IL302873A - 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

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IL302873A
IL302873A IL302873A IL30287323A IL302873A IL 302873 A IL302873 A IL 302873A IL 302873 A IL302873 A IL 302873A IL 30287323 A IL30287323 A IL 30287323A IL 302873 A IL302873 A IL 302873A
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compound
therapeutic agent
additional therapeutic
independently selected
optionally substituted
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IL302873A
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Vertex Pharma
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    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—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
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—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
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    • 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

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  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (1)

1.WO 2022/109573 PCT/US2021/072475 CLAIMS 1. A compound selected from compounds of Formula I: and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein: X is selected from -N(RX1)- andRing A is a 4- to 6-membered heterocyclyl optionally substituted with 1-groups independently selected from C1-C6 alkyl and oxo,RX1 is selected from H, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, oxo, -ORX2, and -N(RX2)2), and C3-Ccycloalkyl;each Rx2 is independently selected from H and C1-C6 alkyl;each ¥ is independently selected from -C(RY)2-, -0-, -CO-, -NRYN-, and יי ' , wherein each RVN is independently selected from H, C1-C4 alkyl, and CO?RVX wherein each RVNi is independently selected from C1-C4 alkyl and C3-C6 cycloalkyl;each R¥ is independently selected from hydrogen, hydroxy, halogen, C1-Calkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-C10 aryl (optionally substituted with 1- groups independently selected from halogen), 5- to 10-membered heteroaryl, - 0RY1,-C02Ry1, -C0Ry؛, -C0N(Ry1)2, and -N(RYi)2;or two RY on the same atom are taken together to form a ring selected from C3- C8 cycloalkyd and. 3- to 7-membered heterocyclyl; or two RY, one of which is on 817 WO 2022/109573 PCT/US2021/072475 one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;each RVi is independently selected from hydrogen and C1-C6 alkyl, or two RYbonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;Ring B is selected from:C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy),■ C3-Cs cycloalkyl,5- to 10-membered heteroaryl, and3- to 6-membered, heterocyclyl (optionally substituted, with 1-3 groups independently selected from C1-C6 alkyl);each Q is independently selected from:C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:o halogen,o oxo,o C6-C10 and (optionally substituted with 1-3 groups independently selected from halogen and -OCF3), ando C3-Cs cycloalkyl,C3-C8 cycloalkyl optionally substituted with 1-3 groups independently selected from:o halogen,o CN,o C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, -NH2, and -NHCOMe),o C1-C6 alkoxy,o C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 alkyl), ando C3-C8 cycloalkyl,C6-C10 aryl optionally substituted with 1-3 groups independently selected, from:o halogen,o CN, 818 WO 2022/109573 PCT/US2021/072475 o C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy),o C1-C6 alkoxy optionally substituted with 1-4 groups independently selected from:halogen,C3-C8 cycloalkyl (optionally substituted with CF3),o C3-C8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF3, OCF3, and C1-C6 alkyl), ando C6-C10 aryl,5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:o halogen,o C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from halogen),o C3-Cs cycloalkyl (optionally substituted with 1-3 CF3 groups), and.o 3-to 10-memberedheterocyclyl,3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:o C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C3-C8 cycloalkyl), ando oxo;each R1 is independently selected from halogen, C1-C6 fluoroalkyl, C1-C6 alkyl (optionally substituted with a group selected from hydroxy, C6-C10 aryl, and 5- to 6-membered heteroaryl), -OR2, -N(R2)2, -CO2R2, -CO-N(R2)2, -CN, C3-Ccycloalkyl, C6-C10 aryl, 5- to 6-membered heteroaryl (optionally substituted with 1-3 groups independently selected from C1-C6 alkyl), 3- to 6-membered heterocyclyl, -B(OR2)2,-SO:R2, -SR2, -SOR2, -PO(OR2)2, and. -PO(R2)2;each R2 is independently selected from hydrogen, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), C1-Cfluoroalkyl, and C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl and C1-C6 