CA3201793A1 - 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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Publication number
CA3201793A1
CA3201793A1 CA3201793A CA3201793A CA3201793A1 CA 3201793 A1 CA3201793 A1 CA 3201793A1 CA 3201793 A CA3201793 A CA 3201793A CA 3201793 A CA3201793 A CA 3201793A CA 3201793 A1 CA3201793 A1 CA 3201793A1
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Prior art keywords
compound
independently selected
optionally substituted
pharmaceutically acceptable
therapeutic agent
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CA3201793A
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French (fr)
Inventor
Jeremy J. Clemens
William Schulz BECHARA
Brett C. Bookser
Thomas Cleveland
Timothy Coon
Michel Gallant
Julie LATERREUR
Mark Thomas Miller
Prasuna PARASELLI
Yeeman K. Ramtohul
Thumkunta Jagadeeswar Reddy
Claudio Sturino
Lino Valdez
Jinglan Zhou
Minson BAEK
Peter Diederik Jan Grootenhuis (Deceased)
Sara Sabina Hadida Ruah
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Publication of CA3201793A1 publication Critical patent/CA3201793A1/en
Pending legal-status Critical Current

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    • 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
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    • 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
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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

Abstract

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:

MACROCYCLES CONTAINING A 1,3,4-0XADIAZOLE RING FOR USE AS MODULATORS OF
CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
100011 This application claims the benefit of U.S. Provisional Application No.
63/115,552, filed on November 18, 2020, the contents of which are incorporated by reference in its entirety.
100021 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.
[0003] Cystic fibrosis (CF) 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.
[0004] In patients with CF, mutations in CIFIR 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. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death. In addition, the majority of males with cystic fibrosis are infertile, and fertility is reduced among females with cystic fibrosis.
100051 Sequence analysis of the CTIR gene has revealed a variety of disease-causing, mutations (Cutting, G R. et al. (1990) Nature 346:366-369; Dean, M. et al.
(1990) Cell 61:863:870; and Kerem, BS. et al. (1989) Science 245:1073-1080; Kerem, B-S et al.
(1990) Proc. Nat! . .Acad. Sci. USA 87:8447-8451). To date, greater than 2000 mutations in the CF gene have been identified; currently, the CFTR2 database contains information on only 322 of these identified mutations, with sufficient evidence to define 281 mutations as disease-causing. The most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as the F508del mutation. This mutation occurs in many of the cases of cystic fibrosis and is associated with severe disease.

100061 CFTR 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. In epithelial cells, normal functioning of CFTR is critical or 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 phosphotylation sites that regulate channel activity and cellular trafficking.
10071 Chloride transport takes place by the coordinated activity of ENaC
(epithelial sodium channel) and CFTR present on the apical membrane and the Na'-E2--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 C1 channels, resulting in a vectorial transport. Arrangement of Na/2C1-/K+ co-transporter, Na+-KtAT.Pase pump and the basolateral membrane K+ channels on the 'basolateral surface and CFTR on the lumina' side coordinate the secretion of chloride. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.
100081 A number of CFTR. modulators have recently been identified, These modulators can be characterized as, for example, potentiators, correctors, potentiator enhancers/co-potentiators, amplifiers, read through 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. Trans" Sci. 3:4-10. There are three CFTR
correctors approved by the U.S. FDA for treatment of cystic fibrosis. However, monotherapy with some CFTR correctors has not been found to be effective enough and as a result combination therapy with a potentiator is needed to enhance CFTR activity.
There is currently only one CFTR potentiator that is approved for the treatment of cystic fibrosis.
Thus, although the treatment of cystic fibrosis has been transformed by these new small
2
3 molecule MR modulators, new and better modulators are needed to prevent disease progression, reduce the severity of the cystic fibrosis and other CFTR-mediated diseases, and to treat the more severe forms of these diseases.
100091 One aspect of the invention provides novel compounds, including compounds of Formulae I, I", la, La', Ha, Ha', lie, He', lid, He, He', HT, Elf, Hg, Iih, and Hie, Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof and pharmaceutically acceptable salts of any of the foregoing.
10010] For example, compounds of Formula I can be depicted as:
n N
(RI) N-N
and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:
1-R11-71-g)A
X is selected from -N(R)- and Ring A is a 4- to 6-membered heterocycly1 optionally substituted with 1-3 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, -0R'2, and -N(Rx2)2), and C3-C8 cycloalkyl;
each Rx2 is independently selected from Hand C t-C6 alkyl;
each V is independently selected from -C(RY)2-, -0-, -CO-, -NR"-, and , wherein each R" is independently selected from H, CI-C4 alkyl, and CO2R"1, wherein each R."1 is independently selected from C1-C4 alkyl. and C3-C6 cycloalkyl;
each RI' is independently selected from hydrogen, hydroxy, halogen, Cr-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-Cio aryl (optionally substituted with 1-3 groups independently selected from halogen.), 5- to 10-membered heteroaryl, --CO2R", -CON(R")2, and -N(RYI)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 le, 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 RY1 is independently selected from hydrogen and C1-C6 alkyl, or two R"
bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;
Ring B is selected from:
= C6-Clo aryl (optionally substituted with 1-3 groups independently selected from halogen, Ci-C6 alkyl, and C1-C6 alkoxy), = C3-C8 cycloalkyl, 81 5- to 10-membered heteroaryl; and = 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from CE-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-Cu) aryl (optionally substituted with 1-3 groups independently selected from halogen and -0CF3), and o C3-C8 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, -NW, and -NI-ICOMe), o Cl-C6 alkoxy,
4 o C6-Clo aryl (optionally substituted with 1-3 groups independently selected from CI-Co alkyl), and o C3-C8 cycloalkyl, ^ C6-C10 aryl 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 and hydroxy), o C1-C6 alkoxy optionally substituted with 1-4 groups independently selected from:
E halogen, C3-C8 cycloalkyl (optionally substituted with CF3), o C3-C8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF3. OM, and C1-C6 alkyl), and o C6-Cto aryl, IE 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-C8 cycloalkyl (optionally substituted with 1-3 CF3 groups), and o 3- to 10-membered heterocyclyl, = 3- to 1.0-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), and o oxo;
each :W is independently selected from halogen, C1-C6 fluoroalkyi, C1-C6 alkyl (optionally substituted with a group selected from hydroxy, C6-C10 aryl, and 5-to 6-membered heteroaryl), -OW, -N(R2)2, -0O2W, -CO-N(W)2, -CN, C3-C8 cycloalkyl, 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(0122)2, -S02R2, -SR2, -SOR2, -P0(0R2)2, and -P0(R2)2;
each R2 is independently selected from hydrogen, CI-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), C1-C6 fluoroalkyl, and C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl and C1-C6 fluoroalkoxy);
''...--2)0_2 z2 , /SI- .7 Z is selected from R Rz3 Rzi -.'-- , and '<' ¨
, wherein Ring C is selected from C6-C10 aryl and 5- to 1.0-membered heteroary1;
lel is selected from hydrogen, -CN, C1-C6 alkyl (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;
Rz2 is selected from hydrogen, halogen, hydroxy, NH2, NH(C0)(C1-C6 alkyl), and C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl), or illz and R" taken together form a group selected from oxo and =N-OH;
each Rz" is independently selected from hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and C6-C to aryl; or two Rz3 are taken together to form a 3- to 6-membered heterocyclyl, n is selected from 4, 5, 6, 7, and 8; and.
m is selected from 0, 1, 2, and 3.
[0011] In some embodiments of Formula I, Xis -N(Rx1)-.
CRII-T-giNYA
A i N--[0012] In some embodiments of Formula I, Xis .'.." , [0013] In some embodiments of Formula I, X is selected from:

NA A
-N(013)-, -N(CH2CH3)-, _L
-/\
, o /..N)..,/N-C-1 /vv`i N
N a N I
õ..õ0 N.Yc 4'N L'N) ThNI)s,14 0/' LL , and Oj 100141 In some embodiments of Formula 1, each le is independently selected from hydrogen, hydroxy, halogen, C
alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-Clo aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, -CO21e1, and -CON(R1)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 heterocycly1;
or two R1, 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.
100151 In some embodiments of Formula I, each R" is independently selected from hydrogen and C1-C6 alkyl, or two RY1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl.
100161 In some embodiments of Formula 1, each Q is independently selected from Co-C10 aryl.
100171 In some embodiments of Formula I, each Q is phenyl.
100181 In some embodiments of Formula!, each RY is independently selected from:

HO,õ HO0 hydrogen, hydroxy, -CH3, -CD3, -CH2CH3, OO A

ON.,"
, and L
or two R' on the same atom are taken together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyryl, and tetrahydrofuryl;
or two It", 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.
100191 In some embodiments of Formula I, Ring B is selected from C6-Clo aryl (optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkoxy) and 5- to 10-membered heteroaryl.
100201 in some embodiments of Formula!, Ring B is selected from phenyl (optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkoxy) and pyridyl.
100211 In some embodiments of Formula I, Ring B is selected from:

N
.== .::
, and 100221 In some embodiments of Formula I, n is selected from 4, 5, 6, and 7.
100231 In some embodiments of Formula!, -(1'),-,7 is a group selected from:

a H\C)----, ' OH

OH .
: OH
/
F
OH s,OH
HO : F
HO
\
z=
\CXofln_ F , i -L...
HO
µ",.... L'`..-.
, .
HO HO
-s]...
. , HO y,0 HO 0 -,,,,...,õ0 0 =,....õ...õ0õ,...7.0 \.-.A..,...--- Vi"...õ,....-^...., =-.., , , , I 1 r------.1 CI' ,-..,---\--1, , c:') 0 j..,, i....
o N=-,,,,-.-,N
F
F F
.....L.
, , , rTh N,,----,--"" ----F
il---1 --.-N ,-,-- N..,T,,-- N N ....- N
µ1]..... 10 N

, and [0024] In some embodiments of Formula I, each RI is independently selected from halogen, C1-C6 fluoroalkyl, CI-C6 alkyl (optionally substituted with a group selected from C6-C10 aryl), -OW, -N(R2)2, -0O2R2, -CO-N(!R2)2, -CN, Ct-C6 alkoxy, C3-C8 cycloalkyl, 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(0R2)2, -S0211.2, -S.R2, -SOR2, and -P0(R2)2, [0025] In some embodiments of Formula I, each le is independently selected from C6-Cm aryl (optionally substituted with 1-3 groups independently selected from C1-fluoroalkoxy).
[0026] In some embodiments of Formula I, each 121 is independently selected from -Br, -CF3, -NH2, -CH3, -CH(CH3)2, -CN, -OH, -OCH3, -NH(CH3), -NH(CH2CH3), -CONH2, -CO2CH3, -S02CH3, -S02Ph, PO(CH3)2, B(OH)2, phenyl, pyridyl, tetrahydropyranyl.
N-N
tetrahydrofuranyl, cyclopropyl, cyclohexyl, imidazolyl, cF3o cF3o eighh tip
5--, and :.:RRzz12 I
Rzi 100271 In some embodiments of Formula I, Z is selected from , , and C -7---(R2 )0_2 ; wherein Ring C is selected from C6-C10 aryl.
100281 In some embodiments of Formula I, the group:
.., c __________ (R22)9_2 is selected from:
N
Rz2 -Z2 un 'I'Z2 Ana r1/4Z2 n22 RZ2 rl , , rµ , t , , F /CCP I \ ...\ -N -N
N)---C1 \>
F \---- -N N N N
Rz2 F 1. H H H H H
, _____________ NH
N
and .
100291 In some embodiments of Formula I, the group:
,--Rz2 .
i s 100301 in some embodiments of Formula!, Rzl is selected from hydrogen. CI-Cs alkyl (optionally substituted with 1-3 hydroxy), Ci-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-C10 aryl, and 5- to 6-membered heteroaryl.
100311 In some embodiments of Formula I, RI-2 is selected from hydrogen, halogen, hydroxy, and C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl).
100321 .. In some embodiments of Formula 1, Rzl is selected from hydrogen. C1-C6 alkyl (optionally substituted with 1-3 hydroxy), Cet-C6 fluoroalkyl, 3-to 6-membered heterocyclyl, C3-C6 cycloalkyl, and C6-C10 aryl; and Rz2 is selected from hydrogen, halogen, and hydroxy;
or lei and :Rz2 taken together form a group selected From oxo and =N-OH.
100331 In some embodiments of Formula I, Rzl is selected from hydrogen, CH3, C173, CH2OH, phenyl, cyclopropyl, and tetrahydropyranyl; and RP is selected from hydrogen, halogen, and hydroxy;
or RZ1 and Rz2 taken together form a group selected from oxo and =N-OH.
100341 In some embodiments of Formula I, IRP is hydroxy.
100351 In some embodiments of Formula I, Z is selected from:
?F3 .CF3 OH OH .. .-<,,_ .t. 1 ¨ _ i CF3 OH OH OH
, ...-,CH3 ."-C-----, C F3 0 N' '" -----7 H
-4... --<,OH -'"OH OH
1 ,-----. CF3, and 61-1 , =
<Rzi 100361 In some embodiments of Formula I, Z is . In some embodiments of "..c,Rzi R
Nii"Rz2 Formula!, Z is . In some embodiments of Formula IL Z is '',. . In sonic (ZRzl poZ2 -,,c 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 Rzi R.-embodiments of Formula I. Z is , wherein (S) refers to the stereochemical designation of the central carbon atom under the Cahn-Ingold-Prelog convention, 100371 In some embodiments of Formula I, m is selected from 1 and 2.

100381 in some embodiments, compounds of the invention are encompassed by Formula -- (Y)n (R1), \
N¨N
and includes deuterated derivatives thereof, and pharmaceutically acceptable salts of those compounds and deuterated derivatives, wherein:
Rrn X is selected from -N(Rx1)- and --i¨

Ring A is a 4- to 6-membered heterocyclyl optionally substituted with 1-3 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, -0Rx2, and -N(R')2), and C3-C8 cycloal ky I
each Rx2 is independently selected from H and C1-C6 alkyl;
each Y is independently selected from -C(RY)2-, -0-, -CO-, -NR"-, and (RZ
, wherein each R." is independently selected from H, C1-C4 and COAle;
each R." is independently selected from hydrogen, hydroxy, halogen. C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, Cl-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 1.0-membered heteroaryl, -OR", -0O212", -CON(RY1)2, and -N(10)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;
each W." is independently selected from hydrogen and C1-C6 alkyl, or two R1{1 bonded 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 Cl-C6 alkoxy), ^ C3-C8 cycloalkyl, = 5- to 10-membered heteroaryl, and = 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from. CI-C6 alkyl);
each Q is independently selected from:
^ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:
o halogen, o MO, o C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen and -0CF3), and o C3-C8 cycloalkyl, = C3-C-8 cycloalkyl optionally substituted with 1-3 groups independently selected from:
o halogen, o CN, o CI-Cc alkyl (optionally substituted. with 1-3 groups independently selected from halogen, and -NHCOMe), o CI-C6 alkoxy, o C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C I-C6 alkyl), and o C3-C8 cycloalkyl, ^ C6-C10 aryl optionally substituted with 1-3 groups independently selected.
from:
o halogen, o CN, o CI-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-Cg cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF3, OCF3, and C1-C6 alkyl), and o C6-C10 aryl, = 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from.:
o halogen, o Ci-C6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), o C3-C8 cycloalkyl (optionally substituted with 1-3 CF3 groups), and.
o 3-- to 10-membered heterocyclyl, ^ 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:
o Ci-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C3-C8 cycloalkyl), and o oxo;
each W is independently selected from halogen, C1-C6 fluoroalkyl, C1-C6 alkyl (optionally substituted with a group selected from C6-Cto aryl and 5- to 6-membered heteroaryl), -N(R2)2, -0O2R2, -CO-N(R2)2, -CN, Ct-C6 alkoxy, C3-C8 cycloalkyl, 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, .-S(I)2R2, -SR2, -SOR2, -P0(0102, and -PO(R2)2;
each R2 is independently selected from hydrogen, CI-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), C1--C6 fluoroalkyl, and C6-Ci6 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl and C1-C6 fluoroalkoxy);

õ.<.,Rz3 Rz2 SL Z3111"

Z is selected from R , and Rzl is selected from hydrogen, -CN, Ci-C6 alkyl (optionally substituted with 1-3 hydroxy), C1-C6 fluoroalkyl, 3-to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-Cto aryl, and 5- to 6-membered heteroaryl;
Rz2 is selected from hydrogen, halogen, hydroxy, and Ci-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl), or BP and RP taken together form a group selected from oxo and =N-Oti;
each le' is independently selected from hydroxy, C1-C6 alkoxy, C1-C6 and C6-C10 aryl; or two R13 are taken together to form a 3- to 6-membered heterocycly1;
n is selected from 4, 5, 6, and 7; and m is selected from 0, I, 2, and 3.
100391 In some embodiments, the compound of Formula I is selected from compounds of Formula :
N
Rzi (R1)rn RZ2 191, and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I.
100401 In some embodiments of Formula I", the portion of the compound represented.
Rz2 (R) Rz2 by: - is , wherein (R) refers to the stereochemical designation of the central carbon atom under the Cahn-Ingold-Prelog convention. In some embodiments of Rz2 (s) Rz2 Formula I", the portion of the compound represented by is ,wherein (S) refers to the stereochernical designation of the central carbon atom under the Cahn-Ingold-Prelog convention.
100411 The compounds of the invention also include compounds of Formulae He, lid, He, III, Hg, and :FM

Y----Y
\I' X---(Y)n x., Y .-Y.Y
X Y
W.,...
Y, ..-N
e7N - N
Y Y
.,..õ...cs,.0 z /7.,.0,,,...._ \ 8,- /...,õ....).õ0õ.....zi \ h R1 N-N Ia, (R16 N-N hlik, (R1)m NN lib, Y-Y
--Y Y--- Yõ
x0.--); k, X \i. y )(--' Y
Y\
N Y
I
oN..-2 (Ri)rn N--N Ile, (R1)(11 N-N lid, R1 N-N He, X
..-Y.Y,. ..-Y,Y c_.--Y X.--Y-Y., -), ' Yly Ri .1õ
W,f N RN y_y 'N''. ''' Y
lyc(N 0 \ \ ir R1 NN ufs f1 N-N lig, and R1 N-N Hh, and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I', 100421 The compounds of the invention also include compounds of -Formulae fa', Ha', Hb', He', lad', He', ur, Hg', and MI':
Y-Y
X¨ X...); kx--()Y ---Y. ....Y...
X Y Y
Y, 0,µ....%
\\ / Rz2 A \ Rzl Rz2 \ // Rz2 , R1 N-N ia,_ (R1)m N-N Ha'. (R1),, N-N H13', Y ---------------------------------------------------------- Y
-Y X.õ---Y-Y...,,, Y o.-\ ';
X-', µ ).( Y
i N VI ---''(-1 N Y
\ R11, - 'N Y
y,,,0Rz1 Rz2 -s-Y---cc. Nr Rz2 (R1), N-N (W), ilk', N-N lid', F4.1 N-N
.-Y--. ..-Y-..
X---Yµ
X Y Y

W Y, W
-..,N Y ``N Y-Vi .õ.-1 0,)...Rzl õ,.-- LoRzi \ / Rz2 \ IT -"Rz2 He', R1 N---N rir, R1 N-N Hg', and X
Osyji;,µRzi N-N
and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula 100431 In some embodiments of Formulae la', Ha', 'Id', Ile', LW, hg', and õI:Ran ,,Rzi Rz2 (R) Rz2 1111', 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. In some embodiments of Formula 1", the portion of the compound RZI
Rz2 (s) Rz2 represented by is , wherein (S) refers to the stereochemical designation of the central carbon atom under the Cahn-ingold-Prelog convention, 100441 Another aspect of the invention provides pharmaceutical compositions comprising at least one compound chosen from compounds of Formulae 1, -1%1", la, If' , Ha, Ha', lib, lib', He, He', lid, lid', He, He', hf, Hf, Hg, Hg', Ilk, and Hle, Compounds I 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. Thus, 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", la, ha', Ha, Ha', Hb, lib', He, lie', lid, ihr, lie, He', HI', iif, hg, hg', iih, and Ilk', Compounds Ito 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, and at least one phannaceutically acceptable carrier, optionally as part of a pharmaceutical composition comprising at least one additional component, to a subject in need thereof 100451 In certain embodiments, the pharmaceutical compositions of the invention comprise at least one compound chosen from compounds of Formulae 1, 1", Ia, Ha, Ha', lib, lib', He, He', lid, lid', He, He', hf, Hf, Hg, Hg', Hit, and Ilk', Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, compositions comprising at least one compound chosen from compounds of Formulae I, I", in, la', Hb', He, lid, lid', He, He', Hf, nr, Hg. Hg', 1141, and Elh', Compounds Ito 213, Compounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing may optionally further comprise at least one compound chosen from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing.
[0046] 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)---(2,2-difittorobenzo[d][ I ,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-ypcyclopropanecarboxamide (Compound II), N42,4-bis(1,1-dimethylethyl)-5-hydroxyphenyli-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound HI) or N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-y1-1,1,1,3,3,3-d6)pheny1)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-y()cyclopropane carboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV), N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[343,3,346 fluoro-2,2-dimethyl-propoxy)pyrazol ethylpyrrolidin-1 -yllpyridine-3-carboxa.mide (Compound V), N-(benzenesulfony1)-6134241-(trifluoromethyl) cyclopropyliethoxylpyrazol-1-0]-244S)-2,2,4-trimethylpyrrolidin-l-ylipyridine-3-carboxamide (Compound VI), (145)-843-(2-{dispiro[2Ø2.1]heptan-eth.oxy)- I H-pyrazol-1-y1H 2,12-di m ethyl-a6-thia-3,9,11,18,23 -pentaazatetracy o [17.3.1. 111,14.05,101tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound VII), (11/)-6-(2,6-dimethyl phenyl )-11-(2-methylpropy1)-12-{spiro[2,3]hexan-5-y1}-9-oxa-2k6-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); N-(benzenesulfony1)-6-(3-fluoro-5-isobutoxy-pheny1)-2-[(45)-2,2,4-trimethylpyrrolidin-1-y1]pyridine-3-carboxamide (Compound IX), and N-[(6-arni no-2-pyridyl)sulfony 1 -6-(3 sobutoxy-phenyl)-2-[(45)-2,2,4-nimethylpyrrolidin-1-yllpyri dine-3-carboxamide (Compound X), 100471 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", :La, la', Ha, Ha', lib, Hb', He, Hs', Hd, lid', He, He', Iif, Hg, Hh, and Illf, 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 C F TR modulating agents selected from:
N
z (ASP-1 1), disclosed in Journal of Cystic Fibrosis (2018), 17(5), 595-606, and:
/

HO (nesolicaftor or PT1-428), disclosed in WO
2016/105485, In one embodiment, the additional GFTR modulating agent is ASP-1.1_, In one embodiment, the additional MR modulating agent comprises P11-428.
100481 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 1, 1', I", Ha, Ha', lib, He, :Lid, lid', lie, He', HI', H, Hg, Hg', Ilk, and Ilk', 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:

HN
OF
OH
6 (galicaftor or ABBV-2222), disclosed in United States Patent Application Publication No. 2016-0120841;
HO2CçN
\

OMe \ N
CF3 (ABBV-3221), disclosed in WO 2018/065921;
r co2H
(posenacaftor or PTI-801), disclosed in WO 2017/062581;
ABBV-2851, disclosed in WO 2017/009804; GLPG2737, disclosed in United States Patent Application Publication No. 2017-0101405; ABBV-3748; ABBV-3903; and ABBV-119.
Brief Description of the Figures 100491 FIG. 1 provides an X-ray power diffraction (XRPD) pattern of amorphous Compound 4 (neat form).
100501 FIG. 2 provides a thermogravimetric analysis (TGA) curve for amorphous Compound 4 (neat form).

100511 HG. 3 provides a DSC analysis of amorphous Compound 4 (neat form).
[0052] FIG. 4 provides an XRPD pattern of amorphous Compound 19 (neat form).
[0053] FIG. 5 provides a TGA curve for amorphous Compound 19 (neat form), [0054] FIG. 6 provides a DSC analysis of amorphous Compound 19 (neat form).
[0055] FIG. 7 provides an XRPD pattern of crystalline Compound 41 Form A, [0056] FIG. 8 provides a TGA curve for crystalline Compound 41 Form A.
[0057] FIG. 9 provides an XRPD pattern of crystalline Compound 52 Form A
(neat).
[0058] FIG. 10 provides a TGA curve for crystalline Compound 52 Form A
(neat).
[0059] FIG. 11 provides a :DSC analysis of crystalline Compound 52 Form A
(neat).
[0060] FIG. 12 provides an XRPD pattern of amorphous Compound 60 (neat form).
[0061] FIG. 13 provides a TGA. curve for amorphous Compound 60 (neat form).
[0062] FIG. 14 provides a DSC analysis of amorphous Compound 60 (neat form).
[0063] FIG. 15 provides an XRPD pattern of amorphous Compound 70 (neat form).
[0064] FIG. 16 provides an XRPD pattern of crystalline Compound 163 Form A
(neat).
[0065] FIG. 17 provides a DSC analysis of crystalline Compound 163 Form A
(neat), [0066] FIG. 18 provides an XRPD pattern of amorphous Compound 173 (neat form).
[0067] FIG. 19 provides al:GA curve for amorphous Compound 173 (neat form).
[0068] FIG. 20 provides a DSC analysis of amorphous Compound 173 (neat form).
Definitions [0069] "Compound II" as used herein, refers to (R)-1-(2,2-uorobenzo[d] [1,31dioxo1-5-y1)--N-(1-(2,3 -di hydroxypropy1)-6-fluoro-2-(1-hydroxy-2 methylpropan-2-y1)-11.1-indol-5-y1)cyclopropanecarboxamide, which can be depicted with the following structure:

H
FX 40 = =....: = OH
0 =
F 0 = == =
Lt0H
OH Compound Compound 11 may be in the form of a pharmaceutically acceptable salt. Compound U. 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.
100701 "Compound III" as used throughout this disclosure refers to .N-(5-hydroxy-2,4-di-tert-butyl-pheny1)-4-oxo- II-/--quinoline-3-carboxamide which is depicted by the structure:
OH
0 0 40. = =
= = = = N
Compound III.
Compound M. may also be in the form of a pharmaceutically acceptable salt.
Compound III and methods of making and using Compound Ul are disclosed in WO
2006/002421, WO 2007/079139, WO 2010/108162, and WO 2010/019239, each incorporated herein by reference.
100711 In some embodiments, a deuterated derivative of Compound III
(Compound Hi-d) is employed in the compositions and methods disclosed herein. A chemical name for Compound HL-d is N-(2-(tert-buty1)-5-hydroxy-4-(2-(tnethyl-d3)propan-2-0-1,1,1,3,3,3-d6)phenyt)-4-oxo-1,4-dihydroquinoline-3-carboxamide, as depicted by the structure:

[4.1-Compound Compound may be in the form of a pharmaceutically acceptable salt.
Compound III-d and methods of making and using Compound 1.11.-4 are disclosed in WO
2012/158885, WO 2014/078842, and US Patent No. 8,865,902, incorporated herein by reference.
100721 "Compound IV" as used herein, refers to 3464142,2-difluorobenzo[d][1,3]dioxo1-5-yl)cyclopropariecarboxamido)-3-methylpyridin-2-yl)benzoic acid, which is depicted by the chemical structure:

NS
F.7)( F 0 0 = = 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 20071056341, WO
2009/073757, and WO 2009/076142, incorporated herein by reference.
100731 "Compound V" as used herein, refers to N-(1,3-dimethylpyrazol-4-yl)sulfonyl-643-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1--yli-2-[(45-2,2,4-trimethylpyrrolidin-1--yllpyridine-3-carboxamide, which is depicted by the chemical structure:
,S
CF34.. N
0*/ N N
Compound V.
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.
100741 "Compound VI" as used herein, refers to N-(benzenesulfony1)-643424 I
-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-ylipyridine-3-carboxamide, which is depicted by the chemical structure:

N
H
N
Compound VI.
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.
100751 "Compound VII" as used herein, refers to (145)-84342-t di spi ro[2Ø2.1] heptan-7-y1 eth.oxy)-1H-pyrazol-1-y I 1-12,12-di m ethy1-2X6-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:
H
N, N
p.õ
Compound VW
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. PCTIUS2020/046116, incorporated herein by reference.
100761 "Compound VIII" as used herein, refers to (111/)-642,6-dimethylpheny1)-11-(2-methylpropy1)-12- { spiro[2.3]hexari-5-y1}-9-oxa-2X6-thia-3,5,12,19-tetraaza.tricyclo[12.3.1.14,81nonadeca-1( 17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, which is depicted by the chemical structure:
h¨N

N N
Compound Vat 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.
100771 "Compound LX" as used herein, refers to N-(benzenesulfonyI)-6-(3--fluoro-5-i sob utoxy-pheny1)-24(4S)-2,2,4-tri ethylpyrrolidin- I -yli pyridine-3 -carboxamide, which is depicted by the chemical structure:
(2, 0 0 N' 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.
100781 "Compound X" as used herein, refers to N-[(6-amino-2-pyridyl)sulfonyli-6-(3-u oro-5-i sob utoxy-pheny1)-24(4S)-2,2,4-tri ethylpyrrolidin- I -ylipyridine-3-carboxamide, which is depicted by the chemical structure:

H

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.
100791 As used herein, the term "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.

100801 As used herein, the term "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.
100811 As used herein, the term "haloalkyl group" refers to an alkyl group substituted with one or more halogen atoms.
100821 As used herein, the term "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.
100831 The term "alkoxy" as used herein refers to an alkyl or cycloalkyl covalently bonded to an oxygen atom. Alkoxy groups may be substituted or unsubstituted.
100841 As used herein, the term "haloalkoxyl group" refers to an alkoxy group substituted with one or more halogen atoms.
100851 As used herein, the term "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.
100861 As used herein, "cycloalkyl" refers to a cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon groups having 3 to 12 carbons (such as, for example 3-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[2Ø2. liheptane. Cycloalkyl groups may be substituted or unsubstituted.
100871 The term "heteroaryl ring" as used herein refers to an aromatic ring comprising at least one ring atom that is a heteroa.tom, such as 0, N, or S.
100881 As used herein, the terms "heterocyclyl ring" and "heterocyc1y1"
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 0, N, S, or Si.
"Heterocycly1" rings encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro rings, including mono spiro and dispiro rings.

100891 "Substituted" indicates that at least one hydrogen of the "substituted" group is replaced by a substituent, Unless otherwise indicated, 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.
[0090] Examples of protecting groups for nitrogen include, for example, /-butyl carbamate (Boc), benzyl (Bn), para-methoxybenzyl (PMB), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Chz), methyl carbamate, ethyl carbamate, 2,2,2-trichloroethyl carbamate (T roc), 2-trimethylsitylethyl carbamate (Teoc), allyl carbamate (Aloc or Alloc), formarnide, acetamide, benzamide, trifluoroacetami de, triphenylmethyl amine, benzylideneamine, and p-toluenesulfonamide.
A comprehensive list of nitrogen protecting groups can be found in Wuts, P. G.
M.
"Greene's Protective Groups in Organic Synthesis: Fifth Edition," 2014, John Wiley and Sons.
[0091] As used herein, "deuterated derivative(s)" means the same chemical structure, with one or more hydrogen atoms replaced by a deuterium atom.
[0092] As used herein, "CFTR" means cystic fibrosis transmenibrane conductance regulator.
100931 As used herein, the term "C:FTR modulator" refers to a compound that increases the activity of (TIP_ The increase in activity resulting from a CFTR modulator includes but is not limited to compounds that correct, potentiate, stabilize and/or amplify CFTR.
100941 As used herein, the term "CFTR corrector" refers to a compound that facilitates the processing and trafficking of CFTR to increase the amount of CFTR at the cell surface.
100951 As used herein, the term "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.
[0096] As used herein, the terms "CFTR potentiator enhancer", CFTR
potentiation enhancer", and "CFTR co-potentiator" are used interchangeably and refer to a compound that enhances CFTR potentiation, 100971 As used herein, the term "active pharmaceutical ingredient" ("API") or "therapeutic agent" refers to a biologically active compound.
100981 The terms "patient" and "subject" are used interchangeably and refer to an animal including humans.
100991 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). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).
1001001 As used herein, the terms "treatment," "treating," and the like 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," as used herein, 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, Improvements in or lessening the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.
1001011 As used herein, 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 phatmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other.
1001021 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. In some embodiments, the terms "about" and "approximately" mean within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. As used herein, the symbol "--" appearing immediately before a numerical value has the same meaning as the terms "about" and "approximately."
[00103] As used herein, the term "solvent" refers to any liquid in which the product is at least partially soluble (solubility of product >1 0).
[001041 As used herein, the term "room temperature" or "ambient temperature"
means 15 C to 30 'C.
[00105] It will be appreciated that certain compounds of this invention may exist as separate stereoisomers or enantiomers and/or mixtures of those stereoisomers or enantiomers. As used in the chemical structures disclosed herein, a "wedge" (-p) or "hash" (.")bond to a stereogenic atom indicates a chiral center of known absolute stereochemistry (i.e. one stereoisomer). A.s used in the chemical structures disclosed herein, a "wavy" bond () to a stereogenic atom indicates a chiral center of unknown absolute stereochemistry (i.e. one stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond ( "sj ) to a double-bonded carbon indicates a mixture of Ea isomers. As used in the chemical structures disclosed herein, a ----("straight") bond, to a stereogenic atom indicates where there is a mixture (e.g., a racemate or enrichment).
As used herein, two ("straight") bonds to a double-bonded carbon indicates that the double bond possesses the E/Z stereochemistry as drawn. As used in the chemical structures disclosed herein, 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, [00106] Certain compounds disclosed herein may exist as tautomers and both tautomeric forms are intended, even though only a single tautomeric structure is depicted.
For example, a description of Compound A is understood to include its tautomer Compound B and vice versa, as well as mixtures thereof:

Compound A Compound B
/

N , =
HO s [001071 As used herein, "minimal function (MU 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.
1001.08] As used herein, 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.
[00109] 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. These phrases are intended to encompass pharmaceutically acceptable salts of any one of the referenced compounds, deuterated derivatives of any one of the referenced compounds, and pharmaceutically acceptable salts of those deuterated derivatives.
[001101 One of ordinary skill in the art would recognize that, when an amount of "a compound or a pharmaceutically acceptable salt thereof' is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. It is noted that the disclosed amounts of the compounds or their pharmaceutically acceptable salts thereof herein are based upon their free base form.

1001111 Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that article provides the following pharmaceutically acceptable salts:
Table 1:
Acetate Iodide 13enzathine Benzenesulfonate Isethionate Chloroprocaine Benzoate Lactate Choline Bicarbonate Lactobionate Diethanolamine Bitartrate Malate Ethylenediamine Bromide Maleate Meglurnine Calcium edetate Mandelate Procaine Camsylate Mesylate Aluminum Carbonate Methylbromide Calcium Chloride Methylnitrate Lithium Citrate Methyl sulfate Magnesium Dihydrochloride Mucate Potassium Edetate Naps)/late Sodium Edisylate Nitrate Zinc Estolate Parnoate (Embonate) Esylate Pan tothenate Fumarate :Phosphate/diphosphate Gluceptate PolIgalacturonate Gluconate Salicylate Glutamate Stearate Glycollylarsanilate Subacetate Hexylresorcinate Succinate Hydra.bamine Sulfate Hydrobromide Tannate Hydrochloride Tartrate Hydroxynaphthoate Teoci ate Triethiodide 1001121 -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, cam phorsulfonate, citrate, cyclopenta.nepropionate, digluconate, dodecylsul fate, ethanesulfonate, formate, fumarate, glueohepton.ate, glycerophosphate, gl.uconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pival ate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.
Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and IV(C14alkyl)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. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.
[001131 As used herein, the term "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. For example, 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, In some embodiments, 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 ciystalline 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.

Other techniques, such as, for example, solid state -NAIR may also be used to characterize crystalline or amorphous forms.
10011.41 As used herein, the terms "crystal form.," "crystalline form," and "Form"
interchangeably refer to a crystal structure (or polymoTh) 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 (app), single crystal X-ray diffraction, and 13C solid state nuclear magnetic resonance ('3C SSNMR). Accordingly, as used herein, the term "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, X1',PD, single crystal X-ray diffraction, and 13C
SSNMR. In some embodiments, 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 C20).
1001151 As used herein, 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.
10011.61 As used herein, the term "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 stoichiornetic or nonstoichiometric amounts. When the solvent is water, the solvate is referred to as a "hydrate."
10011.71 In some embodiments, a solid material may compiise 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, In some embodiments, 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. In embodiments wherein the solid material contains a mixture of crystalline solids and amorphous solids, the characterizing data, such as XRPD, may contain indicators of both crystalline and amorphous solids. In some embodiments, a crystalline form of this disclosure may contain up to 30% amorphous compound. In some embodiments, a crystalline preparation of a compound of Formula. I may contain up to 25%, 20%, 15%, 10%, 5%, or 2% of an amorphous solid.

