a and Formula II-6b: wherein R 1a and R 1b are independently chosen from halogen, H, C1-C4 alkyl, and C1-C4 haloalkyl groups; R 1c is chosen from halogen, H, CH3, -OH, and CH3OH; and wherein R2 in Formula II-6a is defined for Formula II.
  • the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is chosen from Compounds 1 to 29 depicted in Table 1, Compounds I5 to I295 depicted in Table 2, Compounds 30 to 44 and depicted in Table 3 and Compounds 45 to 68 depicted in Table 4, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • a wavy line in a compound depicted in any one of Tables 1 - 4 i.e., represents a bond between two atoms and indicates a position of mixed stereochemistry for a collection of molecules, such as a racemic mixture, cis/trans isomers, or (E)/(Z) isomers.
  • a straight line i.e., emanating from a chiral center (e.g., , wher W X Y e R , R , R , and R Z are different) in a compound depicted in Table 2 represents a position of mixed stereochemistry for a collection of molecules.
  • Some embodiments of the disclosure include derivatives of Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing.
  • the derivatives are silicon derivatives in which at least one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by silicon.
  • the derivatives are silicon derivatives in which at least one halogen atom (e.g., a fluorine) in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by a silicon derivative (e.g., -Si(CH3)3).
  • a silicon derivative e.g., -Si(CH3)3
  • the derivatives are boron derivatives, in which at least one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by boron.
  • the derivatives are phosphorus derivatives, in which at least one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by phosphorus.
  • the derivative is a silicon derivative in which one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by silicon or a silicon derivative (e.g., -Si(CH3)2- or -Si(OH)2-).
  • silicon or a silicon derivative e.g., -Si(CH3)2- or -Si(OH)2-
  • the carbon replaced by silicon may be a non-aromatic carbon.
  • a fluorine has been replaced by a silicon derivative (e.g., -Si(CH3)3).
  • the silicon derivatives of the disclosure may include one or more hydrogen atoms replaced by deuterium.
  • a silicon derivative of compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-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 salt of any of the foregoing, may have silicon incorporated into a heterocycle ring.
  • the derivative is a boron derivative in which one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by boron or a boron derivative.
  • the derivative is a phosphorus derivative in which one carbon atom in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, or compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, has been replaced by phosphorus or a phosphorus derivative.
  • compositions comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one formula chosen from Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic- 6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, and Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • the pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, and Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered to a patient in need thereof.
  • a pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier.
  • 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. [00169] It will also be appreciated that a pharmaceutical composition of this disclosure can be employed in combination therapies; that is, the pharmaceutical compositions described herein can further include at least one additional active therapeutic agent.
  • a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising at least one other active therapeutic agent.
  • a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising at least one other active therapeutic agent.
  • pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier.
  • the at least one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles.
  • the at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
  • Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as, e.g., human serum albumin), buffer substances (such as, e.g., phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as, e.g., lactose, glucose, and sucrose), starches (such as, e.g., corn starch and potato starch), cellulose and its derivatives (
  • the compounds and the pharmaceutical compositions described herein are used to treat FSGS and/or NDKD.
  • FSGS is mediated by APOL1.
  • NDKD is mediated by APOL1.
  • the compounds and the pharmaceutical compositions described herein are used to treat cancer.
  • the cancer is mediated by APOL1.
  • the compounds and the pharmaceutical compositions described herein are used to treat pancreatic cancer.
  • the pancreatic cancer is mediated by APOL1.
  • the methods of the disclosure comprise administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • said patient in need thereof possesses APOL1 genetic variants, i.e., G1: S342G:I384M and G2: N388del:Y389del.
  • Another aspect of the disclosure provides methods of inhibiting APOL1 activity comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • compounds of Formulae I, Ia, Ib, Ic, Ic-1, Ic-2, Ic-3, Ic-4, Ic-5, Ic-6, II, II-1, II-2, II-3, II-4, II-5, II-6, II-6a and II-6b tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • the methods of inhibiting APOL1 activity comprise contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from Compounds 1 to 29, Compounds I5 to I295, Compounds 30 to 44, and Compounds 45 to 68, tautomers thereof, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • Solid Forms [00176] Some embodiments of the disclosure provide a solid form of Compound 16. In some embodiments, the solid form of Compound 16 is Form A. In some embodiments of the disclosure, Compound 16 Form A is substantially pure. In some embodiments of the disclosure, Compound 16 Form A is substantially crystalline.