fluoroalkoxy); 819 WO 2022/109573 PCT/US2021/072475 wherein Ring C is selected from C6-C10 aryl and 5- to 10-membered heteroaryl;RZ1 is selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1- hydroxy), C1-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-C10 aryl, and 5- to 6-membered heteroaryl;Rz2 is selected from hydrogen, halogen, hydroxy, NH:, NH(CO)(C؛־C6 alkyl), and C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl),or RZ1 and Rz2 taken together form a group selected from oxo and :::N-0H;each Rz3 is independently selected from hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and C6-C10 aiyl; or two Rz3 are taken together to form a 3- to 6-membered, heterocyclyl;n is selected from 4, 5, 6, 7, and 8; andm is selected from 0, 1, 2, and 3.The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein X. is -N(RX1)-.The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein X isThe compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein X is selected from: -NH-, -N(CH3)-, -N(CH2CH3)-, 820 WO 2022/109573 PCT/US2021/072475 5. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein:each Rv is independently selected from hydrogen, hydroxy, halogen, C1-Calkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-C10 aryl (optionally substituted with 1- groups independently selected from halogen), 5- to 10-membered heteroaryl, - CO2R¥1, and -CON(RY1)2;or two RY on the same atom are taken together to form a ring selected from C3- C8 cycloalkyl and 3- to 7-membered heterocyclyl;or two RY, 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.6. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein each RY1 is independently selected from hydrogen and C1-C6 alkyl, or two RV1 bonded to the same nitrogen taken together form a 3 - to 6-membered heterocyclyl.7. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein each Q is independently selected from C6-C10 aryl.8. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein each Q is phenyl.9. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein;each RY is independently selected from: 821 WO 2022/109573 PCT/US2021/072475 or two RY on the same atom are taken together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyryl, and tetrahydrofuryl;or two RY, 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.10. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 9, wherein Ring B is selected from C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkoxy) and 5- to 10-membered heteroaryl.11. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 10, wherein Ring B is selected from phenyl (optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkoxy) and pyridyl.12. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims I to 11, wherein Ring B is selected from: 13. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 12, wherein 85 is selected from 4, 5, 6, and 7.14. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein -(Y)n- is a group selected from: 822 WO 2022/109573 PCT/US2021/072475 823 WO 2022/109573 PCT/US2021/072475 Y-~ Y—^ Y~^ mm،u> mmww jw»w»»»w P P Pp y n y p- v A y י י י יF a) ?Cl n'Tn Ca A, Y Y ^p לליי 824 WO 2022/109573 PCT/US2021/072475 F 15. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 14, wherein each R1 is independently selected from halogen, C1-C6 fluoroalkyl, C1-C6 alkyl (optionally substituted with a group selected from C6-C10 aryl), -OR2, -N(R2)2, -CO:R2, -CO-N(R2)2, -CN, C1-Calkoxy, C3-C8 cycloalkyl, C6-C10 aryl, 5- to 6-membered heteroaiyl (optionally substituted with 1-3 groups independently selected from C1-C6 alkyl), 3- to 6- membered heterocyclyl, -B(OR2)2, -SO2R2, -SR2, -SOR2, and -PO(R2)2.16. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 15, wherein each R2 is independently selected from C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkoxy).17. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 16, wherein each R؟ is independently selected from -Br, -CF3,-NH2, -CH3, -CH(CH3)2, -CN, -OH, -OCH3, -NH(CH3), -NH(CH2CH3), -CONH2, 825 WO 2022/109573 PCT/US2021/072475 -CO2CH3, -SO2CH3, -SO2Ph, PO(CH3)2, B(OH)2, phenyl, pyridyl, tetrahydropyranyl, tetrahydrofuranyl, cyclopropyl, cyclohexyl, imidazolyl, N-t/ The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 17, wherein Z is selected from Z1; wherein Ring C is selected from C6-C10 aryl.The compound, deuterated derivative, or pharmaceutically acceptable saltaccording to any one of claims 1 to 18, wherein the group: 20. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 19, wherein the group: 826 WO 2022/109573 PCT/US2021/072475 21. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 20, wherein RZ1 is selected from hydrogen, Ci- C6 alkyd (optionally substituted, with 1-3 hydroxy), C1-C6 fluoroalkyl, 3- to 6- membered heterocyclyl, C3-C6 cycloalkyl, C6-C10 aryl, and 5- to 6-membered heteroaryl.22. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 21, wherein Rz2 is selected from hydrogen, halogen, hydroxy, and C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl).23. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 22, wherein:RZI is selected from hydrogen, C1-C6 alkyl (optionally substituted with 1-hydroxy), C1-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, and C6-C10 aryl; andRz2 is selected from hydrogen, halogen, and hydroxy;or RZ1 and Rz2 taken together form a group selected from oxo and =N-0H.24. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 23, wherein:RZ1 is selected from hydrogen, CH3, CF3, CH2OH, phenyl, cyclopropyl, and tetrahydropyranyl; andRz2 is selected from hydrogen, halogen, and. hydroxy;or RZ1 and Rz2 taken together form a group selected from oxo and =N-0H.25. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 24, wherein Rz2 is hydroxy.26. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 25, wherein Z is selected from: 827 WO 2022/109573 PCT/US2021/072475 27. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 26, wherein mis selected from 1 and 2.28. A compound selected from compounds of Table 10, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.29. A compound, according to claim 28, wherein the compound is selected from: 828 WO 2022/109573 PCT/US2021/072475 829 WO 2022/109573 PCT/US2021/072475 30. A pharmaceutical composition comprising a. compound, salt, or deuterated derivative of any one of claims 1 to 29 and a pharmaceutically acceptable carrier.31. The pharmaceutical composition according to claim 30, further comprising one or more additional therapeutic agent(s). 830 WO 2022/109573 PCT/US2021/072475 32. The pharmaceutical composition according to claim 31, wherein the one or more additional therapeutic agent(s) comprise(s) a compound with CFTR modulating activity or a salt or deuterated derivative thereof.33. The pharmaceutical composition according to claim 31 or 32, wherein the one or more additional therapeutic agent(s) comprise(s) a. CFTR corrector.34. The pharmaceutical composition according to any one of claims 31 to 33, wherein the one or more additional therapeutic agent( s) compri sets) (/C-1 -(2,2- difluorobenzo[d] [ 1,3]dioxol-5-yl)-A r-(l -(2,3 -dihy droxypropyl)-6-fluoro-2-( 1 - hydroxy-2-methylpropan-2-yl)-1 H-indol-5-yl )cyclopropanecarboxamide (Compound II):V7 h n /־~oh ^0X7 ° F Aa/p ^OH J! 35. The pharmaceutical composition according to any one of claims 31 to 34, wherein the one or more additional therapeutic agent(s) comprise(s) 3-(6-(l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyri din-2- yl)benzoic acid (Compound IV):O^OH V H F ° Compound. IV. 36. The pharmaceutical composition according to any one of claims 31 to 35, wherein the one or more additional therapeutic agent(s) comprise(s) A'-(l,3- dimethylpyrazol-4-yl)sulfonyI-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol ־ l-yl]-2-[(4S')-2,2,4-trimethylpyrrolidin-l-yl]pyridine-3-carboxamide (Compound V): 831 WO 2022/109573 PCT/US2021/072475 37. The pharmaceutical composition according to any one of claims 31 to 36, wherein the one or more additional therapeutic agent(s) comprise(s) JV-(benzenesulfonyl)-6- [3-[2-[l-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4- trimethyl pyrrol! din-1 -yl Jpyridi ne-3-carboxamide (Compound VI): / CompoundVI.38. The pharmaceutical composition according to any one of claims 31 to 37, wherein the one or more additional therapeutic agent(s) comprise(s) (145)-8-[3-(2- {dispiro[2.0.2.1]heptan-7-yl}ethoxy)-177-pyrazol-l-yl]-12,12-dimethyl-2X°-thia- 3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,lOjtetracosa-I (22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound VII); 39. The pharmaceutical composition according to any one of claims 31 to 38, wherein the one or more additional therapeutic agent(s) comprise(s) (117?)