[00118-1 As used herein, the term "substantially amorphous" refers to a solid material having little or no long-range order in the position of its molecules. For example, substantially amorphous materials have less than 15% crystallinity (e.g., less than 10%
crystallinity, less than 5% crystallinity, or less than 2% crystallinity). It is also noted that the term "substantially amorphous" includes the descriptor, "amorphous," which refers to materials having no (0%) crystallinity.
[00119] A.s used herein, the term "substantially crystalline" refers to a solid material having little or no amorphous molecules. For example, 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.
1001201 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. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 95% of the sum of all solid forn(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."
[00/21] As used herein, the term ")PD" 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 diffra.ctometer.
[00122] As used herein, the term "ambient conditions" means room temperature, open air condition and uncontrolled humidity condition. The terms "room temperature" and "ambient temperature" mean 15 C. to 30 'C.
[00123] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," "XRPD pattern," "XRPD spectrum" interchangeably refer to an experimentally obtained pattern plotting signal position.s (on the abscissa) versus signal intensities (on the ordinate). For an amorphous material, 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 20 ( 20), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed as "a signal a õ 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 MUD
pattern where the intensity as measured in counts is at a local maximum. One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement.
[00125] As used herein, "a signal at ... degrees two-theta" refer to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments ( 20).
[00126] The repeatability of the measured angular values is in the range of 0.20 20, 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).
[00127] The terms "signal intensifies" 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).
1001281 As used herein, 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. In determining "substantial similarity," one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in XRPD diffractograms even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal 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.
[00129] As used herein, 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.
In determining "substantial similarity," one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in SSNMR
spectra even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the chemical shifts in SSNM-R spectra (in parts per million (ppm) referred to herein) generally mean that value is identified as 0.2 ppm of the reported value, an art-recognized variance.
1001301 The term "X-ray powder diffractogram having a signal at ... two-theta values"
as used herein refers to an XRPD pattern that contains X-ray reflection positions as measured and observed in X-ray powder diffraction experiments ( two-theta).
1001311 As used herein, the term "DSC" refers to the analytical method of Differential Scanning Calorimetiy.
1001321 As used herein, the term "onset of decomposition" refers to the intersection point of the baseline before transition and the interflection tangent.
1001331 As used herein, the term "glass transition temperature" or "Tg" refers to the temperature above which a hard and brittle "glassy" amorphous solid becomes viscous or rubbery.
1001341 As used herein, the term "melting temperature", "melting point", or "Tm" refers to the temperature at which a material transitions from a solid to a liquid phase.
1001351 As used herein, the term "TGA" refers to the analytical method of Thermo Gravimetric (or thermogravimetric) Analysis.
Detailed Description of Embodiments 1001361 in addition to compounds of -Formula I, pharmaceutically acceptable salts thereof, and deuterated derivatives of those compounds and salts, the invention provides compounds of -Formulae I', 1", -Ia, Ha, Ha', Hb, lib', He, lie', Hid, !Id', lie, He', HT, Hg, !lib, and Compounds I to 213, Corn. .pounds 214 to 222, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing.
1001371 For example, in some embodiments, the compound of -Formula I is selected from compounds of any one of Formulae :La, Ha, [lb, He. Rd, He, Elf, fig, and Hh:

Y ----------------------------- Y

,,Y Y., X---( X
Y),-, y X Y Y
RI N Yi -1,, õ.. \
..' -"`"N '''T ,- --N
?-/.,;')1=.õ1,-= ,,,,Z
\\
R'i N-N ta, (R1)m N-N Ha, (R1)m N-N fib, Y-Y

X
Xõ X Y., Y Y
\
[IAN - - -\i---Y N \ y Ri -1-,,, - =, , [ri 1 '''' N V
I
(R1)rn N-N He (R1)m NN lid, R1 NN He, , X...-Y, ,Y,. ---Y Y-YN, Y Y .),c µ X-- Y
1 : Y-Y, \
R1 Y., R1 : R1,J., y Y-Y, 0 I 1 I rl \
' 0 ' .õ..=-= %./ z ,--- ,_ z R1 N-N ut R1 N-N Hg, and R1 NN Hh., and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I', [00138] In some embodiments, the compound of Formula I is selected from compounds of Formula I":
x------(Y),, Cl'sN
\ / (R1 Rz2 r, and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I.
[00139] In some embodiments, the compound of Formula I is selected from compounds of any one of Formulae !a', tbe, lib', Ile, Lid', He', Hir, Elg', and 111k':
.,.. :lc X-------Mr, X Y
X Y Y
.' N --.-LN Y .r).''' Y
,- 0 .0 Rzl R1 N-N :La% (R1)rn N-N Ha', (R1), ' NN lib%

Y ¨ Y
--Y ,.....--Y¨Y., .)? 1,',.
X
X Y X` Y
( N Y -Y ,,,t,"=

=-..õ-- -. N
Y L. I
ratRzi Rz2 \ / Rz2 (R1), N-N Re (Ri)rn N¨N Ltd', R1 N¨N lie, , x-...A"
X Y y ' : Y-Y, R1 ---, -\;`=, RI.,,,,-1., -c.,-1 -\)----1.
R1 N-N lir, R1 NN fig', and Y
\
RN
Y

---- O., _ ...1Rzi , IT- R.
R1 N¨N Ulf, and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein all variables are as defined for Formula I.
[00140] Also disclosed herein are compounds having a formula chosen from any one of the formulae depicted in Table 10, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of those compounds and deuterated derivatives.
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', Ha, Ha', fib, :Ilb', He, He', lid, lid', He, He', Hf, 1.1f, lig, Hg', Ilh, andllb), 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) [00142] In some embodiments, the invention provides neat solid forms of Compound 4.
In some embodiments, the invention provides a neat amorphous foi ______ ni 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.

[001431 in some embodiments, 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 Ka radiation, [00144] In some embodiments, amorphous Compound 4 (neat form) is characterized by an X-ray powder diffractogram substantially similar to FIG.
Crystalline Compound 5 Form A (neat) [00145] In some embodiments, the invention provides neat solid forms of Compound 5.
In some embodiments, the invention provides neat crystalline forms of Compound 5. In some embodiments, the invention provides crystalline Compound 5 Form A (neat).
[00146] In some embodiments, crystalline Compound 5 Form A (neat) is substantially pure. In some embodiments, crystalline Compound 5 :Form A (neat) is substantially crystalline.
[00147] In some embodiments, crystalline Compound 5 Form A (neat) is characterized by a tetragonal crystal system, an 141 space group, and the following unit cell dimensions measured at 100 K on a Balker diffractometer utilizing Cu Ka radiation (2,-1.54178 A):
a 18.1 .1 A a 90 b 18.1+ .1 A 13 900 c 13.1 .1 A, y 900.
.Amorphous Compound 19 (neat form) 1001481 In some embodiments, the invention provides neat solid forms of Compound 19, In some embodiments, the invention provides a neat amorphous form of Compound 19. In some embodiments, 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.
[00149] In some embodiments, amorphous Compound 19 (neat form) is substantially pure. in some embodiments, amorphous Compound 19 (neat form) is substantially amorphous. In some embodiments, 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 Ka radiation.

1001501 In some embodiments, amorphous Compound 19 (neat form) is characterized by an X-ray powder diffractogram substantially similar to FIG. 4.
Crystalline Compound 41 Form A
1001511 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.
1001521 In some embodiments, crystalline Compound 41 Form A is substantially pure.
In some embodiments, crystalline Compound 41 Form A is substantially crystalline. In some embodiments, 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 Ka radiation.
1001531 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. In some embodiments, 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.
1001541 In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, crystalline Compound 41 Form A is characterized by an X-ray powder diffractogram haying 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.
[00155] In some embodiments, 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 It 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.
1001561 in some embodiments, crystalline Compound 41 Form A is characterized by an X-ray powder diffractogram substantially similar to FIG. 7.
Crystalline Compound 52 :Form A (neat) [001571 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).
[00158] In some embodiments, crystalline Compound 52 Form A (neat) is substantially pure. In some embodiments, crystalline Compound 52 Form A (neat) is substantially crystalline. In some embodiments, crystalline Compound 52 Form A (neat) is characterized by an X-ray powder ditIractograrn generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation.
[00159] In some embodiments, crystalline Compound 52 Form A (neat) 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. In some embodiments, crystalline Compound 52 Form A (neat) 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. In some embodiments, 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.
1001601 In some embodiments, crystalline Compound 52 Form A (neat) 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. In some embodiments, crystalline Compound :52 Form A. (neat) 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. In some embodiments, crystalline Compound 52 Form A (neat) 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. In some embodiments, crystalline Compound 52 Form A
(neat) 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.
1001611 In some embodiments, crystalline Compound 52 Form A (neat) 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.
1001621 In some embodiments, crystalline Compound 52 Form A (neat) is characterized by an X-ray powder diffractogram substantially similar to FIG. 9.
Amorphous Compound 60 (neat form) 1001631 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.

1001641 in some embodiments, amorphous Compound 60 (neat form) is substantially pure. In some embodiments, amorphous Compound 60 (neat form) is substantially amorphous. In some embodiments, amorphous Compound 60 (neat form) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation.
1001651 In some embodiments, amorphous Compound 60 (neat fornil is characterized by an X-ray powder diffractogra.m substantially similar to FIG 12.
Amorphous Compound 70 (neat form) 1001661 In some embodiments, the invention provides neat solid forms of Compound.
70. In some embodiments, the invention provides a neat amorphous form of Compound 70. In some embodiments, the invention provides amorphous Compound 70 (neat form).
FIG. 15 provides an X-ray powder diffraetogram of amorphous Compound 70 (neat form) at room temperature.
1001671 in some embodiments, amorphous Compound 70 (neat form) is substantially pure. In some embodiments, amorphous Compound 70 (neat form) is substantially amorphous. In some embodiments, amorphous Compound 70 (neat form) is characterized by an. X-ray powder ditfractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu ha radiation.
1001681 In some embodiments, amorphous Compound 70 (neat form) is characterized by an X-ray powder diffractogra.m substantially similar to FIG 15.
Crystalline Compound 163 Form A (neat) 1001691 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 Form A (neat).
1001701 In some embodiments, crystalline Compound 163 Form A (neat) is substantially pure. In some embodiments, crystalline Compound 163 Form A (neat) is substantially crystalline. In some embodiments, crystalline Compound 163 Form A (neat) is characterized by an X-ray powder diffraztograrn generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation.

[00171] in some embodiments, crystalline Compound 163 Form A (neat) is characterized by an X-ray powder diffractogram haying a signal at 7.4 0.2 degrees two-theta.
[00172] In some embodiments, crystalline Compound 163 Form A (neat) 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. In some embodiments, crystalline Compound 163 Form A (neat) 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.
1001731 In some embodiments, crystalline Compound 163 Form A (neat) 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. In some embodiments, crystalline Compound 163 Form A (neat) 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. In some embodiments, crystalline Compound 163 Form A (neat) 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. 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, 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.
[00174] In some embodiments, crystalline Compound 163 Form A (neat) 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.
[00175] In some embodiments, crystalline Compound 163 Form A (neat) 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] In some embodiments, the invention provides neat solid forms of Compound 173. In some embodiments, the invention provides a neat amorphous form of Compound 173. In some embodiments, the invention provides amorphous Compound 173 (neat form). FIG. 18 provides an X-ray powder diffractogram of amorphous Compound (neat form) at room temperature.
[00177] In some embodiments, amorphous Compound 173 (neat form) is substantially pure. In some embodiments, amorphous Compound 173 (neat form) is substantially amorphous. In some embodiments, amorphous Compound 173 (neat form) is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Ka radiation.
[00178] In some embodiments, amorphous Compound 173 (neat form) is characterized by an X-ray powder diffractogram substantially similar to FIG. 18.
100179] In some embodiments, the invention provides neat crystalline forms of Compound 173. In some embodiments, the invention provides crystalline Compound Form A (neat).
[00180] In some embodiments, crystalline Compound 173 Form A (neat) is substantially pure. In some embodiments, crystalline Compound 173 Form A (neat) is substantially crystalline.
[00181] In some embodiments, crystalline Compound 173 Form A (neat) is characterized by a triclinic crystal system, a PI space group, and the following unit cell dimensions measured at 150 K on a Balker diffractometer utilizing Cu Ka radiation (k=1. ,54178 A):
a 6,7 a 76.0 .1 "
b 11.9 .i A i3 82.2 .1 c 13.1 .1 A 7 85.4 .1 ".

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).
1001831 In some embodiments, crystalline Compound 175 Form A (neat) is substantially pure. In some embodiments, crystalline Compound 175 Form A (neat) is substantially crystalline.
[00184] In some embodiments, crystalline Compound 175 Form A (neat) is characterized by an orthorhombic crystal system, a P212121 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer utilizing Cu Kci radiation (2,--1.54178 A):
a 9.8 -1- .1 A a 900 b 10,1 .1 A. ri 900 c 20.5 .1 A 900.
Crystalline Compound 188 Dichloromethane Solvate Form A
[00185] In some embodiments, the invention provides solvated crystalline forms of Compound 188. In some embodiments, the solvated crystalline form is a dichloromethane solvate. In some embodiments, the invention provides crystalline Compound 188 dichloromethane solvate Form A.
1001861 In some embodiments, crystalline Compound 188 dichloromethane solvate Form A is substantially pure. In some embodiments, crystalline Compound 188 dichloromethane solvate Form A is substantially crystalline.
[00187] in some embodiments, crystalline Compound 188 dichloromethane solvate Form A is characterized by a monoclinic crystal system, a P21 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer utilizing Cu Ka radiation (A,=1.54178 A):
a 16.2 .1 A a 90 b 13.3 If .1 A. ri 99.7 .1 "
c 23.2 .1 A y 90 .
Methods of Treatment 1001881 Any of the novel compounds and solid forms disclosed herein, such as for example, compounds of Formulae I, I", la, La', Ha, Ha', lib, [lb', He, RC, :Lid, lid', He, He', Hf, Hg, hg', Rh, Hh', Compounds I 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 MR activity in the body.
Individuals suffering from a mutation in the gene encoding CFTR may benefit from receiving a CFTR modulator. A CFTR mutation may affect the MR.. 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 MR
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). Some CFTR mutations exhibit characteristics of multiple classes.
Certain mutations in the CFTR gene result in cystic fibrosis.
1001891 Thus, in some embodiments, 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", la, :la', Ha, Ha', fib, lib', He, Ile', Hd, lid', He, He', 1ff. nr, hg', Iih. IIh', Compounds I 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. In some embodiments, the patient has an F508del/minimal function (ME) genotype, F508del/F508del genotype (homozygous for the F508del mutation), F508del/gating genotype, or 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.
1001901 In some embodiments, I 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, 1001911 in some embodiments, the patient is heterozygous and has an F508de1 mutation on one allele and a mutation on the other allele selected from Table 2:
Table 2: CFIR Mutations Mutation Q2X 1_218X Q525X R792X E1.104X

W19X Y275X G550X W882X R I.158X

E6OX W401X G673X Q890X 11,1254X
R.75X Q414X Q685X S91.2X S1255X
I,88X S434X R709X Y913X W1282X

Y1.22X Q493X 1_,732X Y1092X E1.371X

185+1G---->T 7 I 1+5G----A 1717-8G¨A 2622+1G---A 3121-1G---A
296+1G¨A 712-1G¨sT 1717-1G¨,A 2790-1G,C 3500-2A¨,G
29611G 1248+1G¨A 1811+1G---- 3040G---->C 3600+2insT
405+1 G---A 1249- IG--A. 181.1+1.6kbA-46 (G970R) 3850-1G--A.
405+3A---C 1341+1G----A 181 H-1643G---,T 31.20G--A 4005+10---A
406-1G¨A 1525-2A¨G 1812-1G¨A 3120+1G¨A 4374+1G¨T
621+1G----.T 1525-1G¨A 1898+1G---A 3121-2A---,G
711.+1G--- T 1898+1G---*C -----------------------------182delT I 078delT 1677delTA 2711deIT 3737delA
306insA 11.19delA 1782delA 2732insA 3791 delC
306de1TAGA 1138insG 1824delA 2869insG 382 'Idea 365-366insT 1154insTC 1833delT 2896insAG 3876delA
394de1TI 1161deIC 2043deIG 2942insT 3878de1G
442delA 1213deIT 2143delT 2957de1T 3905insT
444detA 1259insA 2183AA-4,3 3007deIG 4016insT
457TAT--G 1288insTA 2184delA 3028de1A 4021dupT
54 ideIC 1343deIG 2184insA 3171deIC 4022insT
574delA 147IdelA 2307insA 31711nsC 4040delA
663delT 1497deIGG 2347deIG 3271 deiGG 4279ins A
849deiG 1548de1G 2585delT 3349insT 4326de1 rC
935de1A 1609de1 CA 2594delGT 3659deIC
CFTRdelel CFTRde1e16-17b 1461ins4 CFTRde1e2 CFTRdele17a,17b 1924de17 CFTRde1e2,3 CFTRdele17a-18 2055de19---->A
CFIRdele2-4 CH:Rd el el.9 2i05211.7de113insA.GAAA
CFTRdele3-10,14b-16 CFTRdele 19-21 2372deI8 Mutation CFTRde1e4-7 CF1Rdele21 272 1 de111 CFIRdele4-11 CFTRde1e22-24 299 1de132 CFTR501(bde1 CF __ IRdele22,23 3667ins4 CFTRdup6b-10 1.24de123bp 4010d.e14 CFIRdcle11 602de114 4209TGIT---*AA
CFTRdele 13,14a 852de122 CFTRde1el4b-17b 991de15 1507del A561E MUNK
[00192] 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). Examples of isotopes which are commercially available and suitable for the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2H, 3H, 13c, NC, "N, 180, 170, 31P, 32P, "S, 18F and 36C1, respectively.
1001.93] 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 (3H)- and/or carbon-14 (14C)-labelled compounds are particularly useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.
For example, deuterium (2H)-labelled ones are therapeutically useful with potential therapeutic advantages over the non-2H-label led compounds. In general, deuterium (211)-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.
[00194] In some embodiments, the isotope-labelled compounds and salts are deuterium (2H)-labelled ones. In some specific embodiments, the isotope-labelled compounds and salts are deuterium (0-labelled, wherein one or more hydrogen atoms therein have been replaced by deuterium, In chemical structures, deuterium is represented as "2.H." or "D."
[00195] When discovering and developing therapeutic agents, the person skilled in the art attempts to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It may be reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism.
[00196] The deuterium (2H)-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. For explanation:
if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of lem,kD = 2-7 are typical. For a flirther discussion, see S. L. Harbeson and :Po D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference, [001971 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. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. In some embodiments, if 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 incoworation at each designated deuteiium 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).
Combination Therapies 1001981 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", lib, Hb', He, He', Hd, lid', He, He', Hf, Hf, Hg, Hh, IIh', Compounds Ito 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.
[00199] Thus, in some embodiments, 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", La, Ha, Ha', :Fib, ID', He, He', lid, HA', He, He', Llf, LW, fig, hg', Hh, Ht', Compounds I 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.
[00200] In some embodiments, at least one additional active pharmaceutical ingredient is selected from mucolytic agents, bronchodilators, antibiotics, anti-infective agents, and anti-inflammatory agents.
[00201] In some embodiments, the additional therapeutic agent is an antibiotic.
Exemplary antibiotics useful herein include tobrarnycin, including tobramycin inhaled powder (TIP), azithromycin, aztreona.m, 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.

1002021 In some embodiments, the additional agent is a mucolyte. Exemplary mucolytes useful herein includes Pulmozymee.
1002031 In some embodiments, the additional agent is a bronchodilator.
Exemplary bronchodilators include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabuline sulfate.
1002041 In some embodiments, 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 (MIA), sildenaffl, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.
1002051 In some embodiments, the additional agent is a nutritional agent.
Exemplary nutritional agents include pancrelipase (pancreating enzyme replacement), including Pancrease414, Pancreacarb , Ultrasee, or Creon , Liprotomase (formerly Trizyteke), Aquadekse, or glutathione inhalation. In one embodiment, the additional nutritional agent is pancrelipase.
1002061 In some embodiments, at least one additional active phartnaceutical ingredient is selected from CFTR modulating agents. In some embodiments, the CFTR
modulating agent is a CFTR corrector. In some embodiments, the CFTR modulating agent is a CFTR
potentiator enhancer/co-potentiator (for exampleõNSP-1 ). 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 CFIR
readthrough agent. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR. nucleic acid therapy.
1002071 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 717MEN116A modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a GPR39 a.gonist.
1002081 In some embodiments, the at least one additional active pharmaceutical ingredient is chosen from (a) Compound -.11 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.
Thus, in some embodiments, the combination therapies provided herein comprise a compound selected from compounds and solid forms of Formulae I, l', I", la, la', ha, ha', I lb, Hb', He, IIc', Hd, Hd', He, He', 'If, HP, Hg, Hg', Hh, Hh', Compounds Ito 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 11, Compound IV, Compound V. Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, the combination therapies provided herein comprise (a) at least one compound chosen from compounds and solid forms of Formulae I, I', I", la, la', Ha, Ha', lib, ilb', lic, Ile', Hd, lid', He, He', Hf, HP, Hg, Hg', 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 H, 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 VIH, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, the combination therapies provided herein comprise (a) at least one compound chosen from compounds and solid forms of Formulae I, l', I", ha, la', Ha, Ha', Hb, He, He', hid, Hd', He, He', Hg, hg', Hh, 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 H 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.
1002091 In some embodiments, the combination therapies provided herein comprise (a) a compound selected from compounds and solid forms of Formulae I, I', I", in, ha', Ha, Ha', lib, lib', Ile, He', lid, lid', lie, He', [If, III', Hg, Hg', la, Ilh', 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 11, 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. 2016-0120841, United States Patent Application Publication No. 2017-0101405, WO 2017/009804, WO 2018/065921, WO
2017/062581; Phuan, P.-W. et al. J. Cyst Fibros. 2018, 17(5), 595-606;
Pedetnonte, N. et al, Sci. Adv. 2020, 6(8), eaay9669; Phuan, P,-W. etal. Sci. Rep. 2019, 9(1), 17640; Bose, S. et al. J. Cyst. Fibros. 2020, 19 Supp11, S25-S32; Crawford, D.K. J.
Pharmacol Exp.
Ther. 2020, 374 (2), 264-272; Brasell, E.J. et al. PLoS One 2019, 14 (12), e0223954;
Smith, NJ, Solovay, C.F., Phartn. Pat. Anal. 2017, 6(4), 179-188; Kunzelmann, K. et al., Front. Pharmacol 2019, 10, 3; or Son, JAI et al., Eur. J. gilt/fed. Chem.
2020, 112888, [002101 In some embodiments, the combination therapies provided herein comprise (a) a compound selected from compounds and solid forms of Formulae I, I", Ia, la', Ha, Ha', Lib, lib', lie, ild, lid', He, lie', 1ff. 1W, hg, Hg', FIb, lib', 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 H, 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 P11-428, ASP-11õABBV-2222, ABBV-2851, GLPG2737, Al3BV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, AR1\123766, PTI-801, FDL-176, PTI-808, GLPG1837, GLPG2451/ABBV-2451 (Icenticaftor), (1LPG30671ABBV-3067 (Navocaftor), ABBV-191, ELX-02, M1R15005, Lunar-CF, RC1223, 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, ARO-ENaC.1001, ETD002, and :DS-11039.
[002111 In some embodiments, the combination therapies provided herein comprise (a) a compound selected from compounds and solid forms of Formulae 1, I', 1", la, Ha, Ha', Hb, Hk', He, ild, lid', Ile, He', HT, nr, Hg, fig', ilk, lih', 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, WO 2018/107100, WO 2019/113476, WO 2018/064632, WO 2019/152940, WO 2016/057572, WO 2021/030554, WO
2020/206080, WO 2016/105485, United States Patent Application Publication No.

0120841, United States Patent Application Publication No. 2017-0101405, WO
2017/009804, WO 2018/065921, WO 2017/062581; Phuan, P.-W. et al. J. Cyst.
.Fibros.
2018, 17(5), 595-606; Pedemonte, N. et al. Sci. Adv. 2020, 6 (8), eaay9669;
Phuan, P.-W.
etal. Sci. Rep. 2019, 9 (1), 17640; Bose, S. et al. J. Cyst. Fibros. 2020, 19 ,Suppl 1, S25-S32; Crawford, D.K. J. Pharmacol. Exp. iher. 2020, 374(2), 264-272; Brasell, E.J. et al.
PLoS One 2019, 14 (12), e0223954; Smith, NI, Solovay, CF., Pharm. Pat. Anal.
2017, 6 (4), 179-188; Kunzelmann, K. et al., Front. Pharmacol. 2019, 10, 3; or Son.
J.4-1. et al., Eur. J ofMed Chem. 2020, 112888.
1002121 In some embodiments, the combination therapies provided herein comprise (a) a compound selected from compounds and solid forms of -Formulae I, I', I", la, Ia', Ha, Ha', lib, lib', He, He', Hid, lid', Re, He', HT, ilg, Hg', 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, A1313V-2222, Al3BV-2851, EiLPG2737, A1313V-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN-23765, ARN23766, PT1-801, FDL-176, PTI-808, GI,P(1i1837, GLPG2451/ABBV-2451 (Icenticaftor), GLPG3067/ABBV-3067 (Na.vocaftor), ABBV-191, ELX-02, MR.T5005, Lunar-CF, RCT223, a.miloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, lbnis-ENaC-2.5 Rx, BI
1265162, AZ5634, ARO-ENaC1001, ETD002, and DS-1039, and deuterated derivatives and pharmaceutically acceptable salts thereof.
1002131 In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, 1', li", la, ha', Ha, Ha', H130, lib', lie, !Hid, lid', He, lie', Hf, Hg, hg', IIh, Hh', 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, is administered in combination with at least one compound chosen from Compound II and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", Ia, Ia', Ha, Ha', Hb, lib', [lc, Hc', lid, [Id', He, lie', HI, lir, 11g, Itg', Ilh, In', Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives of those compounds, and pharmaceutically acceptable salts of those compounds and deuterated derivatives, is administered in combination with at least one compound chosen from Compound IV and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds and solid forms Formulae I, I', I", la, Fa', Ha, lb', lib, Hb', Ile, Hc', lid, Lid', He, Ile', hf, iir, Ilg, Hg', Hh, Ilh', Compounds 1 to 213, Compounds 214 to 222, deuterated derivatives of those compounds, and pharmaceutically acceptable salts of those compounds and deuterated derivatives, is administered in combination with at least one compound chosen from Compound V
and deuterated derivatives and pharmaceutically acceptable slats thereof. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", Ia, Ia', Ha, Ha', Hb, Hb', Hc, He', Hd, Hd', He, He', Hf, Hg, hg', Ilh, Ih', Compounds Ito 213, Compounds 214 to 222, deuterated derivatives of those compounds, and pharmaceutically acceptable salts of any of those compounds and deuterated derivatives, is administered in combination with at least one compound chosen from Compound VI and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", Ia, Ia', Ha, IIa', Hb, Hb', Iic, IIc', Hd, Hd', He, He', 'If, III", Jig, lig', Iih, Ilk', Compounds I to 213, Compounds 214 to 222, deuterated derivatives of those compounds, and pharmaceutically acceptable salts of any of the foregoing compounds and deuterated derivatives, is administered in combination with at least one compound chosen from Compound VII and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, l', I", Ia, la', ha, Ha', Lib, Ilb', He, He', lid, hid', He, He', Hf, 'If, IIg, hg', Hh, 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, is administered in combination with at least one compound chosen from Compound VIII
and deuterated derivatives and pharmaceutically acceptable salts thereof.
1002141 Each of the compounds and solid forms of Formulae I, I', I", Ia, la', Ha, Ha', lib, In', lie, lid, lid', Ile, He', lif, 1W, Hg, Hg', Hh, ID% Compounds 1 to 213, Compounds 214 to 222, Compound H, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and their deuterated derivatives and pharmaceutically acceptable salts thereof, independently can be administered once daily, twice daily, or three times daily. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", la, la', Ha, Ha', lib, He, He', lid, Hd', He, He', Hf, III', lig, hg', Hh, Hh', Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof is administered once daily. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", :la, Ia.', lb, Ha', lib, nw, He, He', lid, lid', He, He', Hi, Hi', hg, hg', Hh, Iih', Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof is administered twice daily. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", ia, la', lb, Lb', Hb, Jib', Ile, He', lid, lid', He, He', 'If, Ili', lig, hg', 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, 1", la, ia', Ha, Ha', lib, lib', Ile, He', lid, lid', He, He', Ill; 1W, lig, hg', Hh, Hh', 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", ha, ha', ha, Ha', Hb, lib', Ile, Ile, lid, Lid', lie, He', Ill, iir, Jig, Jig', Ilh, Hh', 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", ha, ha', Ha, Ha', lib, lib', Hc, lid, Hd', He, He', = Hg, hg', IA, Hit', 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, II', 1", la, la', Ha, Ha', lib, lib', Hc, Hc', lid, Hd', He, He', Hf, = Hg, hg', Hh, Hh', 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", ia, ia', Ha, Ilb, 1 lb', 11c, Ik', Hd, He, He', [If, III', Jig, Hh, 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", ia, ia', Ha, Ha', lib, H= e, He', Hd, lid', He, He', Ills, If', Hg, hg', Hh, Hh', 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae 1, l', 1", la, la', lila, Ha', lib, H= e, He', Hd, I'd', He, He', Ills, If', Hg, I Ig', Hh, 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", ia, ha', Ha, lb', 1lb, 111:1', Ilc, Hc', lid, Lid', lie, Ile', llf, iir, Ilg, Hg', Hh, ilh', 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", ia, ha', Ha, lb', 1lb, 111:1', Ilc, Hc', lid, Lid', lie, Ile', llf, iir, Ilg, Hg', Hh, ilh', 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, l', I", la, la', Ha, Ha', lib, lib', He, He', lid, lid', He, He', His, Hf, Hg, hg', Hh, 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", In, Ia', Ha, Ha', Hb, Hb', He, IIc', Hd, Hd', He, He', Hf, Hg, Hg', illh, Ilh', 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.
1002151 In some embodiments, at least one compound chosen from compounds and solid forms of Formulae 1, l', 1", la, la', lila, Ha', nb, Hb', lic, hid, inkr, 'le, Ile', Hf, iir, Hg, Hg', Hh, Hh', 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae II, l', 1", la, la', Ha, Ila', 1lb, lib', Itc, Hc', lid, IId', He, He', Hg, hg', Hh, Hh', 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. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", ha, ha', Ha, Ha', IlIb, Ilb', 11c, He', lid, Ild', Ile, lie', llf, llf, Hg, Ilg', Ilh, IIh', Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof; at least one compound chosen from Compound H and pharmaceutically acceptable salts thereof; and at least one compound chosen from Compound VII
and pharmaceutically acceptable salts thereof are administered once daily. In some embodiments, at least one compound chosen from compounds and solid forms of Formulae 1, I', I", Ia, la', Ha, Ha', Hb, lib', He, Ile', Ild, lid', He, He', HT, Jig, Hg', 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.
1002161 Compounds and solid forms of Formulae I, I', I", Ia, Ia', Ha, Ha', lib, iib', Hc, lid, lid', Ile, He', Hf, 1W, Hg, Hg', ilh, 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. As used herein, the phrase that a given amount of API (e.g., Compound II, Compound VII, or pharmaceutically acceptable salts thereof) is administered once or twice daily or per day means that said given amount is administered per dosing, which may occur once or twice daily.
1002171 In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", Ia, Ia', Ha, Ha', Hb, Hb', Ile, He', Hd, Hd', He, He', ur, 11g. Hg', lih, iih', Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a first pharmaceutical composition; and at least one compound chosen from Compound VII
and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition.
1002181 In some embodiments, at least one compound chosen from compounds and solid forms of Formulae I, I', I", Ia, Ia', Ha, Ha', Hb, lib', Ile, He', lid, Hd', lie, Ile', HI, 1W, lig, hg', iih, In', Compounds I 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, 1002191 Any suitable pharmaceutical compositions known in the art can be used for compounds and solid forms of Formulae I, I", Ia, Ia', Ha, Ha', lib, He, He', lid, ih-P, lie, lie', Hf. nr, lag, lag', Elh, ilh', 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 H 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 HI and its pharmaceutically acceptable salts can he 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 1Hd 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.
Pharmaceutical Compositions 1002201 Another aspect of the invention provides a pharmaceutical composition comprising at least one compound chosen from compounds and solid forms of Formulae I.
I", la, la', Ha, ha', Hb, ID', He, Ile', lid, He, He', III, Hf, fig, hg', 1111, In', Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.
1002211 In some embodiments, the invention provides pharmaceutical compositions comprising at least one compound chosen from compounds and solid forms of Formulae I, I', I", Ia, Ia', Ha, Ha', lib, lib', Hc, Hd, lid', He, He', Hf, lir, 11g, hg'. Hh, IIh', Compounds 1 to 213, Compounds 21.4 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, 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 modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a GPR39 agonist. In some embodiments, the pharmaceutical composition comprises at least one compound chosen from compounds and solid forms of Formulae I, I', I", Ia, Ia', Ha, Ha', lib, lib', Hc, Hd, lid', He, He', Hf, Hg, hg', Hh, Compounds I 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. In some embodiments, the pharmaceutical composition comprises at least one compound chosen from compounds and solid forms of Formulae I, I', I", la, Ia', Ha, Ha', lib, Hb', lic, He, Lid, lid', He, He', Iif, HP, Hg, Hg', 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.
1002221 In some embodiments, the invention provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds and solid forms of Formulae I, I', I", In, Ia', Ha, ha', Hb, Hb', Hc, IIc', Hd, Hd', He, He', Hf, Hg, Hg', iih, Ilh', Compounds I 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.
1002231 In some embodiments, the invention provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds and solid forms of Formulae I, I', I", Ia, Ia', Ha, Ha', Hb, Hb', Hc, He', Hd, Hd', He, He', Lit = Hg, lih, ilh'. Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof, (b) at least one compound chosen from Compound H and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.
1002241 In some embodiments, the invention provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds and solid forms of Formulae I, I', I", Ia, Ia', Ha, ha', Hb, lib', He, He', Hd, lid', He, He', His, Hf, Hg, Hg', I lh, lih', 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.
1002251 In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds and solid forms of Formulae I, I', I", Ia, la', Ha, Ha', Hb, Hb', He, He', Hd, Hd', He, He', Iif, lir, Hg, hg', Hh, 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 H, Compound IV, and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from Compound V, Compound VI, Compound VII, Compound VHI, Compound IX, Compound X, and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.
1002261 In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds and solid forms of Formulae 1, l', I", Ca, la', ha, I Ca', lib, lib', lie, I Cc', lId, lid', lie, lie', [if, I= lg, Hg', Hh, 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 H 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.
1002271 In some embodiments, the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds and solid forms of Formulae I, I", la, :La', Ha, Ha', lib, lib', lie, He', Hd, He, He', IIf, lir, Ilig, Hg', 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. 2016-0120841, United States Patent Application Publication No. 2017-0101405, WO 2017/009804, WO
2018/065921, WO 2017/062581; Phuan, P.-W. et al. J. Cyst Fibros. 2018, 17(5), 606; Pedemonte, -.N. et al. Sci. Adv, 2020, 6 (8), eaay9669; Phuan, P.-W. et al. Sci. Rep, 2019, 9 (1), 17640; Bose, S. et al. J. Cyst. Fibros. 2020, 19 Suppl 1, S25-S32; Crawford, D.K. J. .Pharmacot .Exp. Ther. 2020, 374(2), 264-272; Brasell, E.J. etal. PLoS
One 2019, 14(12), e0223954; Smith, N.J, Soiovay, C.F., Pharm. Pat. Anal. 2017, 6(4), 179188;
Kunzelmann, K. et al., Front. Pharmacol. 2019, 10, 3; or Son, et al., .Eur. J. ofitled.
Chem. 2020; 112888; and (d) at least one pharmaceutically acceptable carrier.
1002281 In some embodiments, the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds and solid forms of Formulae I, I', 1", Ia, ia', Ha, Ha', Jib, lib', He, He', lid, lid', Fie, Hf, Hg, 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, A1313V-119, FDL-169; ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, pTI-808, GLPG1837, GLPG2451/A1313 V-2451 (icenticaftor), GLPG3067/ABBV--3067 (Navocaftor), ABB-V-191, EIX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, C17552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, lonis-ENaC-2.5 Rx, B1 1265162, AZ5634, ARO-ENa.C1001, ETD002, and DS-1039; and (d) at least one pharmaceutically acceptable carrier.
[00229] In some embodiments, the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds and solid forms of Formulae 1, 1", Ia, Ia', Ha, Ha', Hb, IIW, 1k, Ik', Hd, He, He', Hf, .. Hg', 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,
7, WO 2007/056341, WO 2009/073757, WO 2009/076142, WO
2018/107100, WO 2019/113476, WO 2018/064632, WO 2019/152940, WO 2016/057572, WO 2021/030554, WO 2020/206080 , WO 2016/105485, United States Patent Application Publication No. 2016-0120841, United States Patent Application :Publication No. 2017-0101405, WO 2017/009804; WO 2018/065921, WO 2017/062581; Phuan, R-W. et al. J. Cyst. Fibros. 2018, 17 (5), 595-606; Pedemonte, N. et al. Svc.
Adv. 2020, 6 (8), eaay9669; Phuan, P.-W. et al. Sel. Rep. 2019, 9 (1), 17640; Bose, S. et al. J.
Cyst. Fibros.
2020, 19 App.' 1, S25-S32; Crawford, D.K. J. Pharmacol. Exp. Ther. 2020, 374 (2), 264-272; Brasell, E.J. et al. PLoS One 2019, 14 (12), e0223954; Smith, N.J, Solovay, C.F., Pharm. Pat. Anal. 2017, 6 (4), 179-188; Kunzelmann, K. et at, Front. Pharmacol 2019, 10, 3; or Son, 1,-H, et al., .Eur. J. of Med. Chem. 2020, 112888, and (c) at least one pharmaceutically acceptable carrier.
[00230] In sonic embodiments, the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds and solid forms of Formulae :I, 1', 1", :la, la', Ha, Ha', lib, 11W, He, He', lid, lid', lie, Iif, Compounds 1 to 213, Compounds 214 to 222, and deuterated derivatives and pharmaceutically acceptable salts thereof; (b) at least two compounds chosen from Compound H, Compound IV, Compound V. Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PT1-428, ASP-11, ABBV-2222, ABBV-2851, GI,PCi2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDI,169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PT1-801, FDL-176, PT1-808, GI,PCil 837, GLPG2451/A1313V-2451 (leenticaftor), GLPG3067/A1313V-3067 (Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RC1223, amiloride, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-E-NaC-2.5 R, BI 1265162, AZ5634, ARO-ENaC1001, ETD002, and DS-1039, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one phannaceutically acceptable carrier.
[00231] Any pharmaceutical composition disclosed herein may comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. in some embodiments, the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, lubricants.
[00232] The pharmaceutical compositions described herein are useful for treating cystic fibrosis and other CFTR-mediated diseases.
[00233] As described above, 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, as used herein, 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. Remington:
The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams &
Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J.
Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure, Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum 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, polywylates, 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, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), MOM c acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.
Non-limiting Exemplary Embodiments 1. A compound selected from compounds of Formula I:
N
(R1) \
N-N
and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:
C:tingy\
A
X is selected from -N(R)- and Ring A is a 4- to 6-membered heterocyclyl optionally substituted with 1-3 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, -0Rx2, and -N(Rx2)2), and C.-C8 cycloaikyi;
each .Rx2 is independently selected from H and C1-C6 alkyl;

