WO2022109573A1 - Macrocycles containing a 1,3,4-oxadiazole ring for use as modulators of cystic fibrosis transmembrane conductance regulator - Google Patents

Macrocycles containing a 1,3,4-oxadiazole ring for use as modulators of cystic fibrosis transmembrane conductance regulator Download PDF

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WO2022109573A1
WO2022109573A1 PCT/US2021/072475 US2021072475W WO2022109573A1 WO 2022109573 A1 WO2022109573 A1 WO 2022109573A1 US 2021072475 W US2021072475 W US 2021072475W WO 2022109573 A1 WO2022109573 A1 WO 2022109573A1
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compound
independently selected
optionally substituted
therapeutic agent
pharmaceutically acceptable
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PCT/US2021/072475
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English (en)
French (fr)
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Jeremy J. Clemens
William Schulz BECHARA
Brett C. Bookser
Thomas Cleveland
Timothy Coon
Michel Gallant
Sara Sabina Hadida Ruah
Julie LATERREUR
Mark Thomas Miller
Prasuna PARASELLI
Yeeman K. Ramtohul
Thumkunta Jagadeeswar Reddy
Claudio Sturino
Lino Valdez
Jinglan Zhou
Peter Diederik Jan Grootenhuis
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Vertex Pharmaceuticals Incorporated
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Priority to IL302873A priority Critical patent/IL302873A/en
Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Priority to KR1020237020002A priority patent/KR20230123522A/ko
Priority to AU2021383176A priority patent/AU2021383176A1/en
Priority to EP21843853.9A priority patent/EP4247817A1/en
Priority to CA3201793A priority patent/CA3201793A1/en
Priority to JP2023529022A priority patent/JP2023549547A/ja
Priority to MX2023005721A priority patent/MX2023005721A/es
Priority to PE2023001653A priority patent/PE20231380A1/es
Priority to CN202180090910.1A priority patent/CN116670140A/zh
Priority to CR20230260A priority patent/CR20230260A/es
Publication of WO2022109573A1 publication Critical patent/WO2022109573A1/en
Priority to DO2023000099A priority patent/DOP2023000099A/es
Priority to CONC2023/0007896A priority patent/CO2023007896A2/es

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates to modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing the modulators, methods of treatment of cystic fibrosis and CFTR-mediated disorders using such modulators and pharmaceutical compositions, and processes for making such modulators.
  • CFTR Cystic Fibrosis Transmembrane Conductance Regulator
  • Cystic fibrosis is a recessive genetic disease that affects approximately 83,000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure.
  • CFTR mutations in CFTR endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lung and accompanying microbial infections that ultimately cause death in CF patients.
  • CF patients In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death.
  • CFTR2 is a cAMP/ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins.
  • CFTR In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue.
  • CFTR is composed of 1480 amino acids that encode a protein which is made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
  • R regulatory
  • Chloride transport takes place by the coordinated activity of ENaC (epithelial sodium channel) and CFTR present on the apical membrane and the Na + -K + -ATPase pump and Cl- channels expressed on the basolateral surface of the cell.
  • Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl- channels, resulting in a vectorial transport.
  • Arrangement of Na + /2Cl-/K + co-transporter, Na + -K + -ATPase pump and the basolateral membrane K + channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride.
  • CFTR modulators have recently been identified. These modulators can be characterized as, for example, potentiators, correctors, potentiator enhancers/co-potentiators, amplifiers, readthrough agents, and nucleic acid therapies. CFTR modulators that increase the channel gating activity of mutant and wild-type CFTR at the epithelial cell surface are known as potentiators. Correctors improve faulty protein processing and resulting trafficking to the epithelial surface. Ghelani and Schneider- Futschik (2020) ACS Pharmacol. Transl. Sci.
  • One aspect of the invention provides novel compounds, including compounds of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, and IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof and pharmaceutically acceptable salts of any of the foregoing.
  • compounds of Formula I can be depicted as: and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein: X is selected from -N(R X1 )- and Ring A is a 4- to 6-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl and oxo; R X1 is selected from H, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, oxo, -OR X2 , and -N(R X2 ) 2 ), and C 3 -C 8 cycloalkyl; each R X2 is independently selected from H and C 1 -C 6 alkyl; each Y is independently selected from -C(R Y ) 2 -, -O-, -CO-, -NR YN -, and , wherein each R YN is independently selected from H, C 1 -C 4 alkyl, and CO
  • X is -N(R X1 )-. [0012] In some embodiments of Formula I, X is [0013] In some embodiments of Formula I, X is selected from: -NH-, -N(CH 3 )-, -N(CH 2 CH 3 )-, [0014] In some embodiments of Formula I, each R Y is independently selected from hydrogen, hydroxy, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C 1 -C 6 alkoxy, and Q), C 3 -C 8 cycloalkyl, C 6 -C 10 aryl (optionally substituted with 1- 3 groups independently selected from halogen), 5- to 10-membered heteroaryl, - CO 2 R Y1 , and -CON(R Y1 ) 2 ; or two R Y on the same atom are taken together to form a ring selected from C 3 - C 8 cyclo
  • each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl.
  • each Q is independently selected from C 6 - C 10 aryl.
  • each Q is phenyl.
  • each R Y is independently selected from: hydrogen, hydroxy, -CH 3 , -CD 3 , -CH 2 CH 3 , or two R Y on the same atom are taken together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyryl, and tetrahydrofuryl; or two R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond.
  • Ring B is selected from C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy) and 5- to 10-membered heteroaryl.
  • Ring B is selected from phenyl (optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy) and pyridyl.
  • Ring B is selected from: [0022] In some embodiments of Formula I, n is selected from 4, 5, 6, and 7. [0023] In some embodiments of Formula I, -(Y) n - is a group selected from:
  • each R 1 is independently selected from halogen, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkyl (optionally substituted with a group selected from C 6 -C 10 aryl), -OR 2 , -N(R 2 ) 2 , -CO 2 R 2 , -CO-N(R 2 ) 2 , -CN, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 6-membered heteroaryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), 3- to 6-membered heterocyclyl, -B(OR 2 ) 2 , - SO 2 R 2 , -SR 2 , -SOR 2 , and -PO(R 2 ) 2 .
  • each R 2 is independently selected from C 6 - C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 fluoroalkoxy).
  • each R 1 is independently selected from -Br, -CF 3 , -NH 2 , -CH 3 , -CH(CH 3 ) 2 , -CN, -OH, -OCH 3 , -NH(CH 3 ), -NH(CH 2 CH 3 ), -CONH 2 , -CO 2 CH 3 , -SO 2 CH 3 , -SO 2 Ph, PO(CH 3 ) 2 , B(OH) 2 , phenyl, pyridyl, tetrahydropyranyl, tetrahydrofuranyl, cyclopropyl, cyclohexyl, imidazolyl, , and [0027] In some embodiments of Formula I, Z is selected
  • the group: is selected from: [0029] In some embodiments of Formula I, the group: [0030] In some embodiments of Formula I, R Z1 is selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 hydroxy), C 1 -C 6 fluoroalkyl, 3- to 6-membered heterocyclyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, and 5- to 6-membered heteroaryl.
  • R Z2 is selected from hydrogen, halogen, hydroxy, and C 1 -C 6 alkoxy (optionally substituted with 1-3 groups independently selected from C 3 -C 10 cycloalkyl).
  • R Z2 is hydroxy.
  • Z is selected from: , , [0036] In some embodiments of Formula I, Z is In some embodiments of Formula I, Z is In some embodiments of Formula I, Z is In some embodiments of Formula I, Z is In some embodiments of Formula I, Z is , wherein (R) refers to the stereochemical designation of the central carbon atom under the Cahn-Ingold-Prelog convention. In some embodiments of Formula I, Z is , wherein (S) refers to the stereochemical designation of the central carbon atom under the Cahn-Ingold-Prelog convention. [0037] In some embodiments of Formula I, m is selected from 1 and 2.
  • compounds of the invention are encompassed by Formula I’: , and includes deuterated derivatives thereof, and pharmaceutically acceptable salts of those compounds and deuterated derivatives, wherein: X is selected from -N(R X1 )- and Ring A is a 4- to 6-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl and oxo; R X1 is selected from H, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, oxo, -OR X2 , and -N(R X2 ) 2 ), and C 3 -C 8 cycloalkyl; each R X2 is independently selected from H and C 1 -C 6 alkyl; each Y is independently selected from -C(R Y ) 2 -, -O-, -CO-, -NR YN -, and , wherein each R YN is
  • the compound of Formula I is selected from compounds of Formula I’’: , and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I.
  • the portion of the compound represented by: is , wherein (R) refers to the stereochemical designation of the central carbon atom under the Cahn-Ingold-Prelog convention.
  • the portion of the compound represented by is wherein (S) refers to the stereochemical designation of the central carbon atom under the Cahn- Ingold-Prelog convention.
  • the compounds of the invention also include compounds of Formulae Ia, IIa, IIb, IIc, IId, IIe, IIf, IIg, and IIh:
  • the compounds of the invention also include compounds of Formulae Ia’, IIa’, IIb’, IIc’, IId’, IIe’, IIf’, IIg’, and IIh’: , and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I.
  • the portion of the compound represented by: is , wherein (R) refers to the stereochemical designation of the central carbon atom under the Cahn-Ingold-Prelog convention.
  • the portion of the compound represented by is , wherein (S) refers to the stereochemical designation of the central carbon atom under the Cahn-Ingold-Prelog convention.
  • compositions comprising at least one compound chosen from compounds of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, and IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier, which compositions may further include at least one additional active pharmaceutical ingredient.
  • another aspect of the invention provides methods of treating the CFTR-mediated disease cystic fibrosis comprising administering at least one of compound chosen from compounds of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, and IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier, optionally as part of a pharmaceutical composition comprising at least one additional component, to a subject in need thereof.
  • the pharmaceutical compositions of the invention comprise at least one compound chosen from compounds of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, and IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing.
  • Another aspect of the invention provides methods of treating the CFTR- mediated disease cystic fibrosis comprising administering to a patient in need thereof at least one compound chosen from the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, and optionally further administering one or more additional CFTR modulating agents selected from (R)- 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1- hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II), N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3- carboxamide (Compound III) or N-(2-(tert-butyl)-5-hydroxy-4-
  • Another aspect of the invention provides methods of treating the CFTR- mediated disease cystic fibrosis comprising administering to a patient in need thereof at least one compound chosen from compounds of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, and IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, and optionally further administering one or more additional CFTR modulating agents selected from: disclosed in Journal of Cystic Fibrosis (2016), 17(5), 595-606, and: (nesolicaftor or PTI-428), disclosed in WO 2016/105485.
  • the additional CFTR modulating agent is ASP-11. In one embodiment, the additional CFTR modulating agent comprises PTI-428.
  • Another aspect of the invention provides methods of treating the CFTR- mediated disease cystic fibrosis comprising administering to a patient in need thereof at least one compound chosen from compounds of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, and IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, and optionally further administering one or more additional CFTR modulating agents selected from:
  • FIG. 1 provides an X-ray power diffraction (XRPD) pattern of amorphous Compound 4 (neat form).
  • XRPD X-ray power diffraction
  • FIG. 2 provides a thermogravimetric analysis (TGA) curve for amorphous Compound 4 (neat form).
  • FIG. 3 provides a DSC analysis of amorphous Compound 4 (neat form).
  • FIG. 4 provides an XRPD pattern of amorphous Compound 19 (neat form).
  • FIG. 5 provides a TGA curve for amorphous Compound 19 (neat form).
  • FIG. 6 provides a DSC analysis of amorphous Compound 19 (neat form).
  • FIG. 7 provides an XRPD pattern of crystalline Compound 41 Form A.
  • FIG. 8 provides a TGA curve for crystalline Compound 41 Form A.
  • FIG. 8 provides a TGA curve for crystalline Compound 41 Form A.
  • FIG. 9 provides an XRPD pattern of crystalline Compound 52 Form A (neat).
  • FIG. 10 provides a TGA curve for crystalline Compound 52 Form A (neat).
  • FIG. 11 provides a DSC analysis of crystalline Compound 52 Form A (neat).
  • FIG. 12 provides an XRPD pattern of amorphous Compound 60 (neat form).
  • FIG. 13 provides a TGA curve for amorphous Compound 60 (neat form).
  • FIG. 14 provides a DSC analysis of amorphous Compound 60 (neat form).
  • FIG. 15 provides an XRPD pattern of amorphous Compound 70 (neat form).
  • FIG. 64 provides an XRPD pattern of amorphous Compound 70 (neat form).
  • FIG. 16 provides an XRPD pattern of crystalline Compound 163 Form A (neat).
  • FIG. 17 provides a DSC analysis of crystalline Compound 163 Form A (neat).
  • FIG. 18 provides an XRPD pattern of amorphous Compound 173 (neat form).
  • FIG. 19 provides a TGA curve for amorphous Compound 173 (neat form).
  • FIG. 20 provides a DSC analysis of amorphous Compound 173 (neat form).
  • Compound II refers to (R)-1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2- methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, which can be depicted with the following structure: Compound II. Compound II may be in the form of a pharmaceutically acceptable salt.
  • Compound II and methods of making and using Compound II are disclosed in WO 2010/053471, WO 2011/119984, WO 2011/133751, WO 2011/133951, and WO 2015/160787, each incorporated herein by reference.
  • “Compound III” as used throughout this disclosure refers to N-(5-hydroxy-2,4- di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide which is depicted by the structure: Compound III.
  • Compound III may also be in the form of a pharmaceutically acceptable salt.
  • Compound III and methods of making and using Compound III are disclosed in WO 2006/002421, WO 2007/079139, WO 2010/108162, and WO 2010/019239, each incorporated herein by reference.
  • a deuterated derivative of Compound III (Compound III-d) is employed in the compositions and methods disclosed herein.
  • a chemical name for Compound III-d is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl- 1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, as depicted by the structure: Compound III-d.
  • Compound III-d may be in the form of a pharmaceutically acceptable salt.
  • Compound III-d and methods of making and using Compound III-d are disclosed in WO 2012/158885, WO 2014/078842, and US Patent No. 8,865,902, incorporated herein by reference.
  • “Compound IV” as used herein, refers to 3-(6-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2- yl)benzoic acid, which is depicted by the chemical structure: Compound IV.
  • Compound IV may be in the form of a pharmaceutically acceptable salt.
  • Compound IV and methods of making and using Compound IV are disclosed in WO 2007/056341, WO 2009/073757, and WO 2009/076142, incorporated herein by reference.
  • “Compound V” as used herein refers to N-(1,3-dimethylpyrazol-4-yl)sulfonyl- 6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4- trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is depicted by the chemical structure: Compound V may be in the form of a pharmaceutically acceptable salt.
  • Compound V and methods of making and using Compound V are disclosed in WO 2018/107100 and WO 2019/113476, incorporated herein by reference.
  • “Compound VI” as used herein refers to N-(benzenesulfonyl)-6-[3-[2-[1- (trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1- yl]pyridine-3-carboxamide, which is depicted by the chemical structure: Compound VI may be in the form of a pharmaceutically acceptable salt.
  • Compound VI and methods of making and using Compound VI are disclosed in WO 2018/064632, incorporated herein by reference.
  • Compound VII refers to (14S)-8-[3-(2- ⁇ dispiro[2.0.2.1]heptan-7-yl ⁇ ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2 ⁇ 6 -thia- 3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20- hexaene-2,2,4-trione, which is depicted by the chemical structure: Compound VII may be in the form of a pharmaceutically acceptable salt.
  • Compound VII and methods of making and using Compound VII are disclosed in WO 2019/161078, WO 2020/102346, and PCT Application No. PCT/US2020/046116, incorporated herein by reference.
  • “Compound VIII” as used herein refers to (11R)-6-(2,6-dimethylphenyl)-11- (2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, which is depicted by the chemical structure: Compound VIII.
  • Compound VIII may be in the form of a pharmaceutically acceptable salt.
  • Compound VIII and methods of making and using Compound VIII are disclosed in WO 2020/206080, incorporated herein by reference.
  • “Compound IX” as used herein, refers to N-(benzenesulfonyl)-6-(3-fluoro-5- isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is depicted by the chemical structure: Compound IX.
  • Compound IX may be in the form of a pharmaceutically acceptable salt.
  • Compound IX and methods of making and using Compound IX are disclosed in WO 2016/057572, incorporated herein by reference.
  • Compound X refers to N-[(6-amino-2-pyridyl)sulfonyl]-6-(3- fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3- carboxamide, which is depicted by the chemical structure: Compound X.
  • Compound X may be in the form of a pharmaceutically acceptable salt.
  • Compound X and methods of making and using Compound X are disclosed in WO 2016/057572, incorporated herein by reference.
  • alkyl refers to a saturated, branched or unbranched aliphatic hydrocarbon containing carbon atoms (such as, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms). Alkyl groups may be substituted or unsubstituted.
  • pi bond refers to a covalent bond formed by the p orbitals of adjacent atoms. Pi bonds exist where there is a multiple bond, i.e., a double or triple bond, between two atoms. For example, a carbon-carbon double bond consists of one pi bond, and a carbon-carbon triple bond consists of two pi bonds.
  • haloalkyl group refers to an alkyl group substituted with one or more halogen atoms.
  • fluoroalkyl refers to an alkyl group substituted with one or more fluorine atoms. In some embodiments, a fluoroalkyl group is substituted by 1-6 fluorine atoms. In some embodiments, a fluoroalkyl group is perfluorinated.
  • alkoxy refers to an alkyl or cycloalkyl covalently bonded to an oxygen atom. Alkoxy groups may be substituted or unsubstituted.
  • haloalkoxyl group refers to an alkoxy group substituted with one or more halogen atoms.
  • fluoroalkoxy refers to an alkoxy group substituted with one or more fluorine atoms. In some embodiments, a fluoroalkoxy group is substituted by 1-6 fluorine atoms. In some embodiments, a fluoroalkoxy group is perfluorinated.
  • cycloalkyl refers to a cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon groups having 3 to 12 carbons (such as, for example 3-10 carbons).
  • Cycloalkyl groups encompass monocyclic, bicyclic, tricyclic, bridged, fused, and spiro rings, including mono spiro and dispiro rings.
  • Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, and dispiro[2.0.2.1]heptane. Cycloalkyl groups may be substituted or unsubstituted.
  • heteroaryl ring refers to an aromatic ring comprising at least one ring atom that is a heteroatom, such as O, N, or S.
  • heterocyclyl ring and “heterocyclyl” refer to a non- aromatic hydrocarbon containing 3 to 12 atoms in a ring (such as, for example 3-10 atoms) comprising at least one ring atom that is a heteroatom, such as O, N, S, or Si.
  • Heterocyclyl” rings encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro rings, including mono spiro and dispiro rings.
  • “Substituted” indicates that at least one hydrogen of the “substituted” group is replaced by a substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at each position.
  • Examples of protecting groups for nitrogen include, for example, t-butyl carbamate (Boc), benzyl (Bn), para-methoxybenzyl (PMB), tetrahydropyranyl (THP), 9- fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), methyl carbamate, ethyl carbamate, 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), allyl carbamate (Aloc or Alloc), formamide, acetamide, benzamide, allylamine, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide.
  • Boc t-butyl carbamate
  • Bn benzyl
  • PMB para-methoxybenzyl
  • THP tetrahydropyranyl
  • CFTR cystic fibrosis transmembrane conductance regulator.
  • CFTR modulator refers to a compound that increases the activity of CFTR. The increase in activity resulting from a CFTR modulator includes but is not limited to compounds that correct, potentiate, stabilize and/or amplify CFTR.
  • CFTR corrector refers to a compound that facilitates the processing and trafficking of CFTR to increase the amount of CFTR at the cell surface.
  • CFTR potentiator refers to a compound that increases the channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport.
  • the novel compounds disclosed herein are CFTR potentiators.
  • CFTR potentiator enhancer CFTR potentiation enhancer
  • CFTR co-potentiator are used interchangeably and refer to a compound that enhances CFTR potentiation.
  • the term “active pharmaceutical ingredient” (“API”) or “therapeutic agent” refers to a biologically active compound.
  • the terms “patient” and “subject” are used interchangeably and refer to an animal including humans.
  • the terms “effective dose” and “effective amount” are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in CF or a symptom of CF, or lessening the severity of CF or a symptom of CF).
  • treatment generally mean the improvement in one or more symptoms of CF or lessening the severity of CF or one or more symptoms of CF in a subject.
  • Treatment includes, but is not limited to, the following: increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and/or liver function, reduction of chest infections, and/or reductions in coughing or shortness of breath.
  • the term “in combination with,” when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other.
  • the terms “about” and “approximately”, when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent.
  • the terms “about” and “approximately” may refer to an acceptable error for a particular value as determined by one of skill in the art, which depends in part on how the values is measured or determined.
  • the terms “about” and “approximately” mean within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.
  • the symbol “ ⁇ ” appearing immediately before a numerical value has the same meaning as the terms “about” and “approximately.”
  • the term “solvent” refers to any liquid in which the product is at least partially soluble (solubility of product >1 g/L).
  • the term “room temperature” or “ambient temperature” means 15 o C to 30 o C.
  • a “wedge” or “hash” bond to a stereogenic atom indicates a chiral center of known absolute stereochemistry (i.e. one stereoisomer).
  • a “wavy” bond to a stereogenic atom indicates a chiral center of unknown absolute stereochemistry (i.e. one stereoisomer).
  • a “wavy” bond to a double-bonded carbon indicates a mixture of E/Z isomers.
  • a (“straight”) bond to a stereogenic atom indicates where there is a mixture (e.g., a racemate or enrichment).
  • two (“straight”) bonds to a double-bonded carbon indicates that the double bond possesses the E/Z stereochemistry as drawn.
  • a i.e., a “wavy” line perpendicular to a “straight” bond to group “A” indicates that group “A” is a substituent whose point of attachment is at the end of the bond that terminates at the “wavy” line.
  • minimal function (MF) mutations refer to CFTR gene mutations associated with minimal CFTR function (little-to-no functioning CFTR protein) and include, for example, mutations associated with severe defects in ability of the CFTR channel to open and close, known as defective channel gating or “gating mutations”; mutations associated with severe defects in the cellular processing of CFTR and its delivery to the cell surface; mutations associated with no (or minimal) CFTR synthesis; and mutations associated with severe defects in channel conductance.
  • the term “pharmaceutically acceptable salt” refers to a salt form of a compound of this disclosure wherein the salt is nontoxic.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • a “free base” form of a compound, for example, does not contain an ionically bonded salt.
  • the phrase “and pharmaceutically acceptable salts and deuterated derivatives thereof” is used interchangeably with “and pharmaceutically acceptable salts thereof and deuterated derivatives of any of the forgoing” in reference to one or more compounds or formulae of the invention.
  • Non-limiting examples of pharmaceutically acceptable acid addition salts include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art, such as ion exchange.
  • Non- limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • 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. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • amorphous refers to a solid material having no long- range order in the position of its molecules.
  • Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well- defined arrangement, e.g., molecular packing, and no long-range order.
  • Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points.
  • an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid. See, US 2004/0006237 for a comparison of XRPDs of an amorphous material and crystalline material.
  • a solid material may comprise an amorphous compound, and the material may, for example, be characterized by a lack of sharp characteristic crystalline peak(s) in its XRPD spectrum (i.e., the material is not crystalline, but is amorphous, as determined by XRPD). Instead, one or several broad peaks (e.g., halos) may appear in the XRPD pattern of the material. See US 2004/0006237 for a comparison of XRPDs of an amorphous material and crystalline material.
  • a solid material, comprising an amorphous compound may be characterized by, for example, a glass transition temperature which is lower than the melting point of a pure crystalline solid.
  • crystal form As used herein, the terms “crystal form,” “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, and 13 C solid state nuclear magnetic resonance ( 13 C SSNMR).
  • XRPD X-ray powder diffraction
  • 13 C SSNMR 13 C solid state nuclear magnetic resonance
  • crystalline Form [X] of Compound (I) refers to a unique crystalline form that can be identified and distinguished from other crystalline forms by one or more characterization techniques including, for example, XRPD, single crystal X-ray diffraction, and 13 C SSNMR.
  • the novel crystalline forms are characterized by an X-ray powder diffractogram having one or more signals at one or more specified two-theta values (o2 ⁇ ).
  • the term “free form” refers to a non-ionized version of the compound in the solid state. Examples of free forms include free bases and free acids.
  • solvate refers to a crystal form comprising one or more molecules of a compound of the present disclosure and, incorporated into the crystal lattice, one or more molecules of a solvent or solvents in stoichiometric or nonstoichiometric amounts. When the solvent is water, the solvate is referred to as a “hydrate.”
  • a solid material may comprise a mixture of crystalline solids and amorphous solids.
  • a solid material comprising an amorphous compound may also, for example, contain up to 30% of a crystalline solid.
  • a solid material prepared to comprise an amorphous compound may also, for example, contain up to 25%, 20%, 15%, 10%, 5%, or 2% of a crystalline solid.
  • the characterizing data such as XRPD, may contain indicators of both crystalline and amorphous solids.
  • a crystalline form of this disclosure may contain up to 30% amorphous compound.
  • a crystalline preparation of a compound of Formula I may contain up to 25%, 20%, 15%, 10%, 5%, or 2% of an amorphous solid.
  • substantially amorphous refers to a solid material having little or no long-range order in the position of its molecules.
  • substantially amorphous materials have less than 15% crystallinity (e.g., less than 10% crystallinity, less than 5% crystallinity, or less than 2% crystallinity).
  • substantially amorphous includes the descriptor, “amorphous,” which refers to materials having no (0%) crystallinity.
  • substantially crystalline refers to a solid material having little or no amorphous molecules.
  • substantially crystalline materials have less than 15% amorphous molecules (e.g., less than 10% amorphous molecules, less than 5% amorphous molecules, or less than 2% amorphous molecules). It is also noted that the term “substantially crystalline” includes the descriptor “crystalline,” which refers to materials that are 100% crystalline form. [00120] As used herein, a crystalline form is "substantially pure" when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by a method in accordance with the art, such as quantitative XRPD.
  • the solid form is “substantially pure” when it accounts for an amount by weight equal to or greater than 95% of the sum of all solid form(s) in a sample. In some embodiments, the solid form is “substantially pure” when it accounts for an amount by weight equal to or greater than 99% of the sum of all solid form(s) in a sample. It is also noted that the term “substantially pure” includes the descriptor “pure.” [00121] As used herein, the term “XRPD” refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns disclosed herein were recorded at ambient conditions in transmission or reflection geometry using a diffractometer.
  • ambient conditions means room temperature, open air condition and uncontrolled humidity condition.
  • room temperature and “ambient temperature” mean 15 oC to 30 oC.
  • X-ray powder diffractogram means room temperature, open air condition and uncontrolled humidity condition.
  • XRPD pattern means 15 oC to 30 oC.
  • XRPD spectrum means 15 oC to 30 oC.
