Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D495/20—Spiro-condensed systems
• • 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
  • A61K31/33—Heterocyclic compounds
  • 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
  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• • 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
  • A61K31/33—Heterocyclic compounds
  • 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
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
• • 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
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the FSGS and/or NDKD is associated with at least one of the 2 common APOL1 genetic variants (G1: 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/year.
• FSGS is a disease of the podocyte (glomerular visceral epithelial cells) responsible for proteinuria and progressive decline in kidney function.
• NDKD is a kidney disease involving damage to the podocyte or glomerular vascular bed that is not attributable to diabetes.
• NDKD is a disease characterized by hypertension and progressive decline in kidney function.
• Human genetics support a causal role for the G1 and G2 APOL1 variants in inducing kidney disease.
• Individuals with 2 APOL1 alleles are at increased risk of developing end-stage kidney disease (ESKD), including primary (idiopathic) FSGS, human immunodeficiency virus (HIV)-associated FSGS, NDKD, arterionephrosclerosis, lupus nephritis, microalbuminuria, and chronic kidney disease.
• EKD end-stage 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 L1 (APOL1) gene termed G1 and G2, which are referred to as the “APOL1 risk alleles.”
• G1 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 G0 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 selected from compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’’, IIIb’’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’’, I’ 0
• the at least one compound is a compound represented by Formula I: wherein X 1 , X 2 , R 1 , R 3a , R 3b , R 4 , R 5 , k, and m are as defined in an embodiment disclosed herein.
• At least one compound of the disclosure is a compound represented by the following structural formula: Formula I a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 is selected from S and -CR 2a and X 2 is selected from S and -CR 2b , wherein: one of X 1 and X 2 is S; when X 1 is S, then X 2 is -CR 2b ; and when X 2 is S, then X 1 is -CR 2a ; R 1 is selected from hydrogen, halogen, -OH, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and phenyl, wherein: the C 1 -C 6 alkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH
• R 4 is selected from C 1 -C 6 alkyl and [0016]
• At least one compound of the disclosure is a compound represented by the following structural formula: Formula I 0 a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 and X 2 are each selected from S and -CR 2 , wherein: one of X 1 and X 2 is S; when X 1 is S, then X 2 is -CR 2b ; and when X 2 is S, then X 1 is -CR 2a ; R 1 is selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and phenyl; wherein: the C 1 -C 6 alkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH
• the compounds of Formula I are chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), such that the at least one entity is chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), 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 pharmaceutical compositions comprising at least one entity chosen from compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’, IIIb’’’’, IVa’’’, IVb’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0 , IIIa’
• the pharmaceutical compositions may comprise at least one compound chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), 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 (e.g., an APOL1-mediated kidney disease) comprising administering to a subject in need thereof, at least one entity chosen from compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’’, IIb’’’, IIIa’’’’, IIIb’’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0
• the methods comprise administering at least one entity chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt 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 entity chosen from compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’, IIIb’’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0 , I
• the methods comprise administering at least one entity chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
• Another aspect of the disclosure provides methods of treating FSGS and/or NDKD comprising administering to a subject in need thereof, at least one entity chosen from compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’’, IIIb’’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0 , IIIa’ 0 , IIIb’ 0 ,
• the methods comprise administering at least one entity chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt 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 entity chosen from compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’, IIIb’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0 , IIIa’ 0 , IIIb’ , I’ 0 , II
• the methods comprise administering at least one entity chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt 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 entity chosen from compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, V, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’, IIIb’’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0 , IIIa’ 0 , IIIb’ 0 , IVa’ 0 , IVa
• the methods of inhibiting APOL1 comprise administering at least one entity chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing or a pharmaceutical composition comprising the at least one entity.
• Compounds 1 to 391 e.g., from Compounds 1 to 220
• a tautomer thereof e.g., from Compounds 1 to 220
• a tautomer thereof e.g., a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing or a pharmaceutical composition comprising the at least one entity.
• FIG.1 depicts an XRPD diffractogram of Compound 181 Phosphate Salt Hydrate at 25 ⁇ 2°C and 40% RH.
• FIG.2 depicts an XRPD diffractogram of Compound 181 Phosphate Salt Hydrate at 25 ⁇ 2°C and 5% RH (black trace) or 90% (gray trace).
• FIG.3 depicts a TGA thermogram of Compound 181 Phosphate Salt Hydrate.
• FIG.4 depicts a DSC curve of Compound 181 Phosphate Salt Hydrate.
• FIG.5 depicts a solid state 13 C NMR spectrum of Compound 181 Phosphate Salt Hydrate.
• FIG.6 depicts a solid state 19 F NMR spectrum of Compound 181 Phosphate Salt Hydrate at 43% RH.
• FIG.7 depicts the effects of relative humidity on solid state 19 F NMR spectrum of Compound 181 Phosphate Salt Hydrate.
• FIG.8 depicts a solid state 31 P NMR spectrum of Compound 181 Phosphate Salt Hydrate at 43% RH.
• FIG.9 depicts the effects of relative humidity on solid state 31 P NMR spectrum of Compound 181 Phosphate Salt Hydrate.
• FIG.10 depicts an XRPD diffractogram of Compound 181 Free Form Monohydrate.
• FIG.11 depicts a TGA thermogram of Compound 181 Free Form Monohydrate.
• FIG.12 depicts a DSC curve of Compound 181 Free Form Monohydrate.
• FIG.13 depicts a solid state 13 C NMR spectrum of Compound 181 Free Form Monohydrate.
• FIG.14 depicts a solid state 13 C NMR spectrum of dehydrated Compound 181 Free Form Monohydrate.
• FIG.15 depicts a solid state 19 F NMR spectrum of Compound 181 Free Form Monohydrate.
• FIG.16 depicts a solid state 19 F NMR spectrum of dehydrated Compound 181 Free Form Monohydrate.
• FIG.17 depicts an XRPD diffractogram of Compound 181 Phosphate Salt Methanol Solvate.
• FIG.18 depicts a solid state 13 C NMR spectrum of Compound 181 Phosphate Salt Methanol Solvate.
• FIG.19 depicts a solid state 19 F NMR spectrum of Compound 181 Phosphate Salt Methanol Solvate.
• FIG.20 depicts a solid state 31 P NMR spectrum of Compound 181 Phosphate Salt Methanol Solvate.
• FIG.21 depicts an XRPD diffractogram of Compound 181 Phosphate Salt MEK Solvate.
• FIG.22 depicts a solid state 13 C NMR spectrum of Compound 181 Phosphate Salt MEK Solvate.
• FIG.23 depicts a solid state 19 F NMR spectrum of Compound 181 Phosphate Salt MEK Solvate.
• FIG.24 depicts an XRPD diffractogram of Compound 174 Phosphate Hemihydrate.
• FIG.25 depicts a TGA thermogram of Compound 174 Phosphate Hemihydrate.
• FIG.26 depicts a DSC curve of Compound 174 Phosphate Hemihydrate.
• FIG.27 depicts a solid state 13 C NMR spectrum of Compound 174 Phosphate Hemihydrate.
• FIG.28 depicts a solid state 13 C NMR spectrum of dehydrated Compound 174 Phosphate Hemihydrate.
• FIG.29A depicts a solid state 31 P NMR spectrum of Compound 174 Phosphate Hemihydrate.
• FIG.29B depicts a solid state 31 P NMR spectrum of dehydrated Compound 174 Phosphate Hemihydrate.
• FIG.30 depicts an XRPD diffractogram of Compound 174 Hemihydrate.
• FIG.31 depicts a TGA thermogram of Compound 174 Hemihydrate.
• FIG.32 depicts a DSC curve of Compound 174 Hemihydrate.
• FIG.33 depicts a solid state 13 C NMR spectrum of Compound 174 Hemihydrate.
• FIG.34 depicts a solid state 13 C NMR spectrum of dehydrated Compound 174 Hemihydrate.
• the terms “selected from” and “chosen from” are used interchangeably herein.
• the term “APOL1,” as used herein, means apolipoprotein L1 protein and the term “APOL1” means apolipoprotein L1 gene.
• the term “APOL1 mediated disease” refers to a disease or condition associated with aberrant APOL1 (e.g., certain APOL1 genetic variants; elevated levels of APOL1). In some embodiments, an APOL1 mediated disease is an APOL1 mediated kidney disease.
• 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.
• the term “APOL1 mediated kidney disease” refers to a disease or condition that impairs kidney function and can be attributed to APOL1. In some embodiments, APOL1 mediated kidney disease is associated with patients having two APOL1 risk alleles, e.g., patients who are homozygous or compound heterozygous for the G1 or G2 alleles.
• 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 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, and in some embodiments, alkyl groups contain 1 to 4 alkyl carbon atoms.
• alkyl groups contain 1 to 3 alkyl carbon atoms, and in yet other embodiments, alkyl groups contain 1 to 2 alkyl carbon atoms. In some embodiments, alkyl groups are substituted. In some embodiments, alkyl groups are unsubstituted. In some embodiments, alkyl groups are linear or straight-chain or unbranched. In some embodiments, alkyl groups are branched.
• cycloalkyl refers to a monocyclic C 3-8 hydrocarbon or a spirocyclic, fused, or bridged bicyclic or tricyclic C8-14 hydrocarbon that is completely saturated, wherein any individual ring in said bicyclic ring system has 3 to 7 members.
• cycloalkyl groups are substituted.