each V is independently selected from -C(RY)2-, -0-, -CO-, -NR-, and n-;\\
, wherein each RYN is independently selected from H, CI-C4 and CO2R"1, wherein each RYN1 is independently selected from C1-C4 alkyl and C3-C6 cycloalkyl;
each RY is independently selected from hydrogen, hydroxy, halogen. Cr-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, Ci-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, -OR", -CO2R", -COR", -CON(R)2, and -N(R")2;
or two RI/ 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;
each RY1 is independently selected from hydrogen and C1.-C6 alkyl, or two R"
bonded 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-C8 cycloalkyl, E 5- to 10-membered heteroaryl, and = 3- 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 aryl (optionally substituted with 1-3 groups independently selected from halogen and -0CF3), and o C3-C8 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), and o C3-C8 cycloalkyl, = C6-C10 aryl 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 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 CI-C6 alkyl), and o C6-C10 aryl, = 5- to 10-membered beteroaryl 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-C8 cycloalkyl (optionally substituted with 1-3 CF3 groups), and o 3- to 10-membered heterocyclyl, 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), and o oxo;
each Ri is independently selected from halogen, C1-C6 fluoroalkyl, CI-C6 alkyl (optionally substituted with a group selected from hydroxy, C6-Cto aryl, and 5-to 6-membered heteroaryl). -N(R2)2, -CO2R2, -CO-N(R2)2, C3-C8 cycloalkyl, 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(0R2)2, -S02R2, -SR2, -S0R2, -P0(0122)2, and -P0(R2)2;
each R2 is independently selected from hydrogen, CI-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), Ci-C6 fluoroalkyl, and C6-C10 aryl (optionally substituted with 1-3 groups independently selected from CI-C6 fluoroalkyl and C1.-C6 fluoroalkoxy);
õRzi 4 ,Rz3 C (Rz2)0_2 Rzz Rzi Z is selected from , and wherein Ring C is selected from C6-C10 aryl and 5- to 10-membered heteroaryl;
Rzl is selected from hydrogen, -CN, Cl-C6 alkyl (optionally substituted with 1-3 hydroxy), CI-C6 fluoroalkyl, 3-to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-C1.0 aryl, and 5- to 6-membered heteroaryl;
Rz2 is selected from hydrogen, halogen, hydroxy, NH?, NH(C0)(C1-C6 alkyl), and C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl), or Itz1 and Rz2 taken together form a group selected from oxo and =N-OH;
each Rz3 is independently selected from hydroxy, CI-C6 alkoxy, C1-C6 alkyl, and C6-Cdo aryl; or two Rz3 are taken together to form a 3- to 6-membered heterocyclyl;
n is selected from 4, 5, 6, 7, and 8; and m is selected from 0, 1, 2, and 3, 2. The compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1, wherein:

i-TNA
RAmg X is selected from --N(Rx1)- and Ring A is a 4- to 6-membered heterocycly1 optionally substituted with 1-3 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, -0R'2, and -N(Rx2)2), and C3-C8 cycloalkyl;
each Rx-2 is independently selected from H and C1-C6 alkyl;
each V is independently selected from -C(R1)2-, -0-, -CO-, -NR"-, and , wherein each R1N is independently selected from H, CI-C4 alkyl, and CO2Me;
each is independently selected from hydrogen, hydroxy, halogen, CI-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy.
C1-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-Cto aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, -0O2RY1, -CORY1, -CON(RY1)2, and -N(R1)2;
or two RI/ on the same atom are taken together to form a ring selected from C3-C8 cycloalkyl and 3- to 7-membered heterocycly1; 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;
each R.' is independently selected from hydrogen and CI-Cc, alkyl, or two R"
bonded 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-C8 cycloalkyl, E 5- to 10-membered heteroaryl; and = 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C1-C6 alkyl);

each Q is independently selected from:
= Ci-C6 alkyl optionally substituted with 1-3 groups independently selected from:
o halogen, o oxo, o C6-C to aryl (optionally substituted with 1-3 groups independently selected from halogen and -0CF3), and o C3-C8 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 CI-C6 alkoxy, o C6-Cio aryl (optionally substituted with 1-3 groups independently selected from C1-c6 alkyl), and o C3-C8 cycloalkyl, = C6-Clo aryl optionally substituted with 1-3 groups independently selected from:
o halogen, o CN, o Ci-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-C,8 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); and o C6-C40 aryl, = 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

o halogen, o CI-C6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), o C3-C8 cycloalkyl (optionally substituted with 1-3 CF3 groups), and o 3- to 10-membered heterocyclyl, 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), and o oxo;
each R3 is independently selected from halogen, C1-C6 fluoroalkyl, C1-C6 alkyl (optionally substituted with a group selected from C6-C10 aryl and 5- to 6-membered heteroaryl), -OW; -N(R2)2, -0O2R2, -CO-N(R2)2, -CN, C1-C6 alkoxy, C3-C8 cycloalkyl, C6-Clo aryl, 5- to 6-membered heteroaryl (optionally substituted with 1-3 groups independently selected from C I-C6 alkyl), 3-to 6-membered heterocyclyl, -S02R2, -SR2, -SOR2, -P0(0R2)2, and -P0(R2)2;
each R2 is independently selected from hydrogen. CI-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), C1-C6 fluoroalkyl, and C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl and CI-C:6 fluoroalkoxy);
.7)<Rzi ,Rz3 Si' Z3 Rz2 Z is selected from , and Rzl is selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-3 hydroxy), Ci-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-Cio aryl, and 5- to 6-membered heteroaryl;
Rz2 is selected from hydrogen, halogen, hydroxy, and C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl), or WI and Rz 2 taken together form a group selected from oxo and =N-OH;
each :R:43 is independently selected from hydroxy, CI-C6 alkoxy, Ci-C6 and C6-C10 aryl; or two Rz3 are taken together to form a 3- to 6-membered heterocyclyl, n is selected from 4, 5, 6, and 7; and in is selected from 0, 1, 2, and 3.
3. The compound, deuterated derivative, or salt according to Embodiment 1 or 2, wherein X is -NR, 4. The compound, deuterated derivative, or salt according to any one of Embodiments 1-3, wherein X is selected from:
HO,, 0 --õ,,OTO
--- --, ,----1 -._N.,-\\ ,,I,NA, \ -AN.N- \ '-µ, N .,-\ =-...1.9-\
...,.... ...1.õ _L. .....,... _L...
H
W\
and ....1._ .
5. The compound, deuterated derivative, or salt according to Embodiment I
or 2, (Ring \\ A) ' N
wherein X is 6. The compound, deuterated derivative, or salt according to Embodiment 1, 2, or 5, wherein Ring A is selected from pyrrolidine, piperazine, morpholine, and isothia.zolidine.
,7,-I. The compound, deuterated derivative, or salt according to Embodiment 1, 2, 5, or 6, wherein X is selected from:
_ ----11 0)N' -------/ 0 -,=::0s5.1 N N N N ,
8. The compound, deuterated derivative, or salt according to any one of Embodiments 1-7, wherein each RY is independently selected from:
I I
V,,,,,OH ,0 -,,,0,õ.0 _L._ hydrogen, hydroxy, methyl, , , , 's:( _ , , , F
=õ, /¨ \ <:''''>`-",,i .
, 0.1,0 H00 N ..--,-,-- , and ¨ ; or wherein two RY on the same atom are taken together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, and tetrahydropyra.nyl; or wherein 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.
9. The compound, deuterated derivative, or salt according to any one of Embodiments 1-8, wherein each Q is independently selected from C6-C10 aryl optionally substituted with 1-3 groups independently selected from halogen and Ci-C6 alkyl.
10. The compound, deuterated derivative, or salt according to any one of Embodiments 1-9, wherein each Q is phenyl.
11. The compound, deuterated derivative, or salt according to any one of Embodiments 1-10, wherein each Ring B is independently 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.
12. The compound, deuterated derivative, or salt according to any one of Embodiments 1-11, wherein each Ring B is indepedently selected from:
1\1--, and
13. The compound, deuterated derivative, or salt according to any one of Embodiments 1-12, wherein AY), is a group selected from:
NC.\y V-N-,õ..,=Y'' y FY H\---y LN, \----\--- kY-\\-----1--- \------ \ 1-Thy¨y, , and Y----1
14. The compound, deuterated derivative, or salt according to any one of Embodiments 1-13, wherein -0011- is a group selected from:
-,, Oa"
, .

cTh\Th \,,,,õ
HO OH;
I

----OH
=

--'-µ11 1, ,,----- os, / -,,----\--ii I i¨N I
\ \/--L----N-11 "
s'l , , , , I
, -- 0 HO .0 -,,,,._õ.õ0,0 N 0 C, -.-' .õ..= ......L.
\
.

, , , F
.---" .----F F
, .
---' OM e ¨, and
15. The compound, deuterated derivative, or salt according to any one of Embodiments 1-14, wherein each Y is -C(W)2-.
16. The compound, deuterated derivative, or salt according to Embodiment 15, wherein each Y is independently selected from -C112- and -C(Me)2-,
17. The compound, deuterated derivative, or salt according to any one of Embodiments 1-16, wherein each R1 is independently selected from C I-C6 fluoroalkyl and -N(R2)2.
18. The compound, deuterated derivative, or salt according to any one of Embodiments 1-16, wherein each W is independently selected from Br, -C,F13, -CF3, -CHF2, -OH, 2 ,,,,,..... N¨NH 7,¨N is2 -OCE13, -CN, --NI-12, .1.--, 1, ..,. .
, , , __ , ,, 2 ,..., 1 J 1 ,0 , __ N -,,,, ..õ0:1:0 H2N 0 ..A1H '''NH ¨\P'"o 'S/------0 ¨1¨ --1¨ _L
, , , , , , . . .
cF,o õ, cF,o cF3o itah ,o io I
s=o st=o s _L _L ¨1-- , and ¨1.õ...
,
19. The compound, deuterated derivative, or salt according to any one of Embodiments 1-18, wherein each -R1 is independently selected from -CF3 and -NII2.
20. The compound, deuterated derivative, or salt according to any one of Embodiments 1-19, wherein Z is selected from:
<Rzi ...,,_ R
, and Z2 ,
21. The compound, deuterated derivative, or salt according to any one of Embodiments 1-20, wherein:
kLI is selected from hydrogen, C1-C6 alkyl (optionally substituted with 1-3 hydroxy), Ca-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, and C6-C10 aryl, Rz2 is selected from hydrogen, hydroxy, and CI-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl), or R13 and Rz2 taken together form a group selected from oxo and =N-01-I;
22. The compound, deuterated derivative, or salt according to any one of Embodiments J.--5<Rzi 1-21, wherein Z is
23. The compound, deuterated derivative, or salt according to any one of Embodiments 0,, :7 z _______,0 ,,,Rziri i / \\ r\z2 1_22, wherein NN is NN .
24, The compound, deuterated derivative, or salt according to any one of !Embodiments 1-23, wherein IZz' is selected from C1-C6 fluoroalkyl.
25. The compound, deuterated derivative, or salt according to any one of Embodiments 1-24, wherein leJ is -CF3.
26. The compound, deuterated derivative, or salt according to any one of Embodiments 1-25, wherein Rz2 is hydroxy,
27, The compound, deuterated derivative, or salt according to any one of Embodiments 1-21, wherein Z is selected from:
:CF3 :
OH /4.'= --CF3 -----OH 0 :------N
\c"' , CF3 , and OH , . = = ' ,
28. The compound, deuterated derivative, or salt according to any one of Embodiments kcco,rz 1-21, wherein NN is selected from:
OH
H3 o/
ii._ 0cF,/Thr\' N-N N-N N-N N-N
iti,_ ,,..0,rqcF3 ......\ fõ.,\ --\\ / 0 N-N
o.Nrq:,Ci o NN NN OH F-CC it OH ---"....õ...-", , ' CF3 11-() 0 11---\-c )7----0 /1----cc T-TN-OH
11-05-7:1:N/7---7cH
N-N N-N N-N N-N , iiThc / i \
NN , and HO .
29, The compound, deuterated derivative, or salt according to any one of Embodiments 1-28, wherein ta is selected from 4, 5, and 6.
30. The compound, deuterated derivative, or salt according to any one of Embodiments 1-29, wherein n is 5.
31. The compound, deuterated derivative, or salt according to any one of Embodiments 1-29, wherein n is 6,
32. The compound, deuterated derivative, or salt according to any one of Embodiments 1-31, wherein in is selected from 1 and 2.
33. The compound, deuterated derivative, or salt according to any one of Embodiments 1-32, wherein in is 2.
34. A compound selected from compounds of Formula NN
and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:
X is selected from -NR'"- and =
Ring A is a 4- to 6-membered heterocycly1 optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and oxo;
Rx1 is selected from 11, CI-C6 alkyl (optionally substituted with 1-3 groups , independently selected from hydroxy, oxo, -0Rx2and -N(R)2), and C3-C8 cycloalkyl, each Rx2 is independently selected from H and C1-C6 alkyl;
each Y is independently selected from -C(RY)2-, -0-, -CO-, -NRYN-, and I Ring , wherein each RYN is independently selected from H, C1-C4 and CO2Me;
each RY is independently selected from hydrogen, hydroxy, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, -0RY1, -CO2RY1, -00RY1, -00N(R")2, and --N-(R")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;
each RY1 is independently selected from hydrogen and C1-C6 alkyl, or two bonded 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-C8 cycloalkyl, = 5- to 10-membered heteroaryl, and = 3- 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-C to aryl (optionally substituted with 1-3 groups independently selected from halogen and -0073), and o C3-C8 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, -N112, and -NHCOMe), o C1-C6 aikoxy, o C6-C10 aryl (optionally substituted with 1-3 groups independently selected from Ci-C6 alkyl), and o C3-C8 cycloalkyl, = C6-Cio aryl 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 and hydroxy), o Ci-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. OM, and C1-C6 alkyl), and o 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 (73-C8 cycloalkyl (optionally substituted with 1-3 CF3 groups), and o 3- to 10-membered heterocyclyl, = 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), and o oxo;
each is independently selected from halogen, C1-C6 fluoroalkyl, C1-C6 alkyl (optionally substituted with a group selected from C6-C10 aryl and 5- to 6-membered heteroaryl), -0R2, -N(R2)2, -0O2R.2, -CO-N(R2)2, -CN, C1-C6 alkoxy, C3-C8 cycloalkyl, C6-C10 aryl, 5- to 6-membered beteroaryl (optionally substituted with 1-3 groups independently selected from C I-C6 alkyl), 3-to 6-membered heterocyclyl, -S02R2, -SR2, -SOR2, -PO(OR2)2, and -P0(R2)2;
each R2 is independently selected from hydrogen, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), CI-C6 fluoroalkyl, and C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 Ii lloroalkyl and CI-C6 11 lloroalkoxy);

,s< R
Z is selected from . and Rz2 Rzl is selected from hydrogen, -CN, Cl-C6 alkyl (optionally substituted with 1-3 hydroxy), CI-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, and Ci-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl), or BP and le2 taken together form a group selected from oxo and =N-011, each Rz3 is independently selected from hydroxy, Ci-C6 alkoxy, C1-C6 and C6-C10 aryl; or two R13 are taken together to form a 3- to 6-membered heterocycly1; and n is selected from 4, 5, 6, and 7.
35. The compound, deuterated derivative, or salt according to Embodiment 34, wherein X is -NRxi,
36. The compound, deuterated derivative, or salt according to Embodiment 34 or 35, wherein X is selected from:

HN ), t9 , and
37. The compound, deuterated derivative, or salt according to Embodiment 34, (Rh-79Y\
wherein X is
38. The compound, deuterated derivative, or salt according to Embodiment 34 or 37, wherein Ring A is selected from pyrrolidine, piperazine, morpholine, and isothia.zolidine.
39. The compound, deuterated derivative, or salt according to Embodiment 34, 37, or 38, wherein X is selected from:

,N

,....L ,and .....L.
,.
40, The compound, deuterated derivative, or salt according to any one of Embodiments 34-39, wherein each RY is independently selected from:

,I.a., V ,õ..OH õõ0 ,,,,-01,0 ,..,N1,0 hydrogen, hydroxy, methyl, , , i , , , F
,---, r---\
NO HO 0 N 7- 2 I. ON:,,,, N K N
Q
_.1._ -......
, ,--, , , , , , --1.- , and ¨ ; or wherein two BY on the same atom are taken together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofiiranyl, and tetrahydropyranyl; or wherein two Rv, 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.
41. The compound, deuterated derivative, or salt according to any one of Embodiments 34-40, wherein each Q is independently selected from C6-Cio aryl optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkyl.
42. The compound, deuterated derivative, or salt according to any one of Embodiments 34-41, wherein each Q is phenyl.
43, The compound, deuterated derivative, or salt according to any one of Embodiments 34-42, wherein each Ring B is independently 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.
44, The compound, deuterated derivative, or salt according to any one of Embodiments 34-43, wherein each Ring B is indepedently selected from:
,F OMe ---- --- ---=µ,41 N
, and f ,
45. The compound, deuterated derivative, or salt according to any one of Embodiments 34-44, wherein -(y)n- is a group selected from:

--õ

____________________________ _ ____________ Vni .'c(-Y
y ' \--...õ..Y., y Y'''' -L,..
H\----\ i k Y-1 , and Y-1
46. The compound, deuterated derivative, or salt according to any one of Embodiments 34-45, wherein -(Y),- is a group selected from:
1.-----\-----ThH \---na..' \xi\ OH
01-ai ...L. -,L.
, , , , HO
OH
HO
-L, , -, , 0,1 OH
. , -,-' ..- 0 'N'IlL
F
-...., õ...--", ,--" µ=-....õ..---;-%
.......- , . , =
, . .

, , µ.1 . , i HO 0 -,õ..,...,- 0 ..,,..0 õ... N 0 al r \ \
F
---' ..i...-.
F F

H
1 0----\_\#, ,..--- ,,,,-;`, `-,,,.-.-ti OMe N -Ni(\('''-') 0,õ,, ¨, and i.w.
47. The compound, deuterated derivative, or salt according to any one of Embodiments 34-45, wherein each 'V is -C(R)2-
48, The compound, deuterated derivative, or salt according to Embodiment 47, wherein each V is independently selected from -C142- and -C(Me)2-.
49. The compound, deuterated derivative, or salt according to any one of Embodiments 34-48, wherein each W is independently selected from C1-C6 fluoroalkyl and --N(R2)2.
50. The compound, deuterated derivative, or salt according to any one of Embodiments 34-48, wherein each W is independently selected from Br, -CH3, -CF3, -CHF2, -N-NH N-N
OH, -OCH3, -CN, -NIF12, Y 1 . I , , 4 2 ?
, , , , N
'''-k'N
...., , ,,,,, =.
...-0,0 1-12N -s'INJH ----"NH -4,-"o oaa,deoar mon mme -t- -L. _L.
, , , , , , , ' cF3o 0 cF3. õ..
. 0 . 0 1 ..,õ õ . = .,/ ..._ ,0 s..0 s.0 s==0 s, and CF30t, S
51. The compound, deuterated derivative, or salt according to any one of Embodiments 34-50, wherein each W is independently selected from -CF3 and -NH2.
52, The compound, deuterated derivative, or salt according to any one of Embodiments 34-51, wherein Z is selected from:

Rzi Dz2 Rzi , and Rz2
53. The compound, deuterated derivative, or salt according to any one of Embodiments 34-52, wherein:
IRLI is selected from hydrogen, CI-C6 alkyl (optionally substituted with 1-3 hydroxy), CI-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, and C6-C10 aryl, s selected from hydrogen, hydroxy, and C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloancyl), or Rzl and Rz2 taken together form a group selected from oxo and =N-OH,
54, The compound, deuterated derivative, or salt according to any one of Embodiments <Rzi Rz2 34-53, wherein Z is
55. The compound, deuterated derivative, or salt according to any one of Embodiments oT ozl t-c-c Rz2 34-54, wherein NN is N¨N
56. The compound, deuterated derivative, or salt according to any one of Embodiments 34-55, wherein Rzl is selected from Ci-C6 fluoroallcyl.
57. The compound, deuterated derivative, or salt according to any one of Embodiments 34-56, wherein Rzi is -CF3.
58, The compound, deuterated derivative, or salt according to any one of Embodiments 34-57, wherein Rz2 is hydroxy.
59. The compound, deuterated derivative, or salt according to any one of Embodiments 34-53, wherein Z is selected from:

,<CF3 ./c<CH3 '''<K,-J =<CF3 ,,, b pH A.. =
=. .
'.------,cF3 -----OH 0 \-CF3, and OH
60. The compound, deuterated derivative, or salt according to any one of Embodiments o ¨I-NN- )2._.-z 34-53, wherein NN is selected from:
A---- OH
q:CH3 0A0)"/ D:CF3 --1 ' f 1\ I OH
N-N N-N N-N N-N
it._,OC F3 CO N-N
i OH " OH
I ,0 1---\-c 1---i%
CF3 ti--?/ OH
N-N N-N N-N N-N

11_,../0Nr jc NN , and HO .
61. The compound, deuterated derivative, or salt according to any one of Embodiments 34-60, wherein n is selected from 4, 5, and 6.
62. The compound, deuterated derivative, or salt according to any one of Embodiments 34-61, wherein n is 5.
63. The compound, deuterated derivative, or salt according to any one of Embodiments 34-62, wherein n is 6.
64. A compound selected from compounds of Formulae Ha, lib, Ik, and lid:

Y¨Y
X Y Y X-- \
Y¨Y, Y¨Y
\ir \
(R1), N¨N (R1)m N¨N ub, (R1)m NN He, and X ¨
N
(W)m Ltd, and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:
(Ring = X is selected from -NRxl- and Ring A is a 4- to 6-membered heterocycly1 optionally substituted with 1-3 groups independently selected from Ci-C6 alkyl and oxo;
Rx1 is selected from H, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, oxo, -OR', and -N(02)2), and C3-C8 cycloalkyl;
each Rx2 is independently selected from HI and C1-C6 alkyl;
each V is independently selected from -C(RY)2-, -0-, -CO-, -NR-, and 171;in¨g.\\
, wherein each RYN is independently selected from H, CI-C.4 alkyl, and CO2Me;
each RY is independently selected from hydrogen, hydroxy, halogen, Ci-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-Cio aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, -0O2RY", -CORY', -00N(RY1)2, and 4\(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;
each is independently selected from hydrogen and C1-C6 alkyl, or two R1{1 bonded 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 Cr-C6 alkoxy), ^ C3-C8 cycloalkyl, = 5- to 10-membered heteroaryl, and = 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from. CI-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 aryl (optionally substituted with 1-3 groups independently selected from halogen and -0C,F3), and o C3-C8 cycloalkyl, = C3-C-8 cycloalkyl optionally substituted with 1-3 groups independently selected from:
o halogen, o CN, o C-C6 alkyl (optionally substituted. with 1-3 groups independently selected from halogen, and -NHCOMe), o CI-C6 alkoxy, o C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C I-C6 alkyl), and o C3-C8 cycloalkyl, ^ C6-C10 aryl 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 and h.ydroxy), o C1-C6 alkoxy optionally substituted with 1-4 groups independently selected from:
= halogen, = C3--C8 cycloalkyl (optionally substituted with CF3), o C3-Cg cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF3, OCF3, and C1-C6 alkyl), and o C6-C10 aryl, = 5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:
o halogen, o Ci-C6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), o C3-C8 cycloalkyl (optionally substituted with 1-3 CF3 groups), and.
o 3-- to 10-membered heterocyclyl, tg 3- to 10-membered heterocyc471 optionally substituted with 1-3 groups independently selected from:
o Ct-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C3-C8 cycloalkyl), and o oxo;
each W is independently selected from halogen, Ci-C6 fluoroalkyl, C1-C6 alkyl (optionally substituted with a group selected from C6-C10 aryl and 5- to 6-membered heteroaryl), -0O2R2, -CO-N(R2)2, -CN, Ci-C6 alkoxy, C3-C8 cycloalkyl, 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, -S02R2, -SOR2, -P0(0R2)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), CI-C6 fluoroalkyl, and C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl and C1-C6 fluoroaikoxy);

::Rz3 ,syl-Rz3 Rzi Z is selected from . and Rz2 , Rzl is selected from hydrogen, -CN, Cl-C6 alkyl (optionally substituted with I-3 hydroxy), CI-C6 fluoroalkyl, 3-to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-Cto aryl, and 5- to 6-membered heteroaryl;
Rz2 is selected from hydrogen, halogen, hydroxy, and Ci-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl), or 1Z1 and RP taken together form a group selected from oxo and =N-Oti;
each le' is independently selected from hydroxy, C1-C6 alkoxy, C1-C6 and C6-C10 aryl; or two R13 are taken together to form a 3- to 6-membered heterocycly1; and m is selected from 0, 1, 2, and 3.
65. The compound according to Embodiment 64, wherein m is selected from 1 and 2.
66. The compound according to Embodiment 64 or 65, wherein in is 2.
67. A compound selected from compounds of Formulae He, Hf, Hg, and ilk Y¨Y
X Y X Y Y X
Y¨Yµ
R1 N Rtsct, Y¨Y
, \ \
NN Re, R1 N¨N nis R1 NN Hg, and X

N
0 \
Ri N¨N
and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:
Ring \\ A
X is selected from -NR- and Ring A is a 4- to 6-membered heterocycly1 optionally substituted with 1-3 groups independently selected from C1-C6 alkyl and Ox0;

Rx1 is selected from H, CI-C.6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, oxo, -0Rx2, and --N(R92), and C3-C8 cycloalkyl;
each Rx2 is independently selected from H and C1-C6 alkyl;
each 'V is independently selected from -C(R)2-, -0-, -CO-, -NR"-, and Ring , wherein each RIN is independently selected from H, Ci-C4 alkyl, and CO2Me;
each R' is independently selected from hydrogen, hydroxy, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, CI-Co alkoxy, and Q), C3-C8 cycloalkyl, C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, -OR", -WIRY!, -COR", -CON(R")2, and -N(R")2-;
or two R" on the same atom are taken together to form a ring selected from C3-Cs cycloalkyl and 3- to 7-membered heterocyclyl; or two R", 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 WI is independently selected from hydrogen and C1-C6 alkyl, or two RYI
bonded 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 Cl-C6 alkoxy), ^ C3-C8 cycloalkyl, = 5- to 10-membered heteroaryl, and = 3- to 6-membered heterocyct,T1 (optionally substituted with 1-3 groups independently selected from. CI-C6 alkyl);
each Q is independently selected from:
^ C1-C6 alkyl optionally substituted with 1-3 groups independently selected from:
o halogen, O Ox0, o C6-Cio aryl (optionally substituted with 1-3 groups independently selected from halogen and -0CF3), and o C3-C8 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, -N112, and -NHCOMe), o C1-C6 alkoxy, o C6-C to aryl (optionally substituted with 1-3 groups independently selected from Ci-C6 alkyl), and o C3-C8 cycloalkyl, = C6-Cio aryl 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 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 Ci-C6 alkyl), and o C6-Clo 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-C8 cycloalkyl (optionally substituted with 1-3 CF3 groups), and o 3- to 10-membered heterocyclyl, 81 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), and o oxo;
each 123 is independently selected from halogen, C
fluoroalkyl, CI-C6 alkyl (optionally substituted with a group selected from. C6-C10 aryl and 5-to 6-membered heteroaryl), -N(122)2, -0O2122, -CO-N(122)2, -CN, Ci-C6 alkoxy, C3-C8 cycloalkyl, C6-C10 aryl, 5- to 6-membered beteroaryl (optionally substituted with 1-3 groups independently selected from C I-C6 alkyl), 3-to 6-membered heterocyclyl, -S02R2, -SR2, -SOR2, -P0(0R2)2, and -P0(R2)2;
each R2 is independently selected from hydrogen, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), C1-C6 fluoroalkyl, and C6-C10 aryl (optionally substituted with 1-3 groups independently selected from Ci-C6 fluoroalkyl and CI-C6 fluoroalkoxy);
<.Rzl 4 , ,Rz3 401 Si RZ2 Re.j RZ1 7.1 is selected from , and RI' is selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-3 hydroxy), Ci-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, and C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl), or RP and Rz2 taken together form a group selected from oxo and =N-OH, and each 12z3 is independently selected from hydroxy, CI-C6 alkoxy, C1-C6 alkyl, and C6-Cto aryl; or two Rz3 are taken together to form a 3- to 6-membered heterocyclyl.
68. The compound, deuterated derivative, or salt according to any one of Embodiments 64-67, wherein X is -NR.
69. The compound, deuterated derivative, or salt according to any one of Embodiments 64-68, wherein X is selected from:

H
N A' and _ ... .
70. The compound, deuterated derivative, or salt according to any one of Embodiments \
Ring A-j N-64-67, wherein X is ¨1-- .
71, The compound, deuterated derivative, or salt according to any one of Embodiments 64-67 or 70, wherein Ring A is selected from pyrrolidine, piperazine, morpholine, and isothiazoli dine.
72. The compound, deuterated derivative, or salt according to any one of Embodiments 64-67, 70, or 71, wherein X is selected from:
_ N f Nr" N 0 _L.. L _ _....L. ,...1._ , and d N
, , .
73, The compound, deuterated derivative, or salt according to any one of Embodiments 64-72, wherein each RY is independently selected from:

- V ,,,, OH 0 --00 ,..N
I , _.--hydrogen, hydroxy, methyl, _.õ,._ i , ,1 , , F
-,, r-----\ C-1 0 0 HO.,,,.,,L.0 NI ,-- 01$ 4110 0y, N Ri -- N Q
-s.,.
, , , , , , ======µw , and ¨ ; or wherein two le on the same atom are taken. together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, and tetrahydropyranyl;
or wherein 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.
74. The compound, deuterated derivative, or salt according to any one of Embodiments 64-73, wherein each Q is independently selected from C6-C10 aryl optionally substituted with 1-3 groups independently selected from halogen and C1-C6
75. The compound, deuterated derivative, or salt according to any one of Embodiments 64-74, wherein each Q is phenyl.
76. The compound, deuterated derivative, or salt according to any one of Embodiments 64-75, wherein each :Ring B is independently selected from C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen and C1-C6 alkoxy) and 5- to I 0-membered heteroaryl.
77. The compound, deuterated derivative, or salt according to any one of Embodiments 64-76, wherein each Ring B is indepedently selected from:
OMe N`
, and
78. The compound, deuterated derivative, or salt according to any one of Embodiments 64-77, wherein (-Y-Y-Y-Y-Y-Y-Y-) is a group selected from:
79. The compound, deuterated derivative, or salt according to Embodiment 78, wherein (-Y-Y-Y-Y-Y-Y-Y-) is 'NY
80. The compound, deuterated derivative, or salt according to any one of Embodiments 64-77, wherein (-Y-Y-Y-Y-Y-Y-) is a group selected from:

y \AnY., _...1._ , and ..õ,
81. The compound, deuterated derivative, or salt according to Embodiment 80, wherein (-Y-Y-Y-Y-Y-Y-) is a group selected from:
/
NCY'Y'''l HO OH

' , ,0 V
¨ . .