  • 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 ⁇ (o 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 ....” [00124] 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 refer to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (o 2 ⁇ ).
  • the repeatability of the measured angular values is in the range of ⁇ 0.2o 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).
  • an X-ray powder diffractogram is “substantially similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms overlap.
  • substantially similarity one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in XRPD diffractograms even for the same crystalline form.
  • the signal maximum values in XRPD diffractograms in degrees two-theta generally mean that value is identified as ⁇ 0.2 degrees two-theta of the reported value, an art-recognized variance.
  • a solid state nuclear magnetic resonance (SSNMR) spectrum is “substantially similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two spectra overlap.
  • SSNMR solid state nuclear magnetic resonance
  • X-ray powder diffractogram having a signal at ... two-theta values refers to an XRPD pattern that contains X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (o two-theta).
  • DSC digital chemical chemical vapor deposition
  • onset of decomposition refers to the intersection point of the baseline before transition and the interflection tangent.
  • glass transition temperature refers to the temperature above which a hard and brittle “glassy” amorphous solid becomes viscous or rubbery.
  • melting temperature refers to the temperature at which a material transitions from a solid to a liquid phase.
  • TGA refers to the analytical method of Thermo Gravimetric (or thermogravimetric) Analysis.
  • the invention provides compounds of Formulae I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, and IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing.
  • the compound of Formula I is selected from compounds of any one of Formulae Ia, IIa, IIb, IIc, IId, IIe, IIf, IIg, and IIh:
  • the compound of Formula I is selected from compounds of Formula I’’: , and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I.
  • the compound of Formula I is selected from compounds of any one of Formulae Ia’, IIa’, IIb’, IIc’, IId’, IIe’, IIf’, IIg’, and IIh’:
  • Solid Forms [00141] Another aspect of the disclosure provides solid forms of the compounds of Formula I (e.g., compounds of Formulae I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, and IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing), which can be used in the methods of treatment and pharmaceutical compositions described herein.
  • Amorphous Compound 4 (neat form)
  • the invention provides neat solid forms of Compound 4.
  • the invention provides a neat amorphous form of Compound 4. In some embodiments, the invention provides amorphous Compound 4 (neat form).
  • FIG. 1 provides an X-ray powder diffractogram of amorphous Compound 4 (neat form) at room temperature.
  • amorphous Compound 4 (neat form) is substantially pure. In some embodiments, amorphous Compound 4 (neat form) is substantially amorphous. In some embodiments, amorphous Compound 4 (neat form) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu K ⁇ radiation.
  • amorphous Compound 4 (neat form) is characterized by an X-ray powder diffractogram substantially similar to FIG. 1.
  • Crystalline Compound 5 Form A (neat)
  • the invention provides neat solid forms of Compound 5.
  • the invention provides neat crystalline forms of Compound 5.
  • the invention provides crystalline Compound 5 Form A (neat).
  • crystalline Compound 5 Form A (neat) is substantially pure.
  • crystalline Compound 5 Form A (neat) is substantially crystalline.
  • Amorphous Compound 19 (neat form)
  • the invention provides neat solid forms of Compound 19.
  • the invention provides a neat amorphous form of Compound 19.
  • the invention provides amorphous Compound 19 (neat form).
  • FIG. 4 provides an X-ray powder diffractogram of amorphous Compound 19 (neat form) at room temperature.
  • amorphous Compound 19 (neat form) is substantially pure.
  • amorphous Compound 19 (neat form) is substantially amorphous.
  • amorphous Compound 19 (neat form) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu K ⁇ radiation.
  • amorphous Compound 19 is characterized by an X-ray powder diffractogram substantially similar to FIG. 4.
  • Crystalline Compound 41 Form A [00151] In some embodiments, the invention provides solid forms of Compound 41. In some embodiments, the invention provides crystalline forms of Compound 41. In some embodiments, the invention provides crystalline Compound 41 Form A. FIG. 7 provides an X-ray powder diffractogram of crystalline Compound 41 Form A. [00152] In some embodiments, crystalline Compound 41 Form A is substantially pure. In some embodiments, crystalline Compound 41 Form A is substantially crystalline.
  • crystalline Compound 41 Form A is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu K ⁇ radiation. [00153] In some embodiments, crystalline Compound 41 Form A is characterized by an X-ray powder diffractogram having a signal at one or more of 14.2 ⁇ 0.2 degrees two- theta, 19.5 ⁇ 0.2 degrees two-theta, and 21.2 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 41 Form A is characterized by an X-ray powder diffractogram having a signal at two or more of 14.2 ⁇ 0.2 degrees two-theta, 19.5 ⁇ 0.2 degrees two-theta, and 21.2 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Compound 41 Form A is characterized by an X-ray powder diffractogram having a signal at 14.2 ⁇ 0.2 degrees two-theta, 19.5 ⁇ 0.2 degrees two-theta, and 21.2 ⁇ 0.2 degrees two- theta.
  • crystalline Compound 41 Form A is characterized by an X-ray powder diffractogram having a signal at three or more of 14.2 ⁇ 0.2 degrees two- theta, 19.5 ⁇ 0.2 degrees two-theta, 21.2 ⁇ 0.2 degrees two-theta, 18.0 ⁇ 0.2 degrees two- theta, 16.6 ⁇ 0.2 degrees two-theta, and 20.7 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 41 Form A is characterized by an X-ray powder diffractogram having a signal at four or more of 14.2 ⁇ 0.2 degrees two-theta, 19.5 ⁇ 0.2 degrees two-theta, 21.2 ⁇ 0.2 degrees two-theta, 18.0 ⁇ 0.2 degrees two-theta, 16.6 ⁇ 0.2 degrees two-theta, and 20.7 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 41 Form A is characterized by an X-ray powder diffractogram having a signal at five or more of 14.2 ⁇ 0.2 degrees two-theta, 19.5 ⁇ 0.2 degrees two-theta, 21.2 ⁇ 0.2 degrees two-theta, 18.0 ⁇ 0.2 degrees two-theta, 16.6 ⁇ 0.2 degrees two-theta, and 20.7 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 41 Form A is characterized by an X-ray powder diffractogram having a signal at 14.2 ⁇ 0.2 degrees two- theta, 19.5 ⁇ 0.2 degrees two-theta, 21.2 ⁇ 0.2 degrees two-theta, 18.0 ⁇ 0.2 degrees two- theta, 16.6 ⁇ 0.2 degrees two-theta, and 20.7 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 41 Form A is characterized by an X-ray powder diffractogram having a signal at one, two, three, four, five, six, seven, eight, or more of 14.2 ⁇ 0.2 degrees two-theta, 16.6 ⁇ 0.2 degrees two-theta, 18.0 ⁇ 0.2 degrees two-theta, 19.5 ⁇ 0.2 degrees two-theta, 20.3 ⁇ 0.2 degrees two-theta, 20.7 ⁇ 0.2 degrees two-theta, 21.2 ⁇ 0.2 degrees two-theta, 22.2 ⁇ 0.2 degrees two-theta, and 25.1 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 41 Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 7.
  • Crystalline Compound 52 Form A (neat) [00157] In some embodiments, the invention provides neat solid forms of Compound 52. In some embodiments, the invention provides neat crystalline forms of Compound 52. In some embodiments, the invention provides crystalline Compound 52 Form A (neat).
  • FIG. 9 provides an X-ray powder diffractogram of crystalline Compound 52 Form A (neat).
  • crystalline Compound 52 Form A (neat) is substantially pure. In some embodiments, crystalline Compound 52 Form A (neat) is substantially crystalline.
  • crystalline Compound 52 Form A is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu K ⁇ radiation.
  • crystalline Compound 52 Form A is characterized by an X-ray powder diffractogram having a signal at one or more of 6.8 ⁇ 0.2 degrees two- theta, 17.3 ⁇ 0.2 degrees two-theta, and 18.6 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 52 Form A is characterized by an X-ray powder diffractogram having a signal at two or more of 6.8 ⁇ 0.2 degrees two-theta, 17.3 ⁇ 0.2 degrees two-theta, and 18.6 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 52 Form A (neat) is characterized by an X-ray powder diffractogram having a signal at 6.8 ⁇ 0.2 degrees two-theta, 17.3 ⁇ 0.2 degrees two-theta, and 18.6 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 52 Form A is characterized by an X-ray powder diffractogram having a signal at three or more of 6.8 ⁇ 0.2 degrees two-theta, 12.7 ⁇ 0.2 degrees two-theta, 17.3 ⁇ 0.2 degrees two-theta, 18.6 ⁇ 0.2 degrees two-theta, 20.6 ⁇ 0.2 degrees two-theta, and 21.4 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 52 Form A is characterized by an X-ray powder diffractogram having a signal at four or more of 6.8 ⁇ 0.2 degrees two-theta, 12.7 ⁇ 0.2 degrees two-theta, 17.3 ⁇ 0.2 degrees two-theta, 18.6 ⁇ 0.2 degrees two-theta, 20.6 ⁇ 0.2 degrees two-theta, and 21.4 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 52 Form A is characterized by an X-ray powder diffractogram having a signal at five or more of 6.8 ⁇ 0.2 degrees two-theta, 12.7 ⁇ 0.2 degrees two-theta, 17.3 ⁇ 0.2 degrees two-theta, 18.6 ⁇ 0.2 degrees two-theta, 20.6 ⁇ 0.2 degrees two-theta, and 21.4 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 52 Form A is characterized by an X-ray powder diffractogram having a signal at 12.7 ⁇ 0.2 degrees two-theta, 17.3 ⁇ 0.2 degrees two-theta, 18.6 ⁇ 0.2 degrees two-theta, 20.6 ⁇ 0.2 degrees two-theta, and 21.4 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 52 Form A is characterized by an X-ray powder diffractogram having a signal at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or more of 6.8 ⁇ 0.2 degrees two-theta, 12.7 ⁇ 0.2 degrees two- theta, 15.1 ⁇ 0.2 degrees two-theta, 15.5 ⁇ 0.2 degrees two-theta, 17.3 ⁇ 0.2 degrees two- theta, 18.6 ⁇ 0.2 degrees two-theta, 19.2 ⁇ 0.2 degrees two-theta, 19.7 ⁇ 0.2 degrees two- theta, 20.4 ⁇ 0.2 degrees two-theta, 20.6 ⁇ 0.2 degrees two-theta, 21.4 ⁇ 0.2 degrees two- theta, and 27.2 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 52 Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 9.
  • Amorphous Compound 60 (neat form) [00163] In some embodiments, the invention provides neat solid forms of Compound 60. In some embodiments, the invention provides a neat amorphous form of Compound 60. In some embodiments, the invention provides amorphous Compound 60 (neat form). FIG. 12 provides an X-ray powder diffractogram of amorphous Compound 60 (neat form) at room temperature. [00164] In some embodiments, amorphous Compound 60 (neat form) is substantially pure. In some embodiments, amorphous Compound 60 (neat form) is substantially amorphous.
  • amorphous Compound 60 is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu K ⁇ radiation.
  • amorphous Compound 60 is characterized by an X-ray powder diffractogram substantially similar to FIG. 12.
  • Amorphous Compound 70 is characterized by an X-ray powder diffractogram substantially similar to FIG. 12.
  • Amorphous Compound 70 is characterized by the invention provides neat solid forms of Compound 70.
  • the invention provides a neat amorphous form of Compound 70.
  • the invention provides amorphous Compound 70 (neat form).
  • amorphous Compound 70 (neat form) provides an X-ray powder diffractogram of amorphous Compound 70 (neat form) at room temperature.
  • amorphous Compound 70 (neat form) is substantially pure.
  • amorphous Compound 70 (neat form) is substantially amorphous.
  • amorphous Compound 70 (neat form) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu K ⁇ radiation.
  • amorphous Compound 70 (neat form) is characterized by an X-ray powder diffractogram substantially similar to FIG. 15.
  • Crystalline Compound 163 Form A (neat) [00169] In some embodiments, the invention provides neat solid forms of Compound 163. In some embodiments, the invention provides neat crystalline forms of Compound 163. In some embodiments, the invention provides crystalline Compound 163 Form A (neat). FIG. 16 provides an X-ray powder diffractogram of crystalline Compound 163 Form A (neat). [00170] In some embodiments, crystalline Compound 163 Form A (neat) is substantially pure. In some embodiments, crystalline Compound 163 Form A (neat) is substantially crystalline.
  • crystalline Compound 163 Form A is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu K ⁇ radiation.
  • crystalline Compound 163 Form A is characterized by an X-ray powder diffractogram having a signal at 7.4 ⁇ 0.2 degrees two- theta.
  • crystalline Compound 163 Form A is characterized by an X-ray powder diffractogram having a signal at one or more of 7.4 ⁇ 0.2 degrees two-theta, 8.4 ⁇ 0.2 degrees two-theta, and 15.0 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 163 Form A is characterized by an X-ray powder diffractogram having a signal at two or more of 7.4 ⁇ 0.2 degrees two-theta, 8.4 ⁇ 0.2 degrees two-theta, and 15.0 ⁇ 0.2 degrees two-theta. In some embodiments, crystalline Compound 163 Form A (neat) is characterized by an X-ray powder diffractogram having a signal at 7.4 ⁇ 0.2 degrees two-theta, 8.4 ⁇ 0.2 degrees two-theta, and 15.0 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 163 Form A is characterized by an X-ray powder diffractogram having a signal at three or more of 7.4 ⁇ 0.2 degrees two-theta, 8.4 ⁇ 0.2 degrees two-theta, 14.1 ⁇ 0.2 degrees two-theta, 15.0 ⁇ 0.2 degrees two-theta, 19.1 ⁇ 0.2 degrees two-theta, and 25.8 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 163 Form A is characterized by an X-ray powder diffractogram having a signal at four or more of 7.4 ⁇ 0.2 degrees two-theta, 8.4 ⁇ 0.2 degrees two-theta, 14.1 ⁇ 0.2 degrees two-theta, 15.0 ⁇ 0.2 degrees two-theta, 19.1 ⁇ 0.2 degrees two-theta, and 25.8 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 163 Form A is characterized by an X-ray powder diffractogram having a signal at five or more of 7.4 ⁇ 0.2 degrees two-theta, 8.4 ⁇ 0.2 degrees two-theta, 14.1 ⁇ 0.2 degrees two-theta, 15.0 ⁇ 0.2 degrees two-theta, 19.1 ⁇ 0.2 degrees two-theta, and 25.8 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 163 Form A is characterized by an X-ray powder diffractogram having a signal at 7.4 ⁇ 0.2 degrees two-theta, 8.4 ⁇ 0.2 degrees two-theta, 14.1 ⁇ 0.2 degrees two-theta, 15.0 ⁇ 0.2 degrees two-theta, 19.1 ⁇ 0.2 degrees two-theta, and 25.8 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 163 Form A is characterized by an X-ray powder diffractogram having a signal at one, two, three, four, five, six, seven, eight, nine, ten, or more of 7.4 ⁇ 0.2 degrees two-theta, 8.4 ⁇ 0.2 degrees two-theta, 14.1 ⁇ 0.2 degrees two-theta, 14.6 ⁇ 0.2 degrees two-theta, 15.0 ⁇ 0.2 degrees two-theta, 16.9 ⁇ 0.2 degrees two-theta, 19.1 ⁇ 0.2 degrees two-theta, 20.0 ⁇ 0.2 degrees two-theta, 22.5 ⁇ 0.2 degrees two-theta, 25.6 ⁇ 0.2 degrees two-theta, and 25.8 ⁇ 0.2 degrees two-theta.
  • crystalline Compound 163 Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 16.
  • Amorphous Compound 173 (neat form) and Crystalline Compound 173 Form A (neat) [00176]
  • the invention provides neat solid forms of Compound 173.
  • the invention provides a neat amorphous form of Compound 173.
  • the invention provides amorphous Compound 173 (neat form).
  • FIG. 18 provides an X-ray powder diffractogram of amorphous Compound 173 (neat form) at room temperature.
  • amorphous Compound 173 (neat form) is substantially pure.
  • amorphous Compound 173 is substantially amorphous.
  • amorphous Compound 173 is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu K ⁇ radiation.
  • amorphous Compound 173 (neat form) is characterized by an X-ray powder diffractogram substantially similar to FIG. 18.
  • the invention provides neat crystalline forms of Compound 173.
  • the invention provides crystalline Compound 173 Form A (neat).
  • crystalline Compound 173 Form A (neat) is substantially pure.
  • crystalline Compound 173 Form A is substantially crystalline.
  • Crystalline Compound 175 Form A (neat) [00182] In some embodiments, the invention provides neat solid forms of Compound 175. In some embodiments, the invention provides neat crystalline forms of Compound 175. In some embodiments, the invention provides crystalline Compound 175 Form A (neat). [00183] In some embodiments, crystalline Compound 175 Form A (neat) is substantially pure. In some embodiments, crystalline Compound 175 Form A (neat) is substantially crystalline.
  • Crystalline Compound 188 Dichloromethane Solvate Form A
  • the invention provides solvated crystalline forms of Compound 188.
  • the solvated crystalline form is a dichloromethane solvate.
  • the invention provides crystalline Compound 188 dichloromethane solvate Form A.
  • crystalline Compound 188 dichloromethane solvate Form A is substantially pure.
  • crystalline Compound 188 dichloromethane solvate Form A is substantially crystalline.
  • any of the novel compounds and solid forms disclosed herein such as for example, compounds of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing can act as a CFTR modulator, i.e., it modulates CFTR activity in the body.
  • a CFTR mutation may affect the CFTR quantity, i.e., the number of CFTR channels at the cell surface, or it may impact CFTR function, i.e., the functional ability of each channel to open and transport ions.
  • Mutations affecting CFTR quantity include mutations that cause defective synthesis (Class I defect), mutations that cause defective processing and trafficking (Class II defect), mutations that cause reduced synthesis of CFTR (Class V defect), and mutations that reduce the surface stability of CFTR (Class VI defect).
  • Mutations that affect CFTR function include mutations that cause defective gating (Class III defect) and mutations that cause defective conductance (Class IV defect).
  • the invention provides methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering to the patient an effective amount of any of the novel compounds and solid forms disclosed herein, such as for example, compounds of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, alone or in combination with another active ingredient, such as another CFTR modulating agent.
  • the patient has an F508del/minimal function (MF) genotype, F508del/F508del genotype (homozygous for the F508del mutation), F508del/gating genotype, or F508del/residual function (RF) genotype.
  • MF F508del/minimal function
  • F508del/F508del genotype homozygous for the F508del mutation
  • F508del/gating genotype F508del/gating genotype
  • F508del/residual function (RF) genotype In some embodiments the patient is heterozygous and has one F508del mutation. In some embodiments the patient is homozygous for the N1303K mutation. [00190] In some embodiments, 1 mg to 1000 mg of a compound disclosed herein, a deuterated derivative thereof or a pharmaceutically acceptable salt of the compound or deuterated derivative are administered daily. [00191] In some embodiments
  • the disclosure also is directed to methods of treatment using isotope-labelled compounds of the afore-mentioned compounds, or pharmaceutically acceptable salts thereof, wherein the formula and variables of such compounds and salts are each and independently as described above or any other embodiments described above, provided that one or more atoms therein have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally (isotope labelled).
  • isotopes which are commercially available and suitable for the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2 H, 3 H, 13 C, 14 C, 1 5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • the isotope-labelled compounds and salts can be used in a number of beneficial ways. They can be suitable for medicaments and/or various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3 H)- and/or carbon-14 ( 14 C)- labelled compounds are particularly useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.
  • deuterium ( 2 H)-labelled ones are therapeutically useful with potential therapeutic advantages over the non- 2 H-labelled compounds.
  • deuterium ( 2 H)- labelled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labelled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which could be desired.
  • the isotope-labelled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.
  • the isotope-labelled compounds and salts are deuterium ( 2 H)-labelled ones.
  • the isotope-labelled compounds and salts are deuterium ( 2 H)-labelled, wherein one or more hydrogen atoms therein have been replaced by deuterium.
  • deuterium is represented as “ 2 H” or “D.”
  • the deuterium ( 2 H)-labelled compounds and salts can modulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect.
  • the primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange.
  • Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially.
  • the concentration of the isotope(s) (e.g., deuterium) incorporated into the isotope-labelled compounds and salt of the disclosure may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of the disclosure is denoted deuterium
  • such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), 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), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • One aspect disclosed herein provides methods of treating cystic fibrosis and other CFTR-mediated diseases using any of the novel compounds and solid forms disclosed herein, such as for example, compounds of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient.
  • the invention provides methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering to the patient an effective amount of any of the novel compounds and solid forms disclosed herein, such as for example, compounds of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of those compounds and deuterated derivatives, alone or in combination with at least one additional active pharmaceutical ingredient, such as, e.g., a CFTR modulating agent.
  • a CFTR modulating agent such as for example, compounds of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’
  • At least one additional active pharmaceutical ingredient is selected from mucolytic agents, bronchodilators, antibiotics, anti-infective agents, and anti-inflammatory agents.
  • the additional therapeutic agent is an antibiotic.
  • Exemplary antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levoflaxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin.
  • the additional agent is a mucolyte.
  • exemplary mucolytes useful herein includes Pulmozyme®.
  • the additional agent is a bronchodilator.
  • Exemplary bronchodilators include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabuline sulfate.
  • the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce the inflammation in the lungs.
  • Exemplary such agents useful herein include ibuprofen, docosahexanoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.
  • the additional agent is a nutritional agent.
  • Exemplary nutritional agents include pancrelipase (pancreating enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation.
  • the additional nutritional agent is pancrelipase.
  • at least one additional active pharmaceutical ingredient is selected from CFTR modulating agents.
  • the CFTR modulating agent is a CFTR corrector. In some embodiments, the CFTR modulating agent is a CFTR potentiator enhancer/co-potentiator (for example, ASP-11). In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR amplifier. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR readthrough agent. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy. [00207] In some embodiments, the at least one additional active pharmaceutical ingredient is a ENaC inhibitor. In some embodiments, the at least one additional active pharmaceutical ingredient is a TMEM16A modulator.
  • the at least one additional active pharmaceutical ingredient is a GPR39 agonist.
  • the at least one additional active pharmaceutical ingredient is chosen from (a) Compound II and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) Compound IV and deuterated derivatives and pharmaceutically acceptable salts thereof; (c) Compound V and deuterated derivatives and pharmaceutically acceptable salts thereof; (d) Compound VI and deuterated derivatives and pharmaceutically acceptable salts thereof; (e) Compound VII and deuterated derivatives and pharmaceutically acceptable salts thereof; and (f) Compound VIII and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • the combination therapies provided herein comprise a compound selected from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives of those compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; and at least one compound chosen from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • the combination therapies provided herein comprise (a) at least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives of those compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; (b) at least one compound chosen from Compound II, Compound IV, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one compound chosen from Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • the combination therapies provided herein comprise (a) at least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives of those compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; (b) at least one compound selected from Compound II and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one compound chosen from Compound VII and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • the combination therapies provided herein comprise (a) a compound selected from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives of those compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; (b) at least one compound chosen from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (c) at least one compound chosen from compounds disclosed in WO 2016/105485, United States Patent Application Publication No.
  • the combination therapies provided herein comprise (a) a compound selected from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives of those compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; (b) at least one compound chosen from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (c) at least one compound chosen from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-
  • the combination therapies provided herein comprise (a) a compound selected from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives of those compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; and (b) at least two compounds chosen from compounds disclosed in WO 2019/195739, WO 2019/200246, WO 2021/030555, WO 2021/030556, WO 2010/053471, WO 2011/119984, WO 2011/133751, WO 2011/133951, WO 2015/160787, WO 2007/056341, WO 2009/073757, WO 2009/076142,
  • the combination therapies provided herein comprise (a) a compound selected from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives of those compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives; and (b) at least two compounds chosen from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof are administered once daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof are administered twice daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from Compound IV and pharmaceutically acceptable salts thereof are administered once daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from Compound IV and pharmaceutically acceptable salts thereof are administered twice daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from Compound V and pharmaceutically acceptable salts thereof are administered once daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from Compound V and pharmaceutically acceptable salts thereof are administered twice daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from Compound VI and pharmaceutically acceptable salts thereof are administered once daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from Compound VI and pharmaceutically acceptable salts thereof are administered twice daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from Compound VII and pharmaceutically acceptable salts thereof are administered once daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from Compound VII and pharmaceutically acceptable salts thereof are administered twice daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from Compound VIII and pharmaceutically acceptable salts thereof are administered once daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from Compound VIII and pharmaceutically acceptable salts thereof are administered twice daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof; at least one compound chosen from Compound II, Compound IV, and pharmaceutically acceptable salts thereof; and at least one compound chosen from Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts thereof are administered once daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof; at least one compound chosen from Compound II, Compound IV, and pharmaceutically acceptable salts thereof; and at least one compound chosen from Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts thereof are administered twice daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof; at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof; and at least one compound chosen from Compound VII and pharmaceutically acceptable salts thereof are administered twice daily.
  • Compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and their deuterated derivatives and pharmaceutically acceptable salts thereof can be administered in a single pharmaceutical composition or separate pharmaceutical compositions. Such pharmaceutical compositions can be administered once daily or multiple times daily, such as twice daily.
  • a given amount of API e.g., Compound II, Compound VII, or pharmaceutically acceptable salts thereof
  • said given amount is administered per dosing, which may occur once or twice daily.
  • At least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a first pharmaceutical composition; at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; and at least one compound chosen from Compound VII and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.
  • any suitable pharmaceutical compositions known in the art can be used for compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • Some exemplary pharmaceutical compositions for Compound II and its pharmaceutically acceptable salts can be found in WO 2011/119984 and WO 2014/014841, incorporated herein by reference.
  • Some exemplary pharmaceutical compositions for Compound III and its pharmaceutically acceptable salts can be found in WO 2007/134279, WO 2010/019239, WO 2011/019413, WO 2012/027731, and WO 2013/130669, and some exemplary pharmaceutical compositions for Compound III-d and its pharmaceutically acceptable salts can be found in US 8,865,902, US 9,181,192, US 9,512,079, WO 2017/053455, and WO 2018/080591, all of which are incorporated herein by reference.
  • Some exemplary pharmaceutical compositions for Compound IV and its pharmaceutically acceptable salts can be found in WO 2010/037066, WO 2011/127421, and WO 2014/071122, incorporated herein by reference.
  • Some exemplary pharmaceutical compositions for Compound V and its pharmaceutically acceptable salts can be found in WO 2019/152940, incorporated herein by reference.
  • Some exemplary pharmaceutical compositions for Compound VI and its pharmaceutically acceptable salts can be found in WO 2019/079760, incorporated herein by reference.
  • compositions [00220] Another aspect of the invention provides a pharmaceutical composition comprising at least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.
  • the invention provides pharmaceutical compositions comprising at least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof in combination with at least one additional active pharmaceutical ingredient.