  • 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 signals at 19.9 ⁇ 0.2 degrees two-theta, 20.0 ⁇ 0.2 degrees two-theta, and 10.9 ⁇ 0.2 degrees two-theta.
  • the Compound 16 Form A is characterized by an X-ray powder diffractogram comprising signals at 19.9 ⁇ 0.2 degrees two- theta, 20.0 ⁇ 0.2 degrees two-theta, and 10.9 ⁇ 0.2 degrees two-theta.
  • 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, 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 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, 2
  • 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 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 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 ⁇
  • 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 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 ⁇
  • 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- 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 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 ⁇
  • 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, 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 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 ⁇
  • 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 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 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 ⁇
  • 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 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 ⁇
  • Compound 16 Form A is characterized by an X-ray powder diffractogram comprising signals 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 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 ⁇
  • Compound 16 Form A is characterized by an X-ray powder diffractogram substantially similar to FIG.1.
  • Compound 16 Form A is characterized by a thermogravimetric analysis that shows minimal weight loss from ambient temperature to 250 °C.
  • Compound 16 Form A is characterized by a TGA thermogram substantially similar to FIG.2.
  • Compound 16 Form A is characterized by a differential scanning calorimetry analysis showing one endotherm peak at 147 °C.
  • Compound 16 Form A is characterized by a DSC thermogram substantially similar to FIG.3.
  • Compound 16 Form A is characterized by solid state NMR.
  • Compound 16 Form A is characterized by a 13 C SSNMR spectrum comprising one or more signals 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.
  • Compound 16 Form A is characterized by a 13 C SSNMR spectrum comprising two or more signals 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.
  • Compound 16 Form A is characterized by a 13 C 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.
  • Compound 16 Form A is characterized by a 13 C SSNMR spectrum comprising four or more signals 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.
  • Compound 16 Form A is characterized by a 13 C SSNMR spectrum comprising five or more signals 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.
  • Compound 16 Form A is characterized by a 13 C SSNMR spectrum comprising six or more signals 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.
  • Compound 16 Form A is characterized by a 13 C NMR spectrum substantially similar to FIG.4.
  • Compound 16 Form A is characterized by a 19 F SSNMR spectrum comprising a signal at -58.0 ⁇ 0.2 ppm.
  • Another aspect of the 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 overnight to yield Compound 16 Form A.
  • Non-Limiting Example Embodiments include: 1. A compound represented by the formula:
  • X is a bond (i.e., X is absent) or is chosen from -(CH 2 )-, and –(CH 2 )SO 2 -;
  • Ring A is chosen from C6 cycloalkyl, C6 aryl and 5- and 6-membered heteroaryl groups;
  • R 2 is chosen from C1-C4 alkyl and the C1-C4 alkyl of R 2 is optionally substituted with 1 to 3 groups independently chosen from halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , C 1 -C 2 alkoxy, C3-C6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl groups; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 5.
  • 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 1, 2, 3, 4, or 5 R a groups; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 8. 10.
  • Ring B is chosen from cyclopropyl, 5- to 10-membered heterocyclyl comprising 1 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 all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 8. 11.
  • Ring B is chosen from cyclopropyl, 5-membered heterocyclyl comprising 1 to 3 heteroatoms chosen from N and O, 6-membered 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 all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 8.
  • 28a A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt chosen from the compounds of Table 2, tautomers thereof, deuterated derivatives 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 derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 28b and a pharmaceutically acceptable carrier.
  • 30. A method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof at least one compound according to any one of Embodiments 1 to 28b or the pharmaceutical composition according to Embodiment 29. 31.
  • At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 28b or a pharmaceutical composition according to Embodiment 29 for the manufacture of the medicament for treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease.
  • a method of inhibiting APOL1 activity comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 28b or the pharmaceutical composition according to Embodiment 29.
  • 34. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 28b or the pharmaceutical composition according to Embodiment 29 for the manufacture of a medicament for inhibiting APOL1 activity.