I
N N N
\c' N
HO -0 Nj: N
and
82. The compound, deuterated derivative, or salt according to any one of Embodiments 64-77, wherein (-Y-Y-Y-Y-Y-) is a group selected from:
y HY-\\----\"". and
83. The compound, deuterated derivative, or salt according to any one of Embodiments 82, wherein (-Y-Y-Y-Y-Y-) is a group selected from:
and
84. The compound, deuterated derivative, or salt according to any one of Embodiments 64-77, wherein (-Y-Y-Y-Y-) is a group selected from:

\ 1 ---1 \Y---1 and Y-1 , .
85. The compound, deuterated derivative, or salt according to Embodiment 84, wherein (-Y-Y-Y-Y-) is a group selected from:

1¨\\----\--d / .%\/--\
''',-----/F
F

i F ----1111" OMe --- K]
, and
86. The compound, deuterated derivative, or salt according to any one of Embodiments 64-77, wherein each Y is-C(RY)2-.
87. The compound, deuterated derivative, or salt according to Embodiment 86, wherein each Y is independently selected from -C112- and -004:02.
88. The compound, deuterated derivative, or salt according to any one of Embodiments 64-87, wherein each Ri is independently selected from C1-C6 fluoroalkyl and -N(R2)2.
89. The compound, deuterated derivative, or salt according to any one of Embodiments 64-87, wherein each RI is independently selected from Br, -CH,, -CF3, -CHF2, _:
'2 ,0 ,.., N¨NH
N¨N
OH, -OCTh -C , N, -NH, I, Y ---- Y.-Y
, , , , , __ L T:
N
,,, 0 ..õ,. ...,N 010 1-12N0 --...NH \ -0 "-NFI -ID--- , , , , , , , õ =
s.0 , and
90. The compound, deuterated derivative, or salt according to any one of Embodiments 64-89, wherein each RI is independently selected from -CF3 and -NEI2.
91. The compound, deuterated derivative, or salt according to any one of Embodiments 64-90, wherein Z is selected from:
@."
::Rzi c-tZ2 and .
92. The compound, deuterated derivative, or salt according to any one of Embodiments 64-91, wherein:
Rzl is selected from hydrogen, CI-C6 alkyl (optionally substituted with 1-3 hydroxy), Ci-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, and C6-C10 aryl, .R/2 is selected from hydrogen, hydroxy, and C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-Cto cycloalkyl), or Rzi and RI' taken together form a group selected from oxo and .:-N-Oft
93. The compound, deuterated derivative, or salt according to any one of Embodiments <Rzi Rz2 64-92, wherein Z s
94. The compound, deuterated derivative, or salt according to any one of Embodiments k .,,Rzl r\z2 64-93, wherein NN is NN
95. The compound, deuterated derivative, or salt according to any one of Embodiments 64-94, wherein Rzl is selected from Ci-C6 fluoroaikyl.
96. The compound, deuterated derivative, or salt according to any one of Embodiments 64-95, wherein lel is -Ch.
97. The compound, deuterated derivative, or salt according to any one of Embodiments 64-96, wherein W2 is hydroxy.
98. The compound, deuterated derivative, or salt according to any one of Embodiments 64-92, wherein Z is selected from:
(CF3 OH --.--N-0 ----CF3 .. OH .'0 -=N' CF3, and OH .
99. The compound, deuterated derivative, or salt according to any one of Embodiments 64-92, wherein N.---N is selected from:

.,C1-13 OH iLe.õ0,,L, 0 õCF3 0,,,r,CF3 _ f Nr) N-N
N-N N-N

, 1LCC i -\\ )1-1-- OH kerk's0 11--e'lrITLN -OH
4., ti k y0 N-N i NN ,and HO .
100. The compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment l, wherein X is -N(Rx1)-,
101. The compound, deuterated derivative, or pharmaceutically acceptable salt Ring A
according to Embodiment 1, wherein X is
102. The compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1, wherein X is selected from:
N-N
-NH-, -N(CH3)-, -N(CH2CH3)-, -\

4.N`c r0 0 L"NI/i 0 N

,and
103. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-102, wherein:
each RY is independently selected from hydrogen, hydroxy, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, CI-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, -Mk", and -CON(R1'1)2;
or two le on the same atom are taken. together to form a ring selected from C3-C8 cycloakl 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,
104. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments I and 100-103, wherein each R.Y1 is independently selected from hydrogen and C1-C6 alkyl, or two RY1 bonded to the same nitrogen taken together form. a 3- to 6-membered heterocyclyl.
105. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-104, wherein each Q is independently selected from C6-C10 aryl.
106. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-105, wherein each Q is phenyl.
107. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-106, wherein:
each RY is independently selected from:
I
1,-- I HO 0 I H(3. 0 hydrogen, hydroxy, -CE13, -0)3, -CI-12013, , , , F
2 N10 CNi0 y ...--- N ,,-= NN ONs:,..,-,N
and . .
¨;
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,
108. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-107, 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,
109. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-108, wherein Ring B is selected from phenyl (optionally substituted with 1-3 groups independently selected from halogen and C i-C6 alkoxy) and pyridyi.
110. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-109, wherein Ring B is selected from:

N
111. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-110, wherein n is selected from 4, 5, 6, and 7.
112. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-111, wherein -(Y)n- is a group selected from:

1¨\\.
\ __ 1 \S/LL
Jn.
OH

OH
OH OH
_L_, OH OH
HO
_L

HO
LF
HO
D C D

H0,1 HO

oi N

l' 'µ(- Nc.---7. =.õ, --,-F F
. , ir---1---- NI ,---.
= 0 --- \C
= 0 F
ri--- ,---, N ,--- N ,.... N NyN
-...õ.õ--F
e-.;=.-/----A /¨ __ \
.......... ..õL , 0 .
v \-1--------- \
,..........., ......õ , s , 0 ,,=
\\P--------1, nNsa,.. . , and ,
113. The compound, cleuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments I and 100-112, wherein each IV is independently selected from halogen, Ci-C6 fluoroalkyl, C1-C6 alkyl (optionally substituted with a group selected from C6-C10 aryl), -0R2, -N(R.2)2, -0O2112, -CO--N(112)2, -CN, C1-C6 alkoxy, C3-C8 cycloalkyl, C6-C10 aryl, 5- to 6-membered heteroaryl (optionally substituted with 1-3 groups independently selected from Ct-C6 alkyl), 3- to 6-membered heterocyclyl, -B(0R2)1, -S02R2, -SR2, -SOR2, and -PO(R2)2.
114, The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-113, wherein each R2 is independently selected from C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkoxy).
115. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-114, wherein each IV is independently selected from -Br, -CF3, -N1-12, -CH3, -CH(CH3)2, -CN, -01-I, -OCH3, --NH(CH3), -NH(CH2CH3), -CONFL, - CO2CH3, -S02CH3, -S02Ph, P0(043)2, B(OH)2, phenyl, pyridyl, tetrahydropyranyl, tetrahydrofuratwl, N¨NI/

cyclopropyl, cyclohexyl, imidazolyl, cF3o oF3o.
o ,and
116. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-115, wherein Z is selected from C (Rz2)0_2 Rzi , and ;
wherein Ring C is selected from C6-C10 aryl.
117. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-116, wherein the group:
0 (Rz2)8.2 is selected from:

N Ae""
vyN
h=-=Z2 IN r7 rµ Z2 sn INZ2 1.2.22 anZ2 RZ2 2 7 1µ
=
N Ax-N
CI `µNI
Rz2 H H
r NH
and N
118. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-117, wherein the group:
C (Rz2)0_2 Rz2 is 118A. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-117, wherein Rzl is selected from hydrogen. Cl-C6 alkyl (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.
118B. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments I and 100-117, wherein Rz2 is selected from hydrogen, halogen, .hydroxy, and C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C10 cycloalkyl).
119. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-118, wherein:
Rzl is selected from hydrogen, Ca-C6 alkyl (optionally substituted with 1-3 hydroxy), CI-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, and C6-Cao aryl; and Rz2 is selected from hydrogen, halogen, and hydroxy;
or WI and R.z2 taken together form a group selected from oxo and =N-OH.
120. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-119, wherein:

Rzl is selected from hydrogen, CH3, CF3, CH?OH, phenyl, cyclopropyl, and tetrahydropyranyl; and Rz2 is selected from hydrogen; halogen, and hydroxy;
or Rzi and Rz2 taken together form a group selected from oxo and =N-OH.
121, The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-120, wherein Rz2 is hydroxy.
122. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-121, wherein Z is selected from:
"cCF3 ,OH OH CF3 OH OH OH -1/4,4 'OH Nt_ -N*

OH F3 CH <A
N44, OH OH OH ,,õz_ OH
OH
CF3 and 6H
123. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-122, wherein m is selected from and 2.
124, The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-123, wherein:
X is selected from -N(Rx1)- and Ring A is a 4- to 6-membered heterocyclyl;
Rx1 is selected from H and C1-C6 alkyl;
B
each V is independently selected from -C(RY)2- and each :IV is independently selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl, C6-00 aryl (optionally substituted with 1-3 groups independently selected from halogen);

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;
Ring B is C6-C40 aryl (optionally substituted with 1-3 groups independently selected from halogen), each :R-1 is independently selected from C1-C6 fluoroaikyl and -N112;

Z iS
RZ1 is CI-05 fluoroalkyl;
:Rz2 is hydroxy, n is selected from 4, 5, and 6; and m is 2.
125. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-124, wherein Ring A is pyrrolidine.
126. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-125, wherein X is selected from:
-NH-, NCH3)-, , , and
127. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-126, wherein:
each RY is independently selected from:
1.
hydrogen, -C113, -0)3, I, and or two RI' on the same atom are taken together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, and tetrahydropyryl;
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.
128. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100427, wherein Ring B is phenyl (optionally substituted with 1-3 groups independently selected from halogen).
129. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-128, wherein Ring B is
130, The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-129, wherein -(Y)n- is a group selected from:
\_\_)õ, F

, and
131. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100430, wherein each R' is independently selected from CF3 and -NH?.
132. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100-131, wherein Rzl is CF.
133. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 100432, wherein Z is selected from:
CF3 'CF3 'CF3 'cCF3 OH OH OH
, and
134. A compound selected from compounds of Table 10, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.
135. A compound according to Embodiment 134, wherein the compound is selected from:
Comp. No. Structure / OH

N

/ OH

g OH
NH2 N¨N

Comp. No. Structure HN
F
163 3C "N

/ OH
NH2 N¨N
HN

/ OH
NH2 N¨N

HN>C-F3Ct 0i73 NH2 N¨N
HN

/ OH
NH2 N¨N
HN

`s. N

Comp. No. Structure / OH
NH2 N¨N
HN

-0¨CHF3 NH2 N¨N
HN

N

\ 8 OH
NH2 N¨N

HN

N

r"CF3 / nu
136, A pharmaceutical composition comprising a compound, salt, or deuterated derivative of any one of Embodiments 1-135 and a pharmaceutically acceptable carrier,
137. The pharmaceutical composition according to Embodiment 136, further comprising one or more additional therapeutic agent(s).
138. The pharmaceutical composition according to Embodiment 137, wherein the one or more additional therapeutic agent(s) comprise(s) a compound with CFIR.
modulating activity or a salt or deuterated derivative thereof.
139. The pharmaceutical composition according to Embodiment 137 or 138, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR corrector.
140. The pharmaceutical 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][1,3idioxo1-5-y1)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-m ethylpropan -2-y1)-iH-indo1-5-yl)cyclopropan ecarboxami de (Compound II):
F-Fr\c) 0 N
'OH H.
141. The pharmaceutical composition according to any one of Embodiments 137-140, wherein the one or more additional therapeutic agent(s) comprise(s) 346-042,2-difluorobenzo[d] [1,3]dioxo1-5-yl)cyciopropanecarboxami do)-3 -methy I pyri di n-2-yObenzoic acid (Compound IV):

N N
Compound IV.
142. The pharmaceutical composition according to any one of Embodiments 137-141, wherein the one or more additional therapeutic agent(s) comprise(s) N-(1,3-di m ethylpyrazol -4-y1 )sulfony1-643-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yli-2-[(4,5)-2,2,4-trimethylpyrrolidin-1-711pyridine-3-carboxamide (Compound :

¨Ni 0 0_ ,µ\S
N' H
N
u=--(/ N
V.
143. The pharmaceutical composition according to any one of Embodiments 137-142, wherein the one or more additional therapeutic agent(s) comprise(s) N-(benzenesulforty1)-6434241-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-y11-2-[(4S)-2,2,4-trimethylpyrrolidi n-l-yl] pyiidine-3-carboxami de (Compound VI):
0 0, A NS=
H
0-*/ N N
Compound VI.
144. The pharmaceutical composition according to any one of Embodiments 137-143, wherein the one or more additional therapeutic agent(s) comptise(s) (14S)-843-(2-{dispiro[2Ø2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yli-12,12-dimethy1-2Xb-thia-3,9,11,18,23-pentaa.zatetracyclo [17,3.1.111,14 .05, 10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound V11):

,_( 012 N rt eN/NH
Compound ifl
145. The pharmaceutical composition according to any one of Embodiments 137-144, wherein the one or more additional therapeutic agent(s) comprise(s) (11R)-6-(2,6-dimethylpheny1)-11-(2-methylpropy1)-12-{spiro[2.3]hexan-5-y11-9-oxa-2X6-thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nona.deca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound VIM:

N 0\ 0 0 Compound VIII,
146. The pharmaceutical composition according to any one of Embodiments 137-145, wherein the one or more additional therapeutic agent(s) comprise(s) at least one compound selected from PT1-428,ABBV-2222õABBV-2851, GLPG2737õABBV-3221, ABBV-3748, ABBV-3903, ABBV-11 9, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765õkRN23766, and PT1-801.
147. The pharmaceutical composition according to any one of Embodiments 137-146, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR
potentiator enhancer.
148. The pharmaceutical composition according to any one of Embodiments 137-147, wherein the one or more additional therapeutic agent(s) comprise(s) ASP-11.,
149. The pharmaceutical composition according to any one of Embodiments 137-148, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR
potentiator.
150. The pharmaceutical composition according to any one of Embodiments 137-149, wherein the one or more additional therapeutic agent(s) comprise(s) a cornpound selected from N-(5-hydroxy-2,4-di4er1-butyl-phenyl)-4-oxo-11/-quinoline-3-carboxamide (Compound M):
OH
101. .1 =
= N
Compound III, and N-(2-(tert-butyl)-5-hydroxy-4-(2-(m ethyl-d3)propan-2-y1-1, 1,1,3,3,3-d6)pheny1)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound III-d):

0 0 " NCD3 Compound In-d.
151, The pharmaceutical composition according to any one of Embodiments 137-150, wherein the one or more additional therapeutic agent(s) comprise(s) at least one compound selected from FDL-176, PT1-808, GLPG1.837, GLPG2451/ABBV-2451 (Icenticaftor), GLPG3067/ABBV-3067 (Navocaftor), and ABBV-191.
152, The pharmaceutical composition according to any one of Embodiments 137-151, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR
amplifier.
153. The pharmaceutical composition according to any one of Embodiments 137-152, wherein the one or more additional therapeutic agent(s) comprise(s) PT1-428.
154, The pharmaceutical composition according to any one of Embodiments 137-153, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR
readthrough agent,
155. The pharmaceutical composition according to any one of Embodiments 137-154, wherein the one or more additional therapeutic agent(s) comprise(s)ELX-02,
156. The pharmaceutical composition according to any one of Embodiments 137-155, wherein the one or more additional therapeutic agent(s) comprise(s) a nucleic acid therapy.
157. The pharmaceutical composition according to any one of Embodiments 137-156, wherein the one or more additional therapeutic agent(s) comprise(s) at least one agent selected from NIRT5005, Lunar-CF, and RCT223.
158. The pharmaceutical composition according to any one of Embodiments 137-157, wherein the one or more additional therapeutic agent(s) comprise(s) an ENaC
inhibitor.
159. The pharmaceutical composition according to any one of Embodiments 137-158, wherein 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, lonis-ENaC-2.5 Rx, B1 1265162, AZ5634, and ARO-ENaC1001.
160. The pharmaceutical composition according to any one of Embodiments 137-159, wherein the one or more additional therapeutic agent(s) comprise(s) a TMEM16A
modulator.
161, The pharmaceutical composition according to any one of Embodiments 137-160, wherein the one or more additional therapeutic agent(s) comprise(s) ETD002,
162. The pharmaceutical composition according to any one of Embodiments 137-161, wherein the one or more additional therapeutic agent(s) comprise(s) a GPR39 Agonist
163, The pharmaceutical composition according to any one of Embodiments 137-162, wherein the one or more additional therapeutic agent(s) comprise(s) DS-1039.
164. 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
165. The method according to Embodiment 164, further comprising administering one or more additional therapeutic agent(s).
166. The method according to Embodiment 165, wherein the one or more additional therapeutic agent(s) comprise(s) a compound with CFTR modulating activity or a salt or deuterated derivative thereof.
167. The method according to Embodiment 165 or 166, wherein the one or more additional therapeutic agent(s) comprise(s) a CTIR corrector.
168. The method according to any one of Embodiments 165-167, wherein the one or more additional therapeutic agent(s) comprise(s) (R)-1-(2,2-difluorobenzo[d][1,3idioxol-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-11/-indol-5-ypeyclopropanecarboxamide (Compound H):
F
-OH Compound It.
169. The method according to any one of Embodiments 165-168, wherein the one or more additional therapeutic agent(s) comprise(s) 346-0.42,2-difluorobenzo[d][1,3idioxo1-5-y1)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV):

H
F-,," ,N
0 Mij Compound IV.
170. The method according to any one of Embodiments 165-169, wherein the one or more additional therapeutic agent(s) comprise(s) N-(1,3-dimethvlpyrazol-4-ypsulfonyl-643-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-y11-2-[(45)-2,2,4-trimethylpyrrolidin-1-ylipyridine-3-carboxamide (Compound V):
9 0, CF3* N
N, H
ON N
¨ Compound V.
171. The method according to any one of Embodiments 165-170, wherein the one or more additional therapeutic agent(s) comprise(s) N-(benzenesultbny1)-6434241-(tritluoromethyl) cyclopropyliethoxy]pyrazol-1-y1]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-ylipyridine-3-carboxamide (Compound VI):
? 0 N, H
ON N
Compound VI.
172, The method according to any one of Embodiments 165-171, wherein the one or more additional therapeutic agent(s) comprise(s) (145)-843 -(2-{dispiro[2Ø2.1]heptan-7-y1}ethoxy)-1H-pyrazol-1-y1]-12,12-dimethyl-26-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):

NSr N N N
NH
Compound VII.
173. The method according to any one of Embodiments 165-172, wherein the one or more additional therapeutic agent(s) comprise(s) (111?)-6-(2,6-dimethylpheny1)-(2-methylpropyi)-124 spiro[2.31hexan-5-y -9-oxa-2X6-thia-3,5,12,19-tetraazatricy cl o[12.3 .1,14,8]nonadeca.-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-tri one (Compound VIII):

N 0 0 = = 0 N N
Compound VIM.
174, The method according to any one of Embodiments 165-173, wherein the one or more additional therapeutic agent(s) comprise(s) at least one compound selected from P11-428, ABBY-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, ABBY-2851, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, and PT1-801.
175, The method according to any one of Embodiments 165-174, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR potentiator enhancer.
176. The method according to any one of Embodiments 165-175, wherein the one or more additional therapeutic agent(s) comprise(s) ASP-11.
177, The method according to any one of Embodiments 165-176, wherein the one or more additional therapeutic agent(s) comprise(s) a MR potentiator.
178. The method according to any one of Embodiments 165-177, wherein the one or more additional therapeutic agent(s) comprise(s) a compound selected from N-(5-hydroxy-2,4-di-tert-butyl-pheny1)-4-oxo-111-quinoline-3-carboxanaide (Compound OH
.1 =
= N
Compound III, and N-(2-(tert-butyl)-5-h ydroxy-442-(m ethyl-d3)propan-2-y1-1, I ,1,3,3,3-d6)pheny1)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound III-d):

Compound III-d.
179. The method according to any one of Embodiments 165-178, wherein the one or more additional therapeutic agent(s) comprise(s) at least one compound selected from FDL-176, P1'1-808, GLPG1.837, GLPG2451/ABBV-2451 (Icenticaftor), GLPG3067/ABBV-3067 (Navocaftor), and ABBV-191.
180. The method according to any one of Embodiments 165179, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR amplifier.
181, The method according to any one of Embodiments 165-180, wherein the one or more additional therapeutic agent(s) comprise(s)1311-428.
182. The method according to any one of Embodiments 165-181, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR readthroug,h agent.
183. The method according to any one of Embodiments 165-182, wherein the one or more additional therapeutic agent(s) comprise(s) ELX-02.
184. The method according to any one of Emboditnents 165-183, wherein the one or more additional therapeutic agent(s) comprise(s) a nucleic acid therapy.
185. The method according to any one of Embodiments 165-184, wherein the one or more additional therapeutic agent(s) comprise(s) at least one agent selected from MRT5005, Lunar-CF, and RC1223.
186. The method according to any one of Embodiments 165-185, wherein the one or more additional therapeutic agent(s) comprise(s) an ENaC inhibitor.
187. The method according to any one of Embodiments 165-186, wherein 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-ENaC1.001.
188. The method according to any one of Embodiments 165-187, wherein the one or more additional therapeutic agent(s) comprise(s) a TMEM16A. modulator.
189. The method according to any one of Embodiments 1.65-188, wherein the one or more additional therapeutic agent(s) comprise(s) ETD002.
190. 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, The method according to any one of Embodiments 165-190, wherein the one or more additional therapeutic agent(s) comprise(s) DS-1039.
192. The compound, salt, or deuterated derivative of any one of Embodiments 1-135 or the pharmaceutical composition according to any one of Embodiments 136-163 for use in the treatment of cystic fibrosis.
193. Use of the compound, salt, or deuterated derivative of any one of Embodiments 1-135 or the pharmaceutical composition according to any one of Embodiments 136-163 in the manufacture of a medicament for the treatment of cystic fibrosis.
194. 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. The substantially amorphous Compound 4 (neat form) according to Embodiment 194, wherein Compound 4 is 100% amorphous.
196. The substantially amorphous Corn. .pound 4 (neat form.) according to Embodiment 194 or 195, characterized by an X-ray powder diffractograrn substantially similar -to FIG. I.
197. Substantially crystalline Compound 5 Form A (neat) (i.e., wherein less than 15%
of Compound 5 is in amorphous form, wherein less than 1.0% of Compound 5 is in amorphous form, Wherein less than 5% of Compound 5 is in amorphous Form).
198. The substantially crystalline Compound 5 Form A (neat) according to Embodiment 197, wherein Compound 5 Form A (neat) is 100% crystalline.
199. The substantially crystalline Compound 5 Form A (neat) according to Embodiment 197 or 198, characterized by a tetragonal crystal system, an141 space group, and unit cell dimensions measured at 100 K on a Bruker diffractometer utilizing Cu Ka radiation (k=1.54178 A) of:

a 18.1 A a 900 b 18.1 .1 A 0 90 ' c 13.1 .1 A y 90 .
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 or 204, characterized by an X-ray powder diffractogram haying 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,
206. 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).
210. The substantially crystalline Compound 52 Form A (neat) according to Embodiment 209, wherein Compound 52 Form A (neat) is 100% crystalline.
211. The substantially crystalline Compound 52 Form A (neat) according to Embodiment 209 or 210, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 6.8 0.2 degrees two-theta, 17.3 0.2 degrees two-theta, and 18.6 0.2 degrees two-theta.
212. 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 7k: 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 _-1= 0.2 degrees two-theta, 21.4 0.2 degrees two-theta, and 27.2 0.2 degrees two-theta.
214. The substantially crystalline Compound 52 Form A (neat) according to any one of Embodiments 209-213, characterized by an X-ray powder diffractogram substantially similar to FIG. 9.
215. Substantially amorphous Compound 60 (neat form) (i.e., wherein less than 15% of Compound 60 is in crystalline form, wherein less than 10% of Compound 60 is in crystalline form, wherein less than 5% of Compound 60 is in crystalline form).
216. The substantially amorphous Compound 60 (neat form) according to Embodiment 215, wherein Compound 60 is 100% amorphous.
217. The substantially amorphous Compound 60 (neat form) according to Embodiment 215 or 216, characterized by an X-ray powder diffractogram substantially similar to FIG. 12.
218, 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. The substantially amorphous Compound 70 (neat form) according to Embodiment 218, wherein Compound 70 is 100% amorphous.
220. The substantially amorphous Compound 70 (neat form) according to Embodiment 218 or 219, characterized by an X-ray powder diffractogram substantially similar to FIG. 15.
221. 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).
222. The substantially crystalline Compound 163 Form A (neat) according to Embodiment 221, wherein Compound 163 Form A (neat) is 100% crystalline.
223. The substantially crystalline Compound 163 Form A (neat) according to Embodiment 221 or 222, characterized by an X-ray powder diffractogram having a signal at 7.4 0.2 degrees two-theta.
224. The substantially crystalline Compound 163 Form A (neat) according to any one of Embodiments 221-223, characterized by an X-ray powder diffractogram. having one, two, or three signals selected from 7.4 0.2 degrees two-theta, 8.4 0.2 degrees two-theta, and 15,0 0.2 degrees two-theta.
225. 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 -4-- 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.
227. 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, wherein Compound 173 is 100% amorphous.
230. 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),
232. The substantially crystalline Compound 173 Form A (neat) according to Embodiment 231, wherein Compound 173 Form A (neat) is 100% crystalline.
233. The substantially crystalline Compound 173 Form A (neat) according to Embodiment 231 or 232, characterized by a triclinic crystal system, a P1 space group, and unit cell dimensions measured at 150 K on a Bruker diffractometer utilizing Cu Ka radiation (2c=1.54178 A) of:
a 6.7 J2.1 A a 760+1 h 11,9 .1 A. 13 82.2 "
c 13.1 .1 A 85.4 .1 0.
234. 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).
235. The substantially crystalline Compound 175 Form A (neat) according to Embodiment 234, wherein Compound 175 Form A (neat) is 100% crystalline.
236. The substantially crystalline Compound 175 Form A (neat) according to Embodiment 234 or 235, characterized by an orthorhombic crystal system, a P212121 space group, and unit cell dimensions measured at 100 K on a Bruker diffractometer utilizing Cu K, radiation (=i.54178 A) of:
a 9.8 A a 90 b 10.1 It, 1 A i3 900 c 20.5 .1 A 7 90
237. 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 amoiphous form, wherein less than 5% of Compound 188 dichloromethane solvate is in amorphous form).
238. The substantially crystalline Compound 188 dichloromethane solvate Form A

according to Embodiment 237, wherein Compound 188 dichloromethane solvate Form A is 100% crystalline.
239. The substantially crystalline Compound 188 dichloromethane solvate Form A

according to Embodiment 237 or 238, characterized by a monoclinic crystal system, a P21 space group, and unit cell dimensions measured at 100 K on a :Bruker diffractometer utilizing Cu K, radiation (2,-1.54178 A) of:
a 16.2 .1 A a 90 b 13.3 .1 A 13 99.7 .1 c 23.2 .1 A. y 90 ".
Examples General Experimental Procedures Abbreviations A.c011: Acetic acid Boc anhydride ((Boc)20): Di-tert-butyl di carbonate Boc: Butoxy carbonyl BOP: Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate t-BuOH: tert-Butanol CDC13: Chloroform-d CDI: 1,1'-Carbonyldiirnidazole CD3OD: :Methyl-d4 alcohol-d CH2C12: Dichloromethane CH3CN: Acetonitrile CO2: Carbon dioxide Cs2CO3: Cesium carbonate Cul: Copper(I) iodide DCE: 1,2-Dichloroethane DCM: Dichloromethane DIEA: (DIPEA; NN-Diisopropylethylamine) DMAP: Ll-Dimethylaminopyridine DMF: NA-Dimethylformamide DMP: Dess-Martin Periodinane DMSO: Dimethyl sulfoxide DMSO-d6: Dimethyl sulfoxide-d6 EDG1: 1-Ethyl-3-(3-dimethylaminopropyl)carbodilmide ESI-MS: Electrospray ionization mass spectrometry Et20: Diethyl ether Et3N or TEA: Thethyla.mine Et0Ac: Ethyl acetate :EMI: Ethanol Et20: Diethyl ether Electrospray ionization mass spectrometry Grubbs catalyst 2nd Generation: [1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidenei-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium H2: Hydrogen HATT]: N-RDimethylarnino)-111-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylenei-N-methylmethanaminium hexafluorophosphateN-oxide Elf I: Hydrochloric acid HOWL Hydroxybenzotriazole HPLC: High performance liquid chromatography H7: Hydrogen 1-1202: Hydrogen peroxide KHSO4: Potassium bisulfate KGH: Potassium hydroxide K2CO3: Potassium carbonate KM1104: Potassium permanganate K1-1CO3: Potassium bicarbonate LC: Liquid chromatography Li Al H4: Lithium aluminum hydride LiOH: Lithium hydroxide MeMgCl: Methyl magnesium chloride MeTHF or 2-MeTHF or 2-Me-THF: 2-Methyltetrahydrofuran MeOH: Methanol MTBE: Methyl tert-butyl ether MgSO4.: Magnesium sulfate MS: Mass spectrometry n-Bu4NF. H20: Tetra-n-butylammonium fluoride monohydrate Na: Sodium NaH: Sodium hydride NaHCO3: Sodium bicarbonate Na0Ac: Sodium acetate NaOH: Sodium hydroxide Na2SO4: Sodium sulfate NBS: N-bromosuccinimide NF13: Ammonia.
NH4C1: Ammonium chloride NII4HCO3: AMMOniUM bicarbonate NAP: N-Methy1-2-pyrrolidone N-MR: Nuclear magnetic resonance N2: Nitrogen Pd/C: Palladium on carbon Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)C12: 1,1LBis(diphenylphosphino)ferrocene palladium(ii) chloride Pd.(0A02: Palladium(II) acetate PhI(0A02: (Diacetoxyiodo)benzene P003: Phosphoryl chloride Pt02: Platinum oxide RI or rt: Room temperature SFC: Supercritical fluid chromatography Silica Cat Pd: Palladium on silica.
5i02: Silica gel Tetra-n-butylammonium 'fluoride Tetrabulammonium iodide TBDPS-C1 or TBDPSC1: teri-Butyldiphenylchlorosilane TEA: Triethylamine TEMPO: 2,2,6,6-Tetramethylpiperidinyloxy TFA: Trifluoroacetic acid THF: Tetrahydrofuran Ti(OEt)4: Titanium (1V)ethoxide TMEDA: Tetramethylethylenediamine TMSCF3: Trifluoromethyltrimethylsilane p-IsC1 or tosyl chloride: p-Toluenesulfonyl chloride or 4-Toluenesulfonyl chloride T313: I -Propanephosphonic anhydride 'AMC: Ultra Performance Liquid Chromatography Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxantbene Zhan catalyst-1B: Dichloro[1,3-bis(2,4,6-trimethylpheny1)-2-imidazolidinylidene][[5-[(di m ethylam ino)sul t7onyl]-2-(1-in ethylethoxy -0)p heny I ]m ethylene-Cirutheni um (I1) General -UPLC-MS/HPLC-IVISIGC Analytical Methods:
[00234] LC Method A: Analytical reverse phase UPLC-MS using an Acquity UPLC-MS BEH Ci8 column (50 x 2.1 mm, 1.7 urn 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 A) tritluoroacetic acid). Mobile phase B
acetonitrile 0.035 % trifluoroacetic acid). Flow rate = 1.2 mUmin, injection volume = 1.5 !AL, and column temperature = 60 C.
[00235] LC Method B: Analytical reverse phase HPLC-MS using a Kinetex C18 column (4.6 X 50 mm, 2.6 1.trn particle size). Temp: 45 C; Flow: 2.0 triLlmin; Run Time:
3 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 1.0 min.
[00236] LC Method C: Analytical reverse phase RPLC-MS using a Kinetex Polar column (3.0 X 50 mm, 2.6 pm particle size), Temp: 45 C; Flow: 1.2 inUrnin;
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.
1002371 LC Method D: Analytical reverse phase UPLC-MS using an Acquity UPLC-MS BEH C15 column (50 x 2.1 mm, 1.7 ll-ri particle size) made by Waters (pn:
186002350), and a dual gradient run from 1 (}/i) to 99 % mobile phase B over 5.0 minutes.
Mobile phase A = water (+ 0.05 % trifluoroacetic acid). Mobile phase B =
acetonitrile (4-0.035 % trifluoroacetic acid), Flow rate = 1,2 miUmin, injection volume = 1.5 uL, and column temperature = 60 C.
1002381 LC Method E: Analytical reverse phase EIPLC-MS using a Kinetex Polar Cis column (3.0 X 50 mm, 2.6 ,tra particle size), Temp: 45 'C; Flow: 1,2 mLlmin, Run time: 3 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 A= formic acid) for 1,0 min, 1002391 LC Method F: Analytical reverse phase HPLC-MS using a Kinetex C18 column (4.6 X 50 mm, 2.6 p.m particle size), Temp: 45 C.; Flow: 2.0 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 A) formic acid) for 4.0 min then hold at 95 % acetonitrile (+ 0.1 % formic acid) for 2.0 min.
1002401 LC Method G: Analytical reverse phase HPLC-MS using a Merckmillipore Chromolith SpeedROD C18 column (50 x 4.6 mm) and a dual gradient run from 5 A) to 100 % mobile phase B over 6 minutes. Mobile phase A = water (+ 0.1 %
trifluoroacetic acid). Mobile phase B = acetonitrile (4-0.1 % trifluoroacetic acid).
1002411 LC Method H.: Analytical reverse phase HPLC-MS using a Waters Cortex column (3.0 X 50 mm, 2,7 jam particle size) made by Waters (pn: 186007370), Temp: 55 C; Flow: 1.2 mUrnin; Mobile phase A: Water (-1- 0.1 A= 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.
1002421 LC Method Analytical reverse phase UPLC-MS using an Acquity UPLC-MS
BEH C18 column (30 X 2.1 mm, 1.7 pm 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). Flow rate = 1.5 mialmin, injection volume = 1.5 pL, and column temperature = 60 'C, 1002431 LC Method J: Analytical reverse phase -UPLC:-.MS using an Acquity UP:LC:-MS BEH Cis column (50 X 2.1 mm, 1.7 pm 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). Flow rate = 1,2 miUmin, injection volume = 1.5 ulL, and column temperature = 60 C.
1002441 LC Method K: Analytical reverse phase HPLC-MS using a Kinetex EVO C18 column (4.6 X 50 mm, 2.6 t,tra particle size), Temp: 45 'C; Flow: 2.0 mialmin, Run time: 4 min, Mobile phase: Initial 95% water (+ 0.1 % formic acid) and 5 %
acetonitrile (-f- 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, 1002451 LCMS Method L: Analytical reverse phase HPLC-MS using an X-Terra MS
Cis column (4.6 X 150 mm, 5 p.m particle size), Temperature: 40 C; Flow: 1.5 mUrnin;
Run Time: 10 min. Mobile phase: Initial 95% water (+ 10 rnM ammonium bicarbonate) and 5 % acetonitrile linear gradient to 95 % acetonitrile for 6.5 min then hold at 95 %
acetonitrile for 3,5 min, 1002461 LC Method NI: Analytical reverse phase UPLC-MS using an Acquity UPLC-MS BEH Cds column (50 x 2.1 mm, 1.7 p.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). Flow rate = 1.2 triLlmin, injection volume az 1.5 pL, and column temperature = 60 'C.
1002471 LC Method N: Analytical reverse phase UPLC-MS using an Acquity UPLC-MS BEH C18 column (50 x 2.1 mm, 1.7 pm particle size) made by Waters (pn:
186002350), and a dual gradient run from 1 (.'a") to 99 % mobile phase B over 3.0 minutes.
Mobile phase A = water (0.05 % ammonium formate). Mobile phase B =
acetonitrile.
Flow rate = 1.2 mUmin, injection volume = 1.5 [IL, and column temperature = 60 C.
1002481 LC Method 0: Analytical reverse phase HPLC-MS using a Kinetex Polar Cis column (3.0 X 50 mm, 2.6 um particle size), Temp: 45 C; Flow: 1.2 mUrnin; 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 (-1- 0,1 % formic acid) for 3.0 min then hold at 95 % acetonitrile (+ 0.1 % formic acid) for 1.0 min.
[00249] LC Method P: Analytical reverse phase UPLC-MS using an Acquity UPLC-MS BEH C18 column (100 X 2.1 mm, 1.7 urn 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). Flow rate = 0.8 mUmin, injection volume = 1.5 pt, and column temperature = 60 C.
[00250] LC Method Q: Analytical reverse phase HPLC-MS using an Onyx Monolithic C13 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). Flow rate = 12 miUmin, injection volume = 50 ItL, and column temperature = 25 'C.
[00251] LC Method R: Analytical reverse phase UPLC-MS using an Acquity UPLC-MS BEH Cds column (30 x 2.1 mm, 1.7 pm particle size) made by Waters (pn:
186002349), and a dual gradient run from 30 A to 99 /-10 mobile phase B over 1,0 minutes.
Mobile phase A = water (+ 0.05 % trifluoroacetic acid). Mobile phase B =
acetonitrile (+
0.035 % ttifluoroacetic acid). Flow rate = 1.2 mUrnin, injection volume = 1.5 pL, and column temperature = 60 C.
[002521 LC Method S: Analytical reverse phase UPLC-MS using an Acquity UPLC-MS BEH C18 column (30 x 2.1 rum, 1.7 pin 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). Flow rate = 1.5 mL/min, injection volume = 1.5 pL, and column temperature = 60 'C.
[00253] LC Method T: Analytical reverse phase UPLC-MS using an Acquity UPLC-MS BEH C18 column (30 X 2.1 mm, 1.7 pm 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). Flow rate = 1.2 mUmin, injection volume = 1.5 ullõ and column temperature = 60 'C.
1002541 LC Method U: Analytical reverse phase LIPLC--MS using an Acquity UPLC-MS BEH Cts column (30 x 2.1 mm, 1.7 i.rn 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 (4-0.035 % trifluoroacetic acid). Flow rate = 1,2 miUmin, injection volume = 1.5 111,, and column temperature = 60 C.
1002551 LC Method V: Analytical reverse phase HPLC-MS using a Kinetex EVO
C18 column (2.1 X 50 mm 2.6 um particle size), Temp: 45 "C; Flow: 1.0 mUmin;
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.
1002561 LC Method W: Analytical reverse phase HPLC-MS using a Kinetex Polar Ci8 column (3.0 X 50 mm, 2.6 pm particle size), Temp: 45 C; Flow: 1.2 mUrnin; 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.
1002571 LC Method X: Analytical reverse phase HPLC-MS using a Kinetex Polar column (3.0 X 50 mm, 2.6 inn particle size), Temp: 45 C; Flow: 1.2 mUmin; Run time: 5 min. Mobile phase: Initial 95 % water (+ 0.1 % formic acid) and 5 %
acetonitrile (+ 0.1 %
formic acid) linear gradient to 95 A) acetonitrile (+ 0,1 % formic acid) for 4,0 min then hold at 95 % acetonitrile (+ 0.1 % formic acid) for 1.0 min.
1002581 LC Method Y: Analytical reverse phase 1-IPLC-MS using a Luna C18 column (3.0 X 50 mm, 3 urn particle size), Temp: 45 C; Flow: 1.5 mUniin; 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, 1002591 LC Method Z: Analytical reverse phase EIPLC-MS using a Luna C18 column (3.0 X 50 Mtn, 3 um particle size), Temp: 45 'C..; Flow: 1.5 inUrnin 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.
1002601 LC Method AA: Analytical reverse phase HPLC-MS using a SunFire Cis column (4.6 X 75 mm, 3.5 trn particle size), Temp: 45 C; Flow: 1,5 miUmin, 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, 1002611 LC Method 1313: Analytical reverse phase HPLC-MS using an )(Bridge C18 column (4.6 X 75 mm, 5 urn particle size); Flow: 1.5 rriL/min, Run time: 6 min. Mobile phase: Initial 95 % water (+ 10 rni\/1 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 ntM ammonium bicarbonate) for 3 min.
1002621 LC Method CC: Analytical GC using a Phenomenex ZB-1MS column (0.25 X
30 mm, 0.25 um particle size); start temp 50 GC, ramp 20 GC/min to 300 GC and hold for 5 min.
1002631 LC Method DD: Analytical reverse phase HPLC-MS using a Merckmillipore Chromolith SpeedROD C18 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 % hifluoroacetic acid).
10026411 LC Method EE: Analytical reverse phase HPLC-MS using a Kinetex EVO
Cis column (4.6 X 50 mm, 2.6 1.trn 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 A) 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.
General X-Ray Powder Diffraction (XRPD) Method 1002651 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 Id 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 Y2 anti-scatter slit. 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.
General Thermogravimetric Analysis (TGA) Method 1002661 TGA was used to investigate the presence of residual solvents in the lots characterized and identify the temperature at which decomposition of the sample occurs.
Unless provided otherwise in the following Examples. TGA data were collected on a Mettler Toledo TGA/DSC 3+ STARe System. TGA data for Compound 4 were collected on a TA instrument Discovery series with TRIOS system.
General Differential Scanning Calorimetry (DSC) Method 1002671 Unless provided otherwise in the following Examples, the melting point or glass transition point of the material was measured using a Mettler Toledo TGA/DSC
3+
STARe System. DSC data for Compound 4 were collected on a TA instrument Disco-very series with TRIOS system.
General Synthetic Schemes:
1002681 Another aspect of the disclosure provides methods for making compounds of Formulae I, I", Ia, Ia', Ha, Ha', Hb, .. He, He', hid, lid', He, He', Hf, Hh', Compounds Ito 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. In some embodiments of the following Schemes and Examples, 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. In some embodiments of the following Schemes and Examples, each compound may be replaced with its deuterated derivative.