  • the at least one additional active pharmaceutical ingredient is a CFTR modulator.
  • the at least one additional active pharmaceutical ingredient is a CFTR corrector.
  • the at least one additional active pharmaceutical ingredient is a CFTR potentiator. In some embodiments, the at least one additional active pharmaceutical ingredient is a compound that enhances CFTR potentiation, i.e., a CFTR potentiator enhancer/co-potentiator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR amplifier. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR readthrough agent. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy. In some embodiments, the at least one additional active pharmaceutical ingredient is a ENaC inhibitor. In some embodiments, the at least one additional active pharmaceutical ingredient is a TMEM16A modulator.
  • the at least one additional active pharmaceutical ingredient is a GPR39 agonist.
  • the pharmaceutical composition comprises at least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least two additional active pharmaceutical ingredients, each of which is a CFTR corrector.
  • the pharmaceutical composition comprises at least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof and at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and one of which is a CFTR potentiator enhancer.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof, (b) at least one compound chosen from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof, (b) at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof, (b) at least one compound chosen from Compound VII and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof, (b) at least one compound chosen from Compound II, Compound IV, and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof, (b) at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from Compound VII and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.
  • the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) at least one compound chosen from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof; (c) at least one compound chosen from compounds disclosed in WO 2016/105485, United States Patent Application Publication No.
  • the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) at least one compound chosen from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof; (c) at least one compound chosen from PTI-428, ASP-11, ABBV- 2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-
  • the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) at least two compounds chosen from compounds disclosed in WO 2019/195739, WO 2019/200246, WO 2021/030555, WO 2021/030556, WO 2010/053471, WO 2011/119984, WO 2011/133751, WO 2011/133951, WO 2015/160787, WO 2007/056341, WO 2009/073757, WO 2009/076142, WO 2018/107100, WO 2019/113476, WO
  • the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds and solid forms of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) at least two compounds chosen from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22
  • any pharmaceutical composition disclosed herein may 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, lubricants.
  • the pharmaceutical compositions described herein are useful for treating cystic fibrosis and other CFTR-mediated diseases.
  • 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 human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as 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 lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt,
  • Non-limiting Exemplary Embodiments 1 A compound selected from compounds of Formula I: , and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein: X is selected from -N(R X1 )- and Ring A is a 4- to 6-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl and oxo; R X1 is selected from H, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, oxo, -OR X2 , and -N(R X2 ) 2 ), and C 3 -C 8 cycloalkyl; each R X2 is independently selected from H and C 1 -C 6 alkyl; each Y is independently selected from -C(R Y ) 2 -, -O-, -CO-, -NR YN -, and , wherein each R YN is independently selected from H, C 1 -C 4 alky
  • X is selected from -N(R X1 )- and ; Ring A is a 4- to 6-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl and oxo; R X1 is selected from H, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, oxo, -OR X2 , and -N(R X2 ) 2 ), and C 3 -C 8 cycloalkyl; each R X2 is independently selected from H and C 1 -C 6 alkyl; each Y is independently selected from -C(R Y ) 2 -, -O-, -CO-, -NR YN -, and , wherein each R YN is independently selected from H, C 1 -C 4 alkyl, and CO 2 Me; each R Y is independently
  • each R Y is independently selected from: hydrogen, hydroxy, methyl, wherein two R Y on the same atom are taken together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, and tetrahydropyranyl; or wherein two R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond.
  • each Q is independently selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl. 10.
  • each Ring B is independently selected from C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy) and 5- to 10-membered heteroaryl. 12.
  • each Y is -C(R Y ) 2 -.
  • each Y is independently selected from -CH 2 - and -C(Me) 2 -.
  • each R 1 is independently selected from C 1 -C 6 fluoroalkyl and - N(R 2 ) 2 . 18.
  • each R 1 is independently selected from Br, -CH 3 , -CF 3 , -CHF 2 , -OH, -OCH 3 , -CN, -NH 2 , 19.
  • R Z1 is selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 hydroxy), C 1 -C 6 fluoroalkyl, 3- to 6-membered heterocyclyl, C 3 -C 6 cycloalkyl, and C 6 -C 10 aryl
  • the compound, deuterated derivative, or salt according to any one of Embodiments 1-21, wherein is selected from: 29.
  • each R Y is independently selected from: hydrogen, hydroxy, methyl, wherein two R Y on the same atom are taken together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, and tetrahydropyranyl; or wherein two R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond.
  • each Q is independently selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.
  • each Q is phenyl.
  • each Ring B is independently selected from C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy) and 5- to 10-membered heteroaryl.
  • each Y is -C(R Y ) 2 -.
  • each Y is independently selected from -CH 2 - and -C(Me) 2 -.
  • each R 1 is independently selected from C 1 -C 6 fluoroalkyl and - N(R 2 ) 2 . 50.
  • each R 1 is independently selected from Br, -CH 3 , -CF 3 , -CHF 2 , - 51.
  • R Z1 is selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 hydroxy), C 1 -C 6 fluoroalkyl, 3- to 6-membered heterocyclyl, C 3 -C 6 cycloalkyl, and C 6 -C 10 aryl
  • R Z1 is selected from C 1 -C 6 fluoroalkyl.
  • each R Y is independently selected from: hydrogen, hydroxy, methyl, wherein two R Y on the same atom are taken together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, and tetrahydropyranyl; or wherein two R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond. 74.
  • each Q is independently selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.
  • each Q is phenyl.
  • each Ring B is independently selected from C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy) and 5- to 10-membered heteroaryl.
  • each Y is-C(R Y ) 2 -. 87.
  • each R 1 is independently selected from Br, -CH 3 , -CF 3 , -CHF2, - OH, -OCH 3 , -CN, -NH 2 , 90.
  • Z is selected from: 92.
  • R Z1 is selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 hydroxy), C 1 -C 6 fluoroalkyl, 3- to 6-membered heterocyclyl, C 3 -C 6 cycloalkyl, and C 6 -C 10 aryl
  • the compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1, wherein X is selected from: -NH-, -N(CH 3 )-, -N(CH 2 CH 3 )-, 103.
  • each R Y is independently selected from hydrogen, hydroxy, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C 1 -C 6 alkoxy, and Q), C 3 -C 8 cycloalkyl, C 6 -C 10 aryl (optionally substituted with 1- 3 groups independently selected from halogen), 5- to 10-membered heteroaryl, - CO 2 R Y1 , and -CON(R Y1 ) 2 ; or two R Y on the same atom are taken together to form a ring selected from C 3 - C 8 cycloalkyl and 3- to 7-membered heterocyclyl; or two R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond.
  • each R Y is independently selected from: hydrogen, hydroxy, -CH 3 , -CD 3 , -CH 2 CH 3 , , , , , or two R Y on the same atom are taken together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyryl, and tetrahydrofuryl; or two R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond.
  • each R 1 is independently selected from halogen, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkyl (optionally substituted with a group selected from C 6 -C 10 aryl), -OR 2 , -N(R 2 ) 2 , -CO 2 R 2 , -CO- N(R 2 ) 2 , -CN, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 6-membered heteroaryl (optionally substituted with 1-3 groups independently selected from C 1 - C 6 alkyl), 3- to 6-membered heterocyclyl, -B(OR 2 ) 2 , -SO 2 R 2 , -SR 2 , -SOR 2 , and - PO(R 2 ) 2 .
  • each R 2 is independently selected from C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 fluoroalkoxy).
  • each R 2 is independently selected from C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 fluoroalkoxy).
  • each R 1 is independently selected from -Br, -CF 3 , -NH 2 , -CH 3 , -CH(CH 3 ) 2 , -CN, -OH, - OCH 3 , -NH(CH 3 ), -NH(CH 2 CH 3 ), -CONH 2 , - CO 2 CH 3 , -SO 2 CH 3 , -SO 2 Ph, PO(CH 3 ) 2 , B(OH) 2 , phenyl, pyridyl, tetrahydropyranyl, tetrahydrofuranyl, cyclopropyl, cyclohexyl, imidazolyl, , , and .
  • R Z2 is selected from hydrogen, halogen, hydroxy, and C 1 -C 6 alkoxy (optionally substituted with 1-3 groups independently selected from C 3 -C 10 cycloalkyl).
  • R Z1 is selected from hydrogen, CH 3 , CF 3 , CH 2 OH, phenyl, cyclopropyl, and tetrahydropyranyl
  • R Z2 is selected from hydrogen, halogen, and hydroxy
  • R Z1 and R Z2 taken together form a group selected from oxo and N-OH.
  • R Z2 is hydroxy.
  • X is selected from -N(R X1 )- and ;
  • Ring A is a 4- to 6-membered heterocyclyl;
  • R X1 is selected from H and C 1 -C 6 alkyl;
  • each Y is independently selected from -C(R Y ) 2 - and each R Y is independently selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen); or two R Y on the same atom are taken together to form a ring selected from C 3 - C 8 cycloalkyl and 3- to 7-membered heterocyclyl; or two R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;
  • Ring B is C 6 -C
  • each R Y is independently selected from: hydrogen, -CH 3 , -CD 3 , or two R Y on the same atom are taken together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyryl; or two R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond. 128.
  • a pharmaceutical composition comprising a compound, salt, or deuterated derivative of any one of Embodiments 1-135 and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition according to Embodiment 136 further comprising one or more additional therapeutic agent(s).
  • the one or more additional therapeutic agent(s) comprise(s) a compound with CFTR modulating activity or a salt or deuterated derivative thereof.
  • the pharmaceutical composition according to Embodiment 137 or 138, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR corrector.
  • composition according to any one of Embodiments 137-139, wherein the one or more additional therapeutic agent(s) comprise(s) (R)-1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1- hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II): . 141.
  • composition according to any one of Embodiments 137-140, wherein the one or more additional therapeutic agent(s) comprise(s) 3-(6-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2- yl)benzoic acid (Compound IV): Compound IV. 142.
  • composition according to any one of Embodiments 137-141, wherein the one or more additional therapeutic agent(s) comprise(s) N-(1,3- dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol- 1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound V): . 143.
  • composition according to any one of Embodiments 137-142, wherein the one or more additional therapeutic agent(s) comprise(s) N- (benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]- 2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound VI): CompoundVI. 144.
  • composition according to any one of Embodiments 137-143, wherein the one or more additional therapeutic agent(s) comprise(s) (14S)-8-[3-(2- ⁇ dispiro[2.0.2.1]heptan-7-yl ⁇ ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2 ⁇ 6 -thia- 3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracosa- 1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound VII): 145.
  • composition according to any one of Embodiments 137-144, wherein the one or more additional therapeutic agent(s) comprise(s) (11R)-6-(2,6- dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15- hexaene-2,2,13-trione (Compound VIII): Compound VIII. 146.
  • composition according to any one of Embodiments 137-149, wherein the one or more additional therapeutic agent(s) comprise(s) a compound selected from N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3- carboxamide (Compound III): and N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3- d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound III-d): Compound III-d. 151.
  • the one or more additional therapeutic agent(s) comprise(s) a CFTR amplifier.
  • the pharmaceutical composition according to any one of Embodiments 137-152, wherein the one or more additional therapeutic agent(s) comprise(s) PTI-428. 154.
  • the one or more additional therapeutic agent(s) comprise(s) amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5 Rx, BI 1265162, AZ5634, and ARO- ENaC1001. 160.
  • a method of treating cystic fibrosis comprising administering an effective amount of the compound, salt, or deuterated derivative according to any one of Embodiments 1-135 or the pharmaceutical composition according to any one of Embodiments 136-163 to a patient in need thereof.
  • the method according to Embodiment 164 further comprising administering one or more additional therapeutic agent(s).
  • the one or more additional therapeutic agent(s) comprise(s) a compound with CFTR modulating activity or a salt or deuterated derivative thereof.
  • the one or more additional therapeutic agent(s) comprise(s) a CFTR corrector.
  • the one or more additional therapeutic agent(s) comprise(s) (R)-1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1- hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II): Compound II. 169.
  • the one or more additional therapeutic agent(s) comprise(s) N-(1,3-dimethylpyrazol-4- yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4- trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound V): 171.
  • the one or more additional therapeutic agent(s) comprise(s) N-(benzenesulfonyl)-6-[3-[2-[1- (trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4- trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound VI): 172.
  • the one or more additional therapeutic agent(s) comprise(s) (11R)-6-(2,6-dimethylphenyl)-11- (2-methylpropyl)-12- ⁇ spiro[2.3]hexan-5-yl ⁇ -9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13- trione (Compound VIII): Compound VIII. 174.
  • the one or more additional therapeutic agent(s) comprise(s) a CFTR potentiator enhancer. 176.
  • the one or more additional therapeutic agent(s) comprise(s) a compound selected from N-(5- hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound III): Compound III, and N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3- d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound III-d): Compound III-d. 179.
  • the one or more additional therapeutic agent(s) comprise(s) at least one compound selected from FDL-176, PTI-808, GLPG1837, GLPG2451/ABBV-2451 (Icenticaftor), GLPG3067/ABBV-3067 (Navocaftor), and ABBV-191.
  • the one or more additional therapeutic agent(s) comprise(s) a CFTR amplifier.
  • the one or more additional therapeutic agent(s) comprise(s) PTI-428. 182.
  • the one or more additional therapeutic agent(s) comprise(s) amiloride, ETD001, CF552, GS- 9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis- ENaC-2.5 Rx, BI 1265162, AZ5634, and ARO-ENaC1001.
  • the one or more additional therapeutic agent(s) comprise(s) amiloride, ETD001, CF552, GS- 9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis- ENaC-2.5 Rx, BI 1265162, AZ5634, and ARO-ENaC1001.
  • the method according to any one of Embodiments 165-180, wherein the one or more additional therapeutic agent(s) comprise(s) a GPR39 Agonist. 191.
  • Substantially amorphous Compound 4 (neat form) (i.e., wherein less than 15% of Compound 4 is in crystalline form, wherein less than 10% of Compound 4 is in crystalline form, wherein less than 5% of Compound 4 is in crystalline form). 195.
  • Substantially crystalline Compound 5 Form A (neat) i.e., wherein less than 15% of Compound 5 is in amorphous form, wherein less than 10% of Compound 5 is in amorphous form, wherein less than 5% of Compound 5 is in amorphous form).
  • the substantially crystalline Compound 5 Form A (neat) according to Embodiment 197 or 198, characterized by a tetragonal crystal system, an I4 1 space group, and unit cell dimensions measured at 100 K on a Bruker diffractometer utilizing Cu K ⁇ radiation ( ⁇ 1.54178 ⁇ ) of: a 18.1 ⁇ .1 ⁇ ⁇ 90 o b 18.1 ⁇ .1 ⁇ ⁇ 90 o c 13.1 ⁇ .1 ⁇ ⁇ 90 o. 200.
  • Substantially amorphous Compound 19 (neat form) (i.e., wherein less than 15% of Compound 19 is in crystalline form, wherein less than 10% of Compound 19 is in crystalline form, wherein less than 5% of Compound 19 is in crystalline form).
  • 201. The substantially amorphous Compound 19 (neat form) according to Embodiment 200, wherein Compound 19 is 100% amorphous.
  • 202. The substantially amorphous Compound 19 (neat form) according to Embodiment 200 or 201, characterized by an X-ray powder diffractogram substantially similar to FIG. 4. 203.
  • Substantially crystalline Compound 41 Form A (i.e., wherein less than 15% of Compound 41 is in amorphous form, wherein less than 10% of Compound 41 is in amorphous form, wherein less than 5% of Compound 41 is in amorphous form).
  • 204. The substantially crystalline Compound 41 Form A according to Embodiment 203, wherein Compound 41 Form A is 100% crystalline.
  • 205. The substantially crystalline Compound 41 Form A according to Embodiment 203 or 204, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 14.2 ⁇ 0.2 degrees two-theta, 19.5 ⁇ 0.2 degrees two-theta, and 21.2 ⁇ 0.2 degrees two-theta.
  • the substantially crystalline Compound 41 Form A according to any one of Embodiments 203-205, characterized by an X-ray powder diffractogram having one, two, three, four, five, or six signals selected from 14.2 ⁇ 0.2 degrees two- theta, 19.5 ⁇ 0.2 degrees two-theta, 21.2 ⁇ 0.2 degrees two-theta, 18.0 ⁇ 0.2 degrees two-theta, 16.6 ⁇ 0.2 degrees two-theta, and 20.7 ⁇ 0.2 degrees two-theta. 207.
  • the substantially crystalline Compound 41 Form A according to any one of Embodiments 203-206, characterized by an X-ray powder diffractogram having one, two, three, four, five, six, seven, eight, or nine signals selected from 14.2 ⁇ 0.2 degrees two-theta, 16.6 ⁇ 0.2 degrees two-theta, 18.0 ⁇ 0.2 degrees two-theta, 19.5 ⁇ 0.2 degrees two-theta, 20.3 ⁇ 0.2 degrees two-theta, 20.7 ⁇ 0.2 degrees two-theta, 21.2 ⁇ 0.2 degrees two-theta, 22.2 ⁇ 0.2 degrees two-theta, and 25.1 ⁇ 0.2 degrees two-theta. 208.
  • the substantially crystalline Compound 41 Form A according to any one of Embodiments 203-207, characterized by an X-ray powder diffractogram substantially similar to FIG. 7. 209.
  • Substantially crystalline Compound 52 Form A (neat) (i.e., wherein less than 15% of Compound 52 is in amorphous form, wherein less than 10% of Compound 52 is in amorphous form, wherein less than 5% of Compound 52 is in amorphous form).
  • the substantially crystalline Compound 52 Form A (neat) according to any one of Embodiments 209-211, characterized by an X-ray powder diffractogram having one, two, three, four, five, or six signals selected from 6.8 ⁇ 0.2 degrees two-theta, 12.7 ⁇ 0.2 degrees two-theta, 17.3 ⁇ 0.2 degrees two-theta, 18.6 ⁇ 0.2 degrees two- theta, 20.6 ⁇ 0.2 degrees two-theta, and 21.4 ⁇ 0.2 degrees two-theta. 213.
  • the substantially crystalline Compound 52 Form A (neat) according to any one of Embodiments 209-212, characterized by an X-ray powder diffractogram having one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve signals selected from 6.8 ⁇ 0.2 degrees two-theta, 12.7 ⁇ 0.2 degrees two-theta, 15.1 ⁇ 0.2 degrees two-theta, 15.5 ⁇ 0.2 degrees two-theta, 17.3 ⁇ 0.2 degrees two-theta, 18.6 ⁇ 0.2 degrees two-theta, 19.2 ⁇ 0.2 degrees two-theta, 19.7 ⁇ 0.2 degrees two-theta, 20.4 ⁇ 0.2 degrees two-theta, 20.6 ⁇ 0.2 degrees two-theta, 21.4 ⁇ 0.2 degrees two- theta, and 27.2 ⁇ 0.2 degrees two-theta.
  • Substantially amorphous Compound 70 (neat form) i.e., wherein less than 15% of Compound 70 is in crystalline form, wherein less than 10% of Compound 70 is in crystalline form, wherein less than 5% of Compound 70 is in crystalline form). 219.
  • Substantially crystalline Compound 163 Form A (neat) i.e., wherein less than 15% of Compound 163 is in amorphous form, wherein less than 10% of Compound 163 is in amorphous form, wherein less than 5% of Compound 163 is in amorphous form).
  • the substantially crystalline Compound 163 Form A (neat) according to any one of Embodiments 221-224, characterized by an X-ray powder diffractogram having one, two, three, four, five, or six signals selected from 7.4 ⁇ 0.2 degrees two-theta, 8.4 ⁇ 0.2 degrees two-theta, 14.1 ⁇ 0.2 degrees two-theta, 15.0 ⁇ 0.2 degrees two- theta, 19.1 ⁇ 0.2 degrees two-theta, and 25.8 ⁇ 0.2 degrees two-theta. 226.
  • the substantially crystalline Compound 163 Form A (neat) according to any one of Embodiments 221-225, characterized by an X-ray powder diffractogram having one, two, three, four, five, six, seven, eight, nine, ten, or eleven signals selected from 7.4 ⁇ 0.2 degrees two-theta, 8.4 ⁇ 0.2 degrees two-theta, 14.1 ⁇ 0.2 degrees two-theta, 14.6 ⁇ 0.2 degrees two-theta, 15.0 ⁇ 0.2 degrees two-theta, 16.9 ⁇ 0.2 degrees two-theta, 19.1 ⁇ 0.2 degrees two-theta, 20.0 ⁇ 0.2 degrees two-theta, 22.5 ⁇ 0.2 degrees two-theta, 25.6 ⁇ 0.2 degrees two-theta, and 25.8 ⁇ 0.2 degrees two- theta.
  • the substantially crystalline Compound 163 Form A (neat) according to any one of Embodiments 221-226, characterized by an X-ray powder diffractogram substantially similar to FIG. 16. 228.
  • Substantially amorphous Compound 173 (neat form) i.e., wherein less than 15% of Compound 173 is in crystalline form, wherein less than 10% of Compound 173 is in crystalline form, wherein less than 5% of Compound 173 is in crystalline form). 229.
  • the substantially amorphous Compound 173 (neat form) according to Embodiment 228 or 229, characterized by an X-ray powder diffractogram substantially similar to FIG. 18. 231.
  • Substantially crystalline Compound 173 (neat form) i.e., wherein less than 15% of Compound 173 is in amorphous form, wherein less than 10% of Compound 173 is in amorphous form, wherein less than 5% of Compound 173 is in amorphous form).
  • Substantially crystalline Compound 175 Form A (neat) (i.e., wherein less than 15% of Compound 175 is in amorphous form, wherein less than 10% of Compound 175 is in amorphous form, wherein less than 5% of Compound 175 is in amorphous form).
  • Substantially crystalline Compound 188 dichloromethane solvate Form A i.e., wherein less than 15% of Compound 188 dichloromethane solvate is in amorphous form, wherein less than 10% of Compound 188 dichloromethane solvate is in amorphous form, wherein less than 5% of Compound 188 dichloromethane solvate is in amorphous form.
  • Mobile phase A water (+ 0.05 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (+ 0.035 % trifluoroacetic acid).
  • LC Method B Analytical reverse phase HPLC-MS using a Kinetex C 18 column (4.6 X 50 mm, 2.6 mm particle size). Temp: 45 °C; Flow: 2.0 mL/min; Run Time: 3 min.
  • LC Method D Analytical reverse phase UPLC-MS using an Acquity UPLC- MS BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle size) made by Waters (pn: 186002350), and a dual gradient run from 1 % to 99 % mobile phase B over 5.0 minutes.
  • Mobile phase A water (+ 0.05 % trifluoroacetic acid).
  • LC Method G Analytical reverse phase HPLC-MS using a Merckmillipore Chromolith SpeedROD C 18 column (50 x 4.6 mm) and a dual gradient run from 5 % to 100 % mobile phase B over 6 minutes.
  • Mobile phase A water (+ 0.1 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (+ 0.1 % trifluoroacetic acid).
  • LC Method H Analytical reverse phase HPLC-MS using a Waters Cortex C 18 column (3.0 X 50 mm, 2.7 mm particle size) made by Waters (pn: 186007370), Temp: 55 °C; Flow: 1.2 mL/min; Mobile phase A: Water (+ 0.1 % trifluoroacetic acid).
  • Mobile phase B Acetonitrile (+ 0.1 % trifluoroacetic acid). Gradient: 5 % to 100 % B over 4 min, with equilibration at 100 % B for 0.5 min, equilibration to 5 % B over 1.5 min.
  • LC Method I Analytical reverse phase UPLC-MS using an Acquity UPLC-MS BEH C 18 column (30 X 2.1 mm, 1.7 ⁇ m particle size) made by Waters (pn: 186002349), and a dual gradient run from 1 % to 99 % mobile phase B over 1.2 minutes.
  • Mobile phase A water (+ 0.05 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (+ 0.035 % trifluoroacetic acid).
  • LC Method J Analytical reverse phase UPLC-MS using an Acquity UPLC- MS BEH C 18 column (50 X 2.1 mm, 1.7 ⁇ m particle size) made by Waters (pn: 186002350), and a dual gradient run from 30 % to 99 % mobile phase B over 3.0 minutes.
  • Mobile phase A water (+ 0.05 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (+ 0.035 % trifluoroacetic acid).
  • LC Method K Analytical reverse phase HPLC-MS using a Kinetex EVO C 18 column (4.6 X 50 mm, 2.6 mm particle size), Temp: 45 °C; Flow: 2.0 mL/min; Run time: 4 min.
  • Mobile phase Initial 95 % water (+ 0.1 % formic acid) and 5 % acetonitrile (+ 0.1 % formic acid) linear gradient to 95 % acetonitrile (+ 0.1 % formic acid) for 2.0 min then hold at 95 % acetonitrile (+ 0.1 % formic acid) for 2.0 min.
  • LCMS Method L Analytical reverse phase HPLC-MS using an X-Terra MS C 18 column (4.6 X 150 mm, 5 ⁇ m particle size), Temperature: 40 °C; Flow: 1.5 mL/min; Run Time: 10 min.
  • Mobile phase Initial 95 % water (+ 10 mM ammonium bicarbonate) and 5 % acetonitrile linear gradient to 95 % acetonitrile for 6.5 min then hold at 95 % acetonitrile for 3.5 min.
  • LC Method M Analytical reverse phase UPLC-MS using an Acquity UPLC- MS BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle size) made by Waters (pn: 186002350), and a dual gradient run from 50 % to 99 % mobile phase B over 3.0 minutes.
  • Mobile phase A water (+ 0.05 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (+ 0.035 % trifluoroacetic acid).
  • LC Method N Analytical reverse phase UPLC-MS using an Acquity UPLC- MS BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle size) made by Waters (pn: 186002350), and a dual gradient run from 1 % to 99 % mobile phase B over 3.0 minutes.
  • Mobile phase A water (0.05 % ammonium formate).
  • Mobile phase B acetonitrile.
  • LC Method O Analytical reverse phase HPLC-MS using a Kinetex Polar C 18 column (3.0 X 50 mm, 2.6 mm particle size), Temp: 45 °C; Flow: 1.2 mL/min; Run time: 4 min.
  • Mobile phase Initial 95 % water (+ 0.1 % formic acid) and 5 % acetonitrile (+ 0.1 % formic acid) linear gradient to 95 % acetonitrile (+ 0.1 % formic acid) for 3.0 min then hold at 95 % acetonitrile (+ 0.1 % formic acid) for 1.0 min.
  • LC Method P Analytical reverse phase UPLC-MS using an Acquity UPLC- MS BEH C 18 column (100 X 2.1 mm, 1.7 ⁇ m particle size) made by Waters (pn: 186002352), and a dual gradient run from 1 % to 99 % mobile phase B over 13.5 minutes.
  • Mobile phase A water (+ 0.05 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (+ 0.035 % trifluoroacetic acid).