-6-(2,6- dimethylphenyl)- 11 -(2-methylpropyl)- 12- {spiro[2.3 hexan-5 -yl }-9-oxa-2X6-thia- 3,5,l2,l9-tetraazatricyclo[l2.3.l.l4,8]nonadeca-l(l7),4(l9),5,7,l4(18),15- hexaene-2,2,13-trione (Compound VIII); 832 WO 2022/109573 PCT/US2021/072475 40. The pharmaceutical composition according to any one of claims 31 to 39, wherein the one or more additional therapeutic agent(s) comprise(s) at least one compound selected from PTI-428, ABBV.2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARX2208L ARN22652, ARN23765, ARN23766, and PTI-801.41. The pharmaceutical composition according to any one of claims 31 to 40, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR potentiator enhancer.42. The pharmaceutical composition according to any one of claims 31 to 41, wherein the one or more additional therapeutic agent(s) comprise(s) ASP-11.43. The pharmaceutical composition according to any one of claims 31 to 42, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR potentiator.44. The pharmaceutical composition according to any one of claims 31 to 43, wherein the one or more additional therapeutic agent(s) comprise(s) a compound selected from A-(5-hydroxy-2,4-di-rerr-butyl-phenyl)-4-oxo-l/7-quinoline-3-carboxamide (Compound III): ompound IIIand A-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)phenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (Compound HI-d): 833 WO 2022/109573 PCT/US2021/072475 Compound Ili-d. 45. The pharmaceutical composition according to any one of claims 31 to 44, wherein the one or more additional therapeutic agent(s) comprise(s) at least one compound selected from FDL-176, PTI-808, GLPG1837, GLPG2451/ABBV-24(Icenticaftor), GLPG3067/ABBV-3067 (Navocaftor), and ABBV-191.46. The pharmaceutical composition according to any one of claims 31 to 45, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR amplifier.47. The pharmaceutical composition according to any one of claims 31 to 46, wherein the one or more additional therapeutic agent(s) comprise(s) PTI-428.48. The pharmaceutical composition according to any one of claims 31 to 47, wherein the one or more additional therapeutic agent(s) compri se(s) a CFTR readthrough agent.49. The pharmaceutical composition according to any one of claims 31 to 48, wherein the one or more additional therapeutic agent(s) comprise(s) ELX-02.50. The pharmaceutical composition according to any one of claims 31 to 49, wherein the one or more additional therapeutic agent(s) comprise(s) a nucleic acid therapy.51. The pharmaceutical composition according to any one of claims 31 to 50, wherein the one or more additional therapeutic agent(s) comprise(s) at least one agent selected from MRT5005, Lunar-CF, and RCT223.52. The pharmaceutical composition according to any one of claims 31 to 51, wherein the one or more additional therapeutic agent(s) comprise(s) an ENaC inhibitor.53. The pharmaceutical composition according to any one of claims 31 to 52, wherein the one or more additional therapeutic agent(s) comprise(s) amiloride, ETDOOl, 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-ENaC 1001.54. The pharmaceutical composition according to any one of claims 31 to 53, wherein the one or more additional therapeutic agent(s) comprise(s) a TMEM16A modulator. 834 WO 2022/109573 PCT/US2021/072475 55. The pharmaceutical composition according to any one of claims 31 to 54, wherein the one or more additional therapeutic agent(s) comprise(s) ETD002.56. The pharmaceutical composition according to any one of claims 31 to 55, wherein the one or more additional therapeutic agent(s) comprise(s) a GPR39 Agonist.57. The pharmaceutical composition according to any one of claims 31 to 56, wherein the one or more additional therapeutic agent(s) comprise(s) DS-1039.58. A method of treating cystic fibrosis, comprising administering an effective amount of the compound, salt, or deuterated, derivative according to any one of claims 1 to or the pharmaceutical composition according to any one of claims 30 to 57 to a patient in need thereof.59. The method according to claim 58, further comprising administering one or more additional therapeutic agent(s).60. The method according to claim 59, wherein the one or more additional therapeutic agent(s) comprise(s) a compound with CFTR modulating activity or a salt or deuterated derivative thereof.61. The method according to claim 59 or 60, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR corrector.62. The method according to any one of claims 59 to 61, wherein the one or more additional therapeutic agent(s) comprise(s) (A)-l-(2,2-difluorobenzo[d][l,3]dioxol- 5-yl)-V-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)- l/f-indol-5-yl)cyclopropanecarboxamide (Compound II): OH Compound II.63. The method according to any one of claims 59 to 62, wherein the one or more additional therapeutic agent(s) comprise(s) 3-(6-(l-(2,2-ditluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyri din-2- yl)benzoic acid (Compound IV): 835 WO 2022/109573 PCT/US2021/072475 Compound IV.64. The method according to any one of claims 59 to 63, wherein the one or moreadditional therapeutic agem(s) comprise(s) V-(l,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-l-yl]-2-[(45 r)-2,2,4-tri m ethylpyrrolidin- 1 -yl]pyridine-3-carboxami de (Compound V): Compound V.65. The method according to any one of claims 59 to 64, wherein the one or more additional therapeutic agent(s) comprise(s) V-(benzenesulfonyl)-6-[3-[2-[l- (trifluoromethyl) cyclopropyl]ethoxy]pyrazol-l-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin- 1 -yl]pyridine-3-carboxamide (Compound VI): 66. The method according to any one of claims 59 to 65, wherein the one or more additional therapeutic agent(s) comprise(s) (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan- 7-yl}ethoxy)-1/7-pyrazol-l-yl]-l2,l2-dimethyl-2X 6-thia-3,9,ll,18,23- pentaazatetracyclo [17.3.1.111,14.05,1 OJtetracosa-1 (22),5,7,9,19(23),20-hexaene- 2,2,4-trione (Compound VII): 836 WO 2022/109573 PCT/US2021/072475 67. 