Scheme ( X 'Mg Alk0,11õ.--11.0 F3 1-2 -- 0y1\ CF3 Oyk. CF3 skik OAlk H O

(pa ,9 CF 3 0 __ 0-"J'CN_N'H 0PG1 1002691 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 C1-C6 linear or branched alkyl groups. X1 is selected from halogens, such as Cl, I, or Br. PG1 is selected.
from suitable oxygen protecting groups, such as benz.,71 and silyl moieties (e.g., TBDPS, TBS, and TMS). a is an integer selected from 2, 3, 4, and 5. V is as defined for Formula I
above.
1002701 Any suitable conditions for a Grignard-type addition can be used to react a compound of Formula 14 with a compound of Formula 1-2 to form a compound of Formula 1-3. For example, the Grignard addition of a compound of Formula 14 with a compound of Formula 1-2 may be performed in Et20 at -78 C, followed by addition of 1 N aqueous 1-IC1 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. For example, 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 HARI
and Et3N in Ma', followed by addition of tert-butyl N-aminocarbamate. Any suitable hydrolysis conditions may be used to convert a carba.mate of Formula 1-6 to a hydra.zide of Formula 1-7. For example, a compound of Formula 1-7 may be obtained by reacting a compound of Formula 1-6 with 1-IC1 in CI-12C12 at ambient temperature.

Scheme 2:
LG LG
rA=-N ( /(-0 0 Ma (R1), 8 ---µ cF,3 (R1), H2NNHOPG HN¨NH opGi -LG
AN
e)=/74-CF3 (R1)m N-N OPG1 [00271] 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. PG1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., 'MI)PS, MS, and TNIS). a is an integer selected from 2, 3, 4, and 5. RI, m, and Y are as defined for Formula I above.
[00272] 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. For example, a compound of Formula 2-1 can be reacted with um 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. For example, a compound of Formula 2-2 can be reacted with D1PEA in acetonitrile, followed by addition ofp-toluenesulfonyl chloride, to yield an oxadiazole of Formula 2-3.

Scheme 3:
- / 7-----\ if.
µr----Mb G N
,y, (A /I
NH: 3-2 ir r1-.
6- -. N
0 Alk _____________________________ ' Y...-'-y0Alk __ , (R1)m I

(Y:1:3 /'---- /_____ ( ,-----'-----) e ( A
/- ' N'N- 0M
a + cOa ' CL Y 0 -ILL_ ( o----(---CF3 i,=!,',...f`' J.,r, 0 H All 6P 1 (R1) 011)m 8 112N -/ 7.---'s\ r ip\r----,,b----,, \, \, N"
NF macrocyclization WI
$ (Y)a N _.'". - r=jk=.
a [i ¨ N¨N OPG1 3-6 3-7 (E/7 mixture) 3-8 1002731 Scheme 3 refers to processes for preparing a compound of Formula 3-8 from a compound of Formula 3-1. Aik is selected from C1-C6 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 is an integer selected from 1, 2, 3, and 4, and b is an integer selected from 0, 1, 2, 3, and 4 provided that a + b is not greater than 5.
Ring A, RI, m, and NI are as defined for Formula 1 above.
1002741 The 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. For example, a compound of Formula 3-5 can be reacted with DIPEA in acetonitrile, followed by addition ofp-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. :For example, a compound of Formula 3-6 may be reacted in the presence of Grubbs 2nd generation catalyst in BCE to yield a macrocycle of Formula 3-7 as a mixture of .EIZ
isomers (as denoted by the bond), Conversion of an unsaturated compound of Formula 3-7 to a macrocycle of Formula 3-8 can be accomplished using any suitable procedure for olefin reduction and alcohol deprotection.
Scheme 4:
LG
12i 3-2 macrocyclization (R16 (R')m N¨N OPG1 N¨N OPG1 A

(R1), - 0,3 (R1), .\ fõ
N¨N OPG ' N¨N
4-2 (Ea mixture) 44 100275] Scheme 4 refers to processes for preparing a compound of Formula 4-3 from a compound of Formula 2-3. LC; is selected from halogen and oxygen-based leaving groups such as OTf and OTs. PG1 is selected from suitable oxygen protecting groups, such as benzyl and sily1 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, Ring A, R1, m, and X' are as defined for Formula I above.
100276] 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. M.acrocyclization 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 44 may be reacted in the presence of Zhan catalyst-1.B in DCE to yield a maerocycle of Formula 4-2 as a mixture of EIZ
isomers (as denoted by the ,=`''' bond). Conversion of an unsaturated compound of Formula 4-2 to a ma.crocycle of Formula 4-3 can be accomplished using any suitable procedure for olefin reduction and alcohol deprotection.
Scheme 5:

CA)¨Mb 3.G2 \
I,.G 1 \--N
1 5-1 LG A \\
G2P sc'. ,-----II Y Ma ------------- 0- i'L; Y (.., Ma i ______________________________________________________________ .
=-+CF3 4,7¨=,'-`'-cc"),----t--CF3 (R16 Ai, fr ' N¨N OPG N¨N OPG1 2-3 5-2 (EJZ mixture) rAD_______ \ CO5 ID---01b NI¨
s'N
LG
) maerocyclization .1. A, , t,,4 A
, k_.,31,,. 0 ' L/='*1-"=.(---L-CF (R1)m = '''' =,-. N,--A----3 Villn \ a \ 3 N¨N OH
(R1), \ CF lir N¨N OPG1 N¨N OPG1 1002771 Scheme 5 refers to processes for preparing a compound of Formula 5-5 from a compound of Formula 2-3. LC- is selected from halogen and oxygen-based leaving groups such as MI and OTs. PG' is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and TMS). PG2 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, 11.1, m, and Y are as defined for Formula I above.
[00278] 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. For example, 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"d 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 can be accomplished using any suitable procedure for olefin reduction and amine deprotection. Macrocyclization of a compound of Formula 5-3 to produce a corn.
.pound of Formula 5-4 may be accomplished by any suitable aromatic substitution conditions.
Conversion of a compound of Formula 5-4 to an alcohol of Formula 5-5 can be accomplished using any suitable procedure for alcohol deprotection.
Scheme 6:
LG
R co xi , =-. -t,"
fe--IN.---01-7... N' rvis'N ,,,-L, ___________________________________ . l! N
/..,./,k,..0Alk __________________________________________ ..
(R1 im d (R1)m il Rx',1. ----(Y)b -r'' + ()la -- '''.

-4.5--,- ..,,,OH
V N 0 k,y) H .. , .e kit4 OPG' :,..;,-:=kirN, (R1),, H2N--- N
(R1)m 0 Fl OPG1 Rxi .)., '-'N -- (Y)""µ maerocyciization Ts, \ fc 'N
0 I (Y).
1/41e _________________________________________ , e-L-/r-..-- --',-(C1',,----(--C1-:
L,e-------(---CF3 i (R )m \/ bpGi R ) m N--N OPGI
6-5 6-6 (Ea mixture) 6-7 [002791 Scheme 6 refers to processes for preparing a compound of Formula 6-7 from a compound of Formula 3-1, Alk is selected from C1-Cc linear or branched alkyl groups.
1A3 is selected from halogen and oxygen-based leaving groups such as OTT and OTs. PG' is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TBDPS, TBS, and 1MS). 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.R1, m, Y and WI are as defined for Formula I above.
[00280] 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. For example, a compound of Formula 6-4 can be reacted with DIE'A in acetonitrile, followed by addition ofp-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. For example, 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 HZ
isomers (as denoted by the -,4"4 bond). Conversion of an unsaturated compound of Formula 6-6 to a macrocycle of Formula 6-7 can be accomplished using any suitable procedure for olefin reduction and alcohol deprotection.
Scheme 7:
R" R' RY\ /RN` "4---.
1..G Rx-1N7--1V-b-(R16 8 ozi)m 11 3.1 7.2 R): RY
, i. +

1-12N -iµl-i OPG1 011)rn - I .,..1Lii C F 3 R %
( m 0 H OPGi 7-3 1.7 7-4 IR'''. RY
\{_ RY Ry Rx-1N/' --(Y)b¨) RY\ µRY bil \i, RX-1N --.--Cnb--) macrocyclization .1- r, N (\he ------------------------------------------------- -,...
7 Ma L/ Ma 7,,,-,,=,,,, I cF (Ri),,, .,.y.-0 c F3 1), \µ Jr-7 .3 (R ' )m 1µ= /I ' 1 N-N
N-N OPG
7.5 7-6 (87 Fll ixture) 7-7 [00281] Scheme 7 refers to processes for preparing a compound of Formula 7-7 from a compound of Formula 3-1, Alk is selected from CI-C6 linear or branched alkyl groups.
LG is selected from halogen and oxygen-based leaving groups such as OTT and OTs. PG
is selected from suitable oxygen protecting groups, such as benzyl and sily1 moieties (e.g., TBDPS,71713S, and TMS). Each of a and his an integer independently selected from 0, 1, 2, and 3, provided that a + b is not greater than 4. Fe, m, Y, le"; and Fe are as defined for Formula 1 above.
[00282] 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. For example; a compound of Formula 7-4 can be reacted with DIEA. in acetonitrile, followed by addition ofp-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. For example, 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 Ea isomers (as denoted by the -,'"4 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 &protection.

Scheme 8:
Rxl LG
)Q(V
N </i N N macrocydjzation H

'µ (111) itr N¨N PG ¨,,, N¨N 0P01 /00a N 0 (Y)9 (R13 ' )rn ¨ N¨N aPG1 " N¨N
8-2 (E2 mixture) 8-3 1002831 Scheme 8 refers to processes for preparing a compound of Formula 8-3 from a compound of Formula 2-3, LC- is selected from halogen and oxygen-based leaving groups such as Ulf 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 h is not greater than 5. RI, m, Y, and R'" are as defined for Formula I above.
1002841 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 any suitable aromatic substitution conditions. For example, a compound of Formula 2-3 can be reacted with DIFA 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 he accomplished by any suitable ring-closing metathesis conditions. For example, 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 EIZ isomers (as denoted by the bond).
Conversion of an unsaturated compound of Formula 8-2 to a macrocycle of Formula 8-3 can he accomplished using any suitable procedure for olefin reduction and alcohol deprotection.

Scheme 9:
N"
L!),r ____________________________________________ B macrocyclization N
Lx 0 N

N¨N ¨

\ 06/c 'tzElv_N
0-rk'N AN
\---1(CFn 0 (R1)õ, // - C
N¨N
("m N¨N HF3 9-4 {Ea mixture) 9-5 1002851 Scheme 9 refers to processes for preparing a compound of Formula 9-5 from a compound of Formula 94. Lx is selected from halogens such as Cl, 1, or Br. c is an integer independently selected from 1, 2, 3, and 4. Ring A, Ring B, 11.1, m, and 'Y are as defined for Formula I above.
[00286] 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. For example, a compound of Formula 9-2 may be reacted with (AT-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. For example, a compound of Formula 9-3 in acetonitrile may be reacted with tris-o-tolylphosphane and Pd(OAc)2, followed by addition of triethylamine, to yield a macrocycle of Formula 9-4 as a mixture of EIZ isomers (as denoted by the Jsr''' bond). Conversion of an unsaturated compound of Formula 9-4 to a macrocycle of Formula 9-5 can be accomplished using any suitable procedure for olefin reduction.

Scheme 10:
/I= 7 ,--- --mb ( A----(Y') LG ../
Br I., =N' ."'",n=N 1!I 3-2 -1OAlk .
...,?,-0Alk ,.
: 1 i41 o sl o i=-----Th---Mb ( A \r----"
A
_____________________________________________________ Br -,..,,..)k, 0 Ma , Br-..õ,--LN 0 ' ----t-CF3 I N H 'Lit_ . NI¨ - oF, 1 ' OH
Yrri H2N_NH OPG1 "--ey'N

---'\

CAMb / (MA ---Ma,_ 1---- \'NI
/ ;, .. , \
macrocyclIzavan 1 "`N-/
I _,- n:_sr,-L-,. 7 )b Isyjo i "-i--- --y: --r-t0F 03 -\c ,..----7-CFa R1 N-41 41 ; OPG1 R1 N--N 0PG1 ( A
\-N-i \
R, A
1 i Mb 11002871 Scheme 10 refers to processes for preparing a compound of Formula 10-8 from a compound of Formula 10-1. Al k is selected from C1-C6 linear or branched alkyl groups.
.1,G is selected from halogen and oxygen-based leaving groups such as O'ff and 071s.
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, RI, and Y are as defined for Formula I above.
1002881 The reaction of a compound of Formula 10-1 with a compound of Formula to yield a compound of Formula 10-2 may be accomplished by any suitable aromatic substitution conditions. For example, 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 oxadiazoie formation. For example, a compound of Formula 10-4 can be reacted with D I
FA in acetonitrile, followed by addition ofp-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.
For example, a compound of Formula 10-5 may he reacted in the presence of Zhan catalyst-IB in DCE to yield a macrocycle of -Formula 10-6 as a mixture of Ell:
isomers (as denoted by the ,srs' 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:
Xl N/R" RYN
Rx1 LG
¨

N
CF3 /63A.'"vri C
R16 OPG1 (R57) OPG1 RYN
rilt) RYN
k HO
rnacrocyclization N
/-==-4-"L's-es.)-----(--C F3 -s= CF3 (R1 )m OP' Ri 6PG1 1002891 Scheme 11 refers to processes for preparing a compound of Formula 11-4 from a compound of Formula 2-3. LC; 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 sily1 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 + h is not greater than 5.
m, Y, R', and R" are as defined for Formula I above.
[00290] The reaction of a compound of Formula 2-3 with a compound of Formula 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 DNB() 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. For example, 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 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. For example, a compound of Formula 11-3 may be reacted in DMF with IDEA, followed by addition of HARI, to yield a compound of Formula 11-4, Scheme 12:
HO
LU ccor.H
1,G
N

(.1 1/4"P`=-=\r-ir---t-CF3 (R1), OPG1 (R
N-N OPG
N-N

(A HQ (A
macrocyclization ettla N
rna -(R1)m \\
N-N PG (R1 \-), NN 0PG1 -[00291] 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' is selected from suitable oxygen protecting groups, such as benzyl and sityl moieties (e.g., TBDPS, TBS, and 'TIVIS). a is an integer selected from 3, 4, 5, and 6. Ring A, 11.1, in, and NI are as defined for Formula I
above.

1002921 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. For example, 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. For example, 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. For example, a compound of -Formula may be reacted with DMA. in Miff, followed by addition of HAM', to produce a compound of Formula 12-4.
Scheme 13:
x---(Y).--, 'IrbF
0 O .-C 31 ).(---000,õ

ri--`=N
(e)5 (R1 ,-,,,:.-----lp (:)õ.õ.1.)\---CF3 1!-A.;.-;,..y,1 OAlk ' (Ry .1, ),, 8 - Alko 1 OPG1 UAW
3-1 13.2 X"---(Y)3"---1 *-----Ma----I
L
---õ, rnacrocyclization \ f01µ)b or , /6 -NI '''e J ch, __________ .
0CF3, itu0 0,,,,)\---CF3 . PO G= µ'''Ir HN, OH HO
H,NH

x.---Ma- xõ---CY1,¨.., i CL.
f--, --(y)b __ . ,-, N N CPb __ = (IL,,,1 /
/".,---- 0 ' õ.--\---CF., (R1)m HN-NH f,___N OPG = N¨N

[00293] Scheme 13 refers to processes for prepating a compound of Formula 13-7 from a compound of Formula 3-1. Each Alk is independently selected from C1¨C6 linear or branched alkyl groups. -laG 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. -R1, m, X, V. Rm, and RY are as defined for Formula I above.
[002941 The reaction of a compound of Formula 3-1 with a compound of Formula to yield a compound of Formula 13-2 may be accomplished by any suitable aromatic substitution conditions. For example, 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 &ester 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. For example, 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. For example, a compound of Formula 13-5 may be reacted with AT,N-diisopropylethylamine in acetonittile, 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:
Rxi 'N _-(Y)5 PG2 -Ma CF3 N.` b OH pi G2 iss OH 14-2 0-=-COPG1 ji \
-,-', ,--L. ,N H
N Ma (R1 ft /,,, 0 hi 0---T H2N ki-z .---(Neo RX1 ./Mb Feil r'n Fil N \
L.G 002 macrocyclization I , "N (Y)st ____ , >
2.=z'''''-'N (--CF i fR)1 ..--= Mb --..., N"-- -----/
M
-,-N liN L'-=, Ma J\ a IN \ N
h 1 ______ r CF3 R '10 -K1-0F1 )rn !\ Y OH -N--N

[00295] Scheme 14 refers to processes for prepating a compound of Formula 14-7 from a compound of Formula 14-1. lik; is selected from halogen and oxygen-based leaving groups such as OTf and OTs. PC-1 is selected from suitable oxygen protecting groups, such as benzyl and sityl moieties (e.g., THEWS, TBS, and TIVIS). PG2 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. IV, m, X, Y, and lel are as defined for Formula 1 above.
[00296] The reaction of a compound of Formula 14-1 with a compound of Formula 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. For example, a compound of Formula 14-3 may be reacted with tdphenylphosphine followed by 2,2,2-trichloroacetonitrile in anhydrous TEIF 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. For example, 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:
RY,,,RY RY R''R)LRY R
\ , .>'---. ._..,,-, OH
Rx"9N/Y----(y)b---) RN' Mu ;
Rx)N,>õ011 1 \I )- 1 -,=""-µ.N ! Iir'' N
,,,,,,, 0 ,- ' , \r--- \--CF =={: (R1 A F3 `).4 ------- C P3 (R '),', 4 = .3 (R)rn N¨N un RY\ ,RY RY RY
Rx.iN >----- 006 OH
11 r'il Ma 'INisy ty)a V-,='' '''''-'c'Cks.--A--CF3 ,/,''''. - =\,-4¨CF3 (R , ' ji, \\ // õ.1 _ (R1 )õ, A // ' N¨N gJt1 . N¨N OH

1002971 Scheme 15 refers to processes for preparing a compound of Formula 15-4 from a compound of Formula 7-6. PG' is selected from suitable oxygen protecting groups, such as benzyl and sityl 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.
R1, m, Y, Rx1, and la are as defined for Formula I above.
1002981 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:
LG ....-01)!, A X N ',,..-:-5-li 16-1 AN
______________________________________ . /1,.õ-Air.OAlk __ ,.
(R1), d (R'), 0 , \
r .."' X"---(Y)b---7-JMs .,-, 1---=
li.N + e" .." N 0 003 0 / H
1.-- OH ----C
( OPG1 L4'r-ri =N 'N' (R'), 0 H2N-NH o(R1)õO. H pol "(Y)b----, ---(Y)b-..:" X' \
(14µ*-1s1 \
8 r =
macrocyc!ization I
/':''kr.\ \,--"( (Y).

(RI), (R1), - ii OPG1 N-N
N-N
16-6 16-7 (E2 mixture) FIN FIN
Mb--' \
HN,Mu---.1 HN./ ==

I
--------------------------------------------------- AN (Y)g (R1) \ 4 OH (R')ni `\ 6 m N-N N-N - 0 N-N N' H

/
..õ-(Y)5----_, FIN I
L'..
A
[Jr y 7).
A.------)---T-0._ (_,Rzi (Ri6 A4 OH

[002991 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 C1-C6 linear or branched alk-y1 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 sily1 moieties (e.g., TBDPS, TBS, and DAS). Each of a and b is an integer independently selected from 1, 2, 3, and 4, provided that a h is not greater than 5.
m, X, Y, and W1 are as defined for Formula I above.
1003001 The reaction of a compound of Formula 3-1 with a compound of Formula 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 oxadia.zole formation. For example, a compound of Formula 16-5 can be reacted with DIEA in acetonitrile, followed by addition of p-toluenesuifonyl chloride, to yield an oxadia.zole of Formula 16-6. Ma.crocyclization 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. For example, a compound of Formula 16-6 may be reacted in the presence of Than catalyst-1B in DCE to yield a macrocycle of Formula 16-7 as a mixture of EIZ 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:
-Mb , 0.,õ..õRz1 x.---M, x- ¨

....-k.
1 N H 17-2 (1" N Rzi (R,), (R1),NOH
a N¨N

x"..- Mo= ----, C Y Rzi macrocyclization ______________________________________________________________ , (R1), A ir 'No N ¨ N ( R1),, N---N OH

Mb- oz- Mb M XV Ai, ,,,,, ..-k.
h N Ma --1 ''' N Ma (R1 )7----\---Rz1 ), (R16 N-N OH N---N OH

17-6 (Ea mixture) [00301] 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. It', m, X, Y, and Rzl are as defined for :Formula I above.
[00302] The reaction of a carboxylic acid of Formula 174 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. For example, 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. For example, a compound of Formula 17-5 may be reacted in the presence of [1,3-bis(2,4,6-tritnethylphenyl)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 ElZ 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:
X". X
%--Ma N

( c) O

xze0i) macrocycli 1q zation \\,1 (R 1 )rn \
N¨N / Ri OPG ' N¨N

18-4 (67 mixture) ¨
frk'N
(R1) N¨N
OH

1003031 Scheme 18 refers to processes for preparing a compound of Formula 18-5 from a compound of Formula 17-1. PC-1 is selected from suitable oxygen protecting groups, such as benzyl and silyl moieties (e.g., TIMPS, MS, 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. m, X, and Y are as defined for Formula I above.
1003041 The reaction of a compound of Formula 17-1 with a compound of Formula 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. For example, a compound of Formula 18-2 can be reacted with diisopropylethylamine and p-toluenesulfonyt 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. For example, a compound of Formula 18-3 may be reacted in the presence of Zhan catalyst-1B in DCE, to yield a ma.crocycle of Formula 18-4 as a mixture of .EIZ isomers (as denoted by the "4 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:
; -N N

(R1)m )r-4 F3 (R1), (R1)õ, [00305] Scheme 19 refers to processes for prepating a compound of Formula 19-2 from a compound of Formula 13-7. Each of a and h is an integer independently selected from 1, 2, 3, and 4, provided that a + b is not greater than 5.R1, m, X, and '1( are as defined for Formula -1 above.
[00306] 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:
/Mb-X
RLI
V X

(R
(R1 NH, N-N OH N-N OH

R2' \ H 204 [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. 11-1, m, X, V. LW, and le are as defined for Formula I above.
1003081 Conversion of an amine of Formula 20-1 to an amine of Formula 20-2 may be accomplished using any suitable amination procedure. For example, an amine of Formula.
20-1 may be reacted with an alkyl halide in the presence of bis(trimethylsilyparninoisodium to yield a compound of Formula 20-2.
Preparation of Intermediates Intermediate 1: Preparation of methyl 34bis(tert-butoxyearbonyl)aminol-6-bromo-(trifluoromethyl)pyridine-2-earboxylate Step 1 0 Step 2 Step 3 I

Pr Br N
r, Step 4 oI
NI-12 0 >r Y

Step 1: Methyl 3-(benzhydrylideneamino)-5-(trifluoromethyl)pyridine-2-carboxylate jo I I

I

7Thl 1003091 A mixture of methyl 3-chloro-5-(triI1uoromethyl)pyridine-2-carboxylate (47.3 g, 197.43 mmol), diphenylmethanimine (47 g, 259.33 mmol), Xantphos (9q)7 g, 15.675 mmol), and cesium carbonate (131 g, 402.06 mmol) in dioxane (800 mt.) was degassed by bubbling nitrogen for 30 minutes. Pd(OAc)2 (3.52g, 15.679 mmol) was added and the system was purged with nitrogen three times. The reaction mixture was heated at 100 C
for 18 h. The reaction was cooled to room temperature and filtered on a pad of Celite. The cake was washed with Et0Ac and solvents were evaporated under reduced pressure to give methyl 3-(benzhydrylidenea.mino)-5-(trifluoromethyl)pyridine-2-carboxy1ate (90 g, 84%) as yellow solid. ES1-MS m/z calc. 384.10855, found 385.1 (M+1)';
Retention time:
2.24 minutes (LC Method B).
Step 2: Methyl 3-amino-5-(trifluorornethyl)pyridine-2-carhoxylate -p F3CN

[00310] To a suspension of methyl 3-(benzhydrylidenea.mino)-5-(trifluoromethyl)pyridine-2-carboxylate (65 g, 124.30 mmol) in methanol (200 inL) was added BC! (3M in methanol) (146 ttiL of 3M, 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). The organic phase was washed with 5 % aqueous sodium bicarbonate solution (3 X 500 mL) and brine (2 X 500 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was triturated with heptanes (2 X 50 mL) and the mother liquors were discarded. The solid obtained was triturated with a mixture of dichloromethane and heptanes (1:1, 40 mL) and filtered to afford methyl 3-amino-5-(trifluoromethyl)pyridine-2-carboxylate (25.25 g, 91 %) as yellow solid. 1H
NMI?. (300 MHz, CDC13) 6 8.24 (s, 1H), 7,28 (s, LH), 5.98 (br. s, 21:1), 4.00 (s, 31-1) ppm. '9F NMR
(282 MHz, CDC13) 6 -63.23 (s, 3F) ppm. EST-MS tn/z calc. 220.046, found 221.1 (M+1)+;
Retention time: 1.62 minutes (LC Method E).
Step 3: Methyl 3-amino-6-brorao-5-(trilluoromethyl)pyridine-2-earhoxylate Br Jo to F3C,, [00311] To a solution of methyl 3-amino-5-(trifluoromethyl)pyridine-2-carboxylate (18.75 g, 80.91 mmol) in a.cetonitrile (300 mL) at 0C was added portion wise N-bromosuccinimide (18.7g, 105.3 mmol). The mixture was stirred overnight at 25 'C. Ethyl acetate (1000 mL) was added. The organic layer was washed with 10 % sodium thiosulfate solution (3 X 200 mL) which were back extracted with ethyl acetate (2 X
200mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (3 X
200 ml.), brine (200 mL), dried over sodium sulfate and concentrated in vacuo to provide methyl 3-amino-6-bri.Dmo-5-(triflui.promethyppyridine-2-carboxylate (25.46 g, 98 %).
NMR (300 MHz, CDC13) 6 3.93-4.03 (m, 3II), 6.01 (br. s., 211), 7.37 (s, 1H) ppm, 19F
NMR (282 MHz, CDC:13) 6 -64.2 (s, 3F) ppm. ESE-MS mtz calc. 297.9565, found 299.0 (M+1)-% Retention time: 2.55 minutes (LC Method F.).
Step 4: Methyl 3-ibis(tert-hutoxyearhonyl)amino1-6-hromo-5-(trifluoromethyl)pyridine-2-carboxylate Br Br I
F3Cõ..7AN

Y-'11t) 0,..<
11003121 A mixture of methyl 3-amino-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (5g, 15.549 mmol), (Boc)20 (11 g, 11.579 mi., 50.402 mmol), DMAP
(310 mg, 2.5375 mmol) and CI-12C12 (150 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purification by silica gel chromatography (0 % to 15 % ethyl acetate in heptane) provided methyl 3-[bis(tert-butoxycarbonypamini.)]-6-bromo-5-(trifluoromethyppyridine-2-carboxylate (6.73 g, 87 %) as light yellow solid. 41 NMR. (300 MHz, CDCI3) 6 1.42 (s, 18H), 3.96 (s, 311), 7.85 (s, 1H) ppm. 19F NMR (282 MHz, CDC13) 6 -63.9 (s, 3F) ppm. ESI-MS m/z calc.
498.06134, Retention time: 2.34 minutes (LC Method B).
Intermediate 2: Preparation of 6-(2-allylpyrrolidin-l-yI)-3-(tert-hutoxycarhonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid Sr ,\ Step I Step 2 N- H .TFA
0O 2oo0 . _0 N., N

Step 3 So tep 4 5-1,T,OH

OyNO_OyNH 0 Step 1: tert-Butyl 2-allylpyreolidine-1-carboxylate 1003131 s-Butyllithiurn (20.4 int, of 1.4 M in cyclohexanes, 28.56 mmol) was added dropwise to a solution of tert-butyl pyrrolidine-l-carboxylate (3.5 g, 20.44 mmol) and tetramethyl.ethylenediamine (2.8675 g, 3.7 tritõ 24.676 mmol) in diethyl ether (80 mL) at -78 C and the mixture was stirred for 2 h. Then zinc chloride (57 mL of 0.5 M
in THF, 28.5 mmol) was added slowly at -78 C and the mixture was stirred for 90 min.
A solution of copper(I) cyanide (2.2 g, 24.564 mmol) in lithium chloride (82 mL of 0.5 M
in THF, 41 mmol) was added slowly at -78 C and the mixture was stirred for 90 min then 3-bromoprop-l-ene (7.4094g, 5.3 mL, 61.247 mmol) was added slowly at -78 C and the mixture was stirred at room temperature overnight. Aqueous ammonium hydroxide (60 mL) was added and the mixture was stirred at room temperature for 1 h. The phases were separated, and the aqueous phase was extracted with diethyl ether (2 X 60 mL).
The organic phases were combined, washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (gradient from 0 % to 20 % of ethyl acetate in heptanes) provided as a clear oil, tert-butyl 2-allylpyrrolidine-1-carboxylate (2.9 g, 67 %).
1\11111k (300 MHz, CDC13) 6 1.46 (s, 911), 1,66-1,95 (m, 4H), 1.99-2.23 (m, 1.11), 2.33-2.62 (m, 1H), 3.22-3.46 (m, 211), 3.67-3.94 (m, 1E1), 4.97-5.11 (m, 2H), 5.62-5.84 (rn, 1H) ppm. EST-MS mtz calc.
211.1572, found 234.2 (Nla-Na)-% Retention time: 2.17 minutes (LC Method B).
Step 2: 2-Allylpyrrolidine (trifluoroacetate salt) 4.N
.TFA
1003141 Trifluoroacetic acid (13.468 g, 9,1 mL, 118.12 mmol.) was added slowly to tent-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 %). NMR
(300 MHz, CDCI3) 6 1.57-1.85 (m, 1H), 1.89-2.31 (m., 311), 2.35-2.71 (m, 21), 3.32 (br.
s., 2H), 3.61 (br. s., 1H), 4.95-5.35 (m, 2H), 5.51-5.91 (m, 111), 8.27 (br. s., 1H), 9.31 (br. s., 1H) ppm.