• cycloalkyl groups are unsubstituted.
• the cycloalkyl is a C3 to C12 cycloalkyl.
• the cycloalkyl is a C3 to C8 cycloalkyl.
• the cycloalkyl is a C 3 to C 6 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 C 3-8 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, carbocyclyl groups are substituted.
• carbocyclyl groups are unsubstituted.
• the carbocyclyl is a C3 to C12 carbocyclyl.
• the carbocyclyl is a C3 to C 10 carbocyclyl.
• the carbocyclyl is a C3 to C8 carbocyclyl.
• the terms “heteroalkyl,” or “heteroaliphatic,” as used herein, refer to alkyl or aliphatic groups as defined above, wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon.
• alkenyl means a straight-chain (i.e., linear or unbranched), branched, substituted or unsubstituted hydrocarbon chain that contains one or more double bonds. In some embodiments, alkenyl groups are substituted. In some embodiments, alkenyl groups are unsubstituted. In some embodiments, alkenyl groups are straight-chain. In some embodiments, 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 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.
• the heterocycle has one heteroatom independently chosen from oxygen, sulfur, nitrogen, and phosphorus.
• the heterocycle has one heteroatom that is a nitrogen atom.
• the heterocycle has one heteroatom that is an oxygen atom.
• the heterocycle has two heteroatoms that are each independently selected from nitrogen and oxygen.
• the heterocycle has three heteroatoms that are each independently selected from nitrogen and oxygen.
• heterocycles are substituted.
• heterocycles are unsubstituted.
• the heterocyclyl is a 3- to 12-membered heterocyclyl.
• the heterocyclyl is a 3- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl.
• 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.
• alkoxy groups include methoxy, ethoxy, methylmethoxy, and the like.
• 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.
• “alkoxy” and/or “thioalkyl” groups are substituted. In some embodiments, “alkoxy” and/or “thioalkyl” groups are unsubstituted.
• haloalkyl refers to 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 -CHF 2 , -CH 2 F, -CF 3 , -CF 2 -, and perhaloalkyls, such as -CF 2 CF 3 .
• Non-limiting examples of haloalkoxy groups include -OCHF2, -OCH 2 F, -OCH 3 , 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.
• Non-limiting examples of 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 (C 6 ) and naphthyl (C 10 ) rings. In some embodiments, aryl groups are substituted.
• aryl groups are unsubstituted.
• 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, 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 are substituted.
• 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.
• heteroaryl groups are unsubstituted.
• the heteroaryl is a 3- to 12-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 8- membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl.
• 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” (CH 2 Cl2), 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-diox
• 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-Pr 2 EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCH 3 ).
• DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
• KtBu potassium tert-butoxide
• K 2 CO 3 N-methylmorpholine
• TEA triethylamine
• i-Pr 2 EtN diisopropyl-ethyl amine
• DIPEA diisoprop
• 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 + (C 1-4 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 the desired effect for which it is administered (e.g., improvement in symptoms 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.
• At least one entity chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), 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 entity chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), 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 entity chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), 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 entity chosen from Compounds 1 to 391 e.g., from Compounds 1 to 220
• 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.
• the amounts of the compounds, pharmaceutically acceptable salts, solvates, and deuterated derivatives disclosed herein are based upon the free base form of the reference compound.
• “1000 mg of at least one compound 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 compounds of Formula I.
• the term “ambient conditions” means room temperature, open air condition, and uncontrolled humidity condition.
• the terms “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
• Form A of Compound [X] or “Compound [X] Form A” refers to a unique crystalline form that can be identified and distinguished from other crystalline forms of Compound I 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
• SSNMR refers to the analytical characterization method of solid state nuclear magnetic resonance.
• SSNMR spectra can be recorded at ambient conditions or at alternative conditions (e.g., at 275 K) on any magnetically active isotope present in the sample.
• the typical 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.
• X-ray powder diffractogram As used herein, 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) selected from ....” [00118] A “signal” or “peak,” as used herein, refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum.
• a signal 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).
• crystalline hydrate is a crystal form comprising either stoichiometric or nonstoichiometric water in the crystal lattice. In the case of nonstoichiometric hydrate, the amount of water present in a crystalline hydrate may vary as a function of at least the relative humidity (“RH”).
• the presence (or absence) of water or different amounts of water may lead to X-ray diffractogram peak position shifts, or the appearance or disappearance of peaks.
• the presence (or absence) of water or different amount of water may lead to peak shifts or even appearances of new peaks in proton, carbon, fluorine, phosphorus, nitrogen, chlorine (or other NMR active nuclei) solid state NMR spectra.
• At least one entity of the disclosure is a compound represented by the following structural formula: a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 is selected from S and -CR 2a and X 2 is selected from S and -CR 2b , wherein: one of X 1 and X 2 is S; when X 1 is S, then X 2 is -CR 2b ; and when X 2 is S, then X 1 is -CR 2a ; R 1 is selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and phenyl, wherein: the C 1 -C 6 alkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH 2
• a compound 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, wherein: R 2a is selected from hydrogen, halogen, cyano, and C 1 -C 4 alkyl; wherein: the C 1 -C 4 alkyl of R 2a is optionally substituted with 1 to 3 groups independently selected from halogen, -OH, and C 1 -C 2 alkoxy; R 2b is selected from hydrogen, halogen, cyano, and C 1 -C 4 alkyl; and k is an integer selected from 0, 1, and 2; and all other variables not specifically defined herein are as defined in the foregoing embodiment.
• R 4 is selected from C 1 -C 4 alkyl and the C 1 -C 4 alkyl of R 4 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , C 1 -C 2 alkoxy, C 3 -C 6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5 to 6-membered heteroaryl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
• R 4 is selected from C 1 -C 2 alkyl and the C 1 -C 2 alkyl of R 4 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, and 5- to 6-membered heterocyclyl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
• R 4 is selected 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.
• a compound 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, wherein: Ring A, for each occurrence, is selected from C 3 -C 6 cycloalkyl, 5- to 10-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl; 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 A is selected from cyclopropyl, 5- to 10-membered heterocyclyl, phenyl, and 5 to 9-membered heteroaryl; 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 A is selected from cyclopropyl, 5- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, phenyl, and 5 to 9-membered heteroaryl containing 1 to 3 heteroatoms selected 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 A is selected from cyclopropyl, 5-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, 9-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, phenyl, 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, and 9-membered heteroaryl containing 1 to 3 heteroatoms selected 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 A is selected 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 A is selected 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 4 is selected from -CH 3 and Ring A; wherein Ring A is selected from ; each of which is optionally substituted with 1, 2, 3, 4, or 5 a R groups; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
• a compound 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.
• R 1 is selected from hydrogen, halogen, cyano, -OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and C 3 -C 6 cycloalkyl; wherein: the C 1 -C 4 alkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, and C 1 -C 2 alkoxy; the C 1 -C 4 alkoxy of R 1 is optionally substituted with 1 to 3 independently selected halogen groups; and the C 3 -C 6 cycloalkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, and C 1 -C 2 alkoxy; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
• R 1 is selected from F, Cl, Br, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl; wherein: the C 1 -C 4 alkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen and -OH; and the C 3 -C 6 cycloalkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen, and -OH; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
• R 1 is selected from F, Cl, Br, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl; wherein: the C 1 -C 4 alkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen and -OH; and the C 3 -C 6 cycloalkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen and -OH; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
• R 1 is selected from Cl, Br, -CH 3 , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CHF2, -CH 2 CH(CH 3 ) 2 , difluorocyclobutyl, and cyclohexyl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
• R 1 is Cl; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
• R 3a is selected from halogen, -OH, and C 1 -C 4 alkyl; wherein: the C 1 -C 4 alkyl of R 3a is optionally substituted with 1 to 3 groups independently selected from halogen and -OH; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
• R 3a is selected from F, Cl, Br, -OH, and C 1 -C 2 alkyl; wherein: the C 1 -C 2 alkyl of R 3a is optionally substituted with 1 to 3 groups independently selected from F, Cl, and -OH; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
• R 3a is selected from F, -OH, -CH 3 , -CHF2, and -CH 2 OH; and all other variables not specifically defined herein are as defined in any one of the foregoing embodiments.
• a compound 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.
• a compound 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.
• a compound of the disclosure is represented by one of the following structural formulae:
• the at least one compound of the disclosure is chosen from Compounds 1 to 220 depicted in Table I, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
• a wavy line in a compound in Table I depicts a bond between two atoms and indicates a position of mixed stereochemistry for a collection of molecules, such as a racemic mixture, cis/trans isomers, or (E)/(Z) isomers.
• An asterisk adjacent to an atom indicates a chiral position in the molecule.
• the at least one compound of the disclosure is chosen from Compounds 221 to 391 depicted in Table II, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
• a wavy line in a compound in Table II depicts a bond between two atoms and indicates a position of mixed stereochemistry for a collection of molecules, such as a racemic mixture, cis/trans isomers, or (E)/(Z) isomers.
• An asterisk adjacent to an atom indicates a chiral position in the molecule.
• the at least one compound of the disclosure is chosen from Compounds 1 to 391 depicted in Table I or II, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
• the at least one compound of the disclosure is chosen from compounds depicted in Table III, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
• a wavy line in a compound in Table III i.e., depicts a bond between two atoms and indicates a position of mixed stereochemistry for a collection of molecules, such as a racemic mixture, cis/trans isomers, or (E)/(Z) isomers.