68. The method according to any one of claims 59 to 66, wherein the one or more additional therapeutic agent(s) comprise(s) (1 l/?)-6-(2,6-dimethylphenyl)-l l-(2- m ethyl propyl)- 12- { spi ro[2.3 ] hexan-5 -yl } -9-oxa-2X6-thia-3,5,12,19- tetraazatricyclo[12.3.1.14,8]nonadeca-l(17),4(19),5,7,14(18)J5-hexaene-2,2,13- trione (Compound VIII): O Compound VIII.The method according to any one of claims 59 to 67, wherein the one or more additional therapeutic agent(s) comprise(s) at least one compound selected from PTI-428, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748,ABBV-3903, ABBV-H9, ABBV-2851, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, and PTI-801.69. The method according to any one of claims 59 to 68, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR potentiator enhancer.70. The method according to any one of claims 59 to 69, wherein the one or more additional therapeutic agent(s) comprise(s) ASP-11.71. The method according to any one of claims 59 to 70, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR potentiator.72. The method according to any one of claims 59 to 71, wherein the one or more additional therapeutic agent(s) comprise(s) a compound selected from A-(5- hydroxy -2,4-di-Vr/-buty I -phenyl )-4-oxo- 17/-quinoline-3 -carboxamide (C ompound III): and /V-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-l,l,I,3,3,3-d6)phenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (Compound Ill-d): 837 WO 2022/109573 PCT/US2021/072475 Compound III-d. 73. The method according to any one of claims 59 to 72, wherein the one or more additional therapeutic agent(s) comprise(s) at least one compound selected from FDL-176, PTI-808, GLPG1837, GLPG2451AABBV-2451 (Icenticaftor), GLPG3067/ABBV-3067 (Navocaftor), and ABBV-191.74. The method according to any one of claims 59 to 73, wherein the one or more additional therapeutic agent( s) comprise(s) a CFTR amplifier.75. The method according to any one of claims 59 to 74, wherein the one or more additional therapeutic agent(s) comprise(s) PTI-428.76. The method according to any one of claims 59 to 75, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR readthrough agent.77. The method according to any one of claims 59 to 76, wherein the one or more additional therapeutic agent(s) comprise(s) ELX-02.78. The method according to any one of claims 59 to 77, wherein the one or more additional therapeutic agent(s) comprise(s) a nucleic acid therapy.79. The method according to any one of claims 59 to 78, wherein the one or more additional therapeutic agent(s) comprise(s) at least one agent selected from MRT5005, Lunar-CF, and RCT223.80. The method according to any one of claims 59 to 79, wherein the one or more additional therapeutic agent(s) comprise(s) an ENaC inhibitor.81. The method according to any one of claims 59 to 80, wherein the one or moreadditional therapeutic agent(s) comprise(s) amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Tonis-ENaC- 2.5 Rx, Bl 1265162, AZ5634, and ARO-ENaClOOl.82. The method according to any one of claims 59 to 81, wherein the one or more additional therapeutic agent(s) comprise(s) a TMEM16A modulator.83. The method according to any one of claims 59 to 82, wherein the one or more additional therapeutic agent(s) comprise(s) ETD002. 838 WO 2022/109573 PCT/US2021/072475 84. The method according to any one of claims 59 to 83, wherein the one or more additional therapeutic agent(s) comprise(s) a GPR39 Agonist.85. The method according to any one of claims 59 to 84, wherein the one or more additional therapeutic agent(s) comprise(s) DS-1039.86. The compound, salt, or deuterated derivative of any one of claims 1 to 29 or the pharmaceutical composition according to any one of claims 30 to 57 for use in the treatment of cystic fibrosis.87. Use of the compound, salt, or deuterated derivative of any one of claims 1 to 29 or the pharmaceutical composition according to any one of claims 30 to 57 in the manufacture of a medicament for the treatment of cystic fibrosis. 839
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