1917 MIR. (282 NI-Hz, CDC13) 6 -75.9 (s, 3F) ppm. ESI-MS m/z calc. 111.1048, found 112.2 (M+1)+, Retention time: 0.36 minutes (LC Method B).
Step 3: Methyl 6-(2-allylpyrrolidin-l-y1)-3-Ibis(tert-butoxycarbonyl)amino1-5-(trifluoromethyl)pyridine-2-earboxylate Br 0 ), H .TFA.
I IS
>,0yN,15.0 o o [00315] In a sealed tube, 2-allylpyrrolidine (trifluoroacetate salt) (338 mg, 1.5008 mmol) was added to methyl 3-[bis(tert-butoxyearbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-earboxylate (500 mg, 1,0015 minol) and D1PEA.
(964.60 mg, 1.3 mL, 7.4635 mmol) in acetonitrile (10 mL). The tube was sealed, and the mixture was heated at 80 C overnight. Saturated sodium bicarbonate solution (25 mL) was added and extracted with ethyl acetate (3 X 25 mL). The organic phases were combined, washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (gradient from 0 %
to 20 % of ethyl acetate in heptanes) provided as a yellow oil, methyl 6-(2-allylpyrrolidin-l-y1)-3-[bis(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)pyridine-2-carboxylate (480 mg, 91 %). NMR (300 MHz, CDCI3) 6 1.42 (s, 18H), 1.65-1.90 (m, 2H), 1.94-2.18 (m, 2H), 2.24-2.40 (m, 1H), 2.51-2.65 (m, 1H), 3.41-3.52 (m, 111), 3.55-3.69 (m, 11:1), 3.88 (s, 3H), 4.46-4.60 (m, 1H), 4.95-5.11 (m, 2H), 5.65-5.87 (m, 1H), 7.63 (s, 1H) ppm. "F
NMR (282 MHz, CDC13) 6 -56.0 (s, 31F) ppm. ES1-MS m/z calc. 529.24, found 530.3 (M+1)+;

Retention time: 2.63 minutes (LC Method E).
Step 4: 6-(2-Allylpyrrolidin-1-y1)-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid N

0 0 < 8 1003161 To a solution of methyl 6-(2-allylpyrrolidin-1.-y1)-3-[bis(tert-butoxycarboirs71)a.mino]-5-(trifluoromethyl)pyridine-2-carboxylate (13.1 g, 24.74 minol) in THE' (156 mL) was added methanol (125 mL) and 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. THE and methanol were removed under reduced pressure and then 70 mL of 10 % aqueous HC1 was added and the resulting mixture was extracted with Et0Ac (3 X 100 mL). The organic phases were combined, washed with brine (50 triL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (gradient from 0 % to 50 %
Et0Ac in hexanes) provided as a yellow solid, 6-(2-allylpyrrolidin-1-y1)-3-(tert-butoxycarbonylamino)-5-(tritluoromethyl)pyridine-2-carboxylic acid (7.85 g, 76 %). 111 MIR (400 MHz, CDC13) 61.52 (s, 9H), 1.74-1.81 (m, 2H), 1.98-2.01 (m, 1H), 2.15-2.26 (m, 2t1), 2.44-2.50 (m, 1H), 3.38-3,43 (m, 1H), 3.63-3.69 (m, 1.H.), 4.25-4.32 (m, 1H), 5.04-5.08 (m, 2H), 5.70-5.80 (m, Hi), 9.13 (s, 11--1), 9.67(s. 1H), 11.11 (br.
s, 1H). ESI-MS m/i calc. 415.1719, found 416.3 (M+1)+; Retention time: 2.01 minutes (LC
Method A).
Intermediate 3: Preparation of (2S)-2-Allylpyrrolicline (trifluoroacetate salt) 0-w/C)H Step I Step 2, 0 '0 Step 3õ.
N N`
.1 FA
Step 1: tert-Butyl (2S)-2-(iodomethyl)pyrrolidine-1-earboxylate vr=a, oo o 1003171 To a solution of imidazole (16.9 g, 248,2 mmol) and triphenylphosphane (35.8 g, 136.5 rnrnol) in 2-methyltetrahydrofuran (300 mL) at 0 C was added iodine (34.8 g, 137,1 m mot) portion-wise over 30 min. The reaction temperature was kept at <
6 C and the mixture became a dark orange taffy which then became light yellow and granular on stirring. The mixture was allowed to warm to ambient temperature and a solution of tert-butyl (2S)-2-(hydroxymethyppyrrolidine-1.carboxylate (25 g, 124.2 mmol) in 2-methyltetrahydrofuran (150 mL) was added portion-wise. The mixture was stirred at ambient temperature for 16 h affording a light yellow slurry. The slurry was filtered over Celite to remove the salts and the filtrate was concentrated in vacuo. The residue was dissolved in 150 mil, of Et0Ac. To the mixture was added 150 m11: of hexane which gave an oil. This oil would not dissolve on addition of Et0Ac 300 mL). 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 vacua .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 Et0Adhexanes) which provided as a light yellow oil, tert-butyl (25)-2-(iodomethyl)pyrrolidine-1-carboxylate (36.5 g, 94 %). NMR (499 MHz, Chloroform-d) 5 3.89 (d, J 14.0 Hz, 1H), 3.42 (d, 1= 34.7 Hz, 4H), 2.06 (s, 1H), 2.00 -1.86 (m, 2E), 1.82 (qõ/. = 6,9 Hz, 1H), 1.47 (s, 9H) ppm, ESI-MS wiz calc.
311,0382, found 312.0 (I'vf+1)+; Retention time: 1.82 minutes (LC Method A.
Step 2: tert-Butyl (2S)-2-allylpyrrolidine-1-carboxylate çL _______________________________ 1003181 lodocopper (103 g, 540.8 mmol) was suspended in 7171-IF (525 mL) under nitrogen and cooled to - 40 C under stirring. Bromo(vinyl)magnesium (1 L of 1 M, 1.000 mot) was slowly added via an addition funnel over 40 minutes keeping the internal temperature bePveen - 40 C and - 45 C. The thick suspension was stirred for 1 h allowing to warm to - 10 C. The black suspension was cooled to - 40 'V and a solution of tert-b utyl (15)-2-(iodomethyl)pyrrolidine-1-carboxylate (105 g, 337.4 mmoi) in THE (260 mL) was added dropwise over 30 min keeping the internal temperature between -40 'V
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. The organic phase was washed twice more with saturated aqueous ammonium chloride solution (2 X 100 ml,) and the aqueous phases were back-extracted once with MTBE (100 mL). The combined organic phases were dried, filtered and evaporated. Purification by silica gel chromatography (hexane to 5 % acetone in hexane (product absorbs at 200-210 nm)) provided tert-butyl (2S)-allylpyrrolidine-i-carboxylate (32g. 45%). HNMR (400 MHz, DMS0-46) 5 5.74 (ddtõ./
17.3, 10.3, 7.2 Hz, 1H), 5.13 - 4.97 (m, 21:1), 3.70 (s, 111), 3.23 (dq, I ¨
19.2, 11.3, 9.4 Hz, 2H), 2.46- 1.52 (m, 6H), 1.40 (s, 9H) ppm. ES1-MS m/z calc. 211.15723, found 212.0 (1\14-1)H-; Retention time: 1.82 minutes (LC Method A).
Step 3: (2S)-2-Allylpyrrolidine (trifluoroacetate salt) H .TFA
10031.91 To a solution of tert-butyl (2S)-2-a1lylpyrrolidine-1-carboxylate (17 g, 80.45 mmol) in DCM (120 mi,) was added 'LTA. (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 mt.) azeotrope. The product was dried under vacuum for 16 h giving as a dark oil, (25)-2-allylpyrrolidine (trifluoroacetate salt) (17 g, 94 %). ESI-MS m/z ca.lc. 111.1048, found 112.1 (M+1)-% Retention time: 0.4 minutes (LC
Method A).
Intermediate 4: Preparation of 6-1(2S)-2-allylpyrrolidin-l-y11-3-(tert-butoxycarbonylamino)-5-(trilluoromethyl)pyridine-2-carboxylic acid Br F3C, 0 F3C,A,N
Step 2 0 + Step I
0,trNyo .TFA I
- I 0 0..< ONO
r ,NH 0 0 0.<
Step 1: Methyl 6-( 2S)-2-allylpyrrolidin-l-y11-3-[bis(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)pyridine-2-earboxylate Br 4. IN

.TFA
.: >OyNO
8 ox 0 0".<
[00320] To a solution of methyl 3-[his(tert-butoxycarbonyl)aminol-6-bromo-5-(trifluoroniethyl)pyii dine-2-carboxyl ate (31.6 g, 63.29 mmol) and (2S)-2-allylpyn-olidine (trifluoroacetate salt) (17 g, 75.49 mmol) in acetonitrile (400 triL) was added DIFA (45 mL, 258.4 mmol) and the mixture heated at 80 C for 2 h. Added more MEA (10 mL, 57.41 mmol) and stirred at 80 C for 18 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was diluted with Et0Ac (700 mL) and washed twice with 250 mt. of brine, dried over MgSO4, filtered and concentrated in vacua Purification by silica gel chromatography (gradient from 0 ,70 to 30 % Et0Ac in hexanes) provided methyl 6-[(25)-2-allylpyrrolidin-1-yli-3-[bis(tert-butoxycarbonyl)amino]-5-(trifluoromethyppyridine-2-carboxylate (15 g, 45 %).
NMR
(400 MHz, Chloroform-d) 5 7.63 (s, 1H), 5.78 (ddt, .1= 17.3, 10.2, 7.2 Hz, 1H), 5.15 -4.91 (in, 2H), 4.54 (cidõ1 7.5, 3,1 Hz, Hi), 3.88 (s, 3H), 3.61 (t, 8.6 Hz, 1T-I), 3.48 (d, 8.4 Hz, 1H), 2.69 - 2.53 (m, 1H), 2.32 (dt, 13.7, 7.5 Hz, 1H), 2.07 (d, J = 5.6 Hz, 1H), 2.02 -1,94 (m, 111), 1.86- 1.69 (m, 211), 1,43 (s, 1SH) ppm. EST-MS
calc.
529.24, found 530.3 (M+1)'; Retention time: 2.06 minutes (LC Method A).
Step 2: 6-(2S)-2-Allylpyrrolidin-1-y11-3-(tert-butoxycarbonylamino)-5-(trilluoromethyl)pyridine-2-carboxylic acid ``fri N

iLOH
oI
r N yO

[00321] Methyl 6-[(25)-2-allylpyrrolidin-l-y1]-3-[bis(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)pyridine-2-carboxylate (20.5 g, 38.71 mmol) was dissolved in THE (150 and Me0E1 (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 C and stirred for 3,5 h. The yellow mixture was concentrated under reduced pressure to remove most of the THF and Me01-1 to give a yellow emulsion which was cooled in an ice bath to give a yellow sticky suspension (pH = 14). The suspension was acidified by slow addition of HO (160 triL of 1 M, 160 mmol), keeping the internal temperature around 10 C
(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 solid was purified by silica gel chromatography eluting with a linear gradient of 100 % hexane to 50 (,'/6 ethyl acetate in hexane giving as a bright yellow solid, 6-[(2S)-2-altylpyrrolidin-l-A-3-(tert-butoxycarbonylamino)-5-(trifluoromethyppyridine-2-carboxylic acid (13.4 g, 83 %) 11-1 NMR (400 MHz, Chloroform-d) 6 11.11 (s, la), 9.68 (s, 1H), 9.13 (s, 1H), 5.83 -5.67 (m, 1H), 5.1.2 - 5.02 (m, 2H), 4.29 (qd, 1- 7.8, 3.1 Hz, 1I1), 3.66 (qõ/- = 9.0 Hz, HI), 3.41 (t, 8.5 Hz, 1H), 2.47 (dddõ.T 13.8, 7.6, 3.2 Hz, -1H), 2.29 - 2.17 (rn, 1H), 2.21 -2.12 (m, 1H), 2.06 - 1.93 (m, 1H), 1,87 - 1.69 (m, 2H), 1.53 (s, 9H) ppm, ESI-MS mtz calc.
415,1719, found 416.0 (M+1)+; Retention time: 1.38 minutes (LC Method NT).
Intermediate 5: Preparation of 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride salt) Step 1 Step 2 step 3 0 10 OH 10 [IT) OCF3 Step 4 y-7-0CF3 Step 5 0 CF.
\70 .HCE
Step 1: Ethyl 2-hydroxy-2-(trilluoromethyl)hex-5-enoate o cF, [00322] To a solution of ethyl 3,3,3-trifluoro-2-oxo-propanoate (25.15 g, 147.87 mmol) in Et70 (270 mL) at -78 C was added bromo(but-3-enyl)magnesium in 'FFIF (190 rni., of 0.817 M, 155.23 mmol) dropwise over a period of 1.5 h (inner temperature -72 C, to -76 'V). The mixture was stirred at -78 C for 20 min. The dry ice-acetone bath was removed.
The mixture was slowly warm to 5 C during 1 h, added to a mixture of 1 N
aqueous HC1 (170 mL) and crushed ice (150 g) (pH= 4). The two layers were separated. The organic layer was concentrated, and the residue was combined with aqueous phase and extracted with Et0Ac (2 .X 150 mL). The combined organic phase was washed with 5 A) aqueous NaHCO3 (50 mL) and brine (20 mL), dried with Na2SO4. The mixture was filtered and concentrated and co-evaporated with THF (2 X 40 mL) to give ethyl 2-hydroxy-2-(trifluoromethyl)hex-5-enoate (37.44 g, 96 A) as colorless oil. tH Nktit (300 MHz, CDC13) 6 5.77 (thltõ! = 17.0, 10.4, 6.4 Hz, 1H), 5.15 -4.93 (m, 2H), 4.49 - -1.28 (m, 2H), 3.88 (s, 1H), 2.35 - 2.19 (m, 1H), 2.17 - 1.89 (m, 3H), 1.34 (tõI 7.0 Hz, 3H) ppm. 19F
NM:R. (282 MHz, CDC13) 5 -78,74 (s, 3F) ppm..
Step 2: Ethyl 2-benzyloxy-2-(trifluoromethyl)hex-5-enoate o 01-rõ,a [00323] To a solution of ethyl 2-hydroxy-2-(trifluoromethyl)hex-5-enoate (24.29 g, 87.6 % purity, 94.070 mmol) in MIT (120 mL) at 0 C was added NaH (60 % in mineral oil, 5.64 g, 141.01 mmol) portion-wise. The mixture was stirred at 0 'V for 10 min, Benzyl bromide (24.13 g, 141.08 mmol) and TBAI (8.68 g, 23.500 mmol) were added. The mixture was stirred at room temperature overnight. NH4C1 (3 g, 0.6 eq) was added. The mixture was stirred for 10 min. 30 mL of EtOAc was added, then ice-water (400 g). The mixture was extracted with CH2C12 and the combined organic layer was concentrated.
Purification by silica gel chromatography (0 % to 20 % CH2C12 in heptanes) provided as a pink oil, ethyl 2-benzyloxy-2-(trifluoromethyl)hex-5-enoate (26.05 g, 88 A).
'H NMR
(300 MHz, CDC13) 5 1,34 (t, J=7.2 Hz, 311), 2,00-2.19 (m., 311), 2.22-2.38 (m, 1.111), 4.33 (q, J=7.2 Hz, 211), 4.64 (dõ.T=10.6 Hz, 1111), 4.84 (dõ/ =10.9 Hz, 1H), 4.91-5.11 (m, 21:1), 5.62-5.90 (m,114), 7.36 (s, 511) ppm. 19F NMR (282 MHz, CDC13) 5 -70.5 (s, 3F) ppm. ES1-MS m/z calc. 316.12863, found 317.1 (M+1)+; Retention time: 2.47 minutes (LC
Method B).
Step 3: 2-Benzyloxy-2-(trifluoromethyl)hex-5-enoic acid oF, o OH?
r,6 OH :
) [00324] A solution of sodium hydroxide (7.86 g, 196.51 mmol) in water (60 mL) was added to a solution of ethyl 2-benzyloxy-2-(trif1uoromethyl)hex-5-enoate (24.86 g, 78.593 mmol) in methanol (210 mL). The reaction was heated at 50 C overnight. The reaction was concentrated to remove methanol, diluted with water (150 mL) and the carboxylate sodium salt was washed with heptane (1 X 100 mL). The aqueous solution was acidified to pH = 2 with aqueous 3 N solution of HCI. The carboxylic acid was extracted with dichloromethane (3 X 100m1) and (hied over sodium sulfate. The solution was -filtered and concentrated to give 2-benzyloxy-2-(trifluorometh-yl)hex-5-enoic acid (22.57 g, 97 %) as pale yellow oil. 1H NMR (300 MHz, DMSO-do) 6 14.31 (hr. s.,114), 7.55 -7.20 (in, 5H), 5.93 - 5.70 (in, 1H), 5,17 - 4.91 (in, 2H), 4.85 4.68 (m, 1,11), 4.67 4.55 (in, I H), 2.32 - 1.94 (m, 4H) ppm. 19F NMR (282 MHz, DMSO-d6) 8 -70.29 (s, 3F) ppm. ESI-MS
m/z calc. 288.09732, found 287.1 (M-1); Retention time: 3.1 minutes (LC Method C).
Step 4: tert-Butyl N-112-benzyloxy-2-(triflooromethyl)hex-5-enoyliaminolcarbamate oy-No-cF, ,NH OH
0- N.
H
[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 :HAUT (37.2 g, 97.836 mmol) and Et3N (15 g, 148,24 mmol). The mixture was stirred for 10 minutes then tert-butyl aminocarbamate (12.2 g, 92.312 mmol) was added. The mixture was stirred at 25 C
overnight and at 40 eC for 1 h. The mixture was diluted with ice-water (500g) and extracted with Cl-12C12. The organic layer dried over anhydrous sodium sulfate and was concentrated. Purification by silica gel chromatography (0 % to 30 % Et0Ac in heptanes) provided as a white solid, tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]aminolcarbamate (26.08 g, 92 ?,./0). 'H NMR (300 MHz, CDC13) 6 1A6 (s, 9H), 2.10-2.31 (m, 3H), 2.34-2.51 (m, liff), 4.60-4,72 (rn, 1H), 4.73-4.86 (m, 11-1), 4.95-5.19 (m, 211), 5.83 (ddt, J=16.7, 10.4, 6.1 Hz, 1H), 6.28 (br. s., 1H), 7.30-7.51 (m, 5H), 8.34 (d, J=2.6 Hz, liff) ppm. 19F NMR (282 MHz, CDC13) 6 -73.6 (s, 3F) ppm.
Step 5: 2-Benzyloxy-2-(trit1uoromethyl)hex-5-enehydrazide (hydrochloride salt) o. 0 0 I- 0 _ 0 )-1-. õNH H2N---NH
0 Vi .H0 [00326] To a solution of tert-butyl N-[[2-benzyloxy-2-(trifluoromethyphex-5-enoy-l]aminolcarbamate (43.12 g, 107.2 mmol) in CH2C12 (200 mL) was added fIC1 (100 mL of 4 M, 400.0 mmol) and the mixture was stirred at ambient temperature for 7 h. The solvent was removed in vacuo, the residue stripped 2 times from heptane and the resultant solid was dried in yacuo using a high vac for 20 h giving 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride salt) (35 g, 96 %)111 NNTR
(400 1\11-1z, Chloroform-d) 6 9.92 (s, 2H), 7.41 -7.31 (m, 2H), 730- 7,24 (m, 2E1), 7.24 - 7.16 (m, 1H), 5.72 - 5.57 (m, 1H), 5.02 - 4.87 (m, 2H), 4.71 (d, I = 10.9 Hz, 1H), 4.62 (d, 1.0 Hz, 1H), 3,70 (s, 2H), 2.34- 1,85 (m, 4E1). ESI-MS mtz cafe. 302.1242, found 303.2 (M+1)H-; Retention time: 1.5 minutes (LC Method A).
Intermediate 6: Preparation of 2-benzyloxy-24trit1uoromethy1)hex-5-enehydrazide Step I

p H2N¨NH H2N¨NH
.HCI
Step 1: 2-Benzyloxy-2-(tritluoromethyl)hex-5-enehydrazide "s1 H2N¨NH
H2N¨NH
.HO ) [00327] 2-Benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride salt) was dissolved in ethyl acetate (500 mL) and carefully treated with saturated aqueous NaHCO3 (500 mL) and stirred for 0.5 h, The phases were separated and the organic phase was washed once with 1:1 saturated aqueous NaHCO3lwater (500 mL), once with 1:4 saturated aqueous NaHCOilwater (500 int), once with water (500 triiõ) and once with brine (300 mL). The aqueous phases were back extracted once with ethyl acetate (200 mL) and the combined organic phases were dried, filtered, evaporated and then co-evaporated with toluene and further dried under vacuum to give as a yellow oil, 2-benzyloxy-2-(trifluoromethyphex-5-enchydra.zide (50 g, 99 %). IHNMR (400 MHz, DMSO-d6) 6 9.33 (s, 11-1), 7.53 - 7.27 (m, 5H), 5.81 (ddt, Jzzz 16.6, 10.2, 6.3 Hz, 11-1), 5.10 -4.93 (m, 2H), 4.71 (s, 2H), 4.57 -4.28 (m, 2H), 2.27 - 1.84 (m, 4H) ppm. ESI-MS m/z calc.
302.1242, found 303.0 OW 0-; Retention time: 1.5 minutes (LC Method A).
Intermediate 7: Preparation of ten-butyl N1245-41-benzyloxy-1-(trifluoromethyl)pent-4-eny11-1,3,4-oxadiazol-2-3/1]-6-bromo-5-(trifluoromethyl)-3-pyridyllearbamate Br Br N
F3C,, õoj 0 0 O CF Step I ________________ CF3 T o Ny.-0,1,,NH A-NH p 0iNH 0 F C
Br Step 2 r .0Y NH N--N

Step 1: tert-.Butyl N42-it[2-benzyloxy-2-(trilluoromethyl)hex-5-enoyl]amino]carbamoy11-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate Br Br N
.),__TO

_% 0 HN-NH b õ0 NH 0 H2N-NH
y 6 .HC1 1003281 To a mixture of 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethvl)pytidine-2-carboxylic acid (239.2 g, 621.1 mmol) and 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride salt) (230.1 g, 761.2 mmol) in Et0Ac (2.2 L) at ambient temperature was added pyridine (200 triL, 2.473 mol) which afforded a precipitate. To the mixture was added 1-propanephosphonic anhydride (500 g of 50 %
Vvi/W, 785.7 mmol) and the reaction mixture was stirred at ambient temperature for 12 h, The reaction was quenched with the slow addition of NaOH (149 g of 50 % w/w, 1.863 mol) in water (2 L) and the mixture was stirred for 15 min. The organic phase was separated, and the aqueous phase extracted with Et0Ac (1 L). The combined organic phases washed with brine, dried over MgSO4, filtered and concentrated in vacua After half of the solvent was removed, the organic phase was washed 2 times with aqueous HO
(1000 ML of I M, 1.000 mol). The organic phase was dried over MgSO4, filtered and concentrated in yacuo. 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 slurr:s7. The slurry was filtered, and the resultant filter cake was washed 2 times with I L of % MTBE/heptane. The off-white solid was air dried for 2 h, then in vacuo at 40 C for h giving tert-butyl N42-[[[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamoy111-6-bromo-5-(trifluoromethyl)-3-pyridyncarbamate (379.9 g, 91 %) NMR
(400 MHz, ,DMSO-do) 6 11.09 (s, 1H), 10.92 (s, 1H), 10.35 (s, 1H), 9.15 (s, 1H), 7.50 (d, 7.4 Hz, 2H), 7.36 (dt, zzz: 24,4, 7,2 Hz, 3H), 5.87 (ddtõ/ 16.0, 10.4, 5.2 Hz, 1H), 5.09 (d, 16.9 Hz, 1H), 5.02 (dõ,/ 10.1 Hz, 1H), 4.84 (q, 11.4 Hz, 2H), 2.35 - 2.12 (m, 4111), 1.49 (s, 9H) ppm, ESI-MS calc.
668,1069, found 670.9 (M+3, Br isotope)'; Retention time: 3.5 minutes (LC Method D).
Step 2: tert-Butyl N-1:24541.-benzyloxy-1,-(trifluoromethyl)pent-4-eny114,3,4-oxadiazol-2-y1]-6-bromo-5-(trifluoromethyl)-3-pyridylicarbamate F3C,c 0 N \ F3C .) N
-sC CF3 HN-NH \c) O NH N-N
oll [00329] tert-Butyl AL[2-[[[2-benzyloxy-2-(trifluoromethyphex-5-enoylrlaminoicarbamoyli-6-bromo-5-(trifluoromethyl)-3-pyridylicarbamate (102 g, 150.8 mmol) was dissolved in anhydrous acetonitrile (1000 nil..) and DIPEA. (92 mL, 528.2 mmol) was added. The resultant orange solution was heated to 70 C (internal temp) making a dear yellow solution. Then p-toluenesulfonyl chloride (37.4 g, 196.2 mmol) was added in 3 equal portions of 12.47 g separated by 10 minutes and then the reaction was heated for another 30 min. The reaction was cooled to room temperature and the acetonitrile was concentrated under reduced pressure. To the mixture was added 1000 mt.
MTBE, then 800 mL water, and the mixture was stirred, and the layers were separated.
The organic layer was washed with a solution of citric acid (36.3 g, 188.9 mmo-l) in 700 iriL water, then 400 rilL saturated NaHCO3, then 300 rnL Mine. The organic layer was then dried over anhydrous MgSO4 and concentrated under reduced pressure. The material was purified using silica gel chromatography with a gradient of 15 % to 50 %
of an 8 %
solution of Et0Ac in hexanes to pure hexanes to provide tert-butyl N-[24541-benzyloxy-1-(trifluoromethyppent-4-enyl]-1,3,4-oxadiazol-2-yli-6-bromo-5-(trifluoromethyl)-3-ppidylicarbarnate (91.7 g, 93%), (400 MHz, Chloroform-d) 6 10,18 (s, 111), 9.35 (s, Hi), 7.55 -7.47 (m, 211), 7.45 -7.37 (m, 214), 7.36 - 7.28 (m, 1F1), 5.83 - 5.68 (m, 11I), 5.10 -4.93 (m, 2H), 4.82 (d, 1¨ 10.5 Hz, 111), 4.69 (d, J ¨ 10.5 Hz, 111), 2.59 - 2.13 (m, 4H), 1.56 (s, 9H) ppm. ESI-MS m/z calc. 650.0963, found 651.0 N I)+;
Retention time: 3.81 minutes (LC Method D).
Intermediate 8: Preparation of tert-butyl 1V-[245-41-benzyloxy-1-(trifluoromethyl)pent-4-enyll-1,3,4-oxadiazol-2-y1]-6-bromo-5-(trifluoromethyl)-3-pyridy11-N-tert-butoxyearbonyl-carbaroate Br Br F3C, T F3C1A,N

Step 1 it N¨N
o Step 1: tert-Butyl N-1245-11-benzyloxy-1-(trifluoromethyl)pent-4-enyli-1,3,4-oxadiazol-2-A-6-bromo-5-(triftuoromethyl)-3-pyridyll-N-tert-butoxyearbonyl-earbamate Br Br "zk-s=
FIG

1, 0 i CF CF3 y y7-0 3 \ o o NH N¨N
y 20 0 o 6õ<
[00330] Into a solution of tert-b _N424541-benzyloxy-1-(nifluoromethyppent-enyl]-1,3,4-oxadiazol-2-yli-6-bromo-5-(trifluoromethyl)-3-pyridyficarbamate (30 g, 41.910 mmol) in MTBE (300 int) was added D1EA. (6.6780 g, 9 mL, 51.670 mmol), DMAP (0.28 g, 2.2919 mmol) and Bipc anhydride (20.1 g, 21.158 mL, 92.097 mmol). The resulting yellow cloudy solution was stirred at 35 C overnight. After cooling to room temperature, the solvent was evaporated The yellow oily residue was then dissolved in 300 mL DCM and was washed with water (300 mL), followed by brine (300 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0 % to 20 % Et0Ac in hexanes) provided ten-butyl .AL[24541-benzyloxy-1-(trifluoromethyl)pent-4-eny1]-1,3,4-oxadiaz61-2-y1]-6-bromo-5-(trifluoromethyl)-3-pyridyli-N-tert-butoxycarbonyl-carbamate (28.68 g, 87%) as white solid, LH -NNIR (500 MHz, DMSO-d6) 8 8.89 (s, 1H), 7.51 (d, J ¨
7.4 Hz, 2H), 7.43 (t, 7.5 Hz, 2H), 7.35 (t, 7.3 Hz, 1H), 5.96 ¨ 5.76 (in, 1H), 5.11 (d, 17,2 Hz, III), 5.01 (d, 1¨ 10.1 Hz, 111), 4.73 (d, I ¨ 10.7 Hz, 1H), 4.66 (d, J ¨ 10,6 Hz, 1H), 2.65 2.51 (m, 2H), 2.36 2.17 (in, 211), 1.27 (dõ./ zzz: 23.5 Hz, 18H) ppm, ESI-MS
m/z calc. 750,1488, found 751.6 (M-1-1)-', Retention time: 3.9 minutes (LC
Method G), Intermediate 9: Preparation of 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride salt) Step I Step 2 Step 3 O113 O.-CF3 OH

I , Step '-' 3 1\--CF Step 5s 0 0 0 yvaCF3 OH
,i11-1 N

,HCi Step 1: Ethyl 2-hydroxy-2-(trilluoromethyl)pent-4-enoate -OH

1003311 To a solution of ethyl 3,3,3-trifluoro-2-oxo-propanoate (30 g, 176.38 mmol) in diethyl ether (300 rill.) at -78 C was added allyl(bromo)magnesium (185 rtiL
of 1 M, 185,00 mino-1) dropwise over a period of 3 hours (internal temperature: -74 "C
-- -76 C).
The mixture was stirred at -78 C for 45 min. The dry ice-acetone bath was removed. The mixture was allowed to warm to about 10 C over a period of 1 h and added to a mixture of IN aqueous HCI (210 rriL) and crushed ice (400 g) (pH 4). The mixture was extracted with Et0Ac, washed with 5 % aqueous NaRC03, brine and (hied over anhydrous Na2SO4.
The mixture was filtered, concentrated and co-evaporated with hexane to give as a light yellow oil, ethyl 2-hydroxy-2-(trititioromethyppent-4-enoate (42.2 g, 90 %).

(300 MHz, CDC13) 6 1.33 (t, ,/ 7.1 Hz, 3H), 2.60 -2.79 (m, 2H), 3.84 (hr. s., IH), 4.24 -4.48 (m, 21-1), 5.09 - 5.33 (m, 2H), 5.59 - 5.82 (m, 1H) nnm. '9F NMR (282 MHz, CDC13) 6 -78.5 (s, 3F) ppm.
Step 2: Ethyl 2-benzyloxy-2-(trilluoromethyl)pent-4-enoate OH

11003321 To a solution of ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate (18.56 g, 83.105 mmol.) in DMF (100 mL) was added Nail (5.3 g, 60% w/w, 132.51 mmol) at 0 C.
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. The mixture was stirred at room temperature overnight. The reaction was quenched with water (300 and extracted with ethyl acetate (3 X 300 mL). The combined organic layers were washed with brine (500 and dried over sodium sulfate. Purification by silica gel chromatography (20 % to 60 % DC1\4 in hexanes) provided ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate (22.01 g, 70 %) as colorless oil. 1H NMR, (2501\111z, CDC13) 8 7.55 - 7.25 (m, 5H), 6.00 - 5.80 (m, 1H), 5.30 - 5.10 (in, 2H), 4.86 (d, I = 10.5 Hz, 1H), 4.68 (d, 1- 10.5 Hz, 1H), 4.33 (qõI - 7,0 Hz, 211), 2.81 (d, 1- 7.0 Hz, 214), 1.34 (t, J 7.1 Hz, 3H) ppm. ESI-MS trvi calc. 302.113, found 303.5 (M+1.)+;
Retention time: 4.14 minutes (LC Method G), Step 3: 2-Benzyloxy-2-(trit1uoromethyl)pent-4-enoic acid Y)<

1003331 Into a solution of ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate (28.99g.
95,902 trimol) in methanol (150 inL) was added a solution of NaOH (7.6714 g, 191,80 mmol) in water (50 mL). The reaction mixture was stirred at 40 C. 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). The aqueous layer was acidified with concentrated HCI to pH 1 and extracted with diethyl ether (3 X. 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to furnish as a light yellow liquid, 2-benzyloxy-2-(trifluoromethyl)pent-4-enoic acid (28.04 g, 99 %). 1F1 NNIR (250 Wiz, CDCI3) 8 7.55 -7.28 (m, 5H), 5.97 - 5.69 (m, 1H), 5.33 - 5.17 (m, 2H), 4.95 - 4.66 (in, 2H), 2.91 (d, I
7.1 Hz, 21:1) ppm. One exchangeable proton not observed in 1\11VER.

Step 4: tert-Butyl N-112-benzyloxy-2-(trifluoromethyl)pent-4-enoyllaminulcarbamate OH ).L.. NH L
0 1\1 H
[00334] To a solution of 2-benzyloxy-2-(trifluoromethyl)pent-4-enoic acid (300 g, 1.094 mol) in :D1\41: (2 L) was added :HAUT (530 g, 1.394 mol) and DIEA (400 rn-L, 2.296 mol) and the mixture was stirred at ambient temperature for 10 min. To the mixture was added tert-butyl .Atarninocarbamate (152 g, 1.150 mot) and the mixture stirred at ambient temperature for 36 h. The reaction was quenched with cold water (4 L) and the mixture extracted with Et0Ac (2 X 2 L). The organic phase was washed brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (0 % to 40 %
Et0Ac/hexanes) provided tert-butvi N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyllaminolearbamate (386.49 g, 91 %) as an oil which slowly crystallized to an off-white solid. Ili -NMR (400 MHz, DMSO) 5 10.00 (d, 1- 37.9 Hz, 1H), 8.93 (s, 1H), 7.46 -7.39 (m, 2H), 7.38 - 7.29 (m, 3H), 6.01 -5.64 (m, 1H), 5.32 (d, 17.-1 Hz, 1H), 5.17 (d, - 10.1 Hz, 1H), 4.77 (s, 2H), 2.96 (qdõ/- - 15.4, 6.8 Hz, 2H), 1.39 (d, I -17.3 Hz, 9H) ppm. ESI-MS intz cale. 388.16098, found 389.0 (1"M-1-1) ; Retention time: 2.51 minutes (LC
Method D).
Step 5: 2-Berizyloxy-2-(trifluoromethyl)pent-4-eriehydrazide (hydrochloride salt) 0 oy-:\o-c F3 T b o N
.HC1 1003351 To a solution of tert-butyl N-[[2-benzyloxy-2-(trifluoromethyppent-4-enoyliaminoicarbamate (98.5 g, 240.94 mmol) in DC1\4 (400 mL) was added HO in dioxane (200 mL, of 4 Ni, 800.00 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and co-evaporated with DCM and hexanes to give 2-benzyloxy-2-(trifluoromethyppent-4-enehydrazide (hydrochloride salt) (81.15 g, 97%) as an off white solid. NMR (500 MHz, DMSO-d6) 6 11.07 (s, 1H), 7.70 7.16 (m, 5H), 5.87-5.61 (m, 1H), 5.45 - 5.09 (m, 21:1), 4.79 (s, 21-1), 3.6 - 3.4 (m, 21:1), 3.23 -3.07 (m, MI 3,04 -2.87 (m, 1H) ppm. ESI-MS m./z calc. 288.10855, found 289.2 (M+1.)+; Retention time: 2.0 minutes (LC Method H).
Intermediate 10: Preparation of methyl 3-ibis(tert-butoxyearbonyl)aminol-6-bromo-5-methylsulfonyl-pyridine-2-carboxylate Brk,N 0, p I
Step 1 1 I Step 2 / - Step 3 NH, 0 NH2 ip Br u'S1 N Step 4 /

o0<
Step 1: Methyl 3-amino-5-bromo-pyridine-2-earboxylate Brs'N
y NH2 o NH, o [00336] Sulfuric acid (10 mL, 187.6 mmol) was added to a solution of 3-amino-5-bromo-pyridine-2-carboxylic acid (10 g, 43.77 mmol) in methanol (250 int:).
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 Et0Ac (3 X 200 mL). The organic layers were combined and washed with water (70 m1), 5 % Nal-IC03 (70 inli) and brine (70 'nib), dried over sodium sulfate, filtered and evaporated to give as a yellow solid, methyl 3-amino-5-bromo-pyridine-2-earboxylate (4.56 g, 45 A-). iNMR (300 MHz, CDC1.3) 5 3.96 (s, 3H), 5.82 (br. s, 2H), 7.24 (d, I ¨ 1.8 Hz, 1 H), 8.06 (d, I ¨ 1.8 Hz, LH) ppm. ESI-MS m/z ca.lc.
229.96909, found 231.1 (141-i-1r; Retention time: 1.51 minutes (LC Method EE).
Step 2: Methyl 3-amino-5-methylsulfonyl-pyridine-2-carboxylate a, P Br N
/ N
' 1003371 A mixture of methyl 3-amino-5-bromo-pyridine-2-carboxyl ate (9.79 g, 42.372 mmol), methylsulfinyloxysodium (8.8 g, 86.2 mmol), copper(i) iodide (8.8 g, 46.206 minor), L-nroline (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 Et0Ac (1.2 L) with stirring. The mixture was filtered through diatomaceous earth and washed with Et0Ac. The filtrate was washed with 28 % aqueous NH3 (1 X 100 mL then 1 X 50 mL) and brine (50 MI), dried with Na2SO4, filtered and concentrated to about 160 mt. resulting in a precipitate. The precipitate was collected by filtration and dried to give as a yellow solid, methyl 3-amino-5-methylsulfonyl-pyridine-2-carboxylate (6.35 g, 65 ?,./0). 11H NAIR
(300 MHz, DMS0-46) 8.23 (dõ .I zzz: 2.1 Hz, 111), 7.73 (d, J= 2.1 Hz, HI), 7.09 (s, 2H), 3.83 (s, 3H), 3.29 (s, 3H) ppm. ESI-MS miz calc. 230.03613, found 231.1 (M+.1).%
Retention time: 1.22 minutes (LC Method E)..
Step 3: Methyl 3-aminn-6-hromn-5-methylstalfonyl-pyricline-2-carboxylate 0Br 0 , N

1003381 To a solution of methyl 3-amino-5-methylsulfonyl-pyridine-2-carboxylate (8 g, 34,746 mmol) in acetonitrile (515 mi.) was added NBS (12.7g. 71.355 minol).
The mixture was stirred at 35 C for 64 h. The mixture was concentrated to remove most of acetonitiile. The residue was diluted with ethyl acetate (200 mL) and treated with a solution of 10 % aqueous sodium thiosulfate solution (100 mL). After stirring for 10 min at room temperature, saturated aqueous sodium bicarbonate solution (100 mL) was added.
After stirring for 5 rain, the resulting precipitate was collected by filtration, washed with water and ethyl acetate then dried to afford as a yellow solid, methyl 3-amino-6-bromo-5-methylsulfonyl-pyridine-2-carboxylate (6.2 g, 55 %). NMR (300 MHz, 1)MSO-d6) 6 7.99 (s, 1H), 7.25 (br. s., 2H), 3.83 (s, 3H), 3.42 (s, 3H) ppm. ESI-MS m/z calc.
307,94666, found 308.8 (M-1-1)+; Retention time: 1.57 minutes (LC Method E).
Step 4: Methyl 34bis(tert-butoxycarbonyl)aminol-6-bromo-5-methylsullonyl-pyridine-2-earboxylate o /9 Tr =-=N
*s=
= N

1003391 A mixture of methyl 3-amino-6-bromo-5-methylsult7onyl-pyridine-2-carboxylate (6.2 g, 19.153 mmol), tert-butoxy carbonyl tert-b utyl 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. The reaction mixture was concentrated under reduced pressure. Purification by silica gel chromatography (gradient from 0 % to 30 %
of ethyl acetate in heptanes) provided as a yellow solid, methyl 3-[bis(ien-butoxycarbonypamino]-6-bromo-5-methylsulfonyl-pyridine-2-carboxylate (8.72 g, 89 %). -NMR. (300 MHz, CDC13) 6 8.33 (s, 1H), 3.97 (s, 3H), 3.38 (s, 3H), 1.43 (s, 18H) ppm. ESI-MS
miz calc.
508.0515, found 352.8 (M-155) ; Retention time: 2.08 minutes (LC Method E).
intermediate 11: Preparation of methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyricline-2-carboxylate Step I Step 2 F3C
oI
OH CI
Step 3 F3C
'N Step 4 Step 1: Methyl 1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate F C

1003401 Urea hydrogen peroxide (62.7 g, 646.53 mmol) was added portion-wise to a stirred solution of methyl 5-(trifluoromethyl)pyridine-2-carboxylate (40 g, 191.09 mmol) in 1,2-di chloroethane (300 at 0 "C. Trifluoroa.cetic anhydride (107.70 g, 72 mL, 507.65 rnmol) was then added over 30 minutes at a temperature of -10 C, with cooling bath (CO2/acetone bath). The reaction mixture was then stirred for a further 30 minutes at a temperature of 0 C and then for 1 hour at ambient temperature. The reaction mixture was then poured into cooled ice-water (600 The mixture was diluted with dichloromethane (300 mL) and then layers were separated. The aqueous phase was extracted with dichloromethane (2 X 200 mL). The combined organic phase was washed with water (2 X 300 mt.) and -brine (1 X 200 mt.), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give as a light yellow solid, methyl 1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (47.6 g, 90 %). 'H NM.
(300 MHz, DMSO-do) 6 8.89 (s, 1H), 8.02 - 7.90 (m, 1H), 7.86 - 7.72 (m, 1H), 3.89 (s, 3H) ppm. 19F

NMR (282 MHz, ,DIVISO-do) 6 -62.00 (s, 3F) ppm. ESI-MS mtz calc. 221.02998, found 222.1 (1\11-1)+, Retention time: 1,24 minutes (LC Method E).
Step 2: Methyl 6-hydroxy-5-(trifluoromethyl)pyricline-2-earboxylate OH
I. 0 1003411 Trifitioroacetic anhydride (291,62g. 193 mL, 1.3885 mol) was added drop-wise to a mixture of methyl 1-oxido-5-(trifluoromethy1)pyridin-l-ium-2-carboxylate (51.058 g, 230.66 mmol.) in DMF (305 nil) at 0 'C. The mixture was then stirred at room temperature overnight. The mixture was concentrated under reduced pressure to remove excess of trifluoroacetic acid. The residual DMF solution was poured dropwise to a 0 eC
cooled and stirring water volume (1000 mL). The precipitated solid was collected by filtration and then washed with water (300 mL). The solid was dried under vacuum to afford methyl 6-hydroxy-5-(triflUoromethyppyridine-2-carboxylate (45.24 g, 86 %) as a white solid. 'H NMR (300 NH-1z, CDC13) 6 7.90 (d, 7.2 Hz, 1H), 7.03 (d, I =
7.2 Hz, I H), 4.02 (s, 3H) ppm, One exchangeable proton not observed in NMR. 19F NMR, (282 MHz, CDCI3) 6 -66.39 (s, 3F) ppm. ESI-MS m/z calc. 221.03, found 222.1 (114+1)+;
Retention time: 1.43 minutes (LC Method E).
Step 3: Methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyricline-2-earboxylate OH OH

o 1003421 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 triL of 15.8 M, 205.40 mmol) dropwise. After 5 min, the ice bath was removed, and the reaction mixture was stirred at 38 C overnight. The reaction was not completed, nitric acid (3 triL of 15.8 M, 47.400 mmol) was added dropwise at room temperature and the reaction was heated at 38 C for 4.5 hours. The reaction was poured slowly on ice-cold water (900 mL) and the mixture was cooled at 0 C. for 15 minutes.
Then the resultant solid was isolated by filtration and washed with water (600 triL), The solid was dried overnight under vacuum to give as a white solid, methyl 6-hydroxy-3-nitro-5-(trifluoromethyppyridine-2-carboxylate (39.49 g, 99 %). 1H. NMR (300 MHz, DMSO-d6) 6 8.54 (s, 1.H), 3.95 (s, 3H) ppm, One exchangeable proton not observed in NMR. 19F NMR (282 MHz, ,DMSO-d6) 6 -64.56 (s, 3F) ppm. ESI-MS tn/z calc.
266.0151, found 267.1 (M+1)+; Retention time: 1.64 minutes (LC Method E), Step 4: Methyl 6-ch1oro-3-nitro-5-(trifluoromethy1)pyridine-2-carboxylate OH
N

[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 C, 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. Purification by silica gel chromatography (0 % to 15 % of ethyl acetate in heptanes) provided methyl 6-chloro-3-nitro-5-(trifluoromethyppyridine-2-carboxylate (5.45 g, 50 %) as a yellow solid. 1.14 NMR (300 MHz, CDC13) 6 8.75 (s, 111), 4.07 (s, 311) ppm. 191; NMR (282 MHz, CDC13) 6 -64.12 (s, 3F) ppm. :ER-MS m/z calc.
283.9812, found 285.0 (M+1)+; Retention time: 1.95 minutes (LC Method E), Intermediate 12: Preparation of 6-hydroxy-3-nitro-54trif1uoromethyl)pyridine-2-carboxylic acid OH OH
N Step 1 OH
I

Step 1: 6-Hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid OH OH
F C

II

[00344] A mixture of methyl 6-hydroxy-3-nitro-5-(trifluoromethyppyridine-2-carboxylate (32 g, 120.24 mmol) in THF (180 mL) and water (180 mL) was treated with lithium hydroxide monohydrate (15,14 g, 360.79 mmol) and stirred at 27 C
overnight, The crude reaction mixture was cooled at room temperature and the pH adjusted to 2 with a 0.5 M aqueous solution of hydrochloric acid (380 mL), then transferred to a separatory funnel with 2-methyl TEFF and extracted. The layers were separated and the organic layer was then washed with water (150 mi,), brine (150 mi,), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford as an off-white solid, 6-hydroxy-3-nitro-5-(trifluoromethyppyridine-2-carboxylic acid (29.61 g, 96 %).