• An asterisk adjacent to an atom indicates a chiral position in the molecule.
• Some embodiments of the disclosure include derivatives of Compounds 1 to 391 (e.g., of Compounds 1 to 220) or compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’, IIIb’’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa
• the derivatives are silicon derivatives in which at least one carbon atom in a compound chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220) or compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’’, IIIb’’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0 , IIIa’ 0 ,
• the derivatives are boron derivatives, in which at least one carbon atom in a compound chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220) or compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’’, IIIb’’’, IVa’’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’’, IIIb’’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0
• the derivatives are phosphorus derivatives, in which at least one carbon atom in a compound chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220) or compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’’, IIIb’’’, IVa’’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’’, IIIb’’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0
• the derivative is a silicon derivative in which one carbon atom in a compound chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220) or compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’’, IIIb’’’, IVa’’’, IVb’’’, Ia’’’, IVb’’’, IVb’’, IVb’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa
• the carbon replaced by silicon may be a non-aromatic carbon.
• a fluorine has been replaced by silicon derivative (e.g., -Si(CH 3 )3).
• the silicon derivatives of the disclosure may include one or more hydrogen atoms replaced by deuterium.
• a silicon derivative of compound chosen from Compounds 1 to 391 e.g., from Compounds 1 to 220 or compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’, IIIb’’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0 , IIIa’ 0 , IIIb’ 0 , IVa’ 0 , IV
• the derivative is a boron derivative in which one carbon atom in a compound chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220) or compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’’, IIIb’’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0 , III 0 , IIIb
• the derivative is a phosphorus derivative in which one carbon atom in a compound chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220) or compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’’, IIIb’’’’, IVa’’’, IVb’’’, Ia’’’, IVb’’’, IVb’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’
• compositions comprising at least one compound according to any one formula chosen from Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’, IIIb’’’’, IVa’’’, IVb’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0 , IIIa’
• the pharmaceutical composition comprising at least one compound chosen from Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’’, IIIb’’’’, IVa’’’, IVb’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb’ 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0 , IIIa’ 0
• 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.
• the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.
• a pharmaceutical composition comprising at least one compound chosen from compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IIb’’’, IIIa’’’’, IIIb’’’’, IVa’’’, IVb’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0 , IIIa’ 0 , IIIb’ 0 , IV
• a pharmaceutical composition comprising at least one compound chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt 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 methods of the disclosure comprise administering to a patient in need thereof at least one entity chosen from compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’’, IIIb’’’’, IVa’’’, IVb’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb
• the compound of Formula I is chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt 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 entity chosen from compounds of Formulae I, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, I’, IIa’, IIb’, IIIa’, IIIb’, IVa’, IVb’, Va’, Vb’, IIa’’, IIb’’, IIIa’’, IIIb’’, IVa’’, IVb’’, IIa’’’, IIb’’’, IIIa’’’, IIIb’’’’, IVa’’’, IVb’’’, I 0 , IIa 0 , IIb 0 , IIIa 0 , IIIb 0 , IVa 0 , IVb 0 , Va 0 , Vb 0 , I’ 0 , IIa’ 0 , IIb’ 0 , IIIa’ 0 , IIIb’ 0 , IVa’ 0 ,
• the methods of inhibiting APOL1 activity comprise contacting said APOL1 with at least one entity chosen from Compounds 1 to 391 (e.g., from Compounds 1 to 220), a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
• Compounds 1 to 391 e.g., from Compounds 1 to 220
• a tautomer thereof e.g., from Compounds 1 to 220
• a tautomer thereof e.g., from Compounds 1 to 220
• a deuterated derivative of that compound or tautomer e.g., a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
• Non-Limiting Exemplary Embodiments 1 include: 1.
• R 4 is selected from C 1 -C 4 alkyl and the C 1 -C 4 alkyl of R 4 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , C 1 -C 2 alkoxy, C 3 -C 6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl; and all other variables not specifically defined herein are as defined in Embodiment 1 or Embodiment 2.
• Ring A is selected from cyclopropyl, 5 to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, phenyl, and 5 to 9-membered heteroaryl containing 1 to 3 heteroatoms selected 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 7. 9.
• Ring A is selected from cyclopropyl, 5-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, 9-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, phenyl, 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, and 9-membered heteroaryl containing 1 to 3 heteroatoms selected 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.
• R 1 is selected from hydrogen, halogen, cyano, -OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and C 3 -C 6 cycloalkyl; wherein: the C 1 -C 4 alkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, and C 1 -C 2 alkoxy; the C 1 -C 4 alkoxy of R 1 is optionally substituted with 1 to 3 independently selected from halogen groups; and the C 3 -C 6 cycloalkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, and C 1 -C 2 alkoxy; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 16.
• R 1 is selected from F, Cl, Br, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl; wherein: the C 1 -C 4 alkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen and -OH; and the C 3 -C 6 cycloalkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen and -OH; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 17. 19.
• R 1 is selected from F, Cl, Br, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl; wherein: the C 1 -C 4 alkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen and -OH; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 18. 20.
• R 3a is selected from F, Cl, Br, -OH, and C 1 -C 2 alkyl; wherein: the C 1 -C 2 alkyl of R 3a is optionally substituted with 1 to 3 groups independently selected from F, Cl, and -OH; and all other variables not specifically defined herein are as defined in any one of Embodiments 1 to 22. 24.
• 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.
• 31. A compound selected from the compounds of Table I, tautomers thereof, deuterated derivative of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.
• 32. A compound selected from the compounds of Table II, tautomers thereof, deuterated derivative of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 33.
• a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 33 and a pharmaceutically acceptable carrier.
• 35. 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 33 or a pharmaceutical composition according to Embodiment 34. 36.
• At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 33 or a pharmaceutical composition according to Embodiment 34 for the manufacture of a 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 33 or a pharmaceutical composition according to Embodiment 34.
• 39. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 33 or a pharmaceutical composition according to Embodiment 34 for the manufacture of a medicament for inhibiting APOL1 activity.
• 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 33 or a pharmaceutical composition according to Embodiment 34.
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease
• Embodiments 1 to 33 Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 33 or a pharmaceutical composition according to Embodiment 34 for the manufacture of a medicament for treating an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease).
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 33 or a pharmaceutical composition according to Embodiment 34 for use in treating an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• 48. The at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt for use or the pharmaceutical composition for use according to Embodiment 47, wherein the APOL1-mediated disease is cancer.
• 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 33 or a pharmaceutical composition according to Embodiment 34.
• 51. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 33 or a pharmaceutical composition according to Embodiment 34 for the manufacture of a medicament for inhibiting APOL1 activity.
• a pharmaceutical composition comprising a silicon derivative of Embodiment 53.
• a method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof a silicon derivative according to Embodiment 53 or a pharmaceutical composition according to Embodiment 54.
• 56. Use of the silicon derivative according to Embodiment 53 or a pharmaceutical composition according to Embodiment 54 for the manufacture of a medicament for treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease. 57.
• a method of treating an APOL1-mediated disease comprising administering to a patient in need thereof a silicon derivative according to Embodiment 53 or a pharmaceutical composition according to Embodiment 54.
• the method according to Embodiment 58, wherein the APOL1-mediated disease is cancer.
• the method according to Embodiment 58 or Embodiment 59, wherein the APOL1-mediated disease is pancreatic cancer. 61.
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease
• a pharmaceutical composition according to Embodiment 54 for the manufacture of a medicament for treating an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease).
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• 62. The use according to Embodiment 61, wherein the APOL1-mediated disease is cancer.
• 63. The use according to Embodiment 61 or Embodiment 62, wherein the APOL1-mediated disease is pancreatic cancer.
• 67. A boron derivative of the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 33.
• 68. A pharmaceutical composition comprising a boron derivative of Embodiment 67. 69.
• 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 67 or a pharmaceutical composition according to Embodiment 68.
• a boron derivative according to Embodiment 67 or a pharmaceutical composition according to Embodiment 68 for the manufacture of a medicament for treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease.
• the boron derivative according to Embodiment 67 or a pharmaceutical composition according to Embodiment 68 for use in treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease.
• a method of treating an APOL1-mediated disease comprising administering to a patient in need thereof a boron derivative according to Embodiment 67 or a pharmaceutical composition according to Embodiment 68.
• the method according to Embodiment 72, wherein the APOL1-mediated disease is cancer.
• the method according to Embodiment 72 or Embodiment 73, wherein the APOL1-mediated disease is pancreatic cancer.
• Use of the boron derivative according to Embodiment 67 or a pharmaceutical composition according to Embodiment 68 for the manufacture of a medicament for treating an APOL1-mediated disease (e.g., an APOL1-mediated kidney disease).
• Embodiment 75 wherein the APOL1-mediated disease is cancer.
• Embodiment 75 or Embodiment 76 wherein the APOL1-mediated disease is pancreatic cancer.
• an APOL1-mediated disease e.g., an APOL1- mediated kidney disease.
• APOL1-mediated disease e.g., an APOL1- mediated kidney disease.
• a pharmaceutical composition comprising a phosphorus derivative of Embodiment 81.
• 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 81 or a pharmaceutical composition according to Embodiment 82. 84.
• phosphorus derivative according to Embodiment 81 or a pharmaceutical composition according to Embodiment 82 for the manufacture of a medicament for treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease.