  • LC Method Q Analytical reverse phase HPLC-MS using an Onyx Monolithic C 18 column (50 X 4.6 mm) sold by Phenomenex (pn: CH0-7644), and a dual gradient run from 1 % to 99 % mobile phase B over 2.9 minutes.
  • Mobile phase A water (+ 0.05 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (+ 0.035 % trifluoroacetic acid).
  • LC Method R Analytical reverse phase UPLC-MS using an Acquity UPLC- MS BEH C 18 column (30 ⁇ 2.1 mm, 1.7 ⁇ m particle size) made by Waters (pn: 186002349), and a dual gradient run from 30 % to 99 % mobile phase B over 1.0 minutes.
  • Mobile phase A water (+ 0.05 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (+ 0.035 % trifluoroacetic acid).
  • LC Method S Analytical reverse phase UPLC-MS using an Acquity UPLC- MS BEH C 18 column (30 ⁇ 2.1 mm, 1.7 ⁇ m particle size) made by Waters (pn: 186002349), and a dual gradient run from 1 % to 99 % mobile phase B over 1.0 minutes.
  • Mobile phase A water (+ 0.05 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (+ 0.035 % trifluoroacetic acid).
  • LC Method T Analytical reverse phase UPLC-MS using an Acquity UPLC- MS BEH C 18 column (30 X 2.1 mm, 1.7 ⁇ m particle size) made by Waters (pn: 186002349), and a dual gradient run from 50 % to 99 % mobile phase B over 1.0 minutes.
  • Mobile phase A water (+ 0.05 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (+ 0.035 % trifluoroacetic acid).
  • LC Method U Analytical reverse phase UPLC-MS using an Acquity UPLC- MS BEH C 18 column (30 ⁇ 2.1 mm, 1.7 ⁇ m particle size) made by Waters (pn: 186002349), and a dual gradient run from 75 % to 99 % mobile phase B over 1.0 minutes.
  • Mobile phase A water (+ 0.05 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (+ 0.035 % trifluoroacetic acid).
  • LC Method V Analytical reverse phase HPLC-MS using a Kinetex EVO C 18 column (2.1 X 50 mm 2.6 mm particle size), Temp: 45 °C; Flow: 1.0 mL/min; Run time: 1.5 min.
  • Mobile phase Initial 98 % of mobile phase A (10mM ammonium formate in water: acetonitrile, 95:5, pH 9) and 2 % mobile phase B (acetonitrile) linear gradient to 98 % acetonitrile for 1.15 min then hold at 98 % acetonitrile for 0.2 min then return to 98 % water and 10mM ammonium formate for 0.05 min and hold for 0.1 min.
  • LC Method W Analytical reverse phase HPLC-MS using a Kinetex Polar C 18 column (3.0 X 50 mm, 2.6 mm particle size), Temp: 45 °C; Flow: 1.2 mL/min; Run time: 4 min.
  • Mobile phase Initial 95 % water (+ 0.1 % formic acid) and 5 % acetonitrile (+ 0.1 % formic acid) linear gradient to 95 % acetonitrile (+ 0.1 % formic acid) for 3.0 min then hold at 95 % acetonitrile (+ 0.1 % formic acid) for 1.0 min.
  • LC Method X Analytical reverse phase HPLC-MS using a Kinetex Polar C 18 column (3.0 X 50 mm, 2.6 mm particle size), Temp: 45 °C; Flow: 1.2 mL/min; Run time: 5 min.
  • Mobile phase Initial 95 % water (+ 0.1 % formic acid) and 5 % acetonitrile (+ 0.1 % formic acid) linear gradient to 95 % acetonitrile (+ 0.1 % formic acid) for 4.0 min then hold at 95 % acetonitrile (+ 0.1 % formic acid) for 1.0 min.
  • LC Method Y Analytical reverse phase HPLC-MS using a Luna C 18 column (3.0 X 50 mm, 3 mm particle size), Temp: 45 °C; Flow: 1.5 mL/min; Run time: 3.5 min.
  • Mobile phase Initial 95 % water (+ 0.1 % formic acid) and 5 % acetonitrile (+ 0.1 % formic acid) linear gradient to 95 % acetonitrile (+ 0.1 % formic acid) for 1.3 min then hold at 95 % acetonitrile (+ 0.1 % formic acid) for 2.2 min.
  • LC Method Z Analytical reverse phase HPLC-MS using a Luna C 18 column (3.0 X 50 mm, 3 mm particle size), Temp: 45 °C; Flow: 1.5 mL/min; Run time: 2.5 min.
  • Mobile phase Initial 95 % water (+ 0.1 % formic acid) and 5 % acetonitrile (+ 0.1 % formic acid) linear gradient to 95 % acetonitrile (+ 0.1 % formic acid) for 1.3 min then hold at 95 % acetonitrile (+ 0.1 % formic acid) for 1.2 min.
  • LC Method AA Analytical reverse phase HPLC-MS using a SunFire C 18 column (4.6 X 75 mm, 3.5 mm particle size), Temp: 45 °C; Flow: 1.5 mL/min; Run time: 6 min.
  • Mobile phase Initial 95 % water (+ 0.1 % formic acid) and 5 % acetonitrile (+ 0.1 % formic acid) linear gradient to 95 % acetonitrile (+ 0.1 % formic acid) for 4.0 min then hold at 95 % acetonitrile (+ 0.1 % formic acid) for 2.0 min.
  • LC Method BB Analytical reverse phase HPLC-MS using an XBridge C 18 column (4.6 X 75 mm, 5 mm particle size); Flow: 1.5 mL/min; Run time: 6 min.
  • Mobile phase Initial 95 % water (+ 10 mM ammonium bicarbonate) and 5 % acetonitrile to 5 % water (+ 10 mM ammonium bicarbonate) and 95 % acetonitrile for 3 min then hold at 95 % acetonitrile and 5 % water (+ 10 mM ammonium bicarbonate) for 3 min.
  • LC Method CC Analytical GC using a Phenomenex ZB-1MS column (0.25 X 30 mm, 0.25 mm particle size); start temp 50 °C, ramp 20 °C/min to 300 °C and hold for 5 min.
  • LC Method DD Analytical reverse phase HPLC-MS using a Merckmillipore Chromolith SpeedROD C 18 column (50 X 4.6 mm) and a dual gradient run from 5 % to 100 % mobile phase B over 12 minutes.
  • Mobile phase A water (+ 0.1 % trifluoroacetic acid).
  • Mobile phase B acetonitrile (+ 0.1 % trifluoroacetic acid).
  • LC Method EE Analytical reverse phase HPLC-MS using a Kinetex EVO C 18 column (4.6 X 50 mm, 2.6 mm particle size), Temp: 45 °C, Flow: 2.0 ml/min, Run Time: 3 minutes.
  • Mobile Phase Conditions Initial 95 % water (+ 0.1 % formic acid) and 5 % acetonitrile (+ 0.1 % formic acid) linear gradient to 95 % acetonitrile (+ 0.1 % formic acid) for 2.0 min then hold at 95 % acetonitrile (+ 0.1 % formic acid) for 1.0 min.
  • XRPD General X-Ray Powder Diffraction
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction (XRPD) pattern was recorded at room temperature in continuous mode using a PANalytical Empyrean X-ray Diffract meter (Almelo, The Netherlands). The X-ray was generated using Cu tube operated at 45kV and 40 mA. Pixel 1d detector was used with anti-scatter slit P8.
  • the Divergence optics was Bragg Brentano High Definition (BBHD) with a 10 mm mask, 1/8 divergence slit, and 1 ⁇ 2 anti-scatter slit.
  • BBHD Bragg Brentano High Definition
  • the continuous scan mode utilized a 0.0131 degree step size and count time of 13.77 seconds per step, integrated over the range from 4 to 40 degrees two-theta.
  • the powder sample was placed on an indented area within a zero background holder and flattened with a glass slide.
  • TGA Thermogravimetric Analysis
  • Another aspect of the disclosure provides methods for making compounds of Formulae I, I’, I’’, Ia, Ia’, IIa, IIa’, IIb, IIb’, IIc, IIc’, IId, IId’, IIe, IIe’, IIf, IIf’, IIg, IIg’, IIh, IIh’, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of those compounds and deuterated derivatives, and intermediates for making any of the foregoing.
  • each nitrogen and oxygen atom may optionally have, in addition to or in place of a specified variable substituent, one or more protecting groups selected from the range of protecting groups disclosed herein.
  • each compound may be replaced with its deuterated derivative.
  • Scheme 1 refers to processes for preparing an intermediate compound of Formula 1-7 from a compound of Formula 1-1.
  • Alk is selected from C 1 -C 6 linear or branched alkyl groups.
  • X 1 is selected from halogens, such as Cl, I, or Br.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • a is an integer selected from 2, 3, 4, and 5.
  • Y is as defined for Formula I above.
  • Any suitable conditions for a Grignard-type addition can be used to react a compound of Formula 1-1 with a compound of Formula 1-2 to form a compound of Formula 1-3.
  • the Grignard addition of a compound of Formula 1-1 with a compound of Formula 1-2 may be performed in Et 2 O at -78 oC, followed by addition of 1 N aqueous HCl to yield a compound of Formula 1-3.
  • Conversion of a compound of Formula 1-3 to a compound of Formula 1-4 may be accomplished by any suitable procedure to install an oxygen protecting group.
  • Conversion of an ester of Formula 1-4 to a carboxylic acid of Formula 1-5 may be accomplished by any suitable hydrolysis conditions.
  • conversion of a carboxylic acid of Formula 1-5 to a compound of Formula 1-6 may be accomplished by reacting a compound of Formula 1-5 with HATU and Et 3 N in DMF, followed by addition of tert-butyl N-aminocarbamate.
  • Any suitable hydrolysis conditions may be used to convert a carbamate of Formula 1-6 to a hydrazide of Formula 1-7.
  • a compound of Formula 1-7 may be obtained by reacting a compound of Formula 1-6 with HCl in CH 2 Cl 2 at ambient temperature.
  • Scheme 2 refers to processes for preparing an intermediate compound of Formula 2-3 from a compound of Formula 2-1.
  • LG is selected from halogen and oxygen- based leaving groups such as OTf and OTs.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • a is an integer selected from 2, 3, 4, and 5.
  • R 1 , m, and Y are as defined for Formula I above.
  • Any suitable conditions to form an amide bond can be used to produce a compound of Formula 2-3 from a compound of Formula 2-1 and a compound of Formula 1-7.
  • a compound of Formula 2-1 can be reacted with CDI in acetonitrile and DMF, followed by addition of a compound of Formula 1-7, to yield a compound of Formula S2-2.
  • a compound of Formula 2-2 can be converted to a compound of Formula 2-3 using any conditions suitable for oxadiazole formation.
  • a compound of Formula 2-2 can be reacted with DIPEA in acetonitrile, followed by addition of p- toluenesulfonyl chloride, to yield an oxadiazole of Formula 2-3.
  • Scheme 3 refers to processes for preparing a compound of Formula 3-8 from a compound of Formula 3-1.
  • Alk is selected from C 1 -C 6 linear or branched alkyl groups.
  • LG is selected from halogen and oxygen-based leaving groups such as OTf and OTs.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • a is an integer selected from 1, 2, 3, and 4
  • b is an integer selected from 0, 1, 2, 3, and 4 provided that a + b is not greater than 5.
  • Ring A, R 1 , m, and Y are as defined for Formula I above.
  • reaction of a compound of Formula 3-1 with a compound of Formula 3-2 to yield a compound of Formula 3-3 may be accomplished by any suitable aromatic substitution conditions. Conversion of an ester of Formula 3-3 to a carboxylic acid of Formula 3-4 may be accomplished by any suitable hydrolysis conditions.
  • a compound of Formula 3-5 may be prepared from a compound of Formula 3-4 and a compound of Formula 1-7 using any suitable amide bond formation conditions. A compound of Formula 3-5 can be converted to a compound of Formula 3-6 using any conditions suitable for oxadiazole formation.
  • a compound of Formula 3-5 can be reacted with DIPEA in acetonitrile, followed by addition of p-toluenesulfonyl chloride, to yield an oxadiazole of Formula 3-6.
  • Macrocyclization of a compound of Formula 3-6 may be accomplished by any suitable ring-closing metathesis conditions.
  • a compound of Formula 3-6 may be reacted in the presence of Grubbs 2 nd generation catalyst in DCE to yield a macrocycle of Formula 3-7 as a mixture of E/Z isomers (as denoted by the bond).
  • Scheme 4 refers to processes for preparing a compound of Formula 4-3 from a compound of Formula 2-3.
  • LG is selected from halogen and oxygen-based leaving groups such as OTf and OTs.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • Ring A, R 1 , m, and Y are as defined for Formula I above.
  • the reaction of a compound of Formula 2-3 with a compound of Formula 3-2 to yield a compound of Formula 4-1 may be accomplished by any suitable aromatic substitution conditions. Macrocyclization of a compound of Formula 4-1 to produce a compound of Formula 4-2 may be accomplished by any suitable ring-closing metathesis conditions. For example, a compound of Formula 4-1 may be reacted in the presence of Zhan catalyst-1B in DCE to yield a macrocycle of Formula 4-2 as a mixture of E/Z isomers (as denoted by the bond). Conversion of an unsaturated compound of Formula 4-2 to a macrocycle of Formula 4-3 can be accomplished using any suitable procedure for olefin reduction and alcohol deprotection.
  • Scheme 5 refers to processes for preparing a compound of Formula 5-5 from a compound of Formula 2-3.
  • LG is selected from halogen and oxygen-based leaving groups such as OTf and OTs.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • PG 2 is selected from suitable nitrogen protecting groups, such as Boc and Fmoc.
  • Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • Ring A, R 1 , m, and Y are as defined for Formula I above.
  • the reaction of a compound of Formula 2-3 with a compound of Formula 5-1 to yield a compound of Formula 5-2 may be accomplished by any cross-metathesis conditions.
  • a terminal olefin-containing compound of Formula 2-3 may be reacted a terminal olefin-containing compound of Formula 5-1 in the presence of Grubbs 2 nd generation catalyst in DCE to yield a cross-metatheis product of Formula 5-2.
  • Conversion of an unsaturated compound of Formula 5-2 to a compound of Formula 5-3 can be accomplished using any suitable procedure for olefin reduction and amine deprotection.
  • Macrocyclization of a compound of Formula 5-3 to produce a compound of Formula 5-4 may be accomplished by any suitable aromatic substitution conditions.
  • Scheme 6 refers to processes for preparing a compound of Formula 6-7 from a compound of Formula 3-1.
  • Alk is selected from C 1 -C 6 linear or branched alkyl groups.
  • LG is selected from halogen and oxygen-based leaving groups such as OTf and OTs.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • R 1 , m, Y and R X1 are as defined for Formula I above.
  • the reaction of a compound of Formula 3-1 with a compound of Formula 6-1 to yield a compound of Formula 6-2 may be accomplished by any suitable aromatic substitution conditions. Conversion of an ester of Formula 6-2 to a carboxylic acid of Formula 6-3 may be accomplished by any suitable hydrolysis conditions.
  • a compound of Formula 6-4 may be prepared from a compound of Formula 6-3 and a compound of Formula 1-7 using any suitable amide bond formation conditions. A compound of Formula 6-4 can be converted to a compound of Formula 6-5 using any conditions suitable for oxadiazole formation.
  • a compound of Formula 6-4 can be reacted with DIEA in acetonitrile, followed by addition of p-toluenesulfonyl chloride, to yield an oxadiazole of Formula 6-5.
  • Macrocyclization of a compound of Formula 6-5 to produce a compound of Formula 6-6 may be accomplished by any suitable ring-closing metathesis conditions.
  • a compound of Formula 6-5 may be reacted in the presence of Zhan catalyst-1B in DCE to yield a macrocycle of Formula 6-6 as a mixture of E/Z isomers (as denoted by the bond).
  • Scheme 7 refers to processes for preparing a compound of Formula 7-7 from a compound of Formula 3-1.
  • Alk is selected from C 1 -C 6 linear or branched alkyl groups.
  • LG is selected from halogen and oxygen-based leaving groups such as OTf and OTs.
  • PG is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • a and b is an integer independently selected from 0, 1, 2, and 3, provided that a + b is not greater than 4.
  • R 1 , m, Y, R X1 , and R Y are as defined for Formula I above.
  • the reaction of a compound of Formula 3-1 with a compound of Formula 7-1 to yield a compound of Formula 7-2 may be accomplished by any suitable aromatic substitution conditions. Conversion of an ester of Formula 7-2 to a carboxylic acid of Formula 7-3 may be accomplished by any suitable hydrolysis conditions.
  • a compound of Formula 7-4 may be prepared from a compound of Formula 7-3 and a compound of Formula 1-7 using any suitable amide bond formation conditions. A compound of Formula 7-4 can be converted to a compound of Formula 7-5 using any conditions suitable for oxadiazole formation.
  • a compound of Formula 7-4 can be reacted with DIEA in acetonitrile, followed by addition of p-toluenesulfonyl chloride, to yield an oxadiazole of Formula 7-5.
  • Macrocyclization of a compound of Formula 7-5 to produce a compound of Formula 7-6 may be accomplished by any suitable ring-closing metathesis conditions.
  • a compound of Formula 7-5 may be reacted in the presence of Zhan catalyst-1B in DCE to yield a macrocycle of Formula 7-6 as a mixture of E/Z isomers (as denoted by the bond).
  • Conversion of an unsaturated compound of Formula 7-6 to a macrocycle of Formula 7-7 can be accomplished using any suitable procedure for olefin reduction and alcohol deprotection.
  • Scheme 8 refers to processes for preparing a compound of Formula 8-3 from a compound of Formula 2-3.
  • LG is selected from halogen and oxygen-based leaving groups such as OTf and OTs.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • TBDPS halogen and oxygen-based leaving groups
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • TBDPS benzyl and silyl moieties
  • Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • R 1 , m, Y, and R X1 are as defined for Formula I above.
  • the reaction of a compound of Formula 2-3 with a compound of Formula 6-1 to yield a compound of Formula 8-1 may be accomplished by
  • a compound of Formula 2-3 can be reacted with DIEA in acetonitrile and heated to yield a compound of Formula 8-1.
  • Macrocyclization of a compound of Formula 8-1 to produce a compound of Formula 8-2 may be accomplished by any suitable ring-closing metathesis conditions.
  • a compound of Formula 8-1 may be reacted in the presence of Zhan catalyst-1B in DCE to yield a macrocycle of Formula 8-2 as a mixture of E/Z isomers (as denoted by the bond).
  • Conversion of an unsaturated compound of Formula 8-2 to a macrocycle of Formula 8-3 can be accomplished using any suitable procedure for olefin reduction and alcohol deprotection.
  • Scheme 9 refers to processes for preparing a compound of Formula 9-5 from a compound of Formula 9-1.
  • L X is selected from halogens such as Cl, I, or Br.
  • c is an integer independently selected from 1, 2, 3, and 4.
  • Ring A, Ring B, R 1 , m, and Y are as defined for Formula I above.
  • the reaction of a compound of Formula 9-1 with a compound of Formula 9-2 to yield a compound of Formula 9-3 may be accomplished by any suitable oxadiazole formation conditions.
  • a compound of Formula 9-2 may be reacted with (N- isocyanoimino)triphenylphosphorane in DCM, followed by dropwise addition of a compound of Formula 9-1, to yield a compound of Formula 9-3.
  • Macrocyclization of a compound of Formula 9-3 to produce a compound of Formula 9-4 may be accomplished by any suitable palladium-catalyzed olefin coupling conditions.
  • Scheme 10 refers to processes for preparing a compound of Formula 10-8 from a compound of Formula 10-1.
  • Alk is selected from C 1 -C 6 linear or branched alkyl groups.
  • LG is selected from halogen and oxygen-based leaving groups such as OTf and OTs.
  • Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • Ring A, R 1 , and Y are as defined for Formula I above.
  • the reaction of a compound of Formula 10-1 with a compound of Formula 3-2 to yield a compound of Formula 10-2 may be accomplished by any suitable aromatic substitution conditions.
  • a compound of Formula 10-1 may be reacted with a compound of Formula 3-2 and DIEA in acetonitrile to yield a compound of Formula 10-2.
  • Conversion of an ester of Formula 10-2 to a carboxylic acid of Formula 10-3 may be accomplished by any suitable hydrolysis conditions.
  • a compound of Formula 10-4 may be prepared from a compound of Formula 10-3 and a compound of Formula 1-7 using any suitable amide bond formation conditions.
  • a compound of Formula 10-4 can be converted to a compound of Formula 10-5 using any conditions suitable for oxadiazole formation.
  • a compound of Formula 10-4 can be reacted with DIEA in acetonitrile, followed by addition of p-toluenesulfonyl chloride, to yield an oxadiazole of Formula 10-5.
  • Macrocyclization of a compound of Formula 10-5 to produce a compound of Formula 10-6 may be accomplished by any suitable ring-closing metathesis conditions.
  • a compound of Formula 10-5 may be reacted in the presence of Zhan catalyst-1B in DCE to yield a macrocycle of Formula 10-6 as a mixture of E/Z isomers (as denoted by the bond).
  • the conversion of a compound of Formula 10-7 to a compound of Formula 10-8 may be accomplished by any suitable aromatic substitution conditions.
  • Conversion of an unsaturated compound of Formula 10-7 to a macrocycle of Formula 10-8 may be accomplished using any suitable procedure for olefin reduction and alcohol deprotection.
  • Scheme 11 [00289] Scheme 11 refers to processes for preparing a compound of Formula 11-4 from a compound of Formula 2-3.
  • LG is selected from halogen and oxygen-based leaving groups such as OTf and OTs.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS). Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • R 1 , m, Y, R X1 , and R YN are as defined for Formula I above.
  • the reaction of a compound of Formula 2-3 with a compound of Formula 11-1 to yield a compound of Formula 11-2 may be accomplished by any suitable aromatic substitution conditions. For example, a compound of Formula 2-3 and a compound of Formula 11-1 may be reacted in DMSO in the presence of heat to yield a compound of Formula 11-2.
  • Conversion of a terminal olefin-containing compound of Formula 11-2 to a carboxylic acid of Formula 11-3 may be accomplished by any oxiditative cleavage conditions.
  • a compound of Formula 11-2 may be reacted in a mixture of dioxane and water in the presence of osmium tetroxide and sodium periodate to yield a compound of Formula 11-3.
  • Macrocyclization of a compound of Formula 11-3 to produce a compound of Formula 11-4 may be accomplished by any suitable amide bond formation conditions.
  • a compound of Formula 11-3 may be reacted in DMF with IDEA, followed by addition of HATU, to yield a compound of Formula 11-4.
  • Scheme 12 refers to processes for preparing a compound of Formula 12-4 from a compound of Formula 2-3.
  • LG is selected from halogen and oxygen-based leaving groups such as OTf and OTs.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • a is an integer selected from 3, 4, 5, and 6.
  • Ring A, R 1 , m, and Y are as defined for Formula I above.
  • Conversion of a terminal olefin-containing compound of Formula 2-3 to a carboxylic acid of Formula 12-1 may be accomplished by any suitable oxidative conditions.
  • a compound of Formula 2-3 can be converted to an alcohol by hydroboration/oxidation, followed by oxidation of the alcohol to a carboxylic acid, to yield a compound of Formula 12-1.
  • the reaction of a compound of Formula 12-1 with a compound of Formula 12-2 to yield a compound of Formula 12-3 may be accomplished by any suitable aromatic substitution conditions.
  • a compound of Formula 12-1 may be reacted with a compound of Formula 12-2 and diisopropylethylamine in a microwave to yield a compound of Formula 12-3.
  • Macrocyclization of a compound of Formula 12-3 to produce a compound of Formula 12-4 may be accomplished by any suitable amide bond formation conditions.
  • Scheme 13 refers to processes for preparing a compound of Formula 13-7 from a compound of Formula 3-1.
  • Each Alk is independently selected from C 1 -C 6 linear or branched alkyl groups.
  • LG is selected from halogen and oxygen-based leaving groups such as OTf and OTs.
  • PG is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • R 1 , m, X, Y, R X1 , and R Y are as defined for Formula I above.
  • the reaction of a compound of Formula 3-1 with a compound of Formula 13-1 to yield a compound of Formula 13-2 may be accomplished by any suitable aromatic substitution conditions.
  • a compound of Formula 3-1 and a compound of Formula 13-1 may be stirred in acetonitrile, followed by dropwise addition of diisopropylethylamine and heating to yield a compound of Formula 13-2.
  • Conversion of a diester of Formula 13-2 to a carboxylic acid of Formula 13-3 or Formula 13-4 may be accomplished by any suitable hydrolysis conditions, followed by suitable amide bond formation conditions.
  • a compound of Formula 13-2 may be reacted with hydrazine monohydrate in methanol to yield a compound of Formula 13-3 or Formula 13- 4.
  • Conversion of a compound of Formula 13-3 or Formula 13-4 to a compound of Formula 13-5 may be accomplished by any suitable amide bond formation conditions.
  • Conversion of a compound of Formula 13-5 to a compound of Formula 13-6 may be accomplished using any conditions suitable for oxadiazole formation.
  • a compound of Formula 13-5 may be reacted with N,N-diisopropylethylamine in acetonitrile, followed by addition of 4-methylbenzenesulfonyl chloride, to yield an oxadiazole of Formula 13-6.
  • Conversion of a compound of Formula 13-6 to an alcohol of Formula 13-7 may be accomplished by any suitable alcohol deprotection procedure.
  • Scheme 14 refers to processes for preparing a compound of Formula 14-7 from a compound of Formula 14-1.
  • LG is selected from halogen and oxygen-based leaving groups such as OTf and OTs.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • PG 2 is selected from suitable nitrogen protecting groups, such as Boc and Fmoc.
  • Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • R 1 , m, X, Y, and R X1 are as defined for Formula I above.
  • reaction of a compound of Formula 14-1 with a compound of Formula 14-2 to yield a compound of Formula 14-3 may be accomplished by any suitable amide bond formation conditions.
  • Conversion of compound of Formula 14-3 to a compound of Formula 14-4 may be accomplished by any suitable procedure to convert an alcohol to a leaving group.
  • a compound of Formula 14-3 may be reacted with triphenylphosphine followed by 2,2,2-trichloroacetonitrile in anhydrous THF to yield a compound of Formula 14-4.
  • Conversion of a compound of Formula 14-4 to a compound of Formula 14-5 may be accomplished by any suitable amine deprotection conditions.
  • Macrocyclization of a compound of Formula 14-5 to produce a compound of Formula 14- 6 may be accomplished by any suitable aromatic substitution conditions.
  • a compound of Formula 14-5 may be reacted with TFA in DCM to yield a compound of Formula 14-6.
  • Conversion of a compound of Formula 14-6 to an alcohol of Formula 14-7 may be accomplished by any suitable alcohol deprotection procedure.
  • Scheme 15 refers to processes for preparing a compound of Formula 15-4 from a compound of Formula 7-6.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • Each of a and b is an integer independently selected from 0, 1, 2, and 3, provided that a + b is not greater than 4.