  • 35. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 28b or a pharmaceutical composition according to Embodiment 29 for use in inhibiting APOL1 activity. 36.
  • a method of treating an APOL1-mediated disease comprising administering to a patient in need thereof at least one compound according to any one of Embodiments 1 to 28b or the pharmaceutical composition according to Embodiment 29.
  • 37. The method according to Embodiment 36, wherein the APOL1-mediated disease is cancer.
  • 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 derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 28b or the pharmaceutical composition according to Embodiment 29 for the manufacture of a medicament for treating an APOL1-mediated disease . 40.
  • Embodiment 39 wherein the APOL1-mediated disease is cancer.
  • Embodiment 39 or Embodiment 40 wherein the APOL1-mediated disease is pancreatic cancer.
  • 42. At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt 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 derivative, or pharmaceutically acceptable salt for use according to Embodiment 42, wherein the APOL1-mediated disease is cancer. 44.
  • a method of inhibiting APOL1 activity comprising contacting said APOL1 with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 28b or a pharmaceutical composition according to Embodiment 29.
  • 48. A silicon derivative of the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 28b.
  • 49. A pharmaceutical composition comprising a silicon derivative of Embodiment 48.
  • a method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof the silicon derivative according to Embodiment 48 or the pharmaceutical composition according to Embodiment 49. 51.
  • the silicon derivative according to Embodiment 48 or the pharmaceutical composition according to Embodiment 49 for the manufacture of a medicament for treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease.
  • 52. The silicon derivative according to Embodiment 48 or the pharmaceutical composition according to Embodiment 49 for use in treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease.
  • 53. A method of treating an APOL1-mediated disease comprising administering to a patient in need thereof the silicon derivative according to Embodiment 48 or the pharmaceutical composition according to Embodiment 49.
  • 54. The method according to Embodiment 53, wherein the APOL1-mediated disease is cancer. 55.
  • Embodiment 53 or Embodiment 54 wherein the APOL1-mediated disease is pancreatic cancer.
  • 56. Use of the silicon derivative according to Embodiment 48 or the pharmaceutical composition according to Embodiment 49 for the manufacture of a medicament for treating an APOL1-mediated disease.
  • 57. The use according to Embodiment 56, wherein the APOL1-mediated disease is cancer.
  • 58. The use according to Embodiment 56 or Embodiment 57, wherein the APOL1-mediated disease is pancreatic cancer.
  • a pharmaceutical composition comprising a boron derivative of Embodiment 62. 64.
  • a method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof a boron derivative according to Embodiment 62 or a pharmaceutical composition according to Embodiment 63.
  • a boron derivative according to Embodiment 62 or a pharmaceutical composition according to Embodiment 63 for the manufacture of a medicament for treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease.
  • the boron derivative according to Embodiment 62 or a pharmaceutical composition according to Embodiment 63 for use in treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease. 67.
  • a method of treating an APOL1-mediated disease comprising administering to a patient in need thereof a boron derivative according to Embodiment 62 or a pharmaceutical composition according to Embodiment 63.
  • the method according to Embodiment 67, wherein the APOL1-mediated disease is cancer.
  • the method according to Embodiment 67 or Embodiment 68, wherein the APOL1-mediated disease is pancreatic cancer.
  • 70. Use of the boron derivative according to Embodiment 62 or the pharmaceutical composition according to Embodiment 63 for the manufacture of a medicament for treating an APOL1-mediated disease.
  • 71. The use according to Embodiment 70, wherein the APOL1-mediated disease is cancer. 72.
  • Embodiment 70 or Embodiment 71 wherein the APOL1-mediated disease is pancreatic cancer.
  • 73 The boron derivative according to Embodiment 62 or the pharmaceutical composition according to Embodiment 63 for use in treating an APOL1-mediated disease.
  • 74 The boron derivative or pharmaceutical composition for use according to Embodiment 73, wherein the APOL1-mediated disease is cancer.
  • 75 The boron derivative or pharmaceutical composition for use according to Embodiment 73 or Embodiment 74, wherein the APOL1-mediated disease is pancreatic cancer. 76.
  • a pharmaceutical composition comprising a phosphorus derivative of Embodiment 76.