(300 MHz, DMS0-46) 6 8.45 (s, 1H) ppm. One exchangeable proton not observed in NMR. 191' NIMR (282 MHz, DMSO-dó) 3-64.53 (s, 3F) ppm. PSI-MS calc.
251.9994, found 253.0 (M 1)'-; Retention time: 0.79 minutes (LC Method E).
Intermediate 13: Preparation of [64541-benzyloxy-1-(trifluoromethyl)pent-4-eny11-1,3,4-oxadiazol-2-y11-5-nitro-3-(trifluoromethyl)-2-pyridy11 trifluoromethanesulfonate OH
OH

JN
11,,r 0 0 F3C-s-AN Step I
, __________________________________________________________ CF3 0 cF-T I H2N¨NH 0 NO2 HN¨NH b Lo)) ,CF3 ?
Step 2 õAD

Step 1: N'42-Benzyloxy-2-(trifluoromethyl)hex-5-enoy11-6-hydroxy-3-nitro-5-(trilluoromethyl)pyridine-2-earbohydrazide OH

()%
. 3 1 0 LoF 3 KIO 2 HN -.NH 0 1003451 To a solution of 6-hydroxy-3-nitro-5-(trifluoromethyl)pytidine-2-carboxylic acid (29.92 g, 102.66 mmol) in acetonitrile (300 rriL) and DMF (60 mlb) was added CD1 (17,48 g, 107,80 mmol), The mixture was stirred for 0,5 h at room temperature, then 2-benzyloxy-2-(trifiuoromethyl)hex-5-enehydrazide (hydrochloride salt) (33.04 g, 97.534 mmol) was added in portions. The reaction mixture was stirred at 26 C. for 19 hours, The reaction mixture was transferred to an extraction funnel rinsing with water (300 triL) and 2-Me Ti-IF (400 mL). The mixture was extracted with 2-Me THE (3 X 400 m11,), The combined organic layer was washed with 0.5 N aqueous solution of HCI (3 X 300 mL), brine (3 X 250 mL), dried over anhydrous Na2SO4, filtered and concentrated by evaporation under reduced pressure. It was then sotubilized twice in dichloromethane (2 X
300 mL) and the volatiles were removed by evaporation under reduced pressure to provide as a brown foam residue, M-12-benzyloxy-2-(trifluoromethyl)hex-5-enoy11-6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide (58.5 g, 94 %). ESI-MS miz ca1c.
536,11304, found 537.2 (M+1)+, Retention time: 2.03 minutes (LC Method E).
Step 2: 16-15-11.-Benzyloxy-1-(trifluoromethyl)pent-4-eny11-193,4-oxadiazol-2-y11-5-nitro-3-(trifluoromethyl)-2-pyridyll trifluoromethanesulfonate R CF

OH
F30AN F,CN .rt?
00 `f f ( Y ________________________ OF, _________ YI')f- >--L-CF3 NO3 NNW-NH \p - NO2 100346] To a 0 C solution of N'42-benzyloxy-2-(trifluoromethyl)hex-5-enoy1]-6-hydroxy-3-nitro-5-(trifluoromethyppyridine-2-carbohydrazide (9.76 g, 16.922 mmol) in dichloromethane (190 was added DIPEA (8.0136 g, 10.8 ml.õ 62.004 mmol) t7ollo,,yed by trifluoromethylsulfonyl trifluoromethanesulfonate (12.410 g, 7.4 mlo, 43.985 mmol).
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 HC1, and Et0Ac (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 HC1 1.0 N aqueous solution (60 mL) and brine (3 X 40 dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0 % to 10 % Et0Ac in heptanes) provided as an orange oil, 16-15-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-y1]-5-nitro-3-(trifluoromethyl)-2-pyridyl]
trifluoromethanesulfonate (5.334 g, 40 %). NMR (300 MHz, cDcio 6 8.74 (s, 1H), 7,50 - 7.27 (m, 5H), 5.87 -5.68 (m, 1H), 5.12 - 4.96 (m, 2H), 4.88 (d, J-= 10.6 Hz, 1H), 4.67 (d, z- 10.9 Hz, ,IH), 2.60 -2.16 (m, 4H) ppm. 19F NM:R. (282 MHz, CDCI3) 6 -62.68 (s, 3F), -71,80 (s, 3F), -73.04 (s, 3F) ppm. ESI-MS m/z calc. 650.0518, found 651.1 (M+1)+; Retention time: 3.94 minutes (LC Method C).
Intermediate 14: Preparation of 6-ch1oro-3-nitro-5-(trit1uoromethyl)pyridine-2-carboxylic acid N Step I
N

Step 1: 6-Chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid F3C--,.-AN, Y1113'' 1003471 To a solution of methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (1,14 g, 4.006 mmol) in TELE (48.51 ml..) and water (24.26 ml..) at 0 C was added lithium hydroxide monohydrate (201,7 mg, 4.807 BIM ol). The reaction was allowed to warm. to room temperature then stirred for 2 hours. Acidified the solution to pH ¨2 - 3 by the addition of IN Ela then extracted with Et0Ac. The organic phase was washed with water and brine, then dried over sodium sulfate, filtered and concentrated to give as a clear syrup, 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid (1.05 g, 97 %). ES 1-MS miz ca1c. 269.9655, found 271.0 (M+1)4; Retention time: 0.37 minutes (LC
Method S).
Intermediate 15: Preparation of tert-butyl N-1245-[(LR)-14enzyloxy-1-(trifluoromethyl)pent-4-eny1l4,3,4-oxadiazo1-2-y11-6-bromo-5-(trifluoromethyl)-pyridyll-N-tert-butoxycarbony1-earbamate Br ER L, Step I
Jc-CF, >,0,riNH

Step 1: tert-Butyl .N-1245-1(1R)-1-benzyloxy-1.-(trifluoromethyl)pent-4-eny11-1,3,4-oxadiazol-2-y1]-6-bromo-5-(trifluoromethy1)-3-pyridyll-N-tert-butoxycarbonyl-carbamate Br Br N N
\ \ 0 .0õN3-1 N-N CyLioN-N
- 0 0..<
1003481 To a solution of tert-b utyl N-[245-[(11)-1-benzyloxy-1-(trifluoromethyppent-4-enyli-1,3,4-oxadiazol-2-yli-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbarnate (222 g, 340.8 mmo1) in MTBE (1.333 L) was added DIPEA (65.3 miõ 374.9 mmol) followed DMAP (2.09 g, 17.11 minol). Added a solution of di-tert-butyl dicarbonate (111.6g.
511,3 mmol) in MTBE (250 mi.) over 8 minutes (no exotherm.), and the reaction was stirred for additional 30 min. Added 1 L of water and separated the layers.
The organic layer was washed with KHSO4 (886 mL of 0.5 M, 443.0 mmol), 300 mL brine, dried with MgSO4 and most (>95 %) of the MTBE was evaporated by rotary evaporation at 45 C, leaving a thick oil. Added 1.125 L of hepta.ne, spun in the 45 C rotovap bath until dissolved, then evaporated out 325 mL of solvent by rotary evaporation. The rotovap bath temp was allowed to drop to room temperature and product started crystallizing out during the evaporation. Then put the flask in a -20 C, freezer overnight. The resultant solid was filtered and washed with cold heptane and dried at room temperature for 3 days to give fen-butyl Ar4245-[(11?)-1-benzyloxy-1-(tritluoromethy 1.)pent-4-eny1]-1,3,4-oxadiazol -2-yli-6-bromo-5-(trifluoromethyl)-3-pyridyli -N-tert-butoxycarbonyl-carbamate (240.8 g, 94 %). 1H. NMR (400 MHz, Chloroform-d) 6 7.95 (s, 1H), 7.52 - 7.45 (m, 2H), 7.44 -7,36 (m, 2H), 7.36 - 7.29 (m, 1H), 5.83 - 5.67 (m, 1H), 5.08 - 5.00 (m, 1H), 5.00 -4.94 (m, 1H), 4.79 (d, I - 10.4 Hz, 1H), 4.64 (d, I- 10.4 Hz, 1H), 2.57 -2.26 (m, 3H), 2.26 -2.12 (m, I H), 1.41 (s, 18H) ppm, ESI-MS mtz calc. 750,14874, found 751.1 (M-1-1)+;
Retention time: 3.76 minutes (LC Method D).

Intermediate 16: Preparation of (2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide and (22-benzyloxy-2-(tritluoromethyl)pent-4-enehydrazide step I Step 2 0 CF
3 +
9 o o T b H2N¨NH L H2N¨NH H2N¨NH H2N¨NH L
.HC1 Step 1: 2-Renzyloxy-2-(trilluoromethyl)pent-4-enehydrazide ft b 3 T
H2N¨NH

.HC1 1003491 tert-Butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-en.oyl]aminoicarbamate (386.49g. 995.1 mmoi) was dissolved in DCM (1.25 L) and toluene (250 mL) and treated with FK1 (750 int, of 4 M, 3.000 mol) at room temperature and the yellow solution was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and diluted with Et(I)Ac (2 L). The mixture was treated with Na(I)l-1 (600 mi. of 2 M, 1200, mol) and stirred at ambient temperature for 10 min. The organic phase was separated, washed with II.. of brine, dried over M8SO4, filtered and concentrated in vacuo and used directly in the ensuing step (trace toluene present), 2-benzy1oxy-2-(trifluoromethyppent-4-enehydrazide (286 g, 100 %). 1-11NMP, (400 MHz, DMSO) 6 9.34 (s, 1H), 7.40 - 7.22 (m, 51-1), 5,69 (ddt, J ---- 17.1, 10.3, 6.9 Hz, 1H), 5.33 - 5.23 (m, 1H), 5.15 (dd, J = 10.3, 1.8 Hz, 1H), 4.73 (s, 2H), 4.51 (s, 2H), 3.05 -2.87 (m, 2H) ppm. ESI-MS m/i calc. 288.10855, found 289.0 (M+1)+; Retention time: 1.32 minutes (LC Method B).
Step 2: (2R)-2-Benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide and (19-2-benzy1oxy-2-(trilluoromethy1)pent-4-enehydrazide ---cF, T b T 0 b H2N¨NH H2N¨NH H2N¨NH
1003501 Racemic 2-benzyloxy-2-(trifluoromethyppent-4-enehydra.zide (5.0 g, 17.35 =lop was separated by chiral SFC using a Clairall'ak 1G column (250 X 21.2 mm;
5 lam) at 40 C using a mobile phase of 7 % Me0H (plus 20 mIN4 NH3)/93 % CO2 at a 70 mUmin flow and concentration of the sample was 111 inglinL in methanol (no modifier), injection volume = 160 pt with an outlet pressure of 136 bar, detection wavelength of 210 rim providing two single enantiomer products:
1003511 The first enantiomer to elute was isolated as (2S)-2-benzyloxy-2-(trifluoromethyppent-4-enehydrazide (1.79 g, 72 %). IFINAIR (400 MHz, DMS046) 9.31 (s, 11-1), 7.45 -7.39 (m, 214), 7.38 - 7.26 (m, 311), 5.77- 5.62 (m, 1111), 5.28 (dq, 17.1, 1.6 Hz, 1H), 5.15 (dq, J = 10.2, 1.3 Hz, 1H), 4.72 (s, 2H), 4.44 (dõ! =
4.2 Hz, 2H), 2.99 (dd, J = 7.4, 1.3 Hz, 114 2.91 ((id, J - 15.4, 6.4 Hz, 111I) ppm. ES1-MS
m/z calc.
288.10855, found 289.2 (M+1)+; Retention time: 1.28 minutes (LC Method 1).
1003521 The second enantiomer to elute was isolated as (2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (1.7 g, 68 %) as a white solid. tEl NMR
(400 MHz, DMSO-d6) 6 9.31 (s, 1H), 7.48 - 7.39 (m, 211), 7.39 - 7.25 (m, 3H), 5.77 -5.62 (rn, 1H), 5.28 (dq, J = 17.1, 1.6 Hz, 1H), 5.15 (dq, 1- 10.2, 1.5 Hz, 111), 4,73 (s, 211), 4.51 (5, 214), 3.00 (dd, 15.3, 7.5 Hz, 1H), 2.91 (dd, 15.3, 6.4 Hz, 1H) ppm. ESI-MS m/z calc.
288.10855, found 289.2 (NT-E-1.), Retention time: 1.28 minutes (LC Method J).
Intermediate 17: Preparation of 1645-111-benzyloxy-1-(trfflunromethyl)but-3-enyll-1,3,4-oxadiazol-2-y1]-5-nitro-34triflu0romethy1)-2-pyridyl]
trilluoromethanesuifonate OH
F3Cy'.z.õ
0 'A-CF 1 Step I

NO2 6 .HCI
\

CF
Step YCV-C) Step 1: NP-42-Benzyloxy-2-(trifluoromethyl)pent-4-enoy11-6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide 0 0 \

NO2 0 .HC1 [00353] To a solution of 6-hydroxy-3-nitro-5-(trifluoromethyppyridine-2-carboxylic acid (8.5 g, 29.165 mmol) in acetonitrile (90 mL) and DMF (18 mL) was added CDT (5 g, 30.836 mmol). The mixture was stirred for 0.5 h at room temperature, then 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride salt) (9 g, 27.716 mmol) was added.
The reaction mixture was stirred at room temperature overnight. The reaction mixture was transferred to an extraction funnel rinsing with water (300 mL) and 2-Me THE
(400 mL).
The mixture was extracted with 2-methyl tetrahydrofuran (3 X 400 mL). The combined organic layer was washed with 0.5 N aqueous solution of FIC1 (3 X 300 mL), brine (3 X
250 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
It was then solubilized twice in dichloromethane (2 X 300 mL) and the vol atiles were removed under reduced pressure giving N42-benzyloxy-2-(trifluoromethyppent-4-enoy1]-6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carhohydrazide (14.7 g, 75 %) as yellow solid. ESI-MS intz cafe. 522.0974, found 523.1 (M+1) ; Retention time: 2.08 minutes (LC
Method E).
Step 2: 164541-Berayloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-y11-nitro-3-(trilluoromethyl)-2-pyridyll trifluoromethanesulfonate R CF

OH 0 µs µ;, ( CF3 NO2 HN¨NH NO2N¨N 6_, [00354] Trifluoromethylsulfonyl trifluoromethanesulfonate (14.758 g, 8.8 mL, 52.308 mmol) was added to N'42-benzyl.oxy-2-(trifluoromethyl)pent-4-enoy1]-6-hydroxy-3-nitro-5-(trifluoromethyppyridine-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 C. The ice-cold bath was removed after 20 min and the reaction was stirred at room temperature for 2.5 it The mixture was transferred to a separatory funnel with ice-cold aqueous 1.0 N
solution of HCI
(180 mL), and Et0A.c (500 in.L). 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 HO 1.0 N aqueous solution (120 mL) and brine (3 X 120 mL), dried over anhydrous Na2SO4, filtered and concentrated by evaporation under reduced pressure.
Purification by silica gel chromatography (0 % to 20 % of ethyl acetate in heptanes) provided [6-[5-[1-benzy oxy-1-(trifl uoromethypbut-3-enyl ]-1,3,4-oxadiazol-2-yli-5-nitro-3-(trifluoromethyl)-2-pyridyli trifluoromethanesulfonate (5.425 g, 40 %) as an orange viscous oil. NMR. (300 MHz, CDCI3) 6 8.65 (s, lft.), 7.36 - 7.21 (m, 5H), 5,93 - 5,74 (m, 1H), 5.28 - 5.10 (m, 2H), 4.78 (d, J ¨ 10.9 Hz, 1H), 4.60 (d, 10.6 Hz, 1H), 3.21 -3.05 (m, 2H) ppm. 19F NMR (282 MHz, CDC13) 6 -62.69 (s, 3F), -71.82 (s, 3F), -73.32 (s, 3F) ppm. ESI-MS m/z calc. 636.03613, found 637.1 (M+1)+; Retention time: 4.0 minutes (LC Method C).
Intermediate 18: Preparation of (2R)-2-benzyloxy-2-(trilluoromethyl)hex-5-enehydrazide -`) Step 1 (CF3 Step 2 0 A-CF
> .
HO Ls. HN¨NH H2N¨NH
N.
A
Step 1: tert-ButylIV-[[(2R)-2-benzyloxy-2-(trilluoromethyphex-5-enovilaminolcarbamate 0 )-(-)CF
! 0 HO HN¨NH
, [00355] To a solution of (2R)-2-benzyloxy-2-(ttifluoromethyphex-5-enoic acid (365 g, 1.266 mop in DMF (2 L) was added HARI (612 g, 1.610 mol) and DEE,A (450 mL, 2,584 mol) and the mixture was stirred at ambient temperature for 10 min. To the mixture was added tert-butyl IV-aminocarbamate (200 g, 1.513 mop (slight exotherm upon addition) and the mixture was stirred at ambient temperature for 16 h. The reaction was poured into ice water (5 L). The resultant precipitate was collected by filtration and washed with water. The solid was dissolved in Et0Ac (2 L) and washed with brine. The organic phase was dried over Mg$04, filtered and concentrated in vacuo. The oil was diluted with Et0Ac (500 mL) followed by heptane (3 L) and stirred at ambient temperature for several hours affording a thick slurry. The slurry was diluted with additional heptane and filtered to collect fluffy white solid (343 g). The filtrate was concentrated and purification by silica.
gel chromatography (0 - 40 % Et0Aclhexanes) provided tert-butyl N-E2R)-2-benzyloxy-2-(trifluoromethyphex-5-enoyflaminoricarbarnate (464 g, 91 %, combined with product from crystallization). :ESI-MS calc. 40217664, found 303,0 (M+-1-Boc)+;
Retention time: 2.68 minutes (LC Method D).
Step 2: (2R)-2-Benzyloxy-2-(trifluoromethy1)hex-5-enehydrazide =
o 9 [00356] To a solution of tert-butyl N-[[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyliaminoicarbaniate (464 g, 1.153 mol) in DCM (1.25 L) and was added HC1 (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 mixture was diluted with isopropyl acetate (11..) and basified to pH = 6 with Na011 (140 g of 50% VaW, 1.750 mol) in 1 L of ice water. 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 1\'igSO4, filtered and concentrated in vacuo affording a dark yellow oil. (2/0-2-benzyloxy-2-(trifluoromethyphex-5-enehydrazide (358 g, quant.) IH 'MIR (400 MHz, CDC13) 5 8.02 (s, 1H), 7.44 - 7.29 (m, 5H), 5.81 (ddt, J¨
16.8, 10.1, 6.4 Hz, 1H), 5.13 -4.93 (m, 2H), 4.75 (ddõI = 10.5, 1.5 Hz, 1H), 4.61 (d, I =
10.5 Hz, 1H), 3.78 (s, 2H), 2.43 (ddd, zzz: 14,3, 11,0, 5,9 Hz, la), 2.26 - 1.95 (m, 3H) ppm. ES1-MS m/i calc. 302.1242, found 303.0 (M+1)+; Retention time: 2.0 minutes (LC
Method D).

Intermediate 19: Preparation of 2-R1R)-1-benzyloxy-1-(trifluoromethyl)but-3-eny11-5-16-chloro-3-nitro-5-(trilluoromethyl)-2-pyridyl]-1,3,4-oxadiazole QH
o OH
Step 2 I I CFI Step 1 H2N¨NH I NO2 HN¨NH 0 Ol N

NO2 N¨N I
Step 1: Y-R2R)-2-Benzyloxy-2-(trifluoromethyl)pent-4-enoy11-6-hydroxy-3-nitro-(tritluoromethyl)pyridine-2-carbohydrazide I OH
OH
F3C)N OH 0 yCFa __________________________________________ r1"CI
, 0,µ
>\--t---CF3 1-12N---NH NO2 H\N¨NH 0 1003571 6-Hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid (28.8 g, 114,24 mmol) and (2R)-2-benzyloxy-2-(tifluoroniethyl)pent-4-enehydrazide (30 g, 104.07 mmol) were dissolved in a mixture of ethyl acetate (300 mL) and triethylamine (42.108 g, 58 mL, 416.13 minol). Propylphosphonic anhydride (106 g, 50% w/w, 166.57 mmol) was added at room temperature (20 'V 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), The organic phase was dried over sodium sulfate and filtered, then heptane (250 mL) was added and the mixture was evaporated to dryness to give as a yellow solid, N-[(2R)-2-berizyloxy-2-(trifluoromethyl)pent-4-enoyli-6-hydroxy-3-nitro-5-(trifluoromethyppyridine-2-carbohydrazide (63 g, 61 %). MAR (400 MHz, DMSO-d6) 6 8.12 (s, 1H), 7.48 (dõ./
7.1 Hz, 2H), 7.42 - 7,33 (m, 3H), 5.96 - 5.83 (ni, 111), 5.35 (d, J = 16.6 Hz, 1H), 5.20 (d, J
10.5 Hz, -1H), 4.90 - 4.81 (m, 2H), 3.12 - 2.94 (m, 21-1) ppm. Three exchangeable protons not observed in the NMR. ESI-MS m./z calc. 522.0974, found 523.1 (M 1) ;
Retention time: 3.102 minutes (LC Method C).
Step 2: 2-1(1R)-1-Benzyloxy-1-(trifluoromethyl)but-3-enyll-5-46-chloro-3-nitro-(trifluoromethyl)-2-pyridy1l-1,3,4-oxadiazole OH CI

(CF 3 0 '1 1003581 N1-[(2R)-2-Benzyl oxy-2-(trifluoromethyl)pent-4-enoy I ]-6-hydroxy-3-nitro-5-(trifluoromethyppyridine-2-carbohydrazide (45 g, 80.979 mmol) was dissolved in a mixture of phosphoryl trichloride (90 mL) and acetonitrile (90 inL) and diinethylformamide (45 mL) was added. The mixture was heated at 70 C for 2 b.
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 inL). 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 % WI:13E 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 C13 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 organic phase was dried over sodium sulfate, filtered and then evaporated to dryness to give more desired pure product. All the lots of the desired product from each purification were combined to give as a light yellow oil, 2-[(1K)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-546-chloro-3-nitro-5-(trifluoromethyl)-2-pytidy11-1,3,4-oxadiazole (13.5 g, 30 %). IF1 NMR (400 MHz, DMSO-d6) 5 9.26 (s, 1H), 7.46 - 7.31 (m, 5H), 5,92 (dd, J¨ 16.9, 9.5 Hz, 11-1), 5.39 (d, J = 16,6 Hz, 1H), 5.26 (d, J
10.3 Hz, 1H), 4.79 (dõI 10.8 Hz, 1H), 4.63 (d, J 10.8 Hz, 1H), 3.31 (dõ./ 6.8 Hz, 2H) ppm. ESI-MS m/z calc. 522.053, found 523.0 (1\4+1)+; Retention time: 3.784 minutes (LC Method C).
Intermediate 20: Preparation of methyl 6-ehloro-5-(difluoromethyl)-3-nitra-pyridine-2-carboxylate F
Step 1 FN Step 2 r--1µ);--Nr 0- Step 3 :;.Z Lco _______ Br Step 4, F 4"- Step 5 F
yN
yO
a N020 Step I: Methyl 5-(difluoromethyl)pyridine-2-earboxylate N
1;' Br 0\
[00359] In an autoclave was added 2-bromo-5-(difluoromethyl)pyridine (25 g, 120.19 trimoi), methanol (250 mL), triethylamine (29.04 g, 40 mL, 286.9S mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(H) (2.6 g, 3.5533 mmol). 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. The residue was purified by silica gel chromatography using a gradient from 20 % to 50 % ethyl acetate in heptanes to afford as an off-white solid, methyl 5-(difluoromethyl)pyridine-2-carboxylate (11.41 g, 51 %). EST-MS
m/z oak.
187.0445, found 188.2 (M-H1)+; Retention time: 1.48 minutes (LC Method E).

Step 2: Methyl 5-(difluoromethyl)4-oxido-pyridin-14um-2-carboxylate ço N ___________________________________________ N
ON
1003601 Urea hydrogen peroxide (13.7 g, 145.64 mmol) was added to a solution of methyl 5-(difluoromethyppyridine-2-carboxylate (8.1 g, 43.282 mmol) in DGE (70 mL).
Trifluoroacetic anhydride (24.025 g, 15.9 mL, 114.39 mmol) was added over 20 minutes at a temperature of-ID "C in cooling bath (CO2/acetone bath). The reaction mixture was stirred for a further 30 minutes at 0 C and then for 1 hour at ambient temperature. The reaction mixture was poured into ice-water (150 mi.) and adjusted to 01 = 2 to 3 with ¨150 mL of 1 N aqueous sodium hydroxide solution. The mixture was diluted with dichlorornethane (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 %). -VAR
(400 MHz, Chloroform-d) 6 8.41 (s, 1H), 7.72 (dõ/ 8.1 Hz, 114), 7.43 - 7.36 (m, 1H), 6.84 - 6.47 (m, 114), 4.03 (s, 314) ppm. 19F NMR
(377 MHz, Chloroform-d) 8 415.27 (d, J = 55.9 Hz, 2F) ppm. ESI-MS 171/7 calc.
203.0394, found 204.1 (M+1)+; Retention time: 0.73 minutes (LC Method E).
Step 3: Methyl 5-(difluoromethyl)-6-hydroxy-pyridine-2-carboxylate +0FN
-o ri 1003611 Trifluoroa.cetic 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 mmo-1) in DMF (130 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 trill uoroacetic anhydride. The residual :MIT solution was poured over 30 minutes into water (1 L) at 0 C.
The precipitated solid was collected by filtration and washed with water (200 In11). The solid was dried under vacuum to give as an off-white solid, methyl 5-(ditluoromethyl)-6-hydroxy-pyridine-2-carboxylate (5.74 g, 60 %). 'H.-IN-MR (400 MHz, DMSO-d6) 6 12.29 (br. s., 1H), 7.88 (d, 1¨ 7.3 Hz, 11:1), 7,13 (5, 1H), 7,07 - 6.76 (m, 1H), 3.87 (s, 3H) ppm, 19F NMR (377 MHz, DMSO-d6) 6-118.60 (br. s., 2F) ppm. ESI-MS m/z calc.
203.0394, found 204.1 (MA)'; Retention time: 1.34 minutes (LC Method E), Step 4: Methyl 5-(difluoromethyl)-6-hydroxy-3-nitro-pyridine-2-earboxylate F pH F 9H
FtN
F N
ikro. _____________________________ N020o 1003621 To an ice-cooled solution of methyl 5-(ditluoromethyl)-6-hydroxy-pyridine-2-carboxylate (7.43 g, 36.575 mmol) in sulfuric acid (48 rriL of 18.4 M, 883.2 mmol) was added nitric acid (2.5 iriL 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). The solution was cooled at 0 C for 15 minutes, then the solid was isolated by filtration and washed with water (200 mL). The solid was dried overnight under vacuum to give as an off-white solid, methyl 5-(difluoromethyl)-6-hydroxy-3-nitro-pyridine-2-carboxylate (5.47 g, 56 %). IHNMR (400 MHz, DMSO-d6) 6 8.41 (s, 1H), 7.19 - 6.75 (m, 1H), 3.94 (s, 3H) ppm. One exchangeable proton not observed in NMR. 19F NMR (377 MHz, DMSO-d6) 6 -118.87 (d, Jzzz 54.5 Hz, 2F) ppm.
EST-MS mtz calc. 248.0245, found 249.1 (M+1)+; Retention time: 1.6 minutes (LC

Method E), Step 5: Methyl 6-ehlor0-5-(difluoromethyl)-3-nitro-pyridine-2-carboxylate F OH Ci F N F
N020 tlq07 1003631 Methyl 5-(difluoromethyl)-6-hydroxy-3-nitro-pyridine-2-carboxylate (2 g, 8.06 mmol) was dissolved in a mixture of phosphoryl trichloride (6.58 g, 4 mL, 42.914 mmol) and acetonitrile (4 mL) at 0 "C (exothermic). IMF (1,888 g, 2 niliõ 25.83 mmol) was added dropwise at 0 C (exothermic). The resulting yellow milky mixture was stirred at 70 C (pre-heated oil bath) for 4 h. More phosphoryl trichloride (3.29 g, 2 mL, 21.457 mmol) was added. The orange solution was stirred at 70 C overnight. Cooled to 0 C
and methanol was added (30 inL)..A 50 % saturated solution of sodium bicarbonate (50 mL) was added dropwise at 0 'C. A solution of potassium carbonate (10 g) in water (50 mL), methanol (50 mL) and ethyl acetate (150 triL) was added. The aqueous layer was separated and extracted with ethyl acetate (3 X 50 mt.), The combined organic layers were washed with brine (50 inL), dried over anhydrous sodium sulfate, filtrated and concentrated under vacuum to give an orange oil which was purified by silica gel chromatography using a gradient from 5 % to 30% NITRE in heptanes to give as a yellow oil, methyl 6-chloro-5-(difluoromethyl)-3-nitro-pyridine-2-carboxylate (1.92 g, 79%). 1141\FMR (400 MHz, Chloroform-d) 5 8.70 (s, IfI), 7,16 - 6.76 (m, 1E). 4.06 (s, 3H) ppm, 19F NW.
(377 MHz, Chloroform-d) 5 -117.39 (d, I = 53.1 Hz, 2F) ppm. ESI-MS in./z calc. 265.9906, found 267,1 (11,1+1) ; Retention time: 1.84 minutes (LC Method E).
Intermediate 21: Preparation of 2-methylhex-5-en-2-amine (hydrochloride salt) 0riK,OH Step I Step 2 Step 3, v '0' N
.HC1 Step 1: tert-Butyl 2,2-dimethylaziridine-l-carboxylate o v >1`o-jcl-N-[003641 To a solution of ter-butyl N-(2-hydroxy-1,1-dimethyl -ethyl)carbarn ate (30 g, 155.35 mmol) in diethyl ether (750 mL) was added p-TsC1 (35.6g, 186.73 mmol) and powdered KOH (103 g, 1.5605 mol) at 0 C. The reaction temperature was raised to reflux temperature and stirred for 16 hours. Another portion of KOH (17 g, 303 mmol) was added and the reaction was refluxed for another 2 hours. The reaction was cooled to room temperature and diluted with ether (500 mL). The formed solid was removed by filtration through a glass fitted funnel and washed with more ether (100 mL). The combined ethereal filtrate was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to furnish as a clear oil, tert-butyl 2,2-dimethylaziridine-1.-carboxylate (24.602 g, 88 %). 11-1NNIR
(500 MHz, Chloroform-d) 5 2.04 (s, 2H), 1.46 (s, 9H), 1.28 (s, 6H) ppm.
Step 2: tert-Butyl N-(1,1-dimethylpent-4-enyl)carbamate - 0 N _____________________ '0 N"

1003651 A reaction flask was charged with allyl(chh.pro)mag,nesium in THF (205 mL, 2 M, 410 mmol) and anhydrous THE (200 rnL). The solution was cooled to -30 C
and copper(1) bromide (dimethyl sulfide complex) (28 g, 136.2 mmol) was added. The reaction mixture was stirred at the same temperature for 30 min, then cooled to -78 'C.
A. solution of tert-butyl 2,2-dimethylaziridine-l-carboxylate (24.602 g, 136,49 mmol) in anhydrous THE (200 rnL) 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 mla) at 0 C. The reaction was stirred at room temperature for 10 minutes, then diluted with diethyl ether (200 mla). The solution was filtered through a pad of Celite and washed with ether (100 mlõ). The two layers were separated, and the aqueous layer was extracted with diethyl ether (2 X 200 mia). The combined organic layers were washed with brine (200 int:), dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography using a gradient from 0 % to 10 %
diethyl ether in hexanes to furnish as a light yellow liquid, tert-butyl N-(1,1-dimethylpent-4-enyt)carbamate (18.6 g, 61 %). 1H1NMR (500 MHz, Chloroforin-d) 6 5.82 (ddtõ!