• the phosphorus derivative according to Embodiment 81 or a pharmaceutical composition according to Embodiment 82 for use in treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease.
• a method of treating an APOL1-mediated disease e.g., an APOL1-mediated kidney disease
• administering comprising administering to a patient in need thereof a phosphorus derivative according to Embodiment 81 or a pharmaceutical composition according to Embodiment 82.
• Embodiment 86 wherein the APOL1-mediated disease is cancer.
• Embodiment 86 or Embodiment 87, wherein the APOL1-mediated disease is pancreatic cancer.
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• 90 The use according to Embodiment 89, wherein the APOL1-mediated disease is cancer.
• 91. The use according to Embodiment 89 or Embodiment 90, wherein the APOL1-mediated disease is pancreatic cancer.
• the phosphorus derivative according to Embodiment 81 or a pharmaceutical composition according to Embodiment 82 for use in treating an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• the phosphorus derivative or pharmaceutical composition for use according to Embodiment 92, wherein the APOL1-mediated disease is cancer.
• the phosphorus derivative or pharmaceutical composition for use according to Embodiment 92 or Embodiment 93, wherein the APOL1-mediated disease is pancreatic cancer. 95.
• 96. A method of treating a patient; an entity (e.g., a compound, tautomer, deuterated derivative, pharmaceutically acceptable salt, silicon derivative, boron derivative, phosphorus derivative) or pharmaceutical composition for use in treating a patient; or use of an entity or pharmaceutical composition in treating a patient as described in any embodiment herein, wherein the patient has 1 APOL1 risk allele.
• a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 97 or Embodiment 98 and a pharmaceutically acceptable carrier.
• 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, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 97 or Embodiment 98 or a pharmaceutical composition according to Embodiment 99.
• Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to according to Embodiment 97 or Embodiment 98 or a pharmaceutical composition according to Embodiment 99 for the manufacture of a 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 Embodiment 97 or Embodiment 98 or a pharmaceutical composition according to Embodiment 99. 104.
• a method of treating an APOL1-mediated disease comprising administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 97 or Embodiment 98 or a pharmaceutical composition according to Embodiment 99.
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease
• administering comprising administering to a patient in need thereof at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 97 or Embodiment 98 or a pharmaceutical composition according to Embodiment 99.
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• At least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 97 or Embodiment 98 or a pharmaceutical composition according to Embodiment 99 for use in treating an APOL1-mediated disease e.g., an APOL1-mediated kidney disease.
• an APOL1-mediated disease e.g., an APOL1-mediated 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 Embodiment 97 or Embodiment 98 or a pharmaceutical composition according to Embodiment 99.
• Non-Limiting Exemplary Embodiments 2 include: 1. A compound represented by the following structural formula: a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 and X 2 are each selected from S and -CR 2 , wherein: one of X 1 and X 2 is S; when X 1 is S, then X 2 is -CR 2b ; and when X 2 is S, then X 1 is -CR 2a ; R 1 is selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and phenyl; wherein: the C 1 -C 6 alkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, -OH, -NH 2 ,
• R 4 is selected from C 1 -C 4 alkyl and wherein: the C 1 -C 4 alkyl of R 4 is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , C 1 -C 2 alkoxy, C 3 -C 6 cycloalkyl, 5 to 6-membered heterocyclyl, phenyl, and 5 to 6-membered heteroaryl; and all other variables not specifically defined herein are as defined in Clause 1 or Clause 2.
• Ring A is selected from cyclopropyl, 5 to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, phenyl, and 5 to 9-membered heteroaryl containing 1 to 3 heteroatoms selected 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 Clauses 1 to 7. 9.
• Ring A is selected from cyclopropyl, 5-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, 9-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from N and O, phenyl, 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, and 9-membered heteroaryl containing 1 to 3 heteroatoms selected 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 Clauses 1 to 8.
• R 1 is selected from hydrogen, halogen, cyano, -OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and C 3 -C 6 cycloalkyl; wherein: the C 1 -C 4 alkyl of R 1 is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and C 1 -C 2 alkoxy; the C 1 -C 4 alkoxy of R 1 is optionally substituted with 1 to 3 groups of halogen; and the C 3 -C 6 cycloalkyl of R 1 is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and C 1 -C 2 alkoxy; and all other variables not specifically defined herein are as defined in any one of Clauses 1 to 16.
• R 1 is selected from F, Cl, Br, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl; wherein: the C 1 -C 4 alkyl of R 1 is optionally substituted with 1 to 3 groups selected from halogen and -OH; and all other variables not specifically defined herein are as defined in any one of Clauses 1 to 18. 20.
• R 3a is selected from F, Cl, Br, -OH, and C 1 -C 2 alkyl; wherein: the C 1 -C 2 alkyl of R 3a is optionally substituted with 1 to 3 groups selected from F, Cl, and -OH; and all other variables not specifically defined herein are as defined in any one of Clauses 1 to 22. 24.
• a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of Clauses 1 to 31 and a pharmaceutically acceptable carrier.
• 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 Clauses 1 to 31 or a pharmaceutical composition according to Clause 32.
• 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 Clauses 1 to 31 or a pharmaceutical composition according to Clause 32.
• 37. Use of at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of Clauses 1 to 31 or a pharmaceutical composition according to Clause 32 for the manufacture of a medicament for inhibiting APOL1 activity. 38.
• a pharmaceutical composition comprising a silicon derivative of Clause 39.
• 41. A method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof a silicon derivative according to Clause 39 or a pharmaceutical composition according to Clause 40. 42.
• the silicon derivative according to Clause 39 or a pharmaceutical composition according to Clause 40 for the manufacture of a medicament for treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease.
• the silicon derivative according to Clause 39 or a pharmaceutical composition according to Clause 40 for use in treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease.
• a pharmaceutical composition comprising a boron derivative of Clause 44. 46.
• 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 Clause 44 or a pharmaceutical composition according to Clause 45. 47. Use of the boron derivative according to Clause 44 or a pharmaceutical composition according to Clause 45 for the manufacture of a medicament for treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease. 48. The boron derivative according to Clause 44 or a pharmaceutical composition according to Clause 45 for use in treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease. 49.
• a pharmaceutical composition comprising a phosphorus derivative of Clause 48.
• 51. 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 Clause 48 or a pharmaceutical composition according to Clause 49.
• 52. Use of the phosphorus derivative according to Clause 48 or a pharmaceutical composition according to Clause 49 for the manufacture of a medicament for treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease. 53.
• the reaction may occur in the presence of an amine catalyst such as L-proline, in the presence of a base such as triethyl amine, and magnesium sulfate reagent.
• Compounds of formula 1-3 may be prepared using any suitable method for the preparation of a piperidone.
• a compound of formula 1-3 may be prepared from a piperidone of formula 1-3 and an alcohol of formula 1-4 using any suitable conditions to perform a Pictet-Spengler reaction.
• the reaction may be performed in the presence of an acid such as trifluoromethyl sulfonic acid and a solvent such as 1,4-dioxane.
• an acid such as methanesulfonic acid may be used.
• Scheme 2 depicts processes for the preparation of compounds of formula 2-3.
• PG 1 is any suitable nitrogen protecting group.
• PG 1 is a trifluoroacetate group.
• a compound of formula 2-2 may be prepared from 2-1 using any suitable method for benzylic oxidation.
• the reaction is performed in the presence of oxygen gas under balloon pressure, N-hydroxypthalamide, and cobalt diacetate catalyst.
• the reaction is performed in the presence of acetonitrile.
• the reaction may be performed in the presence of added heat (e.g., at 60 o C).
• Compounds of formula 2-3 may be prepared from a compound of formula 2-2 using any suitable method for the reduction of a ketone to an alcohol.
• a Corey–Bakshi–Shibata catalyst CBS catalyst
• transition metal catalyzed transfer hydrogenation system may be used.
• transition metal transfer hydrogenation reaction may result in an asymmetric reduction of the ketone.
• Scheme 2 [00181]
• Scheme 3 shows processes for the preparation of compounds of formula 3-4.
• PG 2 is any suitable alcohol protecting group, for example, THP.
• a heterocyclic bromide of formula 3-1 may be coupled with a trifluoroboronate salt of formula 3-2 using any suitable method for the coupling of a halide with an alkyl boronate.
• the reaction may be performed in the presence of a catalyst system such as palladium (II) dicyclohexyl-[2- (2,6-diisopropoxyphenyl)phenyl]phosphane methanesulfonate N-methyl-2-phenyl-aniline and a base such as Cs2CO3.
• the reaction may be performed in the presence of added heat (e.g., 100 o C).
• the reaction is performed in a solvent such as toluene.
• Any suitable method for the removal of an alcohol protecting group may be used to prepare a compound of formula 3-4.
• PG 2 is THP
• an acid such as p-toluene sulfonic acid in a solvent such as methanol may be used.
• the reaction may be performed at room temperature.
• Scheme 3 [00182]
• Scheme 4 shows processes for the preparation of alcohols of formula 4-5 from aryl halides of formula 3-1.
• Any suitable reagent for performing a lithium-halogen exchange on an heteroaryl bromide, such as treatment with n-butyl lithium, may be used to generate a heteroaryl organometallic reagent in situ.
• the reaction may be performed in a solvent such as THF or diethyl ether at low temperature (e.g., 0 to -78 o C).
• a solvent such as THF or diethyl ether at low temperature (e.g., 0 to -78 o C).