  • a method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof a phosphorus derivative according to Embodiment 76 or a pharmaceutical composition according to Embodiment 77.
  • a method of treating an APOL1-mediated disease comprising administering to a patient in need thereof a phosphorus derivative according to Embodiment 76 or the pharmaceutical composition according to Embodiment 77.
  • 82. The method according to Embodiment 81, wherein the APOL1-mediated disease is cancer.
  • the method according to Embodiment 81 or Embodiment 82, wherein the APOL1-mediated disease is pancreatic cancer. 84.
  • phosphorus derivative according to Embodiment 76 or the pharmaceutical composition according to Embodiment 77 for the manufacture of a medicament for treating an APOL1-mediated disease.
  • the phosphorus derivative or pharmaceutical composition for use according to Embodiment 87, wherein the APOL1-mediated disease is cancer.
  • Embodiment 87 or Embodiment 88 wherein the APOL1-mediated disease is pancreatic cancer.
  • 90. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1, wherein the variable X is a bond (i.e., X is not present).
  • a pharmaceutical composition comprising the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 91 or Embodiment 92. 94.
  • a method of treating an APOL1-mediated disease comprising administering to a patient in need thereof the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 91 or Embodiment 92, or the pharmaceutical composition according to Embodiment 93.
  • the method according to Embodiment 94, wherein the APOL1-mediated disease is cancer.
  • the method according to Embodiment 94 or Embodiment 95, wherein the APOL1-mediated disease is pancreatic cancer. 97.
  • a method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 91 or Embodiment 92, or the pharmaceutical composition according to Embodiment 93.
  • 98. Use of the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 91 or Embodiment 92, or the pharmaceutical composition according to Embodiment 93 for the manufacture of a medicament for treating an APOL1- mediated disease.
  • Embodiment 98 or Embodiment 99 wherein the APOL1-mediated disease is pancreatic cancer.
  • 101 Use of the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 91 or Embodiment 92, or the pharmaceutical composition according to Embodiment 93 for the manufacture of the medicament for treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease.
  • 102. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 91 or Embodiment 92 or the pharmaceutical composition according to Embodiment 93 for use in treating an APOL1-mediated disease.
  • 103 Use of the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 91 or Embodiment 92 or the pharmaceutical composition according to Embodiment 93 for use in treating an APOL1-mediated disease.
  • the piperidinone S1 can be optionally substituted with a protecting group reagent such as allyl bromide to provide the protected piperidinone depicted by S2.
  • a protecting group reagent such as allyl bromide
  • 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.
  • Scheme 1 Representative scheme using n-hexyllithium to form aryl lithium nucleophiles for 1,2-addition
  • Scheme 2 shows an alternative process for the preparation of a compound of formula 2-2 from the protected piperidinone S2.
  • Suitable aryl halides are treated with t-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.
  • Scheme 2 Representative scheme using tert-butyllithium to form aryl lithium nucleophiles for 1,2-addition
  • Scheme 3 shows an alternative process for the preparation of a compound of formula 3-2 from the protected piperidinone S2.
  • Suitable aryl halides are treated with n-butylithium in a solvent such as THF, which are then combined with S2 to form compounds depicted by formula 3-1.
  • Scheme 3 Representative scheme using n-butyllithium to form aryl lithium nucleophiles for 1,2-addition
  • Scheme 4 shows an alternative process for the preparation 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.
  • Scheme 4 Representative scheme using sec-butyllithium to form aryl lithium nucleophiles for 1,2-addition
  • Scheme 5 shows an alternative process for the preparation of a compound of formula 5-2 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.
  • Scheme 5 Representative scheme of 1,2-addition using phenyl lithium to aryl lithium nucleophiles
  • Scheme 6 shows an alternative process for the preparation of a compound of formula 6-2 from the protected piperidinone S2.
  • Suitable aryl Grignard reagents (ArMgX) which in some embodiments are prepared by treatment of appropriate aryl halides with magnesium in a solvent such as THF, are then combined with S2 to form compounds depicted by formula 6-1. This is followed by deprotection of the allyl group to provide compounds depicted by formula 6- 2.