  • R 1 , m, Y, R X1 , and R Y are as defined for Formula I above.
  • Conversion of a compound of Formula 7-6 to an alcohol of Formula 15-1 may be accomplished by any suitable olefin oxidation procedure.
  • Conversion of compound of Formula 15-1 to a compound of Formula 15-2 may be accomplished by any suitable alcohol deprotection conditions.
  • Conversion of an alcohol of Formula 15-2 to a carbonyl- containing compound of Formula 15-3 may be accomplished by any suitable oxidation procedure.
  • Conversion of a carbonyl-containing compound of Formula 15-3 to produce a compound of Formula 15-4 may be accomplished by any suitable reduction conditions.
  • Scheme 16 refers to processes for preparing compounds of Formula 16-10 and Formula 16-11 from a compound of Formula 3-1.
  • Alk is selected from C 1 -C 6 linear or branched alkyl groups.
  • LG is selected from halogen and oxygen-based leaving groups such as OTf and OTs.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS).
  • Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • R 1 , m, X, Y, and R Z1 are as defined for Formula I above.
  • reaction of a compound of Formula 3-1 with a compound of Formula 16-1 to yield a compound of Formula 16-2 may be accomplished by any suitable aromatic substitution conditions. Conversion of an ester of Formula 16-2 to a carboxylic acid of Formula 16-3 may be accomplished by any suitable hydrolysis conditions.
  • a compound of Formula 16-5 may be prepared from a compound of Formula 16-3 and a compound of Formula 16-4 using any suitable amide bond formation conditions. A compound of Formula 16-5 can be converted to a compound of Formula 16-6 using any conditions suitable for oxadiazole formation.
  • a compound of Formula 16-5 can be reacted with DIEA in acetonitrile, followed by addition of p-toluenesulfonyl chloride, to yield an oxadiazole of Formula 16-6.
  • Macrocyclization of a compound of Formula 16-6 to produce a compound of Formula 16-7 may be accomplished by any suitable ring-closing metathesis conditions.
  • a compound of Formula 16-6 may be reacted in the presence of Zhan catalyst-1B in DCE to yield a macrocycle of Formula 16-7 as a mixture of E/Z isomers (as denoted by the bond).
  • the conversion of a compound of Formula 16-7 to a compound of Formula 16-8 may be accomplished using any suitable procedure for olefin reduction and alcohol deprotection.
  • the conversion of a compound of Formula 16-8 to a carbonyl-containing compound of Formula 16-9 may be accomplished using any suitable oxidation conditions.
  • Conversion of a carbonyl-containing compound of Formula 16-9 to an oxime of Formula 16-10 may be accomplished using any suitable oxime formation procedure.
  • Conversion of a carbonyl-containing compound of Formula 16-9 to an alcohol of Formula 16-11 may be accomplished using any suitable procedure for nucleophilic addition to carbonyls.
  • Scheme 17 refers to processes for preparing a compound of Formula 17-7 from a compound of Formula 17-1.
  • Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • R 1 , m, X, Y, and R Z1 are as defined for Formula I above.
  • the reaction of a carboxylic acid of Formula 17-1 with an aldehyde of Formula 17-2 to yield a compound of Formula 17-3 may be accomplished using any conditions suitable for oxadiazole formation.
  • a compound of Formula 17-1 may be reacted with a compound of Formula 17-2 and N-isocyanoimino)triphenylphosphorane in DCM to yield a compound of Formula 17-3.
  • Conversion of an alcohol of Formula 17-3 to a carbonyl-containing compound of Formula 17-4 may be accomplished by any suitable oxidation conditions.
  • Conversion of a carbonyl-containing compound of Formula 17-4 to an alcohol of Formula 17-5 may be accomplished using any suitable procedure for nucleophilic addition to carbonyls.
  • Macrocyclization of a compound of Formula 17-5 to produce a compound of Formula 17-6 may be accomplished by any suitable ring-closing metathesis conditions.
  • a compound of Formula 17-5 may be reacted in the presence of [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2- isopropoxy-5-nitro-phenyl)methylene]ruthenium in DCE to yield a macrocycle of Formula 17-6 as a mixture of E/Z isomers (as denoted by the bond).
  • the conversion of a compound of Formula 17-6 to a compound of Formula 17-7 may be accomplished using any suitable procedure for olefin reduction.
  • Scheme 18 [00303] Scheme 18 refers to processes for preparing a compound of Formula 18-5 from a compound of Formula 17-1.
  • PG 1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS). Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • R 1 , m, X, and Y are as defined for Formula I above.
  • the reaction of a compound of Formula 17-1 with a compound of Formula 18-1 to yield a compound of Formula 18-2 may be accomplished using any suitable amide bond formation conditions.
  • a compound of Formula 18-2 can be converted to a compound of Formula 18-3 using any conditions suitable for oxadiazole formation.
  • a compound of Formula 18-2 can be reacted with diisopropylethylamine and p- toluenesulfonyl chloride to yield an oxadiazole of Formula 18-3.
  • Macrocyclization of a compound of Formula 18-3 to produce a compound of Formula 18-4 may be accomplished by any suitable ring-closing metathesis conditions.
  • a compound of Formula 18-3 may be reacted in the presence of Zhan catalyst-1B in DCE to yield a macrocycle of Formula 18-4 as a mixture of E/Z isomers (as denoted by the bond).
  • the conversion of a compound of Formula 18-4 to a compound of Formula 18-5 may be accomplished using any suitable procedure for olefin reduction and alcohol deprotection.
  • Scheme 19 refers to processes for preparing a compound of Formula 19-2 from a compound of Formula 13-7.
  • Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • R 1 , m, X, and Y are as defined for Formula I above.
  • Conversion of an alcohol of Formula 13-7 to an olefin of Formula 19-1 may be accomplished using any suitable dehydration procedure.
  • Conversion of a compound of Formula 19-1 to a compound of Formula 19-2 may be accomplished using any suitable olefin reduction conditions.
  • Scheme 20 [00307] Scheme 20 refers to processes for preparing a compound of Formula 20-2 from a compound of Formula 20-1.
  • Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.
  • R 1 , m, X, Y, R Z1 , and R 2 are as defined for Formula I above.
  • Conversion of an amine of Formula 20-1 to an amine of Formula 20-2 may be accomplished using any suitable amination procedure.
  • an amine of Formula 20-1 may be reacted with an alkyl halide in the presence of bis(trimethylsilyl)amino]sodium to yield a compound of Formula 20-2.
  • Step 2 Methyl 3-amino-5-(trifluoromethyl)pyridine-2-carboxylate [00310] To a suspension of methyl 3-(benzhydrylideneamino)-5- (trifluoromethyl)pyridine-2-carboxylate (65 g, 124.30 mmol) in methanol (200 mL) was added HCl (3 M in methanol) (146 mL of 3 M, 438.00 mmol). The mixture was stirred at room temperature for 1.5 hour then the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (2 L) and dichloromethane (500 mL).
  • Step 3 Methyl 3-amino-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate [00311] To a solution of methyl 3-amino-5-(trifluoromethyl)pyridine-2-carboxylate (18.75 g, 80.91 mmol) in acetonitrile (300 mL) at 0 oC was added portion wise N- bromosuccinimide (18.7g, 105.3 mmol). The mixture was stirred overnight at 25 oC. Ethyl acetate (1000 mL) was added.
  • Step 4 Methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5- (trifluoromethyl)pyridine-2-carboxylate [00312] A mixture of methyl 3-amino-6-bromo-5-(trifluoromethyl)pyridine-2- carboxylate (5 g, 15.549 mmol), (Boc) 2 O (11 g, 11.579 mL, 50.402 mmol), DMAP (310 mg, 2.5375 mmol) and CH 2 Cl 2 (150 mL) was stirred at room temperature overnight.
  • Step 2 2-Allylpyrrolidine (trifluoroacetate salt)
  • Trifluoroacetic acid (13.468 g, 9.1 mL, 118.12 mmol) was added slowly to tert- butyl 2-allylpyrrolidine-1-carboxylate (1.6 g, 7.5721 mmol) in dichloromethane (12 mL) at 0 °C. The mixture was stirred for 3 h at room temperature then concentrated. Toluene (10 mL) was added and the mixture was concentrated (repeated 4 times) to afford as an amber oil, 2-allylpyrrolidine (trifluoroacetate salt) (1.9 g, 99 %).
  • Step 3 Methyl 6-(2-allylpyrrolidin-1-yl)-3-[bis(tert-butoxycarbonyl)amino]-5- (trifluoromethyl)pyridine-2-carboxylate [00315]
  • 2-allylpyrrolidine (trifluoroacetate salt) (338 mg, 1.5008 mmol) was added to methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5- (trifluoromethyl)pyridine-2-carboxylate (500 mg, 1.0015 mmol) and DIPEA (964.60 mg, 1.3 mL, 7.4635 mmol) in acetonitrile (10 mL).
  • Step 4 6-(2-Allylpyrrolidin-1-yl)-3-(tert-butoxycarbonylamino)-5- (trifluoromethyl)pyridine-2-carboxylic acid
  • methanol 125 mL
  • water 100 mL
  • Lithium hydroxide anhydrous (2.116 g, 86.6 mmol) was added to the mixture in three portions. The mixture was stirred at 60 °C for 3.5 h. THF and methanol were removed under reduced pressure and then 70 mL of 10 % aqueous HCl was added and the resulting mixture was extracted with EtOAc (3 X 100 mL). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the oil was removed by aspiration and was found by analysis to be triphenylphosphine oxide.
  • the solvent phase left after removal of the oil was concentrated in vacuo.
  • a precipitate formed upon standing and was stirred in 100 mL of MTBE.
  • the precipitate was removed by filtration and washed with MTBE.
  • the filtrate was concentrated in vacuo and purified by silica gel chromatography (0 % to 40 % EtOAc/hexanes) which provided as a light yellow oil, tert- butyl (2S)-2-(iodomethyl)pyrrolidine-1-carboxylate (36.5 g, 94 %).
  • Step 2 tert-Butyl (2S)-2-allylpyrrolidine-1-carboxylate
  • Iodocopper 103 g, 540.8 mmol
  • THF 525 mL
  • Bromo(vinyl)magnesium 1 L of 1 M, 1.000 mol
  • the thick suspension was stirred for 1 h allowing to warm to - 10 °C.
  • the black suspension was cooled to - 40 °C and a solution of tert-butyl (2S)-2-(iodomethyl)pyrrolidine-1-carboxylate (105 g, 337.4 mmol) in THF (260 mL) was added dropwise over 30 min keeping the internal temperature between - 40 °C and - 45 °C.
  • the thick suspension was stirred for additional 3 h with slow warming to 18 °C.
  • the black suspension was concentrated under reduced pressure and treated with saturated aqueous ammonium chloride solution (300 mL) and MTBE (300 mL). The solid was removed by filtration and the phases separated.
  • Step 3 (2S)-2-Allylpyrrolidine (trifluoroacetate salt) [00319] To a solution of tert-butyl (2S)-2-allylpyrrolidine-1-carboxylate (17 g, 80.45 mmol) in DCM (120 mL) was added TFA (30 mL, 389.4 mmol) dropwise. The mixture was stirred at ambient temperature for 24 h. The solvent was removed in vacuo and the product treated 3 times with a toluene (200 mL) azeotrope. The product was dried under vacuum for 16 h giving as a dark oil, (2S)-2-allylpyrrolidine (trifluoroacetate salt) (17 g, 94 %).
  • Step 2 6-[(2S)-2-Allylpyrrolidin-1-yl]-3-(tert-butoxycarbonylamino)-5- (trifluoromethyl)pyridine-2-carboxylic acid [00321] Methyl 6-[(2S)-2-allylpyrrolidin-1-yl]-3-[bis(tert-butoxycarbonyl)amino]-5- (trifluoromethyl)pyridine-2-carboxylate (20.5 g, 38.71 mmol) was dissolved in THF (150 mL) and MeOH (150 mL) (yellow solution) then treated with water (150 mL) (yellow emulsion) followed by LiOH (3.5 g, 146.1 mmol).
  • the mixture was heated to 60 oC and stirred for 3.5 h.
  • the suspension was acidified by slow addition of HCl (160 mL of 1 M, 160 mmol), keeping the internal temperature around 10 oC (foaming) and then stirred in a cold-water bath for 1 h.
  • the solid was collected by filtration and washed with cold water and dried overnight.
  • the mixture was stirred at -78 oC for 20 min.
  • the dry ice-acetone bath was removed.
  • the two layers were separated.
  • the organic layer was concentrated, and the residue was combined with aqueous phase and extracted with EtOAc (2 X 150 mL).
  • the combined organic phase was washed with 5 % aqueous NaHCO 3 (50 mL) and brine (20 mL), dried with Na 2 SO 4 .
  • Step 2 Ethyl 2-benzyloxy-2-(trifluoromethyl)hex-5-enoate [00323] To a solution of ethyl 2-hydroxy-2-(trifluoromethyl)hex-5-enoate (24.29 g, 87.6 % purity, 94.070 mmol) in DMF (120 mL) at 0 oC was added NaH (60 % in mineral oil, 5.64 g, 141.01 mmol) portion-wise. The mixture was stirred at 0 oC for 10 min.
  • Step 3 2-Benzyloxy-2-(trifluoromethyl)hex-5-enoic acid
  • Step 4 tert-Butyl N-[[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamate [00325] To a solution of 2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid (21.92 g, 92.4 % purity, 70.263 mmol) in DMF (130 mL) was added HATU (37.2 g, 97.836 mmol) and Et 3 N (15 g, 148.24 mmol). The mixture was stirred for 10 minutes then tert-butyl N- aminocarbamate (12.2 g, 92.312 mmol) was added.
  • Step 5 2-Benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride salt) [00326] To a solution of tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)hex-5- enoyl]amino]carbamate (43.12 g, 107.2 mmol) in CH 2 Cl 2 (200 mL) was added HCl (100 mL of 4 M, 400.0 mmol) and the mixture was stirred at ambient temperature for 7 h.
  • the organic phase was dried over MgSO 4 , filtered and concentrated in vacuo.
  • the crude product was slurried in warm heptane (2.5 L) and MTBE (0.25 L) and the mixture stirred at ambient temperature for 12 h affording a light yellow slurry.
  • the slurry was filtered, and the resultant filter cake was washed 2 times with 1 L of 10 % MTBE/heptane.
  • Step 2 tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4- oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [00329] tert-Butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)hex-5- enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (102 g, 150.8 mmol) was dissolved in anhydrous acetonitrile (1000 mL) and DIPEA (92 mL, 528.2 mmol)
  • the mixture was stirred at -78 oC for 45 min.
  • the dry ice-acetone bath was removed.
  • the mixture was allowed to warm to about 10 oC over a period of 1 h and added to a mixture of 1N aqueous HCl (210 mL) and crushed ice (400 g) (pH 4).
  • the mixture was extracted with EtOAc, washed with 5 % aqueous NaHCO 3 , brine and dried over anhydrous Na 2 SO 4 .
  • the mixture was filtered, concentrated and co-evaporated with hexane to give as a light yellow oil, ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate (42.2 g, 90 %).
  • Step 2 Ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate [00332] To a solution of ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate (18.56 g, 83.105 mmol) in DMF (100 mL) was added NaH (5.3 g, 60 % w/w, 132.51 mmol) at 0 oC. The reaction was stirred for 15 minutes and benzyl bromide (21.14 g, 15 mL, 121.12 mol) and tetrabutyl ammonium iodide (8.5 g, 23.012 mmol) were added.
  • Step 3 2-Benzyloxy-2-(trifluoromethyl)pent-4-enoic acid
  • a solution of ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate (28.99 g, 95.902 mmol) in methanol (150 mL) was added a solution of NaOH (7.6714 g, 191.80 mmol) in water (50 mL).
  • the reaction mixture was stirred at 40 oC for 3 hours.
  • the reaction mixture was concentrated under vacuum, the residue was diluted with water (200 mL) and washed with diethyl ether (200 mL).
  • Step 4 tert-Butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate
  • HATU 530 g, 1.394 mol
  • DIEA 400 mL, 2.296 mol
  • Step 5 2-Benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride salt) [00335] To a solution of tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4- enoyl]amino]carbamate (98.5 g, 240.94 mmol) in DCM (400 mL) was added HCl in dioxane (200 mL of 4 M, 800.00 mmol).
  • the reaction was heated at 75 °C for 3 days.
  • the reaction mixture was cooled to room temperature and about 2/3 of the solvent was removed under reduced pressure.
  • the resulting mixture was poured onto a mixture of brine (200 mL) and ice (200 mL).
  • the aqueous layer was extracted with EtOAc (3 X 200 mL).
  • the organic layers were combined and washed with water (70 mL), 5 % NaHCO 3 (70 mL) and brine (70 mL), dried over sodium sulfate, filtered and evaporated to give as a yellow solid, methyl 3-amino-5-bromo-pyridine-2- carboxylate (4.56 g, 45 %).
  • Step 2 Methyl 3-amino-5-methylsulfonyl-pyridine-2-carboxylate [00337] A mixture of methyl 3-amino-5-bromo-pyridine-2-carboxylate (9.79 g, 42.372 mmol), methylsulfinyloxysodium (8.8 g, 86.2 mmol), copper(I) iodide (8.8 g, 46.206 mmol), L-proline (34 mg, 0.2953 mmol) and DMF (195 mL) under nitrogen was heated at 130 °C for 3 h. The mixture was cooled to room temperature and added to EtOAc (1.2 L) with stirring.
  • Step 3 Methyl 3-amino-6-bromo-5-methylsulfonyl-pyridine-2-carboxylate [00338] To a solution of methyl 3-amino-5-methylsulfonyl-pyridine-2-carboxylate (8 g, 34.746 mmol) in acetonitrile (515 mL) was added NBS (12.7 g, 71.355 mmol). The mixture was stirred at 35 °C for 64 h. The mixture was concentrated to remove most of acetonitrile. The residue was diluted with ethyl acetate (200 mL) and treated with a solution of 10 % aqueous sodium thiosulfate solution (100 mL).
  • Step 4 Methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-methylsulfonyl- pyridine-2-carboxylate [00339] A mixture of methyl 3-amino-6-bromo-5-methylsulfonyl-pyridine-2- carboxylate (6.2 g, 19.153 mmol), tert-butoxycarbonyl tert-butyl carbonate (12.825 g, 13.5 mL, 58.764 mmol), DMAP (373 mg, 3.0532 mmol) and DCM (185 mL) was stirred at room temperature overnight.
  • Trifluoroacetic anhydride (107.70 g, 72 mL, 507.65 mmol) was then added over 30 minutes at a temperature of -10 oC, with cooling bath (CO 2 /acetone bath). The reaction mixture was then stirred for a further 30 minutes at a temperature of 0 oC and then for 1 hour at ambient temperature. The reaction mixture was then poured into cooled ice-water (600 mL). The mixture was diluted with dichloromethane (300 mL) and then layers were separated. The aqueous phase was extracted with dichloromethane (2 X 200 mL).
  • Step 2 Methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate
  • Trifluoroacetic anhydride (291.62 g, 193 mL, 1.3885 mol) was added drop-wise to a mixture of methyl 1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (51.058 g, 230.66 mmol) in DMF (305 mL) at 0 oC. The mixture was then stirred at room temperature overnight.
  • Step 3 Methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate [00342] To an ice-cooled solution of methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2- carboxylate (33.04 g, 149.41 mmol) in sulfuric acid (200 mL of 18.4 M, 3.6800 mol) was added nitric acid (13 mL of 15.8 M, 205.40 mmol) dropwise. After 5 min, the ice bath was removed, and the reaction mixture was stirred at 38 oC overnight.
  • Step 4 Methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate [00343] A mixture of methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2- carboxylate (10 g, 37.575 mmol) and phenyl dichlorophosphate (48.008 g, 34 mL, 227.55 mmol) was heated at 170 oC for 90 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate (400 mL) and washed with brine (2 X 200 mL). The organic phase was dried on anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 2 [6-[5-[1-Benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5- nitro-3-(trifluoromethyl)-2-pyridyl] trifluoromethanesulfonate [00346] To a 0 oC solution of N'-[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]-6- hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide (9.76 g, 16.922 mmol) in dichloromethane (190 mL) was added DIPEA (8.0136 g, 10.8 mL, 62.004 mmol) followed by trifluoromethylsulfonyl trifluoromethanesulfonate (12.410 g, 7.
  • the ice-cold bath was removed after 20 min and the reaction was stirred at room temperature for 2.5 hours.
  • the mixture was transferred to a separatory funnel provided with ice-cold aqueous 1.0 N solution of HCl, and EtOAc (300 mL).
  • the organic layer was separated, and the aqueous phase extracted with ethyl acetate (2 X 150 mL).
  • the combined organic layer was washed again with ice-cold HCl 1.0 N aqueous solution (60 mL) and brine (3 X 40 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 2 [6-[5-[1-Benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5- nitro-3-(trifluoromethyl)-2-pyridyl] trifluoromethanesulfonate
  • Trifluoromethylsulfonyl trifluoromethanesulfonate (14.758 g, 8.8 mL, 52.308 mmol) was added to N'-[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-hydroxy-3-nitro- 5-(trifluoromethyl)pyridine-2-carbohydrazide (14.7 g, 20.712 mmol) and DIPEA (9.79 g, 13.2 mL, 75.783 mmol) in dichloromethane (175 mL) at 0 oC.
  • the ice-cold bath was removed after 20 min and the reaction was stirred at room temperature for 2.5 h.
  • the mixture was transferred to a separatory funnel with ice-cold aqueous 1.0 N solution of HCl (180 mL), and EtOAc (500 mL).
  • the organic layer was separated, and the aqueous phase extracted with ethyl acetate (2 X 120 mL).
  • the combined organic layer was washed again with ice-cold HCl 1.0 N aqueous solution (120 mL) and brine (3 X 120 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated by evaporation under reduced pressure.
  • Step 2 (2R)-2-Benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide
  • tert-butyl N-[[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5- enoyl]amino]carbamate (464 g, 1.153 mol) in DCM (1.25 L) and was added HCl (925 mL of 4 M, 3.700 mol) and the mixture stirred at ambient temperature for 20 h. The mixture was concentrated in vacuo removing most of the DCM.
  • the organic phase was separated and washed with 1L of brine and the combined aqueous phases were extracted with isopropyl acetate (1 L).
  • the combined organic phases were dried over MgSO 4 , filtered and concentrated in vacuo affording a dark yellow oil.
  • Propylphosphonic anhydride (106 g, 50 % w/w, 166.57 mmol) was added at room temperature (20 °C to 25 °C) and the reaction was stirred for 2 h. The reaction was then quenched with 1 M aqueous ammonium chloride (400 mL), the phases were separated and the organic phase was washed with 1 M aqueous ammonium chloride (400 mL) and then 1 M potassium bicarbonate (2 X 300 mL).
  • Step 2 2-[(1R)-1-Benzyloxy-1-(trifluoromethyl)but-3-enyl]-5-[6-chloro-3-nitro-5- (trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole [00358] N'-[(2R)-2-Benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-hydroxy-3-nitro-5- (trifluoromethyl)pyridine-2-carbohydrazide (45 g, 80.979 mmol) was dissolved in a mixture of phosphoryl trichloride (90 mL) and acetonitrile (90 mL) and dimethylformamide (45 mL) was added.
  • phosphoryl trichloride 90 mL
  • acetonitrile 90 mL
  • dimethylformamide 45 mL
  • the mixture was heated at 70 °C for 2 h.
  • the reaction was then quenched with a 1 M aqueous potassium bicarbonate solution (1.3 L) while monitoring the pH and adjusting with 6 M sodium hydroxide (300 mL).
  • the product was then extracted with ethyl acetate (3 X 500 mL).
  • the organic phases were combined and dried over sodium sulfate (150 g), then filtered and concentrated.
  • the product was then dry packed using 125 g of silica gel and purified on a 600 g silica pad, eluting with heptanes (2 L) and then 10 % MTBE in heptanes (8 L) giving some pure product and some contaminated product.
  • This contaminated product was dry packed using 50 g of silica and purified on a 400 g silica pad eluting with heptanes (1 L) and then 10 % MTBE in heptanes (6 L) again giving pure product and some contaminated product.
  • This contaminated product was further purified by reverse phase chromatography using a 100 g C 18 column and eluting with a gradient from 0.1 % aqueous formic acid to methanol (product elutes at ⁇ 80 % methanol). The fractions containing the product were combined, the methanol evaporated under vacuum and then the aqueous solution was extracted with ethyl acetate (2 X 50 mL).
  • the autoclave was purged with nitrogen, then with carbon monoxide.
  • the mixture was heated at 130 °C and the carbon monoxide pressure was adjusted to 120 psi.
  • the mixture was stirred for 3 h at 130 °C, then cooled to 25 °C.
  • the mixture was purged with nitrogen and concentrated under vacuum.
  • the resulting solid was diluted with ethyl acetate (500 mL) then water (200 mL) and sodium carbonate (20 g) were added.
  • the mixture was vigorously stirred for 10 minutes and the layers were separated.
  • the organic layer was washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure.
  • Step 2 Methyl 5-(difluoromethyl)-1-oxido-pyridin-1-ium-2-carboxylate
  • Urea hydrogen peroxide (13.7 g, 145.64 mmol) was added to a solution of methyl 5-(difluoromethyl)pyridine-2-carboxylate (8.1 g, 43.282 mmol) in DCE (70 mL).
  • Trifluoroacetic anhydride (24.025 g, 15.9 mL, 114.39 mmol) was added over 20 minutes at a temperature of -10 °C in cooling bath (CO 2 /acetone bath). The reaction mixture was stirred for a further 30 minutes at 0 °C and then for 1 hour at ambient temperature.
  • the mixture was diluted with dichloromethane (200 mL) and the layers were separated.
  • the aqueous phase was extracted with dichloromethane (2 X 150 mL).
  • the combined organic phases were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give as a yellow solid, methyl 5-(difluoromethyl)-1-oxido-pyridin-1- ium-2-carboxylate (8.39 g, 87 %).
  • Step 3 Methyl 5-(difluoromethyl)-6-hydroxy-pyridine-2-carboxylate
  • Trifluoroacetic anhydride (84.616 g, 56 mL, 402.87 mmol) was added dropwise to a mixture of methyl 5-(difluoromethyl)-1-oxido-pyridin-1-ium-2-carboxylate (11.63 g, 47.060 mmol) in DMF (130 mL) at 0 °C over 30 minutes. The mixture was stirred at 48 °C for 4 h, then the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to remove trifluoroacetic anhydride.