• Addition of the organometallic reagent to an epoxide such as ethylene oxide in the presence of a Lewis acid such as trifluoroboron diethyl etherate affords alcohols of formula 4-2.
• the lithium halogen exchange reaction may be performed under continuous flow conditions.
• an aldehyde of formula 4-3 may undergo a Wittig reaction with a reagent such as an ylide of formula 4-4 to afford an enol ether of formula 4-5.
• the reaction is performed in the presence of a base such as potassium tert-butoxide in a solvent such as diethyl ether.
• enol ethers of formula 4-5 may be converted to compounds of formula 4-6 by treatment with an acid such as HCl.
• a compound of formula 4-2 may be prepared from a compound of formula 4-6 using any suitable reagent for reduction of an aldehyde to an alcohol, for example, sodium borohydride in methanol may be used.
• Scheme 4 [00184] Scheme 5 shows processes for the preparation of compounds of formula 1-1.
• PG 3 is any suitable nitrogen protecting group.
• Compounds of formula 5-1 may be protected with any suitable nitrogen protecting group.
• a compound of formula 5-3 (Weinreb amide) may be prepared from a compound of formula 5-2 and N-methyl N-methoxy amine using any suitable amide coupling reagent.
• the reaction may be performed in a solvent such as dichloromethane in the presence of T3P and DIPEA.
• a compound of formula 5-5 may be prepared from a compound of formula 5-3 by addition of an organometallic reagent such as methyl magnesium iodide.
• the reaction may be performed in a solvent such as THF at low temperature (e.g., 0 o C).
• Compounds of formula 1-1 may be prepared from compounds of formula 5-5 using any suitable method for the removal of a nitrogen protecting group.
• PG 3 is Boc
• Scheme 6 shows an alternative process for the preparation of a compound of formula 1-3 from N-protected beta-amino acids of formula 6-1.
• PG 4 may be Boc or any suitable nitrogen protecting group.
• Compound 6-2 dimagnesium salt may be coupled to compounds of formula 6-1 using a reagent such as CDI in a solvent such as THF. Condensation of compounds of formula 6-3 with aldehydes of formula 6-4 affords compounds of formula 6-5.
• the reaction may be performed by treatment of a compound of formula 6-3 with an acid such as TFA in a solvent such as dichloromethane, followed by the addition of aldehyde of formula 6-4.
• a compound of formula 1-3 may be prepared from a compound of formula 6-5 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).
• the reaction mixture was diluted with MTBE (500 mL) and washed with water (200 mL), 0.5 N HCl (200 mL), water (200 mL), and brine (200 mL).
• the organic layer was dried, filtered, and concentrated in vacuo.
• the organic layer was dissolved in heptane and passed through a silica gel plug; which was washed with 1-5% MTBE/Heptane. Solvent was removed to afford tert-butyl-dimethyl-[2-(3-thienyl)ethoxy]silane C1 (34 g, 99%).
• the reaction was stirred at 0 °C for 2 hours and then was warmed to room temperature.
• the reaction mixture was quenched with water (700 mL) and saturated NH 4 Cl (200 mL) and the THF was evaporated.
• the product was extracted with EtOAc (1 x 400 mL; 2 x 150 mL).
• the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
• the organic layer was passed through a silica gel plug washing with DCM (1000 mL), 80% EtOAc/Heptane (2 x 200 mL), and DCM (2 x 250 mL) to afford 2-(5-ethyl-2-thienyl)ethanol S5 (71.25 g, 93%).
• the racemic compound,2-[5-(trifluoromethyl)-2-thienyl]propan-1-ol (1.6 g, 7.3067 mmol) was separated from the dimethyl over alkylation byproduct using chiral SFC separation.
• Trimethylboroxine (0% solution in THF) (24.605 mL of 50% (w/v), 0.0980 mol) was added and heated to 80 °C for 16 hours.
• the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. Purification by column chromatography (Eluent: 20% EtOAc in petroleum ether) afforded the product S142-(5-methyl-3-thienyl)ethanol (950 mg, 66%) as a yellow liquid.
• the reaction mixture was allowed to reach ambient temperature, filtered, and solids were washed with MeCN (200 mL). The solids were discarded and the filtrate was concentrated. The residue was partitioned between EtOAc (400 mL) and water (400 mL). The organic layer was separated, washed with water (400 mL) and brine (400 mL), dried over MgSO 4, filtered, and concentrated.
• the mixture was diluted with heptane (25 mL) to further precipitate imidazole/imidazole HCl, filtered, and the solid was rinsed with additional heptane (10 mL). The mixture was concentrated, which precipitated additional solid.
• the mixture was heated to 130 °C. After 3 hours the mixture was cooled to room temperature, diluted with water (100 mL) and heptane (100 mL). The layers were mixed, and the aqueous layer was washed with heptane (2 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL) and the organic layer was dried over Na 2 SO 4 and concentrated.
• 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 N NaOH solution (700 mL) was added and the solution stirred for 15 minutes.
• T3P 600 g of 50% (w/w) in EtOAc, 942.9 mmol
• step 1 Reaction was stirred over the weekend (step 1) 2. The crude residue was diluted with water and saturated sodium bicarbonate solution and extracted with DCM (5x) through a phase separator. (step 1) 3. Purification by silica gel chromatography (Gradient: 0-50% of 20% MeOH/DCM in DCM) yielded the product. (step 1) 4. The minor isomer was purged via chromatography and step 2 was not performed. 5. Purification by silica gel chromatography (Gradient: 0-100% of 20% MeOH/DCM in DCM) yielded the product.
• step 1 Compound 1 (2'S,6'S,7S)-2-chloro-2'-methyl-6'-(1-methyltriazol-4-yl)spiro[4,5-dihydrothieno[2,3-c]pyran- [00259]
• (2S,6S)-2-methyl-6-(1-methyltriazol-4-yl)piperidin-4-one S26 (1380 mg, 7.11 mmol, S26 was prepared by Method A) in DCM (30 mL) was added 2-(5-chloro-3- thienyl)ethanol S2 (1100 ⁇ L, 8.894 mmol) followed by MsOH (3 mL, 46.23 mmol).
• the reaction was heated to reflux for 90 minutes at which time it was cooled to room temperature and quenched with 2 N NaOH until the pH reached 14.
• the mixture was diluted with DCM (20 mL) and the organic layer separated, washed with brine (30 mL), dried over MgSO 4 , and concentrated in vacuo.
• Compounds 3-16 were prepared from a single Oxa-Pictet Spengler step with isolated piperidones (S26, S29, or C56) and the relevant thiophene ethanols as described for compounds 1 and 2. Thiophene ethanols and piperidone were prepared by methods described above or obtained from commercial sources. In examples where S26 was used, S26 was prepared by Method A, therefore the piperidone used may contain minor amounts of the other cis-isomer. Any modifications to methods are noted in Table 2 and accompanying footnotes. Table 2. Method of preparation, structure and physicochemical data for Compounds 3-16.
• Product was isolated as a 4.5:1 mixture of diastereomers with unknown absolute stereochemistry. 8. Step 1 was stirred at room temperature for one week. 9. The pH was carefully adjusted to pH 7 with 2 N NaOH prior to DCM extraction. 10. Product was isolated as a 2:1 mixture of diastereomers with unknown absolute stereochemistry. 11. Product was isolated as a 3:1 mixture of diastereomers with unknown absolute stereochemistry. 12. Product was isolated as a 5:1 mixture of diastereomers with unknown absolute stereochemistry. 13. Product was isolated as a 3.5:1 mixture of diastereomers with unknown absolute stereochemistry. 14. The product was impure after the purification and was repurified by reversed- phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron).
• the resulting mixture was heated to 40 °C for 40 minutes. More methanesulfonic acid (800 ⁇ L, 12.33 mmol) was added and the reaction was continued heating for another 30 minutes. The reaction was cooled to room temperature, diluted with water, and basified with 2 N NaOH solution.
• the mixture was heated to 60 °C and stirred. After an hour and a half the reaction was cooled to room temperature. The mixture was vacuum purged with nitrogen three times and then diluted with MTBE (25 mL) and saturated aqueous bicarbonate (25 mL). The layers were separated, and the organic layer was washed with aqueous NaHCO3 (2 x 50 mL) and brine (50 mL). The organic layer was dried with Na2SO4, filtered, and concentrated.
• Reaction was diluted with DCM, water, and saturated sodium bicarbonate. Extracted with DCM (3x) and collected through a phase separator (step 1) 9. Reaction was diluted with DCM, water, and saturated sodium bicarbonate. Extracted with DCM (3x) and collected through a phase separator (step 2) 10. Purification by silica gel chromatography (0-100% EtOAc in heptane) yielded the product (step 2) 11. Purification by silica gel chromatography (0-80% EtOAc in heptane) yielded the product (step 2) 12. Purification by silica gel chromatography (0-45% EtOAc in heptane) yielded the product (step 2) 13. Reaction stirred overnight (step 2) 14. S36 has an approximately 85% e.r.
• the mixture was heated to 45 °C and stirred for 18 hours before cooling to room temperature.
• the reaction was diluted with DCM, water, and saturated sodium bicarbonate, then extracted with DCM (3 x 150 mL) and collected through a phase separator.
• the organic layer was dried with Na2SO4, filtered, and concentrated.