  • Scheme 6 Representative scheme of 1,2-addition using arylmagnesium bromide nucleophiles
  • Scheme 7 shows an alternative process for the preparation of a compound of formula 7-2 from the protected piperidinone S2. Suitable aryl halides may be treated with iPrMgCl-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.
  • Scheme 7 Representative scheme to generate arylmagnesium halide nucleophiles and their addition
  • Scheme 8 shows an alternative process for the preparation of a compound of formula 8-2 from the protected piperidinone S2.
  • Suitable aryl Grignard reagents ArMgX
  • Suitable aryl Grignard reagents ArMgX
  • LaCl3 ⁇ 2LiCl and S2 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.
  • Scheme 8 Representative scheme using arylmagnesium halide Grignard reagents with LaCl3 ⁇ 2LiCl as nucleophiles
  • Scheme 8a shows an alternative process for the preparation of a compound of formula 16 from piperidinones of formula S1. Note that this chemistry can proceed in the absence of a N-protecting group.
  • Suitable aryl Grignard reagents (ArMgX) which in some embodiments are prepared by treatment of appropriate aryl halides with magnesium in a solvent such as THF or 2- MeTHF, are then combined with S1 to form compounds depicted by formula 16.
  • Scheme 8a Representative scheme to generate arylmagnesium halide nucleophiles and their addition
  • Scheme 9 shows an alternative process for the preparation of a compound of formula 9-6 from N-protected beta-amino acids of formula 9-1.
  • PG 4 may be Boc or any suitable nitrogen protecting group.
  • Compound 9-2 dimagnesium salt may be coupled to compounds of formula 9-1 using a reagent such as CDI in a solvent such as THF. Condensation of compounds of formula 9-3 with aldehydes of formula 9-4 affords compounds of formula 9-5.
  • 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 aldehyde 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 Representative scheme to synthesize 2,6-disubstituted piperidinones
  • Scheme 10 shows a process for the preparation 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.
  • Suitable aryl halides such as 1-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.
  • the reaction was stirred for 30 minutes at 0 °C, removed from the cooling bath, and stirred at room temperature overnight.
  • the reaction was filtered 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 1 L of diethyl ether and filtered.
  • the filter-cake was washed with Et 2 O and dried in vacuo.
  • the filtrate was evaporated in vacuo again and was then triturated with a small volume of Et2O and filtered 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.
  • the mixture was diluted with TBME/EtOAc/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 MgSO 4 , 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 removed from the bath and stirred. After about 5 minutes, significant precipitation was observed. At this time, the mixture was cooled with an ice bath for 10 minutes, filtered, and rinsed with TBME (2 x 15 mL).
  • Step 1 Synthesis of (3S)-3-(tert-butoxycarbonylamino)butanoic acid (C8) [00210] To a solution of (3S)-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 temperature for 12 hours. The reaction was partitioned with MTBE (1 L) and water (300 mL). The layers were separated, and the aqueous layer was extracted again with MTBE (500 mL).
  • 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 temperature 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.
  • Compound 2 4-(3-chlorophenyl)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]piperidin-4-ol (2) [00216]
  • 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.
  • the suspension was diluted with water (1 mL) and ethyl acetate (4 mL).
  • the aqueous layer was washed with additional ethyl acetate (2 x 2 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.
  • 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 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.
  • Compound 7 was synthesized from compound S2 following the method described for Compound 5, with 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) to afford the title Compound 7 (8.9 mg, 25%) as a white solid.
  • 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 temperature. The suspension was diluted with water (2 mL) and EtOAc (2 mL), extracted with EtOAc (2 x 2 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo to yield a crude residue. [00226] ii. The crude mixture was diluted with THF (0.4 mL), and 2-sulfanylbenzoic acid (56 mg, 0.3632 mmol) was added.
  • a solution of dppb (4 mg, 0.009379 mmol) and Pd2(dba)3 (4 mg, 0.004368 mmol) 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, 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 M, 1.7 mL) followed by saturated aqueous ammonium chloride to achieve pH ⁇ 9.
  • Compound 12 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 12 (4.6 mg, 12%) as a white solid.
  • Compound 15 (2S,4S,6S)-4-(4-fluorophenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (15) [00235]
  • Compound 15 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: 5-98% Acetonitrile in Water with 5 mM Hydrochloric Acid) afforded the title Compound 15 (17 mg, 46%) as a white solid.