  • Step 4 Methyl 5-(difluoromethyl)-6-hydroxy-3-nitro-pyridine-2-carboxylate [00362] To an ice-cooled solution of methyl 5-(difluoromethyl)-6-hydroxy-pyridine-2- carboxylate (7.43 g, 36.575 mmol) in sulfuric acid (48 mL of 18.4 M, 883.2 mmol) was added nitric acid (2.5 mL of 15.8 M, 39.5 mmol) dropwise. After 5 min, the ice bath was removed, and the reaction mixture was stirred at 45 °C overnight. The reaction was precipitated in ice-water (300mL).
  • Step 2 tert-Butyl N-(1,1-dimethylpent-4-enyl)carbamate
  • a reaction flask was charged with allyl(chloro)magnesium in THF (205 mL, 2 M, 410 mmol) and anhydrous THF (200 mL). The solution was cooled to -30 °C and copper(I) bromide (dimethyl sulfide complex) (28 g, 136.2 mmol) was added.
  • reaction mixture was stirred at the same temperature for 30 min, then cooled to -78 °C.
  • a solution of tert-butyl 2,2-dimethylaziridine-1-carboxylate (24.602 g, 136.49 mmol) in anhydrous THF (200 mL) was added to the reaction mixture dropwise.
  • the reaction was stirred at the same temperature for 30 min, and then moved to a -20 °C freezer and stored for 3 hours.
  • the reaction was quenched with a saturated aqueous ammonium chloride solution (200 mL) at 0 °C.
  • the reaction was stirred at room temperature for 10 minutes, then diluted with diethyl ether (200 mL).
  • Step 3 2-Methylhex-5-en-2-amine (hydrochloride salt) [00366] A solution of tert-butyl N-(1,1-dimethylpent-4-enyl)carbamate (26.6 g, 124.7 mmol) and HCl in diethyl ether (350 mL, 2 M, 700 mmol) was stirred at room temperature for 2 days. The solvent was removed and the residue was triturated with hexanes to furnish as a white solid, 2-methylhex-5-en-2-amine (hydrochloride salt) (15.198 g, 77 %).
  • the resulting mixture was stirred at room temperature overnight.
  • the reaction mixture was diluted with ethyl acetate (50 mL) and washed with aqueous 1 N HCl (30 mL), saturated aqueous sodium bicarbonate (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 2 tert-Butyl N-[6-(2-allylpyrrolidin-1-yl)-2-[5-[1-benzyloxy-1- (trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3- pyridyl]carbamate
  • Step 3 tert-Butyl N-6-(benzyloxy)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,9,17,19-hexaen-20- yl]carbamate (E/Z mixture) [00369] To a degassed solution of tert-butyl N-[6-(2-allylpyrrolidin-1-yl)-2-[5-[1- benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3- pyridyl]carbamate (155 mg, 0.2274 mmol) in 1,2-dichloroethane (15 mL) was added Grubbs catalyst, 2nd generation (40 mg, 0.047 mmol).
  • the resultant mixture was stirred at 80 °C for 0.75 h.
  • the reaction mixture was cooled to 0 °C and di(ethylene glycol) vinyl ether (125.84 mg, 0.13 mL, 0.9522 mmol) was added to quench the catalyst, then stirred at room temperature for 10 min and concentrated.
  • Step 4 tert-Butyl N-[6-hydroxy-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-20-yl]carbamate [00370] To a nitrogen degassed solution of tert-butyl N-6-(benzyloxy)-6,18- bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa- 1(21),2,4,9,17,19-hexaen-20-yl]carbamate (E/Z mixture) (30 mg, 0.0459 mmol) in methanol (4 mL) was added SiliaCat Pd 0 (73 mg, 0.24 mmol/g, 0.0175 mmol) and reaction was stirred for 64 hours under hydrogen balloon
  • reaction mixture was filtered over Celite, washed with methanol and concentrated.
  • residue was purified by silica gel chromatography using a gradient from 0 % to 30 % ethyl acetate in heptanes giving as a yellow gum, tert-butyl N-[6-hydroxy-6,18-bis(trifluoromethyl)-22- oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-20- yl]carbamate (15 mg, 58 %).
  • Step 5 20-Amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(20),2,4,17(21),18-pentaen-6-ol (mixture of 4 stereoisomers) (Compound 1) [00371] TFA (1.4800 g, 1 mL, 12.98 mmol) was added to tert-butyl N-[6-hydroxy-6,18- bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa- 1(21),2,4,17,19-pentaen-20-yl]carbamate (30 mg, 0.053 mmol) in DCM (2 mL) at room temperature and the mixture was
  • Example 2 Preparation of 20-amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(20),2,4,17(21),18-pentaen-6-ol (diastereomer pair 1) (Compound 2) and 20-amino-6,18-bis(trifluoromethyl)-22-oxa- 3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(20),2,4,17(21),18-pentaen-6- ol (diastereomer pair 2) (Compound 3) Step 1: tert-Butyl N-[6-hydroxy-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- te
  • Step 2 20-Amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(20),2,4,17(21),18-pentaen-6-ol (diastereomer pair 1) (Compound 2) [00374] TFA (2.9600 g, 2 mL, 25.96 mmol) was added to tert-butyl N-[6-hydroxy-6,18- bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa- 1(21),2,4,17,19-pentaen-20-yl]carbamate (diastereomer pair 1) (190 mg, 0.336 mmol) in DCM (4 mL) at room temperature and the mixture was stirred for 2 h.
  • Step 3 20-Amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(20),2,4,17(21),18-pentaen-6-ol (diastereomer pair 2) (Compound 3) [00375] TFA (2.9600 g, 2 mL, 25.96 mmol) was added to tert-butyl N-[6-hydroxy-6,18- bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa- 1(21),2,4,17,19-pentaen-20-yl]carbamate (diastereomer pair 2) (165 mg, 0.2918 mmol) in DCM (4 mL) at room temperature and the mixture was stirred for 2 h.
  • reaction mixture was stirred at room temperature for 2.5 h then the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 X 50 mL). The organic phases were combined and dried over MgSO 4 , filtered, and concentrated.
  • Step 2 tert-Butyl N-[6-[(2S)-2-allylpyrrolidin-1-yl]-2-[5-[1-benzyloxy-1- (trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3- pyridyl]carbamate [00377] tert-Butyl N-[6-[(2S)-2-allylpyrrolidin-1-yl]-2-[[[2-benzyloxy-2- (trifluoromethyl)hex-5-enoyl]amino]carbamoyl]-5-(trifluoromethyl)-3-pyridyl]carbamate (19.3 g, 27.58 mmol) was dissolved in acetonitrile (3
  • Step 3 tert-Butyl N-[(12S)-6-benzyloxy-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetrazatetracyclo[15.3.1.12,5.012,16]docosa-1(20),2,4,9,17(21),18-hexaen-20- yl]carbamate (E/Z mixture) [00378] A degassed solution of tert-butyl N-[6-[(2S)-2-allylpyrrolidin-1-yl]-2-[5-[1- benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3- pyridyl]carbamate (10.47
  • Zhan catalyst-1B (2 g, 2.722 mmol) was then added and the mixture was heated to 70 °C and kept at this temperature overnight. More Zhan catalyst-1B (0.5 g, 0.6805 mmol) was added and heating was continued for 4 h. The reaction mixture was cooled down and concentrated under reduced pressure.
  • X-Ray Powder Diffraction [00382] The XRPD diffractogram for amorphous Compound 4 (neat form) produced by Step 4 was acquired using the General X-Ray Powder Diffraction (XRPD) Method and is provided in FIG. 1.
  • XRPD General X-Ray Powder Diffraction
  • FIG. 2 Thermogravimetric Analysis
  • the TGA data for amorphous Compound 4 (neat form) were collected on a TA instrument Discovery series with TRIOS system.
  • the TGA curve for amorphous Compound 4 (neat form) is provided in FIG. 2.
  • the TGA curve shows 1.69% weight loss from ⁇ 40-155 °C, with a ramp of 10.00 °C/min to 350.00 °C.
  • the DSC data for amorphous Compound 4 were collected on a TA instrument Discovery series with TRIOS system.
  • the DSC was run using the following modulated DSC method: 1. Equilibrated at -20.00 °C, 2. Modulated by +/- 1.00 °C every 60 seconds, 3. Isothermal for 5.00 min, then 4. Ramp of 2.00 °C/min to 250.00 °C.
  • the DSC thermogram for amorphous Compound 4 (neat form) is provided in FIG. 3. The thermogram shows a Tg midpoint at 77.6 °C. Step 6: Solid form characterization of crystalline Compound 5 Form A (neat) A.
  • Example 6 Preparation of 16-amino-10,18-bis(trifluoromethyl)-20-oxa-2,12,13,19- tetraazatetracyclo[13.3.1.12,5.111,14]henicosa-1(19),11,13,15,17-pentaen-10-ol (diastereomer pair 1) (Compound 8) and 16-amino-10,18-bis(trifluoromethyl)-20- oxa-2,12,13,19-tetraazatetracyclo[13.3.1.12,5.111,14]henicosa-1(19),11,13,15,17- pentaen-10-ol (diastereomer pair 2) (Compound 9) Step 1: tert-Butyl 3-vinylpyrrolidine-1-carboxylate [00389] n-Butyllithium (26.6 mL of 2.5 M in hexanes, 66.5 mmol) was slowly added to a suspension of methyl
  • Step 2 3-Vinylpyrrolidine (trifluoroacetate salt)
  • Trifluoroacetic acid 47.360 g, 32 mL, 415.35 mmol
  • tert- butyl 3-vinylpyrrolidine-1-carboxylate 8 g, 40.553 mmol
  • dichloromethane 32 mL
  • Toluene 40 mL was added and concentrated to provide as a brown oil
  • 3-vinylpyrrolidine (trifluoroacetate salt) (13.3 g, 93 %).
  • Step 3 9H-Fluoren-9-ylmethyl 3-vinylpyrrolidine-1-carboxylate
  • 9H-Fluoren-9-ylmethyl carbonochloridate 550 mg, 2.126 mmol
  • 3-vinylpyrrolidine (trifluoroacetate salt) 500 mg, 1.4206 mmol
  • diisopropylethylamine 556.50 mg, 0.75 mL, 4.3058 mmol
  • Step 6 tert-Butyl N-[2-[5-[1-benzyloxy-5-pyrrolidin-3-yl-1-(trifluoromethyl)pentyl]- 1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate
  • Piperidine 172.20 mg, 0.2 mL, 2.0224 mmol
  • 9H-fluoren-9- ylmethyl 3-[5-benzyloxy-5-[5-[6-bromo-3-(tert-butoxycarbonylamino)-5- (trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazol-2-yl]-6,6,6-trifluoro-hexyl]pyrrolidine-1- carboxylate (75 mg, 0.0794 mmol) in THF (5 mL) and the mixture was stirred overnight at room temperature then concentrated under reduced pressure.
  • Step 7 tert-Butyl N-[10-(benzyloxy)-10,18-bis(trifluoromethyl)-20-oxa-2,12,13,19- tetraazatetracyclo[13.3.1.12,5.111,14]henicosa-1(18),11,13,15(19),16-pentaen-16- yl]carbamate [00395] DIPEA (51.940 mg, 0.07 mL, 0.4019 mmol) was added to tert-butyl N-[2-[5-[1- benzyloxy-5-pyrrolidin-3-yl-1-(trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5- (trifluoromethyl)-3-pyridyl]carbamate (32 mg, 0.0443 mmol) in acetonitrile (7 mL) and the mixture was heated at 80 °C overnight.
  • the residue was purified by silica gel chromatography using a gradient from 0 % to 10 % of ethyl acetate in heptanes giving as a green-yellow gum, tert- butyl N-[10-(benzyloxy)-10,18-bis(trifluoromethyl)-20-oxa-2,12,13,19- tetraazatetracyclo[13.3.1.12,5.111,14]henicosa-1(18),11,13,15(19),16-pentaen-16- yl]carbamate (23 mg, 79 %).
  • Step 8 10-(Benzyloxy)-10,18-bis(trifluoromethyl)-20-oxa-2,12,13,19- tetraazatetracyclo[13.3.1.12,5.111,14]henicosa-1(18),11,13,15(19),16-pentaen-16- amine
  • TFA 1.800 g, 1 mL, 12.98 mmol
  • Step 9 16-Amino-10,18-bis(trifluoromethyl)-20-oxa-2,12,13,19- tetraazatetracyclo[13.3.1.12,5.111,14]henicosa-1(19),11,13,15,17-pentaen-10-ol [00397] To a nitrogen degassed solution of 10-(benzyloxy)-10,18-bis(trifluoromethyl)- 20-oxa-2,12,13,19-tetraazatetracyclo[13.3.1.12,5.111,14]henicosa-1(18),11,13,15(19),16- pentaen-16-amine (42 mg, 0.0776 mmol) in methanol (6 mL) was added SiliaCat Pd 0 (120 mg, 0.24 mmol/g, 0.0288 mmol) and the reaction was stirred for 2 days under a hydrogen balloon at room temperature.
  • SiliaCat Pd 0 120 mg, 0.24 mmol
  • reaction mixture was filtered over Celite, washed with methanol and the filtrate was evaporated.
  • residue was purified by silica gel chromatography using a gradient from 0 % to 30 % of ethyl acetate in heptanes giving as a yellow solid and racemic mixture of 4 stereoisomers, 16-amino-10,18- bis(trifluoromethyl)-20-oxa-2,12,13,19-tetraazatetracyclo[13.3.1.12,5.111,14]henicosa- 1(19),11,13,15,17-pentaen-10-ol (17 mg, 48 %).
  • Step 10 16-Amino-10,18-bis(trifluoromethyl)-20-oxa-2,12,13,19- tetraazatetracyclo[13.3.1.12,5.111,14]henicosa-1(19),11,13,15,17-pentaen-10-ol (diastereomer pair 1) (Compound 8) and 16-amino-10,18-bis(trifluoromethyl)-20- oxa-2,12,13,19-tetraazatetracyclo[13.3.1.12,5.111,14]henicosa-1(19),11,13,15,17- pentaen-10-ol (diastereomer pair 2) (Compound 9) [00398] 16-Amino-10,18-bis(trifluoromethyl)-20-oxa-2,12,13,19- tetraazatetracyclo[13.3.1.12,5.111,14]henicosa-1(19),11,13,15,
  • Example 7 Preparation of (6E,12R)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,6,17,19-hexaen-20-amine (Compound 10) Step 1: tert-Butyl N-[(12R)-6-hydroxy-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetrazatetracyclo[15.3.1.12,5.012,16]docosa-1(20),2,4,17(21),18-pentaen-20- yl]carbamate [00401] Into a solution of tert-butyl N-[(12S)-6-benzyloxy-6,18-bis(trifluoromethyl)-22- oxa-3,4,16,21-tetrazatetracyclo[15.3.1.12,5.012,16]
  • reaction mixture was purged with nitrogen three times then back-filled with hydrogen two times before it was subjected to 60 psi hydrogenation for 67 h.
  • the reaction mixture was filtered over a bed of Celite and the filter bed was washed with MeOH (3 X 100 mL).
  • MeOH 3 X 100 mL
  • the combined filtrates were concentrated by rotary evaporation yielding as a yellow solid, tert-butyl N- [(12R)-6-hydroxy-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetrazatetracyclo[15.3.1.12,5.012,16]docosa-1(20),2,4,17(21),18-pentaen-20-yl]carbamate (5.71 g, 95 %).
  • Step 2 tert-Butyl N-[(6E,12R)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,6,17,19-hexaen-20- yl]carbamate [00402] tert-Butyl N-[(12R)-6-hydroxy-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetrazatetracyclo[15.3.1.12,5.012,16]docosa-1(20),2,4,17(21),18-pentaen-20-yl]carbamate (14 mg, 0.02476 mmol) was dissolved
  • Example 12 Preparation of (6S,12R)-20-(ethylamino)-6,18-bis(trifluoromethyl)-22- oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6- ol (Compound 16) Step 1: (6S,12R)-20-(Ethylamino)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-ol (Compound 16) [00411] To (6S,12R)-20-amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docos
  • Example 13 Preparation of 19-amino-6,17-bis(trifluoromethyl)-21-oxa-3,4,15,20- tetraazatetracyclo[14.3.1.12,5.011,15]henicosa-1(20),2,4,16,18-pentaen-6-ol (diastereomer pair 1) (Compound 17) and 19-amino-6,17-bis(trifluoromethyl)-21- oxa-3,4,15,20-tetraazatetracyclo[14.3.1.12,5.011,15]henicosa-1(20),2,4,16,18-pentaen- 6-ol (diastereomer pair 2) (Compound 18) Step 1: Methyl 3-[bis(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)-6-(2- vinylpyrrolidin-1-yl)pyridine-2-carboxylate [00412] In a 250-mL sealed vessel, 2-viny
  • the reaction mixture was cooled to ambient temperature and the solvent removed in vacuo.
  • the residue was diluted with EtOAc (50 mL) and washed brine (2 X 25 mL) dried over sodium sulfate, filtered and concentrated.
  • the residue was purified by silica gel chromatography (120 gram column) using a gradient from 100 % hexanes to 50 % ethyl acetate in hexanes giving as a tan solid, methyl 3-[bis(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)-6-(2-vinylpyrrolidin- 1-yl)pyridine-2-carboxylate (1.93 g, 75 %).
  • Step 2 3-(tert-Butoxycarbonylamino)-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-1- yl)pyridine-2-carboxylic acid [00413] To a solution of methyl 3-[bis(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)- 6-(2-vinylpyrrolidin-1-yl)pyridine-2-carboxylate (1.93 g, 3.744 mmol) in THF (20 mL), methanol (19 mL) and water (15 mL) was added anhydrous lithium hydroxide (350 mg, 14.32 mmol).
  • the residue was purified by silica gel chromatography (80 gram column) using a gradient from 100 % hexanes to 80 % ethyl acetate in hexanes giving as a yellow solid, 3-(tert- butoxycarbonylamino)-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-1-yl)pyridine-2- carboxylic acid (1.35 g, 90 %).
  • Step 3 tert-Butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)hex-5- enoyl]amino]carbamoyl]-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-1-yl)-3- pyridyl]carbamate [00414] To a solution of 3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)-6-(2- vinylpyrrolidin-1-yl)pyridine-2-carboxylic acid (1.3 g, 3.239 mmol) in NMP (16.5 mL) was added 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride salt) (1.10 g, 3.247 mmol) and DIEA
  • the reaction mixture was stirred at room temperature for 18 h.
  • the reaction was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution.
  • the organic layer was further washed with 10 % citric acid solution followed by brine.
  • the organics were separated, dried over sodium sulfate, filtered and evaporated.
  • Step 4 tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4- oxadiazol-2-yl]-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-1-yl)-3-pyridyl]carbamate [00415] A solution of tert-butyl N-[2-[[[[2-benzyloxy-2-(trifluoromethyl)hex-5- enoyl]amino]carbamoyl]-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-1-yl)-3- pyridyl]carbamate (1.75 g, 2.552 mmol) and DIEA (1.55 mL, 8.899 mmol) in acetonitrile (40
  • the resulted mixture was heated at 70 °C for 2 hours.
  • the reaction mixture was cooled and quenched with a saturated solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate. The organics were separated, dried over sodium sulfate, filtered and evaporated.
  • the residue was purified by silica gel chromatography (80 gram column) using a gradient from 100 % hexanes to 50 % ethyl acetate in hexanes giving as a yellow residue, tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4- oxadiazol-2-yl]-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-1-yl)-3-pyridyl]carbamate (1.69 g, 99 %).
  • Zhan catalyst-1B 300 mg, 0.4089 mmol was added in two portions over 10 minutes. The resulting mixture was heated at 70 °C for 2 h, then 80 °C for 3 h. Added more Zhan catalyst-1B (300 mg, 0.4089 mmol) and heated at 85°C for additional 18 h to complete the reaction. The reaction mixture was cooled to room temperature and concentrated under reduced pressure.
  • Step 6 tert-Butyl N-[6-hydroxy-6,17-bis(trifluoromethyl)-21-oxa-3,4,15,20- tetraazatetracyclo[14.3.1.12,5.011,15]henicosa-1(20),2,4,16,18-pentaen-19- yl]carbamate (diastereomer pair 1) and tert-butyl N-[6-hydroxy-6,17- bis(trifluoromethyl)-21-oxa-3,4,15,20-tetraazatetracyclo[14.3.1.12,5.011,15]henicosa- 1(20),2,4,16,18-pentaen-19-yl]carbamate (diastereomer pair 2) [00417] To a solution of tert-butyl N-[6-(benzyloxy)-6,17-bis(trifluoromethyl)-21-oxa-3,4,15,20- tetraazatetracyclo
  • the mixture was put in a Parr Shaker and degassed under vacuum and filled with nitrogen gas three times. Then, all nitrogen gas was removed, and the reactor was pressurized to 60 psi with hydrogen gas. The mixture was shaken for 17 h. After that time, the reactor was depressurized, and the reaction was filtered and concentrated under vacuum.
  • the residue was purified by reverse-phase preparative chromatography utilizing a C 18 column and a gradient from 30 % to 99 % acetonitrile and water (5 mM HCl as modifier) for 15 minutes giving as yellow residues, two diastereomer pairs of products: [00418]
  • the first diastereomer pair to elute was isolated as tert-butyl N-[6-hydroxy- 6,17-bis(trifluoromethyl)-21-oxa-3,4,15,20- tetraazatetracyclo[14.3.1.12,5.011,15]henicosa-1(20),2,4,16,18-pentaen-19-yl]carbamate (diastereomer pair 1) (15 mg, 77 %).
  • Step 7 19-Amino-6,17-bis(trifluoromethyl)-21-oxa-3,4,15,20- tetraazatetracyclo[14.3.1.12,5.011,15]henicosa-1(20),2,4,16,18-pentaen-6-ol (diastereomer pair 1) (Compound 17) [00420] tert-Butyl N-[6-hydroxy-6,17-bis(trifluoromethyl)-21-oxa-3,4,15,20- tetraazatetracyclo[14.3.1.12,5.011,15]henicosa-1(20),2,4,16,18-pentaen-19-yl]carbamate (diastereomer pair 1) (15 mg, 0.0272 mmol) was dissolved in DCM (250 ⁇ L) and to the mixture was added TFA (50 ⁇ L, 0.649
  • Step 8 19-Amino-6,17-bis(trifluoromethyl)-21-oxa-3,4,15,20- tetraazatetracyclo[14.3.1.12,5.011,15]henicosa-1(20),2,4,16,18-pentaen-6-ol (diastereomer pair 2) (Compound 18) [00421] tert-Butyl N-[6-hydroxy-6,17-bis(trifluoromethyl)-21-oxa-3,4,15,20- tetraazatetracyclo[14.3.1.12,5.011,15]henicosa-1(20),2,4,16,18-pentaen-19-yl]carbamate (diastereomer pair 2) (16 mg, 0.02901 mmol) was dissolved in DCM (250 ⁇ L) and to the mixture was added TFA (50 ⁇ L, 0.649
  • Example 14 Preparation of 17-amino-13-methyl-6,15-bis(trifluoromethyl)-19-oxa- 3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 1) (Compound 19) and 17-amino-13-methyl-6,15-bis(trifluoromethyl)- 19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 2) (Compound 20) Step 1: Methyl 3-[bis(tert-butoxycarbonyl)amino]-6-[but-3-enyl(methyl)amino]-5- (trifluoromethyl)pyridine-2-carboxylate [
  • Step 2 6-[But-3-enyl(methyl)amino]-3-(tert-butoxycarbonylamino)-5- (trifluoromethyl)pyridine-2-carboxylic acid [00423] To a solution of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-[but-3- enyl(methyl)amino]-5-(trifluoromethyl)pyridine-2-carboxylate (360 mg, 0.715 mmol) in THF (3.6 mL) was added methanol (3.6 mL) and water (1.8 mL).
  • Step 3 tert-Butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)hex-5- enoyl]amino]carbamoyl]-6-[but-3-enyl(methyl)amino]-5-(trifluoromethyl)-3- pyridyl]carbamate [00424] To a solution of 6-[but-3-enyl(methyl)amino]-3-(tert-butoxycarbonylamino)-5- (trifluoromethyl)pyridine-2-carboxylic acid (415 mg, 1.066 mmol) in NMP (5.5 mL) was added 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (325 mg, 1.075 mmol) and DIEA (750 ⁇ L, 4.3
  • the reaction mixture was stirred at room temperature for 18 h.
  • the reaction was diluted with ethyl acetate and washed with sodium bicarbonate solution.
  • the organic layer was further washed with 10 % citric acid solution followed by brine.
  • the organics were separated, dried over sodium sulfate, filtered and evaporated.
  • Step 4 tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4- oxadiazol-2-yl]-6-[but-3-enyl(methyl)amino]-5-(trifluoromethyl)-3- pyridyl]carbamate [00425] A solution of tert-butyl N-[2-[[[[2-benzyloxy-2-(trifluoromethyl)hex-5- enoyl]amino]carbamoyl]-6-[but-3-enyl(methyl)amino]-5-(trifluoromethyl)-3- pyridyl]carbamate (575 mg, 0.8536 mmol) and DIEA (550 ⁇ L, 3.158 mmol)
  • the resulted mixture was heated at 70 oC for 3 hours.
  • the reaction mixture was cooled and quenched with a saturated solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate. The organics were separated, dried over sodium sulfate, filtered and evaporated.
  • the mixture was degassed under vacuum and filled with nitrogen gas three times. Then, all nitrogen gas was removed, and the reactor was pressurized to 60 psi with hydrogen gas. The mixture was shaken for 4 h in a Parr shaker. The reactor was depressurized and an additional 0.2 eq Pd/C (134 mg of 10 % w/w) was added. The mixture was returned to the Parr shaker and degassed under vacuum and filled with nitrogen gas three times. Then, all nitrogen gas was removed, and the reactor was pressurized to 55 psi with hydrogen gas. The mixture was shaken for 3 hours. After that time, the reactor was depressurized and an additional 0.7 eq Pd/C (465 mg of 10 % w/w) was added.
  • the mixture was returned to the Parr shaker and degassed under vacuum and filled with nitrogen gas three times. Then, all nitrogen gas was removed, and the reactor was pressurized to 45 psi with hydrogen gas. The mixture was shaken for 6 h more. After that time, the reactor was depressurized and filtered then concentrated under vacuum. EtOAc (25 mL) was added plus AcOH (5 mL), then purged the mixture under nitrogen and 1.0 equivalents of fresh Pd/C (665 mg of 10 % w/w, 0.6214 mmol) was added. The mixture was put in a Parr shaker and degassed under vacuum and filled with nitrogen gas three times. Then, all nitrogen gas was removed, and the reactor was pressurized to 35 psi with hydrogen gas.
  • Step 8 17-Amino-13-methyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 1) (Compound 19) and 17-amino-13-methyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 2) (Compound 20) [00429] Racemic 17-amino-13-methyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (130 mg, 0.2959 m
  • Step 9 Solid form characterization of amorphous Compound 19 (neat form)
  • A. X-Ray Powder Diffraction [00432] The XRPD diffractogram for amorphous Compound 19 (neat form) was acquired using the General X-Ray Powder Diffraction (XRPD) Method and is provided in FIG. 4.