• the flask was fitted with an empty balloon to capture the CO 2 off-gas byproduct. After two hours, the mixture was washed with saturated aqueous sodium bicarbonate (150 mL). The organic phase was separated, passed through a phase separator, and concentrated.
• Step 1 Formic acid and triethylamine were added before Ketone intermediate (step 1) 2. Silica gel purification (0-60% EtOAc in Heptane) afforded product (step 1) 3. Product was not washed with EtOH (step 2) 4. Reaction was stirred for 15 minutes before quenching 5. Stirred at 40 oC for four hours after quenching with NaOH and MeOH (step 2) 6. Step 1 was run with both the CBS-(S) catalyst and the CBS-(R) catalysts in two separate reactions. However, both reactions proceeded with poor d.r. and so they were combined to make the racemic which was separated by SFC as in Step 2. 7.
• step 3 After extracted with DCM, purification by silica gel chromatography (Gradient: 0-20% MeOH in DCM) yielded the product (step 3) 8. Reaction was stirred overnight (step1) 9. Stirred at 50 oC for two hours after quenching with NaOH and MeOH (step 2) 10. Compound 182 contained approximately 15% of a diastereomer created via differentiation from the enantiomer of S36 present in S36.
• reaction mixture was filtered, washed with water (100 mL), and dried to afford tert-butyl N-[1- (p-tolylsulfonyl)propyl]carbamate C68 (46 g, 85%).
• reaction mixture was filtered, washed with water (200 mL) and diethyl ether (50 mL), and dried under vacuum to afford crude tert-butyl N-[2-methyl-1-(p- tolylsulfonyl)propyl]carbamate C71 (45 g, 73%) as an off white solid.
• reaction mixture was concentrated to dryness and re-dissolved in DCM (12.7 mL). To this solution at 0 °C was added TEA (1.34 g, 13.24 mmol) and TFAA (1.8 g, 8.570 mmol). The reaction was warmed to room temperature and stirred for two hours until the reaction had gone to completion. The reaction was quenched with saturated sodium bicarbonate and extracted with EtOAc (2x). The organics were washed with brine, dried over Na2SO4, and concentrated in vacuo.
• the vial was purged and refilled with N2 (3x). To the vial was added sequentially tert-butyl (2R,6S)-2-bromo-2',6'- dimethyl-spiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-carboxylate C86 (70 mg, 0.1680 mmol), bis(trimethylsilyl)silyl-trimethyl-silane (51 mg, 0.2051 mmol), 2,6- dimethylpyridine (45 mg, 0.4200 mmol) and DME (2 mL).
• the reaction was purged and evacuated with oxygen (3x) and then heated to 45 °C under an oxygen balloon. The reaction was stirred for 7 hours. The reaction was diluted with water and DCM. The organic phase was separated, passed through a phase separator, and concentrated in vacuo. The material was brought up in a minimal amount of DCM and a solid began crashing out of solution. The liquid was decanted off.
• Triethylamine (30 ⁇ L, 0.2152 mmol) was added to each vial. The reaction was stirred at room temperature over the weekend. The reaction mixture was evaporated under a stream of nitrogen. A solution of 2-(5-chloro-3-thienyl)ethanol (25 ⁇ L, 0.2075 mmol) in dioxane (750 ⁇ L) was added. A solution of triflic acid (100 ⁇ L, 1.130 mmol) in dioxane (750 ⁇ L) was added. The resulting mixture was stirred at room temperature for 30 minutes.
• reaction mixture was quenched with NaOH (2.0 mL of 2 M, 4.000 mmol) and DCM (1.5 mL), and the resulting biphasic mixtures were stirred for several minutes.
• the mixture was passed through a 25 ⁇ M polypropylene filter plate, and the resulting DCM layers were isolated and evaporated. Purification by reversed-phase HPLC (Method: C18 Waters Sunfire column (30 x 150 mm, 5 micron).
• the mixture was vacuum purged with an oxygen balloon three times.
• the mixture was heated to 45 °C and stirred. After 6 hours, the reaction was cooled to room temperature.
• the mixture was vacuum purged with nitrogen three times and then diluted with MTBE (3 mL) and saturated sodium bicarbonate (3 mL). The layers were separated, and the organic layer was washed with water (2 x 2 mL) and brine (20 mL). The organic layer was dried with Na 2 SO 4 , filtered, and concentrated.
• the mixture was vacuum purged with an oxygen balloon six times and oxygen balloon placed into septum to maintain oxygen atmosphere.
• the mixture was heated to 55 °C and stirred overnight.
• the mixture was cooled to room temperature, then vacuum purged with nitrogen three times and diluted with MTBE (200 mL) and saturated bicarbonate (100 mL).
• the layers were separated, and the organic layer was washed with saturated bicarbonate (4 x 100 mL). Brine (100 mL) was added and the layers were separated.
• the organic layer was dried with MgSO4, filtered, and concentrated.
• DAST 5 mL, 37.84 mmol
• the reaction was heated to 40 °C for 36 hours.
• the mixture was cooled to room temperature and added dropwise into a stirring solution of saturated sodium bicarbonate (25 mL) maintained at 0 °C.
• the mixture was diluted with DCM (25 mL) and layers separated.
• the aqueous layer was extracted with additional DCM (25 mL), and the combined organic layer was dried with MgSO 4 , filtered, and concentrated.
• the reaction mass was allowed to stir for 16 hours at room temperature.
• the reaction mixture was diluted with saturated NaHCO3 (50 mL) and extracted with EtOAc (3 x 100 mL).
• the combined organic layer was washed with 0.15 N aqueous HCl (3 x 50 mL), and then the aqueous layer pH was adjusted to 12 by using 1 N NaOH solution.
• the aqueous layer extracted with EtOAc (3 x 100 mL), and the combined organic layer was dried over Na 2 SO 4 , filtered, and evaporated under vacuum to provide the crude material.
• reaction mixture was stirred for 10 minutes, and T3P (3.12 g, 2.92 mL of 50 %w/w, 0.0049 mol) was slowly added at 0 °C.
• the reaction mixture was stirred at room temperature for 16 hours.
• the reaction mixture was diluted with DCM (25 mL) and cooled to 0 °C.1 N NaOH solution (10 mL) was slowly added, and the organic layer was separated and washed with saturated NH 4 Cl solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtained the crude material.
• Step 2.1-(dimethylamino)cyclopropanecarbaldehyde (S58) [00378] To a stirred suspension of LAH (988 mg, 0.0255 mol) in diethyl ether (50 mL) was added 1-(dimethylamino)-N-methoxy-N-methyl-cyclopropanecarboxamide C128 (2 g, 0.0102 mol) dropwise at 0 °C. The reaction mixture was allowed to stir for 4 hours at 0 °C. The reaction was quenched with water (3.2 mL), 1 N NaOH solution (3.2 mL), and water (3.2 mL).
• reaction mixture was heated to 50 °C for 2 hours, and additional THF (1 mL) was added to help dissolve the starting material. After heating for almost 3 days, the reaction was cooled to room temperature. The reaction mixture was then concentrated to remove the solvent and redissolved in DMSO. Purification by reversed-phase HPLC (Method: Waters XSelect CSH C18 OBD Prep Column; 30 x 150 mm, 5 micron.
• (2R,6S)-2-cyclopropyl-6-(1-methyltriazol-4-yl)piperidin-4-one C132 45 mg, 0.20 mmol
• 2-(5-chloro-3-thienyl)ethanol 43 mg, 0.26 mmol
• MsOH 90 ⁇ L, 1.4 mmol
• the material was dried overnight to remove residual solvent.
• the crude foam was diluted with DMSO (1 mL) in a flame-dried flask and vacuum purged with nitrogen 5 times. The mixture was heated to 60 °C, triethylamine (75 ⁇ L, 0.54 mmol) was added, and the dark brown solution was heated further to 65 °C (internal temperature). After 75 minutes, the mixture was cooled to room temperature and diluted with water (5 mL) and ethyl acetate (5 mL). The aqueous layer was washed with ethyl acetate (2 x 5 mL), and then the combined organic layer was dried with sodium sulfate, filtered, and concentrated.
• the resulting reaction mixture was warmed to 40 °C, and stirred at this temperature for 5 days.
• the reaction mixture was extracted with DCM (2 x 100 mL).
• the combined organic fraction was dried over MgSO 4 , filtered, and concentrated under reduced pressure.
• the crude residue was treated with MTBE (200 mL), aged for 1 hour, and then filtered through medium fritted funnel, washed with MTBE (50 mL), and dried under vacuum to afford one crop of the desired product in 12 g as a white solid.
• the mother liquor was concentrated under reduced pressure.
• N-ethyl-N-isopropyl-propan-2-amine 13 mL, 74.63 mmol
• (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate 7.5 mL, 53.96 mmol
• the resulting reaction mixture was stirred at this temperature for 1 hour.
• the reaction mixture was quenched with a saturated NaHCO 3 solution (100 mL).
• the layers were separated, and organic layer was washed with 2 M aqueous HCl (2 x 60 mL), water (100 mL), brine (100 mL), then dried over MgSO 4 , filtered and concentrated.
• the resulting reaction mixture was degassed with a stream of nitrogen via gas dispersion tube for 15 minutes.
• N-bromosuccinimide (10.2 g, 57.31 mmol) was added, followed by AIBN (200 mg, 1.218 mmol).
• AIBN 200 mg, 1.218 mmol
• the resulting reaction mixture was stirred under 100 W CFL irradiation for 4 hours.