  • Step i [00237] To a suspension of magnesium (1.712 g, 70.44 mmol) in THF (100 mL) under nitrogen atmosphere was added one drop of 1,2-dibromoethane followed by 1-bromo-4- (trifluoromethyl)benzene (14.88 g, 66.13 mmol). The mixture was sonicated for 5 minutes and allowed to stir at ambient temperature for 1 hour.
  • 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 magnesium 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).
  • 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 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 1 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 ⁇ 1 mL saturated aqueous 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 (20 mL) that was pH adjusted with saturated aqueous ammonium chloride to pH ⁇ 9.
  • the organic layer was dried with magnesium 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 filtered and concentrated.
  • the foam was diluted in 30 mL TBME and to the yellow solution was added a dioxane solution of HCl (1.2 mL of 4 M, 4.800 mmol) dropwise, which immediately resulted in a loss of color in the mixture and a white precipitate.
  • a solution of dppb (17.47 mg, 0.04096 mmol) and Pd2dba3 (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.
  • X-Ray Powder Diffraction [00241] The X-ray powder diffraction (XRPD) diffractogram of Compound 16 Form A was acquired at room temperature in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 3D Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 ⁇ ). 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°2 ⁇ with a step size of 0.0131303° and 49s per step.
  • XRPD X-ray powder diffraction
  • Thermogravimetric analysis (TGA): [00242] Thermal gravimetric 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): [00243] DSC analysis of Compound 16 Form A was measured using the TA Instruments TA2500 DSC.
  • 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 ⁇ L of 2.3 M, 0.196 mmol) was added, and the mixture was stirred at this temperature for 15 minutes. The reaction turned blue within 5 minutes.
  • Step ii The intermediate was diluted with THF (250 ⁇ L), and 2-sulfanylbenzoic acid (17 mg, 0.110 mmol) was added.
  • a solution of dppb (2 mg, 0.00469 mmol) and Pd2(dba)3 (2 mg, 0.00218 mmol) in THF (250 ⁇ L) 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 observed.
  • the mixture was diluted and split with 1 M HCl (2 x 750 ⁇ L).
  • Compound 20 (2S,4S,6S)-4-(4-chloro-2-methoxy-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (20) [00250]
  • Compound 20 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: Acetonitrile in Water with 0.1 % trifluoroacetic acid) afforded the title Compound 20 (7.3 mg, 16%) as a clear oil.
  • Compound 22 (2S,4S,6S)-4-(4-chloro-2-fluoro-phenyl)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-ol (22) [00252]
  • Compound 22 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 22 (5.7 mg, 12%) as a clear oil.
  • Compound 26 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 26 (12.6 mg, 28%) as a white solid.
  • Step i A mixture of 1,4-dibromobenzene (120.8 mg, 0.512 mmol) in THF (800 ⁇ L) was cooled to -78 °C. At this time, butyllithium (260 ⁇ L of 1.6 M, 0.416 mmol) was added dropwise, and the mixture was stirred at -78 °C for 15 minutes.
  • Step ii The intermediate was diluted with THF (400 ⁇ L) and 2-sulfanylbenzoic acid (56 mg, 0.363 mmol) was added.
  • a solution of dppb (4 mg, 0.00938 mmol) and Pd2(dba)3 (4 mg, 0.00437 mmol) in THF (400 ⁇ L) 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 complete conversion.
  • 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 M, 1.7 mL) followed by saturated aqueous ammonium chloride to achieve pH ⁇ 9.
  • Step i A mixture of 4-bromo-2-methoxy-1-(trifluoromethyl)benzene (220 mg, 0.863 mmol) in THF (1000 ⁇ L) was cooled to -78 °C. At this time, sec-butyllithium (600 ⁇ L of 1.4 M, 0.840 mmol) was added, and the mixture was stirred at this temperature for 40 minutes.
  • 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 Pd 2 (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 1 mL), which was then pH adjusted to pH >10 and then extracted with DCM (2 mL).
  • Step i A mixture of 1-bromo-4-cyclopropyl-benzene (120 mg, 0.609 mmol) in THF (800 ⁇ L) was cooled to -78 °C. At this time, butyllithium (260 ⁇ L of 1.6 M, 0.416 mmol) was added dropwise, and the mixture was stirred at -78 °C for 10 minutes.