  • B. Thermogravimetric Analysis (TGA) [00433] The TGA curve for amorphous Compound 19 (neat form) is provided in FIG. 5.
  • the TGA curve shows 5.71% weight loss from ⁇ 40-198.6 °C, with a ramp of 10.00 °C/min to 350.00 °C.
  • the DSC data for amorphous Compound 19 (neat form) were collected using the following method: 1. 25 °C to 200.00 °C, 10 °C/min, 2. 200 °C to -20 °C, -50 °C/min, then 3. -20 °C to 150 °C, 10 °C/min.
  • the DSC thermogram for amorphous Compound 19 (neat form) is provided in FIG. 6. The thermogram shows a Tg midpoint at 69.6 °C.
  • Example 15 Preparation of (12R)-20-amino-18-(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-ol (enantiomer 1) (Compound 21) and (12R)-20-amino-18-(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-ol (enantiomer 2) (Compound 22) Step 1: Ethyl 2-oxohex-5-enoate [00436] A solution of diethyl oxalate (58.5 g, 400.3 mmol) in THF (290 mL) in 2 L flask with mechanical stirring under nitrogen was cooled in a dry ice bath and brom
  • Step 2 Ethyl 2-hydroxyhex-5-enoate [00437] To a solution of ethyl 2-oxohex-5-enoate (12.4 g, 79.4 mmol) in dichloromethane (317.6 mL) was added sodium triacetoxyborohydride (33.66 g, 158.8 mmol) and the mixture was stirred overnight at room temperature. The reaction was carefully quenched with the addition of saturated aqueous NaHCO 3 . The resulting layers were separated and the aqueous layer was further extracted with DCM (2 X 150 mL).
  • Step 3 Ethyl 2-benzyloxyhex-5-enoate [00438] To a solution of ethyl 2-hydroxyhex-5-enoate (12.3 g, 77.75 mmol) in DMF (65.89 mL) at 0 oC was added sodium hydride (3.9 g of 60 % w/w, 97.51 mmol) portion- wise. The mixture (cream suspension) was stirred at 0 oC for 30 min. To the mixture was added bromomethylbenzene (11.61 mL, 97.61 mmol) and the mixture allowed to warm to ambient temperature and stirred for 18 h.
  • the reaction was quenched with slow addition of 200 mL of saturated aqueous NH 4 Cl and the resulting mixture was stirred at ambient temperature for 10 min.
  • the mixture was diluted with MTBE (415.2 mL) and the organic phase separated.
  • the organic phase was washed with water (166.2 mL), brine (50 mL), dried over MgSO 4 , filtered and concentrated to afford as an orange oil, ethyl 2- benzyloxyhex-5-enoate (19 g, 98 %).
  • Step 4 2-Benzyloxyhex-5-enoic acid [00439] To a solution of ethyl 2-benzyloxyhex-5-enoate (19.3 g, 77.72 mmol) in MeOH (112.6 mL) and THF (38.6 mL) was added NaOH (72.2 mL of 2 M, 144.4 mmol) and the mixture stirred at ambient temperature for 6 h. The organic solvents were removed in vacuo and the residue was diluted with 1 M NaOH (25 mL) and extracted with MTBE (2 X 300 mL).
  • the aqueous phase was extracted with ethyl acetate (2 X 150 mL) and the organic phases were combined and washed with brine (150 mL).
  • the organic phase was dried over MgSO 4 , filtered and concentrated in vacuo providing as an orange oil, 2-benzyloxyhex-5-enoic acid (13.5 g, 79 %).
  • Step 5 tert-Butyl N-(2-benzyloxyhex-5-enoylamino)carbamate
  • 2-benzyloxyhex-5-enoic acid (13.5 g, 61.29 mmol) in DMF (112.2 mL) was added HATU (30.71 g, 80.77 mmol) and DIEA (22.83 mL, 131.1 mmol) and the mixture was stirred at ambient temperature for 10 min.
  • tert-butyl N-aminocarbamate (8.424 g, 63.74 mmol) (slight exotherm upon addition) and the mixture was stirred at ambient temperature for 3 h.
  • the reaction was diluted with water and extracted with ethyl acetate (3 X 20 mL). The organic layers were washed with brine (25 mL), dried over MgSO 4 , filtered and concentrated in vacuo to give an orange colored oil.
  • the crude material was then purified on silica gel chromatography (12 gram column) using a gradient from 0 % to 50 % ethyl acetate in hexanes which afforded as a colorless oil, tert-butyl N-(2-benzyloxyhex-5-enoylamino)carbamate (20 g, 76 %).
  • Step 6 2-Benzyloxyhex-5-enehydrazide (hydrochloride salt) [00441] To a solution of tert-butyl N-(2-benzyloxyhex-5-enoylamino)carbamate (515 mg, 1.54 mmol) in dichloromethane (2.962 mL) was added HCl (1.782 mL of 4 M in dioxane, 7.128 mmol). The mixture was stirred at room temperature overnight, concentrated and co-evaporated with dichloromethane and heptanes to give as a white solid, 2- benzyloxyhex-5-enehydrazide (hydrochloride salt) (417 mg, 99 %).
  • Step 7 tert-Butyl N-[6-[(2S)-2-allylpyrrolidin-1-yl]-2-[(2-benzyloxyhex-5- enoylamino)carbamoyl]-5-(trifluoromethyl)-3-pyridyl]carbamate
  • NMP 44.87 mL
  • 2-benzyloxyhex-5-enehydrazide hydrochloride salt
  • reaction mixture was stirred at room temperature for 3 h.
  • the reaction was extracted with ethyl acetate (3 X 20 mL). The organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated.
  • Step 8 tert-Butyl N-[6-[(2S)-2-allylpyrrolidin-1-yl]-2-[5-(1-benzyloxypent-4-enyl)- 1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyl]carbamate [00443] A solution of tert-butyl N-[6-[(2S)-2-allylpyrrolidin-1-yl]-2-[(2-benzyloxyhex- 5-enoylamino)carbamoyl]-5-(trifluoromethyl)-3-pyridyl]carbamate (2.53 g, 4.005 mmol) and DIEA (2.425 mL, 13.92 mmol) in acetonitrile (57.84 mL) was heated to 50 °C, then p- toluenesulfonyl chloride (840 mg, 4.406 mmol) was added
  • the mixture was heated at 70 °C for 2 hours.
  • the reaction mixture was cooled and quenched with a saturated aqueous solution of sodium bicarbonate (25 mL) and extracted with ethyl acetate (3 X 25 mL). The combined organics were dried over sodium sulfate, filtered and evaporated.
  • Step 9 tert-Butyl N-[(12S)-6-(benzyloxy)-18-(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,9,17,19-hexaen-20- yl]carbamate (E/Z mixture) [00444] To a degassed solution of tert-butyl N-[6-[(2S)-2-allylpyrrolidin-1-yl]-2-[5-(1- benzyloxypent-4-enyl)-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyl]carbamate (2.0 g, 3.259 mmol) in DCE (481.2 mL) was added Zhan catalyst-1B (358.7 mg, 0.4889 mmol) at 50 °C under nitrogen atmosphere in two portions over
  • Example 16 Preparation of 21-amino-6,19-bis(trifluoromethyl)-23-oxa-3,4,17,22- tetraazatetracyclo[16.3.1.12,5.013,17]tricosa-1(22),2,4,18,20-pentaen-6-ol (enantiomer 1) (Compound 23), 21-amino-6,19-bis(trifluoromethyl)-23-oxa-3,4,17,22- tetraazatetracyclo[16.3.1.12,5.013,17]tricosa-1(22),2,4,18,20-pentaen-6-ol (enantiomer 2) (Compound 24), 21-amino-6,19-bis(trifluoromethyl)-23-oxa-3,4,17,22- tetraazatetracyclo[16.3.1.12,5.013,17]tricosa-1(22),2,4,18,20-pentaen-6-ol (enantio
  • reaction was heated at 120 °C for 30 min under microwave irradiation.
  • the reaction mixture was then diluted with ethyl acetate, washed with saturated ammonium chloride solution then brine, dried over anhydrous sodium sulphate, filtered and concentrated.
  • Step 2 tert-Butyl N-[6-(benzyloxy)-6,19-bis(trifluoromethyl)-23-oxa-3,4,17,22- tetraazatetracyclo[16.3.1.12,5.013,17]tricosa-1(22),2,4,9,18,20-hexaen-21- yl]carbamate (E/Z mixture) [00451] To a degassed solution of tert-butyl N-[2-[5-[1-benzyloxy-1- (trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-(2-but-3-enylpyrrolidin-1-yl)-5- (trifluoromethyl)-3-pyridyl]carbamate (170 mg, 0.2444 mmol) (contaminated with some starting material possess
  • the flask was placed on a hydrogen Parr Shaker and degassed under vacuum and filled with nitrogen gas three times. Then, all nitrogen gas was removed, and the reactor was pressurized to 50 psi with hydrogen gas and shaken for 2 days. The flask was depressurized, and the mixture was filtered through Celite and the filtrate was concentrated.
  • Step 4 21-Amino-6,19-bis(trifluoromethyl)-23-oxa-3,4,17,22- tetraazatetracyclo[16.3.1.12,5.013,17]tricosa-1(22),2,4,18,20-pentaen-6-ol [00453] tert-Butyl N-[6-hydroxy-6,19-bis(trifluoromethyl)-23-oxa-3,4,17,22- tetraazatetracyclo[16.3.1.12,5.013,17]tricosa-1(22),2,4,18,20-pentaen-21-yl]carbamate (38 mg, 0.06557 mmol) in a pre-made solution of TFA (250 ⁇ L, 3.245 mmol) and dichloromethane (750 ⁇ L) was stirred at room temperature for about 1 h.
  • TFA 250 ⁇ L, 3.245 mmol
  • dichloromethane 750 ⁇ L
  • Example 17 Preparation of 20-amino-14,14-dimethyl-6,18-bis(trifluoromethyl)-22- oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6- ol (enantiomer 1) (Compound 27), 20-amino-14,14-dimethyl-6,18- bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa- 1(21),2,4,17,19-pentaen-6-ol (enantiomer 2) (Compound 28), 20-amino-14,14- dimethyl-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),
  • Step 2 tert-Butyl 2-(iodomethyl)-4,4-dimethyl-pyrrolidine-1-carboxylate
  • imidazole 2.9 g, 42.599 mmol
  • triphenylphosphine 6.2 g, 23.638 mmol
  • 2-methyl tetrahydrofuran 75 mL
  • iodine 6.5 g, 25.61 mmol
  • the residue was purified by silica gel chromatography (120 g column) using a gradient from 0 % to 20 % ethyl acetate in heptanes giving as a light-yellow oil, tert-butyl 2- (iodomethyl)-4,4-dimethyl-pyrrolidine-1-carboxylate (6.7 g, 92 %).
  • Step 3 tert-Butyl 2-allyl-4,4-dimethyl-pyrrolidine-1-carboxylate
  • a suspension of copper iodide (4.8 g, 25.203 mmol) in degassed 2-methyl tetrahydrofuran (56 mL) was cooled to -50 °C and vinyl magnesium bromide (50 mL of 1 M, 50 mmol) in tetrahydrofuran was added dropwise keeping the reaction temperature ⁇ - 40 oC. Following the addition (20 min), the thick suspension was stirred for 30 minutes allowing the temperature to rise to -10 oC, at which time it became a thinner black suspension.
  • the black suspension was cooled to -60 oC and a solution of tert-butyl 2- (iodomethyl)-4,4-dimethyl-pyrrolidine-1-carboxylate (5.6 g, 16.509 mmol) in 2-methyl tetrahydrofuran (14 mL) was added dropwise keeping the reaction temperature ⁇ -50 oC.
  • the mixture was stirred for 30 min allowing the reaction temperature to rise to -15 °C.
  • the reaction was quenched with saturated ammonium chloride (25 mL) and the organic phase was separated and washed with saturated ammonium chloride (75 mL).
  • the aqueous phase was extracted with diethyl ether (75 mL) and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
  • the resultant light orange oil was purified by silica gel chromatography (80 g column) using a gradient from 0 % to 20 % dichloromethane in hexanes giving as a light yellow oil, tert-butyl 2-allyl-4,4-dimethyl- pyrrolidine-1-carboxylate (1.6 g, 40 %).
  • Step 4 2-Allyl-4,4-dimethyl-pyrrolidine (trifluoroacetate salt)
  • Trifluoroacetic acid 13.320 g, 9 mL, 116.82 mmol
  • tert-butyl 2-allyl-4,4-dimethyl-pyrrolidine-1-carboxylate 2.35 g, 9.8181 mmol
  • dichloromethane 15 mL
  • the cold bath was removed, the resulting mixture was stirred at room temperature for 2 hours and then solvents were removed under vacuum.
  • Step 5 tert-Butyl N-[6-(2-allyl-4,4-dimethyl-pyrrolidin-1-yl)-2-[5-[1-benzyloxy-1- (trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3- pyridyl]carbamate [00463] To a solution of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4- enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert- butoxycarbonyl-carbamate (10 g, 1.331 mmol) in DMSO (5 mL) was added cesium carbonate (2.2 g, 6.752 mmol) and 2-allyl-4,4-dimethyl-pyrrolidine (tri
  • reaction mixture was poured on crushed ice and after the ice melted, the water was decanted and the resultant pasty material was dissolved in ethyl acetate, washed with brine solution, dried over sodium sulfate, filtered and concentrated.
  • the resultant brown residue was purified by silica gel chromatography using a gradient 0 % to 30 % ethyl acetate in hexanes which provided tert-butyl N-[6-(2-allyl-4,4-dimethyl- pyrrolidin-1-yl)-2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]- 5-(trifluoromethyl)-3-pyridyl]carbamate (654 mg, 69 %).
  • Step 6 tert-Butyl N-[6-(benzyloxy)-14,14-dimethyl-6,18-bis(trifluoromethyl)-22-oxa- 3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,9,17,19-hexaen-20- yl]carbamate (E/Z mixture) [00464] To a degassed solution of tert-butyl N-[6-(2-allyl-4,4-dimethyl-pyrrolidin-1-yl)- 2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5- (trifluoromethyl)-3-pyridyl]carbamate (650 mg, 0.9159 mmol) (contaminated with some starting material possessing bis-N-Boc protection, see previous step) in DCE (200
  • Step 7 tert-Butyl N-[6-hydroxy-14,14-dimethyl-6,18-bis(trifluoromethyl)-22-oxa- 3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-20- yl]carbamate [00465] To a solution of tert-butyl N-[6-(benzyloxy)-14,14-dimethyl-6,18- bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa- 1(21),2,4,9,17,19-hexaen-20-yl]carbamate (E/Z mixture) (420 mg, 0.6161 mmol) (contaminated with some starting material possessing bis-N-Boc protection, see previous step) in AcOH (5 mL) was added Pd/
  • the flask was placed on a hydrogen Parr Shaker and degassed under vacuum and filled with nitrogen gas three times. Then, all nitrogen gas was removed, and the reactor was pressurized to 40 psi of hydrogen gas and shaken overnight.
  • the flask was depressurized and additional Pd/C (182 mg, 0.171 mmol, 10 % w/w, 50 % water wet) and a few drops of 1 M HCl were added.
  • the mixture was put on the hydrogen Parr Shaker and degassed under vacuum and filled with nitrogen gas three times. Then, all nitrogen gas was removed, and the reactor was pressurized to 60 psi with hydrogen gas and shaken overnight.
  • Step 8 20-Amino-14,14-dimethyl-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-ol (diastereomer pair 1) and 20-amino-14,14-dimethyl-6,18-bis(trifluoromethyl)-22-oxa- 3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-ol (diastereomer pair 2) [00467] tert-Butyl N-[6-hydroxy-14,14-dimethyl-6,18-bis(trifluoromethyl)-22-oxa- 3,4,
  • the crude products obtained from the two reactions were combined and dissolved in 5 mL of DMSO and purified by reverse phase HPLC using a dual gradient run from 85 % to 90 % acetonitrile in water (+5 mM HCl) over 30 minutes which gave two separate diastereomer pairs: [00468]
  • the first diastereomer pair to elute was isolated as a yellow solid, 20-amino- 14,14-dimethyl-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-ol (diastereomer pair 1) (40 mg, 67 %).
  • Step 9 20-Amino-14,14-dimethyl-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-ol (enantiomer 1) (Compound 27), and 20-amino-14,14-dimethyl-6,18-bis(trifluoromethyl)-22-oxa- 3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-ol (enantiomer 2) (Compound 28) [00470] 20-Amino-14,14-dimethyl-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21- t
  • Step 2 (12R)-6-(Hydroxyimino)-18-(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-20-amine (Compound 31) [00477] To a solution of tert-butyl N-[(12R)-6-oxo-18-(trifluoromethyl)-22-oxa- 3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-20- yl]carbamate (18 mg, 0.03544 mmol) in dichloromethane (400 ⁇ L) was added TFA (27.30 ⁇ L, 0.3543 mmol) and the mixture was stirred for 2 h.
  • reaction mixture was concentrated, dissolved in EtOH (200 ⁇ L) and then added hydroxylamine (hydrochloride salt) (3.773 mg, 0.05429 mmol) followed by NaOAc (4.858 mg, 0.05922 mmol). The mixture was heated at 75 oC for 5 h. The reaction mixture was cooled to room temperature, filtered and purified by reverse phase HPLC using a gradient from 30 % to 99 % acetonitrile in water (+5 mM HCl). Combined fractions of the second eluting, and major diastereomer and evaporated.
  • the reaction mixture was stirred at room temperature for 18 h.
  • the reaction was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution.
  • the organic layer was further washed with 10 % citric acid solution followed by brine.
  • the organics were separated, dried over sodium sulfate, filtered and evaporated.
  • Step 2 tert-Butyl N-[6-[(2S)-2-allylpyrrolidin-1-yl]-2-[5-[1-benzyloxy-1- (trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3- pyridyl]carbamate [00479] A solution of tert-butyl N-[6-[(2S)-2-allylpyrrolidin-1-yl]-2-[[[2-benzyloxy-2- (trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-5-(trifluoromethyl)-3-pyridyl]carbamate (3.16 g, 4.609 mmol) and DIEA (3 mL
  • the resulted mixture was heated at 70 °C for 2 hours.
  • the reaction mixture was cooled and quenched with saturated aqueous solution of sodium bicarbonate (50 mL) and stirred for 15 minutes.
  • the mixture was extracted with ethyl acetate (3 X 100 mL) and the combined organic layers were dried over sodium sulfate, filtered and evaporated.
  • Step 3 tert-Butyl N-[(11S)-6-(benzyloxy)-6,17-bis(trifluoromethyl)-21-oxa-3,4,15,20- tetraazatetracyclo[14.3.1.12,5.011,15]henicosa-1(20),2,4,8,16,18-hexaen-19- yl]carbamate (E/Z mixture) [00480] To a degassed solution of tert-butyl N-[6-[(2S)-2-allylpyrrolidin-1-yl]-2-[5-[1- benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3- pyridyl]carbamate (2.
  • Step 4 tert-Butyl N-[(11R)-6-hydroxy-6,17-bis(trifluoromethyl)-21-oxa-3,4,15,20- tetraazatetracyclo[14.3.1.12,5.011,15]henicosa-1(20),2,4,16,18-pentaen-19- yl]carbamate (enantiomer 1) and tert-butyl N-[(11R)-6-hydroxy-6,17- bis(trifluoromethyl)-21-oxa-3,4,15,20-tetraazatetracyclo[14.3.1.12,5.011,15]henicosa- 1(20),2,4,16,18-pentaen-19-yl]carbamate (enantiomer 2) [00481] To a solution of tert-butyl N-[(11S)-6-(benzyloxy)-6
  • the mixture was placed in a Parr shaker and degassed under vacuum and filled with nitrogen gas three times. Then, all nitrogen gas was removed, and the reactor was pressurized with hydrogen gas. The mixture was shaken at 80 psi for three hours, then at 100 psi for four more hours. The reactor was depressurized, and the reaction was filtered and concentrated.
  • the residue was purified by silica gel chromatography (40 gram column) using a gradient from 100 % hexanes to 60 % ethyl acetate in hexanes giving two enantiomeric products: [00482]
  • the first enantiomer to elute was isolated as a yellow residue, tert-butyl N- [(11R)-6-hydroxy-6,17-bis(trifluoromethyl)-21-oxa-3,4,15,20- tetraazatetracyclo[14.3.1.12,5.011,15]henicosa-1(20),2,4,16,18-pentaen-19-yl]carbamate (enantiomer 1) (58.7 mg, 57 %).
  • Example 20 Preparation of 17-amino-13-(2-methoxyethyl)-6,15-bis(trifluoromethyl)- 19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 1) (Compound 34) and 17-amino-13-(2-methoxyethyl)-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol (enantiomer 2) (Compound 35)
  • Step 1 tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4- oxadiazol-2-yl]-6-[but-3-enyl(2-methoxyethyl)amino]-5-(trifluoromethyl)-3-pyridyl]- N-tert-butoxycarbonyl-carbamate [00486] In a 250-mL sealed vessel, N-(2-methoxyethyl)but-3-en-1-amine (180 mg, 1.393 mmol), DIEA (1000 ⁇ L, 5.741 mmol) and tert-butyl N-[2-[5-[1-benzyloxy-1- (trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3- pyridyl]-N-tert-but
  • Step 2 tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4- oxadiazol-2-yl]-6-[but-3-enyl(2-methoxyethyl)amino]-5-(trifluoromethyl)-3- pyridyl]carbamate [00487] To a solution of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4- enyl]-1,3,4-oxadiazol-2-yl]-6-[but-3-enyl(2-methoxyethyl)amino]-5-(trifluoromethyl)-3- pyridyl]-N-tert-butoxycarbonyl
  • Step 3 tert-Butyl N-[6-benzyloxy-13-(2-methoxyethyl)-6,15-bis(trifluoromethyl)-19- oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,9,14(18),15-hexaen-17- yl]carbamate (E/Z mixture) [00488] In a 500 mL round-bottom flask, a degassed solution of tert-butyl N-[2-[5-[1- benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-[but-3-enyl(2- methoxyethyl)amino]-5-(trifluoromethyl)-3-pyridyl
  • Zhan catalyst-1B 35 mg, 0.04770 mmol was added in two portions over 10 minutes. The resulting mixture was heated at 70 °C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 gram column) using a gradient from 100 % hexanes to 30 % ethyl acetate in hexanes to afford as a yellow residue, tert-butyl N-[6-benzyloxy-13-(2- methoxyethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,9,14(18),15-hexaen-17-yl]carbamate (E/Z mixture) (103 mg, 60 %).
  • Step 4 tert-Butyl N-[6-hydroxy-13-(2-methoxyethyl)-6,15-bis(trifluoromethyl)-19- oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17- yl]carbamate [00489] To a solution of tert-butyl N-[6-benzyloxy-13-(2-methoxyethyl)-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(17),2,4,9,14(18),15-hexaen-17-yl]carbamate (E/Z mixture) (103 mg, 0.
  • the mixture was placed on a Parr shaker and degassed under vacuum and filled with nitrogen gas three times. Then, all nitrogen gas was removed, and the reactor was pressurized with hydrogen gas. The mixture was shaken at 80 psi for 3 hours and at 100 psi for 4 additional hours.
  • Step 5 17-Amino-13-(2-methoxyethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol [00490] To a solution of tert-butyl N-[6-hydroxy-13-(2-methoxyethyl)-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-17-yl]carbamate (64 mg, 0.1097 mmol) in DCM (1.0 mL) was added TFA (750 ⁇ L, 9.735 mmol) and the mixture was stirred at room temperature for 1 h.
  • TFA 750 ⁇ L, 9.735 mmol
  • Step 6 17-Amino-13-(2-methoxyethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 1) (Compound 34) and 17-amino-13-(2-methoxyethyl)-6,15-bis(trifluoromethyl)-19-oxa- 3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 2) (Compound 35) [00491] Racemic 17-amino-13-(2-methoxyethyl)-6,15-bis(trifluoromethyl)-19-oxa- 3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(
  • Example 21 Preparation of (12R)-20-amino-18-(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-one (Compound 36) Step 1: (12R)-20-amino-18-(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-one (Compound 36) [00494] A solution of tert-butyl N-[(12R)-6-oxo-18-(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-20-y
  • Example 22 Preparation of 5-amino-11-hydroxy-3,11-bis(trifluoromethyl)-21-oxa- 1,8,9,16,22-pentaazatetracyclo[14.2.2.12,6.17,10]docosa-2,4,6(22),7,9-pentaen-15-one (enantiomer 1) (Compound 37) and 5-amino-11-hydroxy-3,11-bis(trifluoromethyl)- 21-oxa-1,8,9,16,22-pentaazatetracyclo[14.2.2.12,6.17,10]docosa-2,4,6(22),7,9-pentaen- 15-one (enantiomer 2) (Compound 38) Step 1: tert-Butyl N-[2-[5-[1-benzyloxy-5-
  • Step 2 tert-Butyl N-[2-[5-[1-benzyloxy-5-oxo-1-(trifluoromethyl)pentyl]-1,3,4- oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate [00496] To a solution of tert-butyl N-[2-[5-[1-benzyloxy-5-hydroxy-1- (trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3- pyridyl]carbamate (135 mg, 0.2017 mmol) in dichloromethane (2.0 mL) was added Dess- Martin periodinane (102.6 mg, 0.2419 mmol).
  • Step 3 5-Benzyloxy-5-[5-[6-bromo-3-(tert-butoxycarbonylamino)-5- (trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazol-2-yl]-6,6,6-trifluoro-hexanoic acid [00497]
  • tert-butyl N-[2-[5-[1-benzyloxy-5-oxo-1- (trifluoromethyl)pentyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3- pyridyl]carbamate 450 mg, 0.6743 mmol
  • 2-methyl-2-butene 1.389 mL, 13.11 mmol
  • tert-butanol 5.44 mL
  • the reaction mixture was stirred room temperature for 2 h.
  • the reaction mixture was partially concentrated under reduced pressure. Water (20 mL) was added and the aqueous layer was acidified with 1 N HCl until pH was ⁇ 1-2 and extracted with dichloromethane (2 X 50 mL).