• the reaction mixture was quenched with aqueous 10 wt% sodium bisulfite (200 mL), stirred for 10 minutes, and then MTBE (300 mL) was added.
• aqueous NaOH 45 mL of 6 M, 270.0 mmol
• the resulting reaction mixture was warmed to 60 °C and stirred at this temperature for 1 hour.
• the reaction mixture was cooled to room temperature, then partitioned between cold water (100 mL) and MTBE (200 mL) and stirred for 20 minutes.
• the organic phase was then separated.
• the aqueous phase was extracted with MTBE (2 x 100 mL).
• the combined organic phases were washed with cold water (60 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated.
• Step 3 To the white crystalline solid from the first step dissolved in DCM (4 mL) was added TFA (900 ⁇ L, 11.68 mmol) The mixture was stirred for 1 hour, and then the mixture was concentrated and azeotroped by DCM (3 x 4 mL) to provide a crude mixture of tert-butyl (5R)- 5-amino-3-oxo-5-phenyl-pentanoate that was directly carried forward to Step 3. [00420] Step 3. To the crude mixture from step 2 dissolved in DCM (4 mL) was added 1- methyltriazole-4-carbaldehyde S17 (225 mg, 2.025 mmol) and the mixture was stirred at room temperature for 2 hours.
• TFA 900 ⁇ L, 11.68 mmol
• the mixture was heated to 75 °C for 15 minutes.
• the mixture was cooled to room temperature and quenched with saturated sodium bicarbonate (1 mL).
• the organic layer was separated, dried with MgSO4, filtered, and concentrated to provide a crude foam.
• the crude foam was dissolved in DMSO (1 mL) under nitrogen atmosphere.
• the mixture was heated to 60 °C and triethylamine (75 ⁇ L, 0.5381 mmol) was added.
• the dark brown solution was heated to 65 °C and stirred for 75 minutes.
• the mixture was cooled to room temperature, and diluted with ethyl acetate (5 mL) and water (5 mL).
• the reaction was heated to 45 °C and stirred under an oxygen balloon atmosphere overnight.
• the mixture was cooled to room temperature, vacuum purged with nitrogen three times, and then diluted with water (10 mL) and saturated aqueous bicarbonate (20 mL).
• the mixture was extracted with DCM (3 x 20 mL), and the organics were dried over sodium sulfate and concentrated in vacuo.
• Step 1 To a mixture of compound 500a (8.84 g, 44.4 mmol) and 489a (9.50 g, 57.7 mmol) in DCM (250 mL) was added MsOH (34.6 mL, 532.8 mmol). The mixture was heated to 40 °C and stirred overnight. TLC showed reaction completed. The mixture was cooled to 0 °C, diluted with water (200 mL) and quenched with aqueous NaOH (6 N, 100 mL). The mixture was separated, and the aqueous layer was extracted with DCM (3 x 300 mL).
• Step 4 Crude compound 503b (14.5 g) was dissolved in DMSO (120 mL), then treated with triethylamine (15.2 mL, 109 mmol). The solution was stirred and heated to 75 °C. After 2 hours, TLC showed conversion was completed. The mixture was cooled to 20 °C, then partitioned between water (200 mL) and EtOAc (200 mL). The layers were separated. The aqueous layer was extracted with EtOAc (2 x 200 mL).
• Step 5 To a 250 mL round-bottom flask was added (Cp*RhCl 2 ) 2 (130 mg, 0.21 mmol) and TsDPEN (116 mg, 0.32 mmol) in CH 3 CN (50 mL). The mixture was degassed with N2 for 5 minutes.
• the CP contact time of carbon as well as phosphorus CPMAS experiments was set to 2 ms.
• a CP proton pulse with linear ramp (from 50% to 100%) was employed.
• the carbon Hartmann-Hahn match was optimized on external reference sample (glycine), while phosphorus Hartmann-Hahn match was optimized on the actual samples. All carbon, phosphorus, and fluorine spectra were recorded with proton decoupling using TPPM15 decoupling sequence with the field strength of approximately 100 kHz.
• the resulting solution was stirred at 5 °C for 1 hour, then warmed to 20 °C and stirred for 18 hours.
• K5 180.76 g, 1.59 mol, 97.8% purity, 0.87 equiv
• the reaction mixture was diluted with saturated brine (1.14 L, 2 vol), cooled to 5 to 10 °C, and then adjusted to pH 10 with 6 N sodium hydroxide (950 mL).
• the organic layer was separated and dried over sodium sulfate (400 g).
• the resulting solution was distilled at 30 °C under reduced pressure to remove DCM (1 L).
• Step 1 J2
• J1 (85.0 kg, 663.1 mol, 1.0 equiv) was dissolved in DMF (162.3 kg) in a 1000 L reactor with stirring under nitrogen and then cooled to -10 - 0 °C.
• NBS (122.7 kg, 689.6 mol, 1.04 eq) was dissolved in DMF (241.0 kg) in a separate, 500 L reactor with stirring under nitrogen.
• the solution of NBS was added slowly to the 1000 L reactor over 5 hours while maintaining the temperature between -10-0 °C. After the addition, the reaction mixture was held at -10-0°C for 1-2 hours. A saturated aqueous solution of NaCl (480 kg) was added to the reaction mixture followed by EtOAc (460.7 kg), and the reaction mixture was stirred for 30 minutes. The organic layer was separated and the aqueous layer was extracted with EtOAc (230.4 kg). The organic layers were combined and washed with 0.5 N HCl (420.0 kg). After separation, a saturated solution of NaCl (300 kg) was added, and the mixture was stirred for 30 minutes.
• Step 2 J2 (147.95 kg, QNMR 75%, 535.8 mol, 1.0 equiv) was treated with AcOH (349.65 kg) and Ac2O (82.05 kg, 803.7mol, 1.5eq) in a 1000 L reactor with stirring under nitrogen. The mixture was heated to 90-100 °C for 5-10 hours and until less than 0.5% J2 remained by GC. The mixture was cooled to 35-40 °C.
• NIS 138.6 kg, 616.2 mol, 1.15 eq
• NIS 138.6 kg, 616.2 mol, 1.15 eq
• the mixture was stirred at 35-40 °C for 6-10 hours.
• the mixture was cooled to 20-30 °C and transferred to a 3000 L reactor.
• a mixture of MTBE/heptane (250 kg/226.4 kg) and water (333 kg) were added.
• the mixture was stirred for 30 minutes and then separated.
• the aqueous layer was extracted with a mixture of MTBE/heptane (250 kg/226.4 kg).
• the organic layers were combined, and a 13% solution of aqueous NaHSO 3 (510.6 kg) was added.
• Step 3 (J4) J3 (111 kg, 85.57% QNMR, 252.2 mol, 1.0 equiv), CuI (12.06 kg, 63.3 mol , 0.25 equiv ), and 2,6-lutidine (6.78 kg, 63.3 mol, 0.25 equiv) were dissolved in DMAc (356.25 kg) in a 3000 L reactor with stirring under nitrogen and then heated to 85-100°C. Methyl fluorosulfonyldifluoroacetate (MFSDA, 194.65 kg, 1013.2 mol , 4.0 equiv) was added to the 3000 L reactor while maintaining the temperature between 85-100°C.
• MFSDA Methyl fluorosulfonyldifluoroacetate
• Step 4 NaOH (61.63 kg, 1540.8 mol, 2.28 equiv) was dissolved in water (493 kg) in a 3000 L reactor with stirring.
• Step 5 J5 (203.2 kg, 89.46% QNMR, 660.8 mol, 1.0 equiv) was dissolved in THF (817.2 kg) in a 2000 L reactor with stirring under nitrogen. The solution was cooled to -50 to -30 °C and charged with n-BuLi (377.5 kg, 1387.7 mol, 2.1 equiv) while maintaining the temperature between -50 to -30 °C.
• Step 6 J6/K8 (147.8 kg, 89.71% purity, 83.62% QNMR, 95.41% yield) as a yellow liquid.
• Step 6 J6/K8 (147.8 kg, 83.62% QNMR, 627.0 mol, 1.0 equiv) and triethylamine (95.2kg, 940.5mol, 1.5 equiv) were dissolved in THF (587.0 kg) in a 3000 L reactor with stirring under nitrogen.
• the reaction mixture was cooled to 30 °C, charged with dichloromethane (280 mL, 4 vol), and further cooled to 0 °C.
• the pH was adjusted to pH 10 with 4 N sodium hydroxide (830 mL).
• the organic layer was separated, and the aqueous phase was back-extracted with DCM (350 mL, 5 vol).
• the combined organics were washed with water (350 mL, 5 vol) and concentrated at reduced pressure to 3.5 total volumes.
• the batch was charged with MTBE (5 vol) and concentrated under reduced pressure to 3.5 total volumes. This put/take cycle was repeated three additional times, and the resulting 3.5 vol. mixture was diluted with MTBE (6.5 vol) to provide a 10 vol. mixture.
• Step 2 The slurry was heated to 50 °C and stirred for 5 hours, then charged with n- heptane (700 mL, 10 vol) over 2 hours. The resulting suspension was cooled to 20 °C over 5 hours and stirred for 18 hours. The suspension was filtered, washed with 1:2 MTBE/n-heptane (2 x 140 mL, 2 x 2 vol), and dried under vacuum while flushing with nitrogen at 50 °C for 18 hours to give 103 g of K9 (77% yield). [00454] Step 2.