  • Step ii The intermediate was diluted with THF (400 ⁇ L) and 2-sulfanylbenzoic acid (55 mg, 0.357 mmol) was added.
  • a solution of dppb (4 mg, 0.00938 mmol) and Pd 2 (dba) 3 (4 mg, 0.00437 mmol) in THF (400 ⁇ L) was prepared and, after 30 minutes of mixing, the light 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 (2 x 5 mL).
  • 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 (3 x 10 mL), and the combined organic layer was filtered 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 white solid.
  • a THF (500 ⁇ L) solution of the tertiary alcohol and 2-sulfanylbenzoic acid was evacuated and back-filled with nitrogen 3 times and then stirred at rt.
  • the catalyst solution was added and the mixture was allowed to continue stirring under nitrogen.
  • the mixture was diluted with TBME (1 mL) and extracted with 1 M HCl (2 x 1 mL) and the aqueous layer was washed with TBME (2 x 1 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 1 mL), and the combined organic layer was washed with brine (1 mL), dried with magnesium sulfate, passed over a florisil cartridge and washed with methanol (2 x 1 mL). The combined organics were concentrated to yield the title compound 30 (2.9 mg, 4%) as a white solid.
  • reaction mixture was cooled to – 10 °C and solid S2 was added in one portion and stirred for 1 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 glove box and the vial was charged with 2-sulfanylbenzoic acid (53 mg, 0.344 mmol) and dissolved in THF (300 ⁇ L).
  • the organic layer was extracted with 2 additional portions of 1 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 ⁇ L), and the combined organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated to yield the title compound 42 (12.2 mg, 15%).
  • Compound 33 also produces Compound 33a .
  • Compound 33a is specifically excluded from the formulae of this disclosure by proviso.
  • Compound 44 (2S,4S,6S)-4-[2-hydroxy-4-(trifluoromethyl)phenyl]-2-methyl-6- (1-methyltriazol-4-yl)piperidin-4-ol (44)
  • the reaction was stirred for 2 hours.
  • the solvent was removed under vacuum then the residue dissolved with a 1M aqueous solution of hydrochloric acid (10 mL).
  • the aqueous phase was washed with MTBE (3 x 10 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.
  • Step 1 Synthesis of (2S,4S,6S)-1-allyl-2-methyl-6-(1-methyltriazol-4-yl)-4-[[3- (trifluoromethyl)phenyl]methyl]piperidin-4-ol (C15)
  • magnesium 147 mg, 6.065 mmol
  • iodine diethyl ether
  • 3- (trifluoromethyl)benzyl bromide 1.064 g, 0.68 mL, 4.45 mmol
  • Step 3 Synthesis of 2-methyl-6-(1H-triazol-4-yl)-4-[4-(trifluoromethyl)phenyl]piperidin-4- ol (62) [00291] To a mixture of 1-bromo-4-(trifluoromethyl)benzene (200 mg, 0.8889 mmol), LiCl (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 reaction was then allowed to warm to rt and stirred, at which time a brown-yellow solid began to precipitate heavily. After 15 min, the reaction was filtered and rinsed with additional DME (3 x 5 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.
  • Step 2 Synthesis of (2S,4S,6S)-4-(5-chloropyridin-2-yl)-2-methyl-6-(1-methyl-1H-1,2,3- triazol-4-yl)piperidine-4-carbonitrile (63) [00293] 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.
  • the reaction was stirred for 1.5 hours.
  • the solvent was removed under vacuum then the residue dissolved with a 1M aqueous solution of hydrochloric acid (10 mL).
  • the aqueous phase was washed with MTBE (3 x 10 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.
  • the MultiTox-Fluor Multiplex Cytotoxicity Assay is a single-reagent-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 bis- AAF-R110 Substrate
  • a ratio of dead to live cells is used to normalize data.