  • Step 4 5-Benzyloxy-5-[5-[3-(tert-butoxycarbonylamino)-6-piperazin-1-yl-5- (trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazol-2-yl]-6,6,6-trifluoro-hexanoic acid [00498]
  • 5-benzyloxy-5-[5-[6-bromo-3-(tert- butoxycarbonylamino)-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazol-2-yl]-6,6,6- trifluoro-hexanoic acid 160 mg, 0.2341 mmol
  • diisopropylethylamine 244.7 ⁇ L, 1.405 mmol
  • piperazine 100.8 mg, 1.17 mmol
  • Step 5 tert-Butyl N-[11-(benzyloxy)-15-oxo-3,11-bis(trifluoromethyl)-21-oxa- 1,8,9,16,22-pentaazatetracyclo[14.2.2.12,6.17,10]docosa-2,4,6(22),7,9-pentaen-5- yl]carbamate [00499] To a solution of 5-benzyloxy-5-[5-[3-(tert-butoxycarbonylamino)-6-piperazin- 1-yl-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazol-2-yl]-6,6,6-trifluoro-hexanoic acid (125 mg, 0.1815 mmol) in DMF (12.5 mL) was added DIEA (158.1 ⁇ L, 0.9077 mmol) followed by HATU
  • reaction mixture was stirred at room temperature for 5 min.
  • the reaction was extracted with ethyl acetate (3 X 20 mL). The organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated.
  • Step 6 tert-Butyl N-[11-hydroxy-15-oxo-3,11-bis(trifluoromethyl)-21-oxa-1,8,9,16,22- pentaazatetracyclo[14.2.2.12,6.17,10]docosa-2,4,6(22),7,9-pentaen-5-yl]carbamate [00500] To a nitrogen flushed solution of tert-butyl N-[11-(benzyloxy)-15-oxo-3,11- bis(trifluoromethyl)-21-oxa-1,8,9,16,22-pentaazatetracyclo[14.2.2.12,6.17,10]docosa- 2,4,6(22),7,9-pentaen-5-yl]carbamate (115 mg, 0.1458 mmol) in acetic acid (2.639 mL
  • the mixture was evacuated and then stirred under a hydrogen atmosphere using a hydrogen-filled balloon at room temperature for 20 h. Filtered the solution through a silica plug, washing well with ethyl acetate and then concentrated the filtrate under reduced pressure. Purified the residue by preparative reverse phase HPLC using a C 18 column with a gradient of 30 % to 99 % acetonitrile in water.
  • Step 7 5-Amino-11-hydroxy-3,11-bis(trifluoromethyl)-21-oxa-1,8,9,16,22- pentaazatetracyclo[14.2.2.12,6.17,10]docosa-2,4,6(22),7,9-pentaen-15-one (enantiomer 1) (Compound 37) and 5-amino-11-hydroxy-3,11-bis(trifluoromethyl)- 21-oxa-1,8,9,16,22-pentaazatetracyclo[14.2.2.12,6.17,10]docosa-2,4,6(22),7,9-pentaen- 15-one (enantiomer 2) (Compound 38) [00501] tert-Butyl N-[11-hydroxy-15-oxo-3,11-bis(trifluoromethyl)-21-oxa-1,8,9,16,22- pentaazatetracyclo[14.2.2.12,6.17,10]docosa-2,
  • Peak 1 was concentrated to afford as a pale yellow solid, 5-amino-11-hydroxy- 3,11-bis(trifluoromethyl)-21-oxa-1,8,9,16,22- pentaazatetracyclo[14.2.2.12,6.17,10]docosa-2,4,6(22),7,9-pentaen-15-one (enantiomer 1) (2.9 mg, 35 %).
  • Example 23 Preparation of 17-amino-13-methyl-15-methylsulfonyl-6- (trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol (enantiomer 1) (Compound 39) and 17-amino-13-methyl- 15-methylsulfonyl-6-(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 2) (Compound 40) Step 1: Methyl 3-[bis(tert-butoxycarbonyl)amino]-6-[but-3-enyl(methyl)amino]-5- methylsulfonyl-pyridine-2-carboxylate [00504] N-Methyl
  • the reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure.
  • the residue was diluted with EtOAc (50 mL) and washed with brine (2 X 25 mL), dried over sodium sulfate, filtered and concentrated.
  • the residue was purified by silica gel chromatography (80 g column) using a gradient from 100 % hexanes to 60 % ethyl acetate in hexanes to afford as a pale yellow residue, methyl 3-[bis(tert- butoxycarbonyl)amino]-6-[but-3-enyl(methyl)amino]-5-methylsulfonyl-pyridine-2- carboxylate (820 mg, 95 %).
  • Step 2 6-[But-3-enyl(methyl)amino]-3-(tert-butoxycarbonylamino)-5-methylsulfonyl- pyridine-2-carboxylic acid [00505] To a solution of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-[but-3- enyl(methyl)amino]-5-methylsulfonyl-pyridine-2-carboxylate (810 mg, 1.577 mmol) in THF (8.5 mL) was added methanol (7.5 mL) and water (6.5 mL) followed by anhydrous lithium hydroxide (150 mg, 6.138 mmol).
  • the crude material was then purified by silica gel chromatography (40 gram column) using a gradient from 100 % hexanes to 80 % ethyl acetate in hexanes which afforded as a yellow solid, 6-[but-3- enyl(methyl)amino]-3-(tert-butoxycarbonylamino)-5-methylsulfonyl-pyridine-2- carboxylic acid (485 mg, 77 %).
  • Step 3 tert-butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)hex-5- enoyl]amino]carbamoyl]-6-[but-3-enyl(methyl)amino]-5-methylsulfonyl-3- pyridyl]carbamate [00506] To a solution of 6-[but-3-enyl(methyl)amino]-3-(tert-butoxycarbonylamino)-5- methylsulfonyl-pyridine-2-carboxylic acid (480 mg, 1.202 mmol) in NMP (7 mL) was added 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (380.9 mg, 1.260 mmol) and DIEA (850 ⁇ L, 4.880 mmol) followed by HATU (565 mg
  • the reaction mixture was stirred at room temperature for 18 h.
  • the reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution.
  • the organic layer was further washed with 10 % citric acid solution followed by brine.
  • the organics were separated, dried over sodium sulfate, filtered and evaporated.
  • Step 4 tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4- oxadiazol-2-yl]-6-[but-3-enyl(methyl)amino]-5-methylsulfonyl-3-pyridyl]carbamate [00507] A solution of tert-butyl N-[2-[[[[2-benzyloxy-2-(trifluoromethyl)hex-5- enoyl]amino]carbamoyl]-6-[but-3-enyl(methyl)amino]-5-methylsulfonyl-3- pyridyl]carbamate (720 mg, 1.053 mmol) and DIEA (750 ⁇ L, 4.306 mmol) in
  • the resulting mixture was heated at 70 °C for 2 hours.
  • the reaction mixture was cooled and quenched with a saturated aqueous solution of sodium bicarbonate (50 mL) and stirred for 15 minutes. Then the mixture was extracted with ethyl acetate (3 X 50 mL). The organics were combined, dried over sodium sulfate, filtered and evaporated.
  • Zhan catalyst-1B (212 mg, 0.2889 mmol) was added in two portions over 10 minutes. The resulting mixture was heated at 70 °C for 4 hours. Added more Zhan catalyst-1B (106 mg, 0.144 mmol) and the mixture was heated at 70 °C for 10 more hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure.
  • Step 6 tert-Butyl N-[6-hydroxy-13-methyl-15-methylsulfonyl-6-(trifluoromethyl)-19- oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-17- yl]carbamate [00509] A solution of tert-butyl N-[6-benzyloxy-13-methyl-15-methylsulfonyl-6- (trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(17),2,4,9,14(18),15-hexaen-17-yl]carbamate (E/Z mixture) (235 mg, 0.3685 mmol) in AcOH (5.0 mL) and
  • Step 7 17-Amino-13-methyl-15-methylsulfonyl-6-(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol [00510] To a solution of tert-butyl N-[6-hydroxy-13-methyl-15-methylsulfonyl-6- (trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(17),2,4,14(18),15-pentaen-17-yl]carbamate (140 mg, 0.2547 mmol) in DCM (2.5 mL) was added TFA (2.0 mL, 25.96 mmol) and the mixture was stirred at room temperature for
  • Step 8 17-Amino-13-methyl-15-methylsulfonyl-6-(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 1) (Compound 39) and 17-amino-13-methyl-15-methylsulfonyl-6-(trifluoromethyl)-19- oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 2) (Compound 40) [00511] Racemic 17-amino-13-methyl-15-methylsulfonyl-6-(trifluoromethyl)-19-oxa- 3,4,13,18-te
  • Example 24 Preparation of 17-amino-13-(2-hydroxyethyl)-6,15-bis(trifluoromethyl)- 19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 1) (Compound 41) and 17-amino-13-(2-hydroxyethyl)-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol (enantiomer 2) (Compound 42) Step 1: N-(2-Benzyloxyethyl)but-3-en-1-amine [00514] A mixture of 4-iodobut-1-ene
  • the mixture was then concentrated to a residue by rotary evaporation using no heat in the water bath and the residue was purified by silica gel chromatography (120 gram column) using a gradient from 100 % hexanes to 100 % ethyl acetate which afforded as a pale amber oil, N-(2-benzyloxyethyl)but-3-en-1- amine (6.69 g, 47 %).
  • Step 2 Methyl 6-[2-benzyloxyethyl(but-3-enyl)amino]-3-nitro-5- (trifluoromethyl)pyridine-2-carboxylate [00515] To a solution of N-(2-benzyloxyethyl)but-3-en-1-amine (3.1 g, 15.10 mmol) and methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (2.11 g, 7.415 mmol) in acetonitrile (41.0 mL) was added DIEA (6.5 mL, 37.32 mmol) and the mixture was stirred for 16 hours at room temperature.
  • DIEA 6.5 mL, 37.32 mmol
  • reaction mixture was concentrated under reduced pressure and the residue was purified twice by silica gel chromatography (120 gram column) using a gradient from 100 % hexanes to 30 % ethyl acetate in hexanes in both columns to afford as a yellow residue, methyl 6-[2-benzyloxyethyl(but-3-enyl)amino]-3- nitro-5-(trifluoromethyl)pyridine-2-carboxylate (3.23 g, 96 %).
  • Step 3 6-[2-Benzyloxyethyl(but-3-enyl)amino]-3-nitro-5-(trifluoromethyl)pyridine-2- carboxylic acid [00516] To a solution of methyl 6-[2-benzyloxyethyl(but-3-enyl)amino]-3-nitro-5- (trifluoromethyl)pyridine-2-carboxylate (3.23 g, 7.124 mmol) in THF (38 mL) was added MeOH (38 mL) and water (30 mL) followed by lithium hydroxide (737.8 mg, 30.81 mmol).
  • Step 4 6-[2-Benzyloxyethyl(but-3-enyl)amino]-N'-[2-benzyloxy-2- (trifluoromethyl)hex-5-enoyl]-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide [00517] To a solution of 6-[2-benzyloxyethyl(but-3-enyl)amino]-3-nitro-5- (trifluoromethyl)pyridine-2-carboxylic acid (1.6 g, 3.641 mmol) in NMP (28 mL) was added 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (1.98 g, 6.550 mmol) and DIEA (3 mL, 17.22 mmol) followed by HATU (2.9 g, 7.627 mmol).
  • the reaction mixture was stirred at room temperature for 18 h.
  • the reaction was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution.
  • the organic layer was further washed with 10 % citric acid solution followed by brine.
  • the organics were separated, dried over sodium sulfate, filtered and evaporated.
  • Step 5 N-(2-Benzyloxyethyl)-6-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4- oxadiazol-2-yl]-N-but-3-enyl-5-nitro-3-(trifluoromethyl)pyridin-2-amine [00518]
  • a solution of 6-[2-benzyloxyethyl(but-3-enyl)amino]-N'-[2-benzyloxy-2- (trifluoromethyl)hex-5-enoyl]-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide (833 mg, 1.151 mmol) and DIEA (1000 ⁇ L, 5.741 mmol) in acetonitrile (25 mL) was heated to 50 °C, then p-toluenesulfonyl chloride (350 mg, 1.836 mmol) was added in one portion.
  • the resulting mixture was heated at 70 °C for 2 hours.
  • the reaction mixture was cooled and quenched with saturated aqueous solution of sodium bicarbonate (50 mL) and stirred for 15 minutes.
  • the mixture was extracted with ethyl acetate (3 X 50 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated.
  • the mixture was degassed with nitrogen for 5 minutes, then purged by a balloon filled with hydrogen gas.
  • the mixture was stirred at 1 atm for 1 h.
  • Added more Pd/C (475 mg of 10 % w/w, 0.4453 mmol) and stirred for 3 more hours.
  • the reaction was filtered over a Celite plug and washed with acetonitrile and ethyl acetate and then concentrated the filtrate.
  • Step 8 17-Amino-13-(2-hydroxyethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 1) (Compound 41) and 17-amino-13-(2-hydroxyethyl)-6,15-bis(trifluoromethyl)-19-oxa- 3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 2) (Compound 42) [00521] Racemic 17-amino-13-(2-hydroxyethyl)-6,15-bis(trifluoromethyl)-19-oxa- 3,4,13,18-
  • the second enantiomer to elute was further purified by reverse-phase preparative HPLC using a gradient of 1 % to 99 % acetonitrile in water (+ 5 mM HCl) over 15 minutes to afford as a yellow solid, 17-amino-13-(2-hydroxyethyl)-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol (enantiomer 2) (51.4 mg, 62 %).
  • the XRPD diffractogram for crystalline Compound 41 Form A produced by Step 8 was acquired using the General X-Ray Powder Diffraction (XRPD) Method.
  • the XRPD diffractogram for crystalline Compound 41 Form A is provided in FIG. 7, and the XRPD data are summarized below in Table 4.
  • Table 4 XRPD signals for crystalline Compound 41 Form A B.
  • Thermogravimetric Analysis (TGA) [00525]
  • the TGA curve for crystalline Compound 41 Form A is provided in FIG. 8.
  • the TGA curve shows 3.89% weight loss from ⁇ 30-181.8 °C, with a ramp of 10.00 °C/min to 350.00 °C.
  • Example 25 Preparation of 17-amino-6-hydroxy-10,13-dimethyl-6,15- bis(trifluoromethyl)-19-oxa-3,4,10,13,18-pentazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-9-one (enantiomer 1) (hydrochloride salt) (Compound 43) and 17-amino-6-hydroxy-10,13-dimethyl-6,15-bis(trifluoromethyl)-19-oxa- 3,4,10,13,18-pentazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-9-one (enantiomer 2) (hydrochloride salt) (Compound 44) Step 1: tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4- oxadiazol-2-yl]
  • Step 2 4-Benzyloxy-4-[5-[3-(tert-butoxycarbonylamino)-6-[methyl-[2- (methylamino)ethyl]amino]-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazol-2-yl]- 5,5,5-trifluoro-pentanoic acid [00527] To a solution of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4- enyl]-1,3,4-oxadiazol-2-yl]-6-[methyl-[2-(methylamino)ethyl]amino]-5-(trifluoromethyl)- 3-pyridyl]carbamate (100 mg, 0.1518 mmol) in 3:1 mixture
  • Step 3 tert-Butyl N-[6-benzyloxy-10,13-dimethyl-9-oxo-6,15-bis(trifluoromethyl)-19- oxa-3,4,10,13,18-pentazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen- 17-yl]carbamate [00528] To a solution of 4-benzyloxy-4-[5-[3-(tert-butoxycarbonylamino)-6-[methyl-[2- (methylamino)ethyl]amino]-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazol-2-yl]-5,5,5- trifluoro-pentanoic acid (62 mg, 0.09163
  • Step 5 17-Amino-6-hydroxy-10,13-dimethyl-6,15-bis(trifluoromethyl)-19-oxa- 3,4,10,13,18-pentazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-9-one (enantiomer 1) (hydrochloride salt) (Compound 43) and 17-amino-6-hydroxy-10,13- dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,10,13,18- pentazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-9-one (enantiomer 2) (hydrochloride salt) (Compound 44) [00530] A racemic mixture of 17-amino-6-hydroxy-10,13-dimethyl-6,15- bis(trifluoromethyl)-19-oxa-3,4,10,13,18-pentazatricyclo[12.3.1.12,
  • Peak 1 was concentrated to afford as a viscous brown oil, 17-amino-6-hydroxy- 10,13-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,10,13,18- pentazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-9-one (enantiomer 1) (hydrochloride salt) (1.8 mg, 17 %).
  • Peak 2 was concentrated to afford as a viscous brown oil, 17-amino-6-hydroxy- 10,13-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,10,13,18- pentazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-9-one (enantiomer 2) (hydrochloride salt) (2.3 mg, 21 %).
  • Example 26 Preparation of (12R)-20-amino-6-methyl-18-(trifluoromethyl)-22-oxa- 3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-ol (enantiomer 2) (Compound 45) Step 1: tert-Butyl N-[(12R)-6-hydroxy-6-methyl-18-(trifluoromethyl)-22-oxa- 3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-20- yl]carbamate [00533] A solution of tert-butyl N-[(12R)-6-oxo-18-(trifluoromethyl)-22-oxa-3,4,16,21- tetraazatetracyclo[15.3.1.12,5.012,16]
  • Example 27 Preparation of ethyl 2-[17-amino-6-hydroxy-6,15-bis(trifluoromethyl)- 19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-13- yl]acetate (enantiomer 1) (Compound 46) and ethyl 2-[17-amino-6-hydroxy-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-13-yl]acetate (enantiomer 2) (Compound 47) Step 1: Ethyl 2-[[6-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2- yl]-5-[bis(tert-
  • Step 2 Ethyl 2-[6-benzyloxy-17-[bis(tert-butoxycarbonyl)amino]-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,9,14,16-hexaen-13-yl]acetate (E/Z mixture) [00537] In a 500 mL round-bottom 3-neck flask, a continuously degassed solution via nitrogen line of Zhan catalyst-1B (110 mg, 0.1499 mmol) in DCE (250 mL) was heated to 50 °C under nitrogen atmosphere.
  • Zhan catalyst-1B 110 mg, 0.1499 mmol
  • Pd/C 64 mg of 10 % w/w, 0.06014 mmol
  • the mixture was degassed with nitrogen for 5 minutes, then purged by a balloon filled with hydrogen gas.
  • the mixture was stirred at 1 atm of hydrogen for 1 h.
  • Pd/C 350 mg of 10 % w/w, 0.3289 mmol
  • the reaction was filtered over a Celite plug washing with acetonitrile, ethyl acetate and then the filtrate was concentrated.
  • Step 4 Ethyl 2-[17-amino-6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-13-yl]acetate [00539] To a solution of ethyl 2-[17-[bis(tert-butoxycarbonyl)amino]-6-hydroxy-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-13-yl]acetate (56 mg, 0.07869 mmol) in DCM (1.5 mL) was added TFA (250 ⁇ L, 3.245 mmol) and the
  • Step 5 Ethyl 2-[17-amino-6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-13-yl]acetate (enantiomer 1) (Compound 46) and ethyl 2-[17-amino-6-hydroxy-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-13-yl]acetate (enantiomer 2) (Compound 47) [00540] Racemic ethyl 2-[17-amino-6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa- 3,4,
  • Example 28 Preparation of 2-[17-amino-6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa- 3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-13-yl]-N- methyl-acetamide (enantiomer 1) (Compound 48) and 2-[17-amino-6-hydroxy-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-13-yl]-N-methyl-acetamide (enantiomer 2) (Compound 49) Step 1: 2-[17-(tert-Butoxycarbonylamino)-6-hydroxy-6,15-bis(trifluoromethyl)-19- oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5
  • Step 2 tert-Butyl N-[6-hydroxy-13-[2-(methylamino)-2-oxo-ethyl]-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(17),2,4,14(18),15-pentaen-17-yl]carbamate [00544] To a solution of 2-[17-(tert-butoxycarbonylamino)-6-hydroxy-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(17),2,4,14(18),15-pentaen-13-yl]acetic acid (51 mg, 0.08741 mmol) in NMP (1 mL) at room temperature
  • Step 4 2-[17-Amino-6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-13-yl]-N-methyl- acetamide (enantiomer 1) (Compound 48) and 2-[17-amino-6-hydroxy-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-13-yl]-N-methyl-acetamide (enantiomer 2) (Compound 49) [00546] Racemic 2-[17-amino-6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(
  • Step 2 Methyl 5-bromo-6-hydroxy-pyridine-2-carboxylate
  • Trifluoroacetic anhydride (298.00 g, 200 mL, 1.4188 mol) was added drop-wise to a mixture of methyl 5-bromo-1-oxido-pyridin-1-ium-2-carboxylate (40 g, 151.70 mmol) in DMF (240 mL) at 0 °C, over 1 hour (temperature should be kept below 10 °C) and the mixture was stirred at room temperature overnight. Then, the mixture was concentrated under reduced pressure to remove excess of trifluoroacetic acid.
  • Step 3 Methyl 5-bromo-6-hydroxy-3-nitro-pyridine-2-carboxylate [00551] To a solution of methyl 5-bromo-6-hydroxy-pyridine-2-carboxylate (10.9 g, 46.976 mmol) in sulfuric acid (65 mL) cooled in ice bath was added nitric acid (4.2280 g, 4 mL, 46.968 mmol) dropwise. After 5 min, the ice bath was removed, and the reaction mixture was stirred at 30 °C overnight.

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PCT/US2021/072475 2020-11-18 2021-11-17 Macrocycles containing a 1,3,4-oxadiazole ring for use as modulators of cystic fibrosis transmembrane conductance regulator WO2022109573A1 (en)

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JP2023529022A JP2023549547A (ja) 2020-11-18 2021-11-17 嚢胞性線維症膜コンダクタンス制御因子のモジュレーターとして使用するための１，３，４－オキサジアゾール環を含有する大環状化合物
KR1020237020002A KR20230123522A (ko) 2020-11-18 2021-11-17 낭성 섬유증 막관통 전도도 조절제로서 사용하기 위한 1,3,4-옥사디아졸 고리를 함유하는 거대환
AU2021383176A AU2021383176A1 (en) 2020-11-18 2021-11-17 Macrocycles containing a 1,3,4-oxadiazole ring for use as modulators of cystic fibrosis transmembrane conductance regulator
EP21843853.9A EP4247817A1 (en) 2020-11-18 2021-11-17 Macrocycles containing a 1,3,4-oxadiazole ring for use as modulators of cystic fibrosis transmembrane conductance regulator
CA3201793A CA3201793A1 (en) 2020-11-18 2021-11-17 Macrocycles containing a 1,3,4-oxadiazole ring for use as modulators of cystic fibrosis transmembrane conductance regulator
IL302873A IL302873A (en) 2020-11-18 2021-11-17 Macrocycles Containing a 1,3,4-OXADIAZOLE Ring for Use as Cystic Fibrosis Conductance Modulators
MX2023005721A MX2023005721A (es) 2020-11-18 2021-11-17 Macrociclos que contienen un anillo de 1,3,4-oxadiazol para su uso como moduladores del regulador de la conductancia transmembrana de la fibrosis quistica.
CR20230260A CR20230260A (es) 2020-11-18 2021-11-17 Macrociclos que contienen un anillo de 1,3,4-oxadiazol para su uso como moduladores del regulador de la conductancia transmembrana de la fibrosis quística
CN202180090910.1A CN116670140A (zh) 2020-11-18 2021-11-17 用作囊性纤维化跨膜转导调节因子的调节剂的含有1,3,4-噁二唑环的大环
PE2023001653A PE20231380A1 (es) 2020-11-18 2021-11-17 Macrociclicos que contienen una anillo de 1,3,4-oxadiazol para su uso como moduladores del regulador de la conductancia transmembrana de la fibrosis quistica
DO2023000099A DOP2023000099A (es) 2020-11-18 2023-05-17 Macrociclos que contienen un anillo de 1,3,4-oxadiazol para su uso como moduladores del regulador de la conductancia transmembrana de la fibrosis quística
CONC2023/0007896A CO2023007896A2 (es) 2020-11-18 2023-06-16 Macrociclos que contienen un anillo de 1,3,4-oxadiazol para su uso como moduladores del regulador de la conductancia transmembrana de la fibrosis quística

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023150237A1 (en) * 2022-02-03 2023-08-10 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
WO2023154291A1 (en) * 2022-02-08 2023-08-17 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2023224924A1 (en) 2022-05-16 2023-11-23 Vertex Pharmaceuticals Incorporated Solid forms of a macrocyclic compounds as cftr modulators and their preparation
WO2023224931A1 (en) * 2022-05-16 2023-11-23 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
WO2024054851A1 (en) * 2022-09-07 2024-03-14 Sionna Therapeutics Macrocyclic compounds, compositions and methods of using thereof
WO2024056798A1 (en) 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Macrocyclic cftr modulators
WO2024056791A1 (en) 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Combination of macrocyclic cftr modulators with cftr correctors and / or cftr potentiators
WO2024056779A1 (en) 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Crystalline form of (3s,7s,10r,13r)-13-benzyl-20-fluoro-7-isobutyl-n-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecino[16,17-f]quinoline-3-carboxamide

Citations (2)

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WO2013038386A1 (en) * 2011-09-16 2013-03-21 Novartis Ag Heterocyclic compounds for the treatment of cystic fibrosis
WO2019161078A1 (en) * 2018-02-15 2019-08-22 Vertex Pharmaceuticals Incorporated Macrocycles as modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions thereof, their use in the treatment of cycstic fibrosis, and process for making them

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013038386A1 (en) * 2011-09-16 2013-03-21 Novartis Ag Heterocyclic compounds for the treatment of cystic fibrosis
WO2019161078A1 (en) * 2018-02-15 2019-08-22 Vertex Pharmaceuticals Incorporated Macrocycles as modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions thereof, their use in the treatment of cycstic fibrosis, and process for making them

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023150237A1 (en) * 2022-02-03 2023-08-10 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
WO2023154291A1 (en) * 2022-02-08 2023-08-17 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2023224924A1 (en) 2022-05-16 2023-11-23 Vertex Pharmaceuticals Incorporated Solid forms of a macrocyclic compounds as cftr modulators and their preparation
WO2023224931A1 (en) * 2022-05-16 2023-11-23 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
WO2024054851A1 (en) * 2022-09-07 2024-03-14 Sionna Therapeutics Macrocyclic compounds, compositions and methods of using thereof
WO2024056798A1 (en) 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Macrocyclic cftr modulators
WO2024056791A1 (en) 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Combination of macrocyclic cftr modulators with cftr correctors and / or cftr potentiators
WO2024056779A1 (en) 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Crystalline form of (3s,7s,10r,13r)-13-benzyl-20-fluoro-7-isobutyl-n-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecino[16,17-f]quinoline-3-carboxamide

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CL2023001398A1 (es) 2023-11-24
IL302873A (en) 2023-07-01
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AR124090A1 (es) 2023-02-15
MX2023005721A (es) 2023-07-25
AU2021383176A1 (en) 2023-06-22
CA3201793A1 (en) 2022-05-27
JP2023549547A (ja) 2023-11-27
CN116670140A (zh) 2023-08-29
ECSP23045439A (es) 2023-08-31
EP4247817A1 (en) 2023-09-27
CR20230260A (es) 2023-10-05
CO2023007896A2 (es) 2023-09-18
DOP2023000099A (es) 2023-08-15

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