• the organic layer was separated and sequentially washed with 5% NaHCO3 (200 mL, 4 vol), 2 N HCl (2 x 200 mL, 2 x 4 vol), and water (2 x 200 mL, 2 x 4 vol).
• the organic layer was concentrated under reduced pressure to 3.5 total volumes.
• MTBE 400 mL, 8 vol was charged, and the batch was concentrated under reduced pressure to 3.5 vol. This put/take cycle was repeated two additional times, and the mixture was concentrated to 3 volumes after the final cycle.
• the solution was heated to 40 °C and charged with n-heptane (190 mL, 2 vol) over 1 hour. The batch was cooled to 20 °C over 2 hours to yield a suspension.
• Step 3 n-Heptane (500 mL, 10 vol) was charged over 2 hours, and the resulting suspension was stirred for 18 hours. The suspension was filtered, washed with 5% MTBE/n-heptane (2 x 125 mL, 2 x 2.5 vol), and dried under vacuum while flushing with nitrogen at 50 °C for 18 hours to give 53 g of K10 (84% yield). [00455] Step 3.
• the reaction mixture was cooled to 60 °C and charged with anhydrous, degassed DMSO (350 mL, 5 vol) over 30 minutes, followed by anhydrous, degassed triethylamine (104 mL, 747 mmol, 5 equiv) over 30 minutes.
• the reactor headspace was well purged with nitrogen, and the batch was heated to 75 °C. After 15 hours, HPLC analysis showed >99% conversion of K11 to K12.
• the batch was cooled to 20 °C and diluted with dichloromethane (210 mL, 3 vol). The batch was further cooled to 5 °C and charged with water (350 mL, 5 vol) while keeping the solution temperature below 30 °C.
• the organic layer was separated, and the aqueous layer was back-extracted with dichloromethane (210 mL, 3 vol).
• the organic phases were combined and washed sequentially with 2 N HCl (350 mL, 5 vol) and water (2 x 350 mL, 2 x 5 vol).
• the organic phase was concentrated under reduced pressure to 3 total volumes.
• the solution was charged with IPA (560 mL, 8 vol) and concentrated under reduced pressure to 3 volumes. This put/take cycle was repeated two additional times, giving a 3-volume solution that was further diluted with IPA (70 mL, 1 vol).
• the resulting 4 vol mixture was heated to 75 °C to provide a homogenous solution and then cooled to 50 °C.
• the solution was seeded (0.1 wt%) at 50 °C, stirred for 1 hour, and further cooled to 20 °C over 2 hours. After stirring an additional 18 hours at 20 °C, the slurry was charged with n-heptane (70 mL, 1 vol) over 1 hour. The slurry was stirred for 4 hours at 20 °C, filtered, washed with 1:1 IPA/n-heptane (2 x 70 mL, 2 x 2 vol), and dried under vacuum while flushing with nitrogen at 50 °C for 18 hours to give 31.2 g of K12 (43% yield from K10). The dried K12 was suspended in IPA (93 mL, 3 vol), heated to 80 °C, and stirred at that temperature for 2 hours.
• Step 5 The solution was cooled to 70 °C over 1 hour and stirred for 1 hour. The suspension was cooled to 20 °C over 5 hours and stirred at that temperature for 18 hours. The suspension was filtered, washed with 1:1 IPA/n-heptane (2 x 35 mL, 2 x 0.5 vol), and dried under vacuum while flushing with nitrogen at 50 °C for 18 hours to give 28.8 g of K12 (40% yield from K10). [00456] Step 5.
• the pentamethylcyclopentadienylrhodium(III)chloride dimer (154 mg, 0.002 eq) and (R,R)-TsDPEN (182 mg, 0.004 eq) were combined in acetonitrile (240 mL, 4 vol), and the mixture was sparged with nitrogen while stirring at 20 °C for 1 hour. The mixture was cooled to -15 °C and a prepared mixture of formic acid (27.0 mL, 5.5 equiv) and triethylamine (38.1 mL, 2.2 eq) was added over 30 minutes and the resultant red/orange solution was stirred for 15 minutes at -15 °C.
• a solution of K12 (60 g, 1.0 equiv) in acetonitrile (240 mL, 4 vol) was separately prepared and added to the cold catalyst solution over 45 minutes.
• the mixture was sparged with subsurface nitrogen bubble for 15 minutes, stirred at -15 °C for 20 hours, warmed to 0 °C, and stirred for an additional 20 hours.
• the temperature was adjusted to 20 °C and the mixture was charged with MTBE (360 mL, 6 vol) and 18% NaCl (aq) (360 mL, 6 vol). The phases were mixed, and the phases separated.
• the organic phase was washed sequentially with 18% NaCl (aq) (2 x 360 mL, 6 vol), 4% NaHCO 3 (aq) (360 mL, 6 vol), and 18% NaCl (aq.) (180 mL, 3 vol).
• the reaction solution was concentrated to 3 total volumes under reduced pressure, then solvent swapped to MTBE by adding MTBE (360 mL, 6 vol) and concentrating to 3 volumes under reduced pressure. This put/take cycle was repeated 3 additional times.
• the resulting solution was diluted to 4 total volumes with MTBE and charged with DCM (240 mL, 4 vol) and MTBE-pre-washed SiliaMetS DMT resin (30 g, 50 wt%).
• the mixture was stirred vigorously at 20 °C for 2 hours.
• the resin slurry was filtered under vacuum.
• the reaction flask was rinsed with a solution of 2:1 DCM:MTBE (120 mL, 2 vol) and the rinse was transferred to the resin.
• the resulting slurry was mixed, then filtered under vacuum.
• the resin was rinsed once more with a solution of 2:1 DCM:MTBE (120 mL, 2 vol) by adding it to the resin, mixing, then filtering under vacuum.
• the rinses and original filtrate were combined and transferred back to the reaction flask using 2:1 DCM:MTBE (30 mL, 0.5 vol) as a final rinse after the transfer.
• the filtrate was combined with MTBE-pre-washed SiliaMetS DMT resin (30 g, 50 wt%) and stirred vigorously for 2 hours at 20 °C.
• the resin slurry was under vacuum.
• a solution of 2:1 DCM:MTBE 120 mL, 2 vol was used to rinse the reaction flask, and the rinse was transferred to the resin in the frit.
• the slurry was mixed and filtered under vacuum.
• a solution of 2:1 DCM:MTBE 120 mL, 2 vol was charged to the resin in the frit and the slurry was mixed, then filtered under vacuum.
• the combined filtrates were transferred back to the reaction flask using 2:1 DCM:MTBE (30 mL, 0.5 vol) as a rinse.
• the filtrate was combined with MTBE-pre-washed SiliaMetS DMT resin (30 g, 50 wt% loading) and stirred vigorously for 18 hours.
• the resultant resin slurry was filtered under vacuum.
• the reaction flask was rinsed with a solution of 2:1 DCM:MTBE (120 mL, 2 vol). The rinse was added to the resin in the frit, and the slurry was mixed then filtered under vacuum. A solution of 2:1 DCM:MTBE (120 mL, 2 vol) was added to the resin in the frit, and the slurry was mixed then filtered under vacuum.
• the combined filtrate was transferred to a flask, then concentrated to 3 total volumes (180 mL) of solution.
• MTBE (480 mL, 8 vol) was added, and the solution was concentrated to 3 total volumes (180 mL). This put/take cycle was repeated two additional times.
• the resulting solution was diluted to 5 vol (300 mL) with MTBE, heated to 50 °C and stirred for 3 hours.
• n-Heptane (240 mL, 4 vol) was added over 60 minutes, and the slurry was maintained at 50 °C for an additional 1 hour.
• the slurry was cooled to 20 °C over 3 hours and stirred overnight.
• the slurry was filtered under vacuum.
• Step 6 K13 (43.5 g, 89 mmol, 1 equiv) and methanol (150.0 mL, 3 vol) were combined and agitated until full dissolution was observed.6 N NaOH (89 mL, 6 eq) was added drop-wise over 30 minutes, and the mixture was heated to 60 °C and stirred for 1 hour at which time complete conversion to Compound 181 was achieved.
• the reaction solution was cooled to 15 °C and treated with isopropyl acetate (250 mL, 5.75 vol). Water (100 mL, 2.3 vol) was then added, and the mixture was agitated for 30 minutes. The phases were separated, and the aqueous phase was back-extracted with isopropyl acetate (250 mL, 5.75 vol). The organics were combined and washed with 10% NaCl (aq.) (2 x 250 mL, 2 x 5.75 vol) and water (250 mL, 5.75 vol). The organics were concentrated to 4.0 total volumes (174 mL). The solution was charged with MTBE (11.5 vol, 500 mL) and concentrated again to 4.0 vol. This put/take cycle was repeated three additional times.
• Step 7 Method A.1 eq. of Compound 181 free form monohydrate was charged to a reactor followed by 6 vol. of MEK. Agitation was started at 20 °C. Once a clear solution was obtained, the solution was polish filtered and charged back to the reactor. Water (0.2 vol.) was added to the clear solution and agitation continued.1 wt% of Compound 181 Phosphate Salt was added as seeds. In a separate container, 1.02 eq. of 85 wt% phosphoric acid was diluted with 3.8 vol. of MEK. This phosphoric acid solution was then added to the reactor slowly over 3 hours. The final slurry was agitated at 20 °C for 2 hours, then filtered under vacuum.

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