  • the tet-inducible transgenic APOL1 T-REx-HEK293 cell lines were incubated with 50 ng/mL tet to induce APOL1 in the presence of 3-(2-(4-fluorophenyl)-1H-indol-3-yl)-N- ((3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl)propenamide at 10.03, 3.24, 1.13, 0.356, 0.129, 0.042, 0.129, 0.0045, 0.0015, 0.0005 ⁇ M 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 complete protocol for the MultiTox assay are described below.
  • HEK293 Human embryonic kidney (HEK293) cell lines containing a tet-inducible expression system (T-RExTM; Invitrogen, Carlsbad, CA) and Adeno-associated virus site 1 pAAVS1-Puro-APOL1 G0 or pAAVS1-Puro-APOL1 G1 or pAAVS1-Puro-APOL1 G2
  • T-RExTM tet-inducible expression system
  • Clones G0 DC2.13, G1 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 penicillin- strepto
  • 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 1.17 x 10 6 cells/mL.20 ⁇ L 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 temperature for one hour.
  • DMEM 2% Tet-free FBS, 2 mM L-glutamine, 100 Units/mL penicillin-streptomycin
  • Tetracycline is needed to induce APOL1 expression.1 mg/mL tet stock in water was diluted to 250 ng/mL (5X) in cell assay media. 60 ⁇ L of cell assay media (no tet control) was dispensed in columns 1 and 24, and 60 ⁇ L of 5X tet in 384-PP-round bottom plate was dispensed in columns 2 to 23 with the Multidrop dispenser. [00308] Assay ready plates from the Global Compound Archive were ordered using template 384_APOL1Cell_DR10n2_50uM_v3. Compounds were dispensed at 200 nL in DMSO.
  • the final top concentration was 10 ⁇ M with a 10 point 3-fold dilution in duplicate in the MultiTox assay.
  • 20 ⁇ L was transferred from the 5X tet plate to the ARP and mixed, then 5 ⁇ L 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 2 incubator for 24 hours.
  • the MultiTox-Fluor Multiplex Cytotoxicity Assay was performed in accordance with the manufacturer’s protocol.
  • IP50 i.e., IC50 for cell proliferation
  • +++ means ⁇ 50 nM
  • ++ means between 50 nM and 500 nM
  • + means ⁇ 500 nM.

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PCT/US2022/051364 2021-11-30 2022-11-30 4-phenyl-2-(1h-1,2,3-triazol-4-yl)piperidin-4-ol derivatives as inhibitors of apol1 and methods of using same Ceased WO2023102022A1 (en)

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EP22843923.8A EP4441032A1 (en) 2021-11-30 2022-11-30 4-phenyl-2-(1h-1,2,3-triazol-4-yl)piperidin-4-ol derivatives as inhibitors of apol1 and methods of using same
KR1020247021706A KR20240131345A (ko) 2021-11-30 2022-11-30 Apol1 억제제로서의 4-페닐-2-(1h-1,2,3-트리아졸-4-일)피페리딘-4-올 유도체 및 이를 사용하는 방법
AU2022402839A AU2022402839A1 (en) 2021-11-30 2022-11-30 4-phenyl-2-(1h-1,2,3-triazol-4-yl)piperidin-4-ol derivatives as inhibitors of apol1 and methods of using same
CN202280089821.XA CN118574809A (zh) 2021-11-30 2022-11-30 作为apol1抑制剂的4-苯基-2-(1h-1,2,3-三唑-4-基)哌啶-4-醇衍生物和其使用方法
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PE2024001215A PE20241628A1 (es) 2021-11-30 2022-11-30 Derivados de 4-fenil-2-(1h-1,2,3-triazol-4-il)piperidin-4-ol como inhibidores de apol1 y metodos para usar los mismos
JP2024531628A JP2024543934A (ja) 2021-11-30 2022-11-30 Ａｐｏｌ１の阻害剤としての４－フェニル－２－（１ｈ－１，２，３－トリアゾール－４－イル）ピペリジン－４－オール誘導体、およびそれを使用する方法
MX2024006473A MX2024006473A (es) 2021-11-30 2022-11-30 Derivados de 4-fenil-2-(1h-1,2,3-triazol-4-il)piperidin-4-ol como inhibidores de apol1 y metodos para usar los mismos.
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US12344610B2 (en) 2022-01-18 2025-07-01 Maze Therapeutics, Inc. APOL1 inhibitors and methods of use

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