16.8, 10.2, 6.6, 6.6 Hz, 1H), 5.09¨ 4.87 (m, 2H), 4.38 (s, 1H), 2.11 ¨ 1.98 (in, 2H), 1.79 ¨
1.64 (m, 2H), 1.43 (s, 9H), 1,26 (s, 6H) ppm.
Step 3: 2-Methylhex-5-en-2-amine (hydrochloride salt) ,N" 112Nr 1003661 A solution of tert-butyl N-(1,1-dimethylpent-4-enyl)carbamate (26.6 g, 124.7 mmol) and HO in dieth.y1 ether (350 triL, 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%). 1H
NMR (500 MHz, DMS046) 6 8.08 (s, 3H), 5.92 ¨ 5.64 (m, 1H), 5.15 4.87 (m, 2H), 2.21 ¨ 1.96 (m, 2H), 1.72 ¨ 1.49 (m, 2H), 1.23 (s, 6H) pprn.
Preparation of Compounds 1-213 and Compounds 214 to 222 Example 1: Preparation of 20-amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,161docosa-1(20),2,4,17(21),18-pentaen-6-ol (mixture of 4 stereoisomers) (Compound 1) 1.N. \)-----/-------&N)--,/-*
,J , H2N, õj1,....õ Step 1.. F..õ--1 Step 2 + = N y,lf.9 i H fs`CF3 t )L
0H .HC

-...ryE :
,..--H : CF3 =-.>õ.Ø.......NH 0 .?"-:1--=-=
L, ) >-- --r-.,.,-4.N,\---/-- õ,...õ---N `====
Step 3 Step 4 F301,.,..N .--=' F3C9 ' N .
.1., ,-' 0,_.õ. cF1 ,,H......-..:10 _=\---: cF
-1\--0 3 õ ,0NH N-N I >i0,11_,Ni-1 N-N c ...---r 1 --------,,...

=-...õ.;-,-- EiZ mixture IS
F3C-L.-,N Step 5 N
.,, F3C,,.,N
1 ....-'1-. \

.,. z.Y OH
`
-,......r.,,- ...,,%-)..7.,,....--CF3 -Ø, NH N---N \\ 11 OH
,....----y NH2 N--N

mixture of 4 stereoisomers Step 1: tert-Buty11146-(2-allylpyrrolidin-l-y1)-24112-benzyloxy-2-(trifluoromethyl)hex-5-enoyliaminoicarbamoyll-5-(trifluoromethyl)-3-pyridyllearbamate 4..N.$)----/'---,- ,- 4.N1-------/''..-------"*

F3C,-1N H2N,Is?L'f.' , F30 ,...,-LN 0 1OH + -HC H CF3 r 1r N" ('ICF3 >,,,OyNil 6 ,...,-)----., --,>,,o,ii NH u (-0 0 0 0 ).
r:-.----,, 1003671 To a solution of 6-(2-allylpyrrolidin-l-y1)-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pytidine-2-carboxylic acid (200 mg, 0.4815 mmol) in acetointrile (5 ml_,) were added successively 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride salt) (180 mg, 0.5314 mmol), 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide (hydrochloride salt) (140 mg, 0.7303 thmol), 1-laydroxybenzotriazole (monohydrate) (100 mg, 0.653 mmol) and triethylamine (101.64 mg, 0.14 mi., 1.0044 mmoi). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with aqueous I N HO
(30 mL), saturated aqueous sodium bicarbonate (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient from 0 % to 10 % ethyl acetate in heptanes giving as yellow solid, tert-butyl N46-(2-allylpyrrolidin-1-0)-2-[[[2-benzyloxy-2-(trifluoromethyphex-5-enoyl]amino]carbamoyli-5-(trifluoromethyl)-3-pyridyl]carbarnate (300 mg, 89%). 11-1 NMR (300 MHz, Chloroform-d) 6 1.51 (s, 9H), 1.65-1.81 (m, 2H), 1.88-2.00 (m2 IH), 2.07-2.34 (m, SIT). 2.37-2.59 (m, 2H), 3.27-3,43 (m, 1H), 3.56-3.71 (m, 1H), 425-4/40 (m, 1H), 4.66-4.77 (m, 1H), 4.78-4.91 (m, 1H), 4.93-3.19 (m, 4H), 5.69-5.91 (m, 2H), 7.32-7.51 (m, 5H), 9,01 (br. s., LH), 9.16 (dd,1=18.8, 5.9 Hz, HI), 9.85-10.01 (m, 1H), 10.05 (br. s., 1H) ppm. 19F1NMR (282 MHz, Chloroform-d) 6 -75.2 to -72,1 (m, 3F), -57.8 (d, J=9.2 Hz, 1F) ppm, Retention time: 2.82 minutes (LC
Method B).
Step 2: tert-Butyl N-16-(2-anylpyrrolidin-l-y1)-24541-benzyloxy-1-(trifluoromethyl)pent-4-enyll-1,3,4-oxadiazol-2-y11-5-(trifluoromethyl)-3-pyridylIcarbamate /

,N.ic.?
H I CF 3 /if 0 NH 0 .r0 OyNH N-N

(.711 [00368] A solution of tert-butyl N-[6-(2-ally pyrroli din-l-y1)-2-[[[2-benzyloxy-2-(trifluoromethyphex-5-enoyl]arninolcarbamoy11-5-(trifluoromethyl)-3-pyridylicarbamate (2.45 g, 3.3016 minol) and DIPE.A (1.1872g. 1.6 1rd,, ).1858 mmol) in acetonitrile (30 mL) was heated at 50 C, then p-toluenesulfonyl chloride (815 mg, 4.2749 mmol) was added portion-wise at 50 C. The resultant mixture was stirred at 70 C for 2 hours.
Reaction mixture was cooled, basified with a saturated solution of sodium bicarbonate (200 mL) and extracted with ethyl acetate (3 X 100 mL). Combined organic layers were washed with brine (100 mL)õ dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase chromatography using a gradient from 70 % to 100 % of a.cetonitrile in water containing 0.1 % of formic acid giving as a yellow gummy material, tert-butyl N46-(2-allylpyrrolidin-l-y1)-24541-benzyloxy-1-(trifluoromethyppent-4-enyl]-1,3,4-oxadiazol-2-y1]-5-(trifluoromethyl)-3-pyridyllcathainate (2.2 g, 92 %). -NMR
(300 MHz, Chloroform-d) 6 1.51 (s, 9.11), 1.64-1.78 (m, 2H), 1.86-2.08 (m, 211), 2.16-2.57 (m, 6E4 3.32-3.44 (m, 1H), 3.53-3.69 (m, 1H), 4.35-4.49 (m, 111), 4,58-4.69 (m, 1H), 4.71-4.87 (m, LH), 4.88-5.10 (m, 411), 5.60-5.84 (m, 2H), 7.24-7.43 (m, 5H), 8.99 (s, 1H), 9.55 (hr. s., 1H) ppm. 191' NMR (282 MHz, Chloroform-d) 6 -73.0 (s, 3F), -57.3 (s, 3F) ppm. ESI-MS rez calc. 681.27496, found.
682.5 (M+1)'; Retention time: 3.19 minutes (LC Method K).
Step 3: tert-Butyl N-6-(benzyloxy)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetrauzatetracyclo115.11.1.2,5.012,161docosa.-1(21),2,4,9,17,19-hexaen-20-ylkarbamate (E/Z mixture) 4.N
N 1:3c'-'")'N

E/Z mixture 1003691 To a degassed solution of tert-butyl .N46-(2-allylpyrrolidin-l-y1)-2-[5-[1-benzyloxy-1-(trifluoromethyppent-4-enyli-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyncarbamate (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. The residue was purified by silica gel chromatography using a gradient from of 0 % to 10 % ethyl acetate in heptanes giving as a green-yellow solid, tert-butyl AT-6-(benzyloxy)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,1.6]docosa-1(21)22,4,9,17,19-hexaen-20-ylicarbarnate (E/Z mixture) (125 mg, 84 %). NMR
(300 MHz, Chloroform-d) 6 1.46 (s, 911), 1,60-1,79 (m, 2H), 1.86-2.00 (m, 1H), 2.00-2.25 (m, 3.H), 2.26-2.53 (m, 2H), 2.58-2.82 (m, 1H), 3.39-3.67 (m, 3H), 3.83-4.05 (m, 1H), 4.51-4.65 (m, 111), 4.89-5.00 (m, 1H), 5.36-5.55 (m, 21-1), 7,11-7.28 (tn., 511), 8.81-8.98 (m, 211) ppm. I9F NMR
(282 MHz, Chloroform-d) 6 -75.0 and -74.1 (2s, 3F), -55.5 (s, 3F) ppm. ESI-MS m./z calc.
653.24365, found 654.4 (M-4-1.)-', Retention time: 2.94 minutes (LC Method K).

Step 4: tert-Butyl N-16-hydroxy-6,18-bis(trifluoromethy1)-22-oxa-3,4,16,21-tetranzatetracyclo[1.5.3.1.12,5.012,161docosa-1(21),2,4,17,19-pentaen-20-Acarbainate I CF

>,..0,(NFE N-N I ,0 .M1 N-N
')f a a E1Z mixture [00370] To a nitrogen degassed solution of iert-butyl N-6-(ben.zyloxy)-6,18-bi s(trifluoromethy 1)-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.,7 mixture) (30 mg, 0.0459 mmol) in methanol (4 nit) was added SiliaCat 13(1 (73 mg, 0.24 mmol/g, 0,0175 mmol) and reaction was stirred for 64 hours under hydrogen balloon at room temperature. The reaction mixture was filtered over Celite, washed with methanol and concentrated. The 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 N16-hydroxy-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraa.zatetracyclo[15.3.1.12,5.012,161d0c0sa-1(21),2,4,17,19-pentaen-20-yl]carba.mate (15 mg, 58 %). 1-11 NMR. (300 MHz, Chloroform-d) 8 1.20-1.27 (m, 21:1), 1.45 (s, 9H), 1.48-1.59 (m, 5H), 1.85-1.98 (rn, 1H), 1.99-2.65 (m, 4H), 130-3.62 (m, 3H), 3.87-4.18 (m, 211), 8.75-8.97 (m, 2H) pptn. One exchangeable proton not observed in NNIR. 19F NN1R (282 MHz, Chloroform-d) (3-80.8 and -77.4 (s, 3F), -55.4 to -54.9 (m, 3F) ppm. ESI-MS in./z calc. 565.2124, found 566.4 (M 1)% Retention time: 2.73 minutes (LC :Method K).
Step 5: 20-Amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetranzatetracyclo[1.5.3.1.12,5.012,161docosa-1(20),2,4,17(21),18-pentaen-6-ol (mixture of 4 stereoisomers) (Compound 1) YL' )71\0--CHF3 Yi'''eYT)CHF3 mixture of 4 stereolsomers [00371] TEA (1.4800 g, 1 ml.., 12,98 rnmol) was added to tert-butyl N46-hydroxy-6,18-bi s(trifluoromethy I)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5 .012, 6]docosa-1(21),2,4,17,19-penta.en-20-yl]carba.mate (30 mg, 0.053 mmol) in DCM (2 int) at room temperature and the mixture was stirred for 2 h. The mixture was poured in saturated sodium bicarbonate solution (20 ml_,) and extracted with DCM (3 X 10 triL).
The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated.
The residue was putified by silica gel chromatography using a gradient from 0 % to 30 %
of ethyl acetate in heptanes giving as a yellow solid, 20-amino-6,18-bi s(trifluoromethyl)-22-oxa-3,4,16,21-tetra.azatetracyclo[ 1 5.3.1.12,5.012,16]docosa-1(20),2,4,17(21),18-pentaen-6-01 (mixture of 4 stereoisoiners) (10 mg, 39 %). NNIlt (300 MHz, CD30D) 6 0.80-1.01 (m, 2H), 1.13-1.36 (m, 3H), 1.42-1.68 (m, 4H), 1.71-1.87 (m, 1H), 1.91-2.08 (m, I H), 2.12-2.29 (m, IH), 2.36-2,75 (m, 2H), 3.31-3.47 (m, 3.52-3.75 (rn, I H), 3.86-4.23 (m, 1H), 7.62 (s, 1H) ppm. '9F NAIR (282 MHz, CD=t0D) 6 -82.0 and -78.8 (s, 3F), -58.1 (s, 3F) pptn. ES1-MS m/z calc, 465.15994, found 466,2 (M-+-1) ;
Retention time:
3.84 minutes (LC Method F).
Example 2: Preparation of 20-amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracy-elo[15.3.1.1.2,5.012,161doeosa-1(20),2,4,17(21 ),18-pentaen-6-oll (diastereomer pair 1) (Compound 2) and 20-amino-6,18-bis(trifinoromethyl)-22-oxa-3,4,16,21-tetraazatetracy-clo[15.3.1.12,5.012,161 docosa-1(20),2,4,17(21),18-pentaen-6-01 (diastereomer pair 2) (Compound 3) Step 1 Fc N F3c I 0 _I

YT)CHF3 NOH 3 ===._ -OyNH N-N
Ea mixture 0 0 diastereomer pair I
diastereomer pair 2 Step 2 Step 3 F3C,LN

wµ\ II OH /1 OH

diastersomer pair I
diastereomer pair 2 Step 1: tert-Butyl N-16-hydroxy-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,161docosa-1(21),2,4,17,19-pentaen-20-Acarbamate (diastereomer pair 1) and tert-butyl N46-hydroxy-6,18-bis(trifluoromethyl)-22-oxa-3,4J6,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-ylkarbamate (diastereomer pair 2) F30 --L,N
Step I
y(õ_.\ 0 _____ CF3 N¨N > 0 NH N¨N
- 0, NH N¨N
r N
C, ElZ Mixture diastereorrter pair I pair 2 11003721 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-ylicarbamate (EIZ mixture) (675 mg, 1.0327 mmol) in methanol (60 mL) was added SiliaCat Pcr (1.6 g, 0.24 minolig, 0.384 nano]) and reaction was stirred for 24 hours under hydrogen balloon at room temperature. The reaction mixture was filtered over Celite, washed with methanol and concentrated. The residue was purified by silica gel chromatography using a gradient from 0 % to 30 % ethyl acetate in heptanes giving as a yellow solid and the first diastereomer pair to elute, tert-butyl N46-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-ylicarbarnate (diastereomer pair 1) (190 mg, 33 %). 111 NMR (300 MHz, Chloroform-d) 6 0.79-0.91 (m, 1H), 0.94-1.10 (m, 1E4 1.25 (br. s., 1H), 1.41-1.68 (m, 13H), 1.70-1.84 (m, 1H), 1.85-2.07 (m, 21-1), 2.08-2.27 (in, 2E1), 2.28-2.44 (m, Hi), 2.54-2,74 (m, 111), 3.40-3.71 (m, 3H), 3.94-4.14 (m, 1H), 8.80-9.10 (m, 2H) ppm. 19F NMR (282 MHz, Chloroform-d) 6 -77.4 (s, 3F), -55.1 (s, 3F) ppm. ESI-MS m/z calc, 565.2124, found 566.3 (M+1)+;
Retention time:
8.407 minutes (LC Method L).
[00373] Continued elution provided as a yellow solid and the second diastereomer pair to elute, tert-butyl N46-hydroxy-6,18-bis(trifluoromet.hyD-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16idocosa-1(21),2,4,17,19-pentaen-20-yi]carbainate (diastereomer pair 2) (165 mg, 28%). -NMR (300 MHz, Chloroform-d) 6 0.81-0.98 (m, 2H), 1.41-1.60 (m, 13H), 1.61-1.89 (m, 3H), 1.93-2.25 (m, 3H), 2.35-2.62 (m, 2H), 3.46-3.69 (m, 3H), 3.95-4.13 (m, 1H), 8.91 (br. s., 2H) ppm. 19F NMR (282 MHz, Chloroform-d) 8 -80.8 (s, 3F), -55.1 (s, IF) ppm. ES1-MS mtz calc. 565.2124, found 566.4 (M 1) ;
Retention time: 8.426 minutes (LC Method 1_:).
Step 2: 20-Amino-6,18-bis(tril1uoromethy4)-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) OF3 Step 2 F3C
N
,>.õ..0,ir NH N¨N // OH
NH2 N¨N

diastersomer pair I diastereorrier pairi [003741 TFA (2.9600 g, 2 mL, 25.96 mato') was added to tert-butyl N46-hydroxy-6,18-bis(trifluoromethy1)-22-oxa-3,4,16,21-tetraazatetracycl.o[15,3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-20-yl]carbarnate (diastereomer pair 1) (190 mg, 0.336 mmol) in DCM (4 mL) at room temperature and the mixture was stirred for 2 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (20 mL) and extracted with DCM (3 X 10 mL). The organic phases were combined, dtied over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient from 0 to 30 % of ethyl acetate in heptanes giving as a yellow solid, 20-ami no-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-penta.en-6-ol (diastereomer pair 1) (117 mg, 71%). 111 NMR (300 MHz, .1)MSO-d6) 8 0.71-0,91 (fm, 1H), 1.32-1.62 (m, 6q), 1.65-1.80 (m, 1H), 1.81-2.00 (m, 21-1), 2.02-2.16 (m, 1.H), 2.18-2.36 (m,114), 238-2.62 (m, 21:1), 3.18-3.31 (m, 111), 3.39-3.56 (m, 111), 3.78-3.94 (m, 1H), 6.10 (s, 2H), 7.59 (s, 1.H), 7.69 (s, 1.H) ppm.I9F NAIR (282 NtHz, DM50-d6) 8 -79.3 (s, 3F), -55,8 (s, 3F) ppm. ES1-MS m/z oak, 465.15994, found 466,2 (.1\44-1r;
Retention time:
3.82 minutes (LC Method F).

Step 3: 20-Amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21.-tetraazatetra cyclo [1, 5.3.1.12,5.012,161docosa-1(20),24,17(21,),18-pentaen-6-ol (diastereomer pair 2) (Compound 3) N
St" 3 Fsc 1+1 it OH CF3 if OH

diastaraorner pair 2 diastereorner pair 2 [00375] TEA (2.9600 g, 2 mL, 25,96 mmol) was added to tert-butyl N46-hydroxy-6,18-bi s(trifluoromethy I)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012, 6]docosa-1(21),2,4,17,19-pentaen-20-7,71]carba.mate (diastereorner pair 2) (165 mg, 0.2918 mmol) in DCM: (4 InL) at room temperature and the mixture was stirred for 2 h. The mixture was poured into saturated sodium bicarbonate solution (20 mL) and extracted with DCM (3 X
mt.). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient from 0% to 30% of ethyl acetate in heptanes giving as a yellow solid, 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 (diastereorner pair 2) (90 mg, 65 %). 111 NMR, (300 DM5046) 8 0.72-0.94 (m, 1.H), 1.21-1.54 (m, 5H), 1.55-1.79 (m, 3H), 1.81-1.93 (ni,114), 1.94-2.18 (in, 211), 2.19-2.41 (m, 21-1), 3,17-3,30 (m, 11:1), 3.41-3.60 (m, 3.88-4.09 (m, 1.H), 6.10 (br. s., 2H), 7.53 (s, 1H), 7.69 (s, 1H) pprn. 19F -NMR (282 MHz, DMSO-do) 8 -76.5 (s, 3F), -55.9 (s, 3F) ppm. ESI-MS m/z calc. 465.15994, found 466.2 (WHO', Retention time: 3,78 minutes (LC Method :17,.).

Example 3: Preparation of (6R,12R)-20-amino-6,18-his(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo115.11.1.2,5.012,161docosa-1(21),2,4,17,19-pentaen-6-ol (Compound 4) and (6S,12R)-20-amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo115.11.1.2,5.012,161docosa-1(21),2,4,17,19-pentaen-6-ol (Compound 5) c? N ...--ii F3 C ,-L, N , ' H2N..N)L'<- Step 1 y F3C-N L_ _____________________________________ . I V .---1' Step 2 ' y0H + H ; 'CF3 H

.HC I r ll-N'iNiCF
>,.Ø..T,NH 0 n --,,>,_Ø.sr NH 0 a F3C,,k,N .r" F30,,....-LN
I I Step 3, ii Stop 4 r >10,11, N' H N-N 1,_,.. ==-, .0 ,NH N-N i 0 11 I a EIZ m ixture 40 Ct3'N=
F30i,...,,N

0.).71-3-CH F3 Yk-cc0Y-70cilF3 Step 1: tert-Butyl IV-164(2S).-2-allylpyrrolidin-1-y11-2-[[[2.-benzyloxy-2-(trifluoromethyl)hex-5-enoyliaminoicarbamoy11-5-(trifluoromethyl)-3-pyridyllearbamate F3C,..,,A.s. + H2N,Nrk., H
<? F3C.,,_,A, 11 l H 6 CF3 I Y V r -- y OH
.HCI r Yirjj'N'icF
: 3 ,O, _,NH 6 --, ,õ,.,,_, 0 NH 0 0 ....
.------ I f ..-' y ak.-...,,,,- o ...)----i --,,...,.., [00376] To a solution of 6-1(2S)-2-allylpyri-olidin-1-y1]-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (7.8 g, 18.78 mmol) in NIVIP (70 mL) was added 2-benzyloxy-2-(trifluorornethyl)hex-5-enehydrazide (hydrochloride salt) (6.4 g, 18,89 rnrnol) and DMA (3.5g. 65.77 mmol) followed by HARI (10.7g. 28.14 mmol).

The reaction mixture was stirred at room temperature for 2.5 h then the mixture was diluted with water (100 riff.) and extracted with ethyl acetate (3 X 50 trill,). The organic phases were combined and dried overMgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient from 0 % to 5 % Et0Ac in hexanes giving tert-buty N-[6-[(2S)-2-allylpyrrolidin-1-y11-2-[[[2-benz y.oxy-2-(trilluoromethyl)hex-5-enoyl]a.mino]carbamoyll-5-(trifluoromethyl)-3-pyridvdcarbamate (10.2 g, 78 %). '1-1 (400 MHz, Chloroform-d) 61.52 (s, 9H), 1.67-1,79 (m, 2E4 1.95-1.97 (m, 1H), 2.14-2.29 (m, 5H), 2.43-2.53 (m, 2H), 3.34-3.38 (m, 1H), 3.61-3.67 (m, 1H), 4.31-4.36 (m, 1H), 4.71-4.75 (m, 11-1), 4,84-4,87 (m, 1H), 4.99-5.14 (m, 41-0, 5.75-5.88 (m, 2H), 7.38-7.43 (m, 5H), 9.01 (dõ! = 2.5 Hz, 1H), 9.12-9.20 (m, 1H), 9.92-9.99 (m, H), 10.06 (d, Jzzz 2.4 Hz, 1H) ppm. ES1-MS m/z calc. 699.2855, found 700.4 (1\14-1)+;
Retention time: 2.39 minutes (LC Method A).
Step 2: tert-Butyl N-16-[(2S)-2-allylpyrrolidin-1-3/B-2-[5-11-benzyloxy-1-(trilluoromethyl)pent-4-eny1]-1,3,4-oxadiazol-2-y11-5-(trilluoromethy1)-3-pyridyl[earbamate (----\"====/
Nr F3C 0 '"
H I
'YThrN'r Y--CF3 >,..0,TiNFI 0 (.0 N-N

[00377] ten-Butyl N-[6-[(25)-2-allylpyrroli din-l-y1]-2-[[[2-benzyloxy-2-(trifluoromethyphex-5-enoyl]aminolcarbamoy11-5-(trifluoromethyl)-3-pyridylicarbamate (19.3 g, 27.58 mmol) was dissolved in acetonitrile (385 mL) then added D1EA
(14.5 mL, 83.25 mmol) and heated to 50 C. To this yellow solution, p-toluenesulfonyl chloride (7.9 g, 41.44 mmol) was slowly added and the orange solution was heated at 70 for 6 h.
Another portion ofp-toluenesulfonyl chloride (0.8 g, 4.196 mmol) was added and stirred the mixture at room temperature overnight. The deep orange solution was washed with a saturated solution of sodium bicarbonate (400 miL) and the bicarbonate phase was back extracted twice with ethyl acetate (2 X 150 mL). The combined organic phases were washed once more with a saturated solution of sodium bicarbonate (200 mt.) and brine (200 mL). The combined organic phases were dried, filtered and evaporated to give a deep orange oil. The residue was purified by silica gel chromatography using a gradient from 0 % to 5 % ethyl acetate and hexan.es giving tert-butyl AL[641.5)-2-al [541-ben.z,yloxy-1-(trifluoromethyl)pent-4-enyli-1,3,4-oxadia.zol-2-y1]-5-(trifluoromethyl)-3-pyridylicarbamate (16.5 g, 88 %). 1111 NMR (400 MHz, Chloroform-d) 8 9.58 (d, I - 3.4 Hz, 111), 9.02 (s, 111), 7,48 - 7.20 (m, 51-1), 5.75 (ddddõI = 17,6, 15.4, 7.0, 4.6 Hz, 2H), 5.10 - 4.93 (m, 4H), 4.82 (dd, J = 31.7, 10.9 Hz, 1H), 4.67 (ddõ.T 10.9, 6.4 Hz, 1H), 4.45 (d, J- 8.0 Hz, LH), 3.64 (q, I = 8.7 Hz, 1H), 3.40 (t, I =
8,4 Hz, 1H), 2.61 - 2,17 (m, 6H), 2.14- 1.87 (m, 2H), 1.84- 1,64 (m., 211), 1.57 (s, 9H) ppm. EST-MS
in/z oak:. 681.27496, found 682.0 (M+1)4% Retention time: 2.52 minutes (LC
Method M).
Step 3: tert-Butyl A1-1(12S)-6-betazyluxy-6j8-his(triftuuromethyt)-22-oxa-3,4,16,21-tetrazatetraeyelo[15.3.1.1295.012,16jdocosa4(20),2,4,9,17(21.),18-hexaen-20-yi]earhamate (E/Z mixture) F3C,c F3C,.A,N
õ0...s, o CF
// y y\--o 3 >,0yNH N-N N-N

Ea mixture [00378] A degassed solution of tert-butyl A46-[(25)-2-al1ylpyrrolidin-l-y1]-benzyloxy-1-(trifluoromethyl)pent-4-enyli-1,3,4-oxadiazol-2-y1]-5-(trifluoromethyl)-3-ppidylicarbarnate (10.47 g, 14,131 minol) in DCE (2000 inL) was heated to 50 C under nitrogen atmosphere for 15 min. 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 Than 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. The residue was purified by silica gel chromatography using a gradient from 0 % to 10 %
IHIOAc in hexanes yielding as an intense yellow green foam, tert-butyl N-[(12S)-6-benzyloxy-6,18-bis(trifluoromethy1)-22-oxa-3,4,16,21-tetrazatetracyclo[15.3.1.12,5.01.2, 16]docosa-1(20),2,4,9,17(21),18-hexa.en-20-ylicarbamate W7 mixture) (5.87g. 61 %). 11-1 NAIR
(500 MHz, CDC13) 6 9.01 (s, 1E1), 8.98 (d, .1 zzz 6.8 Hz, 111), 7.38 7.21 (m, 511), 5.64 --5.47 (m, 211), 5.02 (q, J 11.3 Hz, 1H), 4.68 (q, J 11.0 Hz, lW, 4.15 -3.92 (m, 1H), 3.75 -3.42 (m, 3H), 2.92 - 2,81 (in, 1H), 2.79 -2.64 (m, 1H), 2,58 - 2,48 (m, 1H), 2.48 -2.35 (m, 1H), 2.31 2.16 (m, 21-1), 2.10 1.99 (m, 1H), 1.82 - 1.71 (m, 2H), 1.55 (s, 9H) ppm. EST-MS m/z We, 653.2437, found 654.1 (M+1)+, Retention time: 4.29 minutes (LC
Method (3).

Step 4: (6R,12R)-20-Amino-6,11.8-his(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo11.5.3.1.12,5.012,161doc0sa4(21),2,4,17,19-pentaen-6-ol (Corn pound 4) and (6S,12R)-20-amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetruazatetracyclo115.11.1.2,5.012,161docosa-1(21.),2,4,17,19-pentuen-6-ol (Compound 5) "sCF3 i/ OH

&mxtJre 1003791 To Pd/C (250 mg of 10 % w/w, 0.2349 mmol) was added tert-butyl N-[(12,9-6-benzyloxy-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetrazatetracyclo[15.3.1.12,5.012,161docosa-1(20),2,4,9,17(21),18-hexaen-20-ylicarbamate (11,7Z mixture) (1.4 g, 2.142 mmol) in degassed Me0H (10 mt.) and the mixture was stirred under a ball 00T1 of1112 (10 mg, 4.961 mmol) for 3 days.
The mixture was filtered over Celi.te and washed with Me0H. The filtrate was evaporated and the crude product was chromatogra.phed on a 40 g silica gel column eluting with a gradient from 0 % to 25 % Et0Ac in hexanes giving the N-Boc-protected product intermediate as a mixture of diastereomers. This material was next dissolved in DCM (10 mL) and TEA (1 inlo, 12.98 mmo1) was added. The mixture was stirred at ambient temperature for 20 h.
The solvent was removed in vacuo and the crude oil was c.hromatogra.phed by reverse phase column chromatography using a Cis column eluting with a gradient from 30 % to 100 % acetonitrile in water affording 650 mg of a mixture of diastereomers, This mixture was subjected to chiral SFC using a ChiralPak AS-H column (250 X 21.2 mm, 5 pm particle size) using 10 % methanol in CO2 mobile phase over 6 minutes (flow rate = 70 mil/min) which gave two diastereomeric products:
1003801 The first diastereomer to elute was isolated as (6R,12R)-20-amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,161d0c05a-1(21),2,4,17,19-pentaen-6-ol (261.4 mg, 52%). -NMR
(400 MHz, Chloroform-d) 6 7.46 (s, 1H), 5.08 (s, 1H), 4.01 (q, 9.8, 9.1 Hz, 2H), 3.65 (d, 1 8.8 Hz, 1H), 3.51 - 3.38 (m, 1H), 2.57 - 2.40 (m, 211), 2.18 (dtd, J ¨ 12.5, 6.3, 3.5 Hz, 11-1), 2.12 -1.95 (m, 2H), 1.84 (põ./ 10.0, 9.5 Hz, 1H), 1.77 - 1.37 (m, 8H), 0.94 (s, 1H) ppm. ES1-MS
tth ca1c.
465,15994, found 466.1 (M+1)+; Retention time: 3.17 minutes (IC Method D).

1003811 The second diastereomer to elute was isolated as (6S,12R)-20-amino-6,18-bis(trift u orom ethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-ol (256.4 mg, 51 %). H NINTR (400 MHz, Chloroform-d) 6 7.59 (s, 111), 4,04 (s, 1H), 3.62 (tõ/ ¨ 8.6 Hz, 111), 3.43 (s, 111), 2.61 (s, 111), 2.36 (t, J = 12,4 Hz, 1H), 2.28 - 2.09 (m, 2H), 2.07 - 1.71 (m, 3H), 1,61 (d, J= 22,0 Hz, 6H), 1.01 (s, 1H) pprn. ESI-MS /wiz calc. 465.15994, found 466.0 (M 1) ; Retention time: 3.12 minutes (LC
Method D).
Step 5: Solid form characterization of amorphous Compound 4 (neat form) A. X-Ray Powder Diffraction [00382] The XRPD dit7fractogram 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. I.
B. Thermogravimetric Analysis (TGA) [003831 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, C. Differential Scanning Calorimetry Analysis 100384] The DSC data for amorphous Compound 4 (neat form) were collected on a TA
instrument Discovery series with TRIOS system. The DSC was run using the following modulated DSC method:
I. Equilibrated at -20.00 C, 2. Modulated by H-1- 1.00 C every 60 seconds, 3. Isothermal for 5,00 min, then 4. Ramp of 2.00 C/min to 250,00 C, 100385] 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. Single Crystal X-Ray Diffraction 1003861 Single crystals of crystalline Compound 5 Form A (neat) were grown from ethanol and pentane. X-ray diffraction data were acquired at 100 K on a Bruker diffractometer equipped with Cu Ka radiation (A,=1.54178 A) and a CCD
detector. The structure was solved and refined using SHELX programs (Sheblack, G.M., Acta Cryst., (2008) A64, 11.2-122) and results are summarized in Table 3 below.
Table 3: Single crystal elucidation of crystalline Compound 5 Form A (neat) Crystal System. Tetragonal Space Group 141 a (A) 18.1053(4) b (A) 18.1053(4) c(A) 13.1201(3) a( ) 90 p (0) 90 V (A3) 4300.8(2) Temperature 100 K
Example 4: Preparation of (6S,12,S)-20-amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.01.2,161docosa-1(21),2,4,17,19-pentaen-6-ol (Compound 6) (N
N ' F3C.yek...N F3O.,L
CF3 -bCHF3 OH
NH, l'J-N NH, N-N
diasterfAmiar pair 'I
Step 1: (6S,12S)-20-Amino-6,18-bis(trifluoroniethyl)-22-oxa-3,4,1.6,21-tetraazatetracyclo115.3.1.12,5.012,161docosa-1(21),2,4,17,19-pentaen-6-ol (Coin pound 6) 1003871 20-Amino-6,18-bi s(trifluoromethy I)-22-oxa-3,4,16,21-tetraazatetracycl o[15.3.1.12,5.012,16]docosa-1(20),2,4,17(21),18-pentaen-6-ol (diastereomer pair 1) (96.7 mg, 0.2078 mmol) was subjected to chiral SFC using a ChiralPak AS-H column (250 X 10 mm, 5 gm particle size) using 8 % methanol in mobile phase over 6 minutes (flow rate = 10 mL/min) which gave as the second single enantiomer to elute, (6S,12S)-20-amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16:jdocosa-1(21),2,4,17,19-pentaen-6-ol (30.8 mg, 64 %) ESI-MS in/1z cale. 465.15994, found 466.0 (M 1)+; Retention time: 2.13 minutes (LC
Method N).
Example 5: Preparation of (6R,12S)-20-amino-6,18-bisttrilluoromethy1)-22-oxa-34,16,21-tetraazatetracyclo[15,3.1.12,5.012,161doeosa-1(21),2,4,17,19-pentaen-6-ol ((I:ompound 7) r-----k, 1OCF3 ____________________________________________ CF
I

Mi2 N¨N
diastereorner pair 2 Step 1: (6R,125)-20-Amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetraey-clo[15.3.1.12,5.012,161doeosa-1(21),24,17,19-pentaen-6-ol (Compound 7) 1003881 20-Amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracycl o[15.3.1.12,5.012,16]docosa-1(20),2,4,17(21),18-pentaen-6-01 (diastereomer pair 2) (80 mg, 0.1719 mmol) was purified by chiral SFC using a ChiralPa.k AS-H (250 X 10 mm) 5p.m column; 40 "C and 8 % Me0I-1 (no modifier) in CO2 as an eluant using a flow rate 10.0 mLlmin with an injection volume of 70 uL to give as the first eluting enantiorner, (6R,128)-20-amino-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 (19.9 mg, 50 %). tH NMR (400 MHz, DMSO-do) 6 7,73 (s, 11H), 7,58 (dõ/ = 2,1 Hz, 1H), 6.12 (s, 211), 4.02 (dõ./ 8.2 Hz, 1H), 3.52 (tõ/ = 8.5 Hz, 1H), 3.30 (d, 9.0 Hz, 2H), 2.35 (ddcl, ,,T --25,1, 14,1, 6.2 Hz, 2H), 2.21 -2.12 (m, 11H), 2,10 - 2.00 (m, 111), 1.94 (d, J
¨ 9.0 Hz, 11H), 1.79 - 1.68 (m, 21:1), 1.64 (s, 1,H), 1.58 - 1.46 (m, 2H), 1.46 - 1.33 (m, 2H), 0.88 (q, 5.7, 4.9 Hz, 1.H.) ppm, ESI-MS in/z, calc. 465,15994, found 466.0 (1M+.1)+;
Retention time:
2.1 minutes (L C Method A).

Example 6: Preparation of 16-amino-10,18-bis(trifluoromethyl)-20-oxa-2,12,13,19-tetraazatetra cyclo [13.3.1.12,5.1 11 ,141heuicosa4(19),11,13,15,17-pentaen-10-ol (diastereomer pair 1) (Compound 8) and 16-amino40,18-bis(trifluoromethyl)-20-oxa-2,12,13,19-tetraazatetracyclo113.11.12,5.111,141llienicosa-1(1.9),11,13,15,17-pentaen40-ol (diastereomer pair 2) (Compound 9) t--,--,0 / \
N N
Step 1 ---L- Step 2 C.N./ Step 3 -,...-_________________________________________ , 0--0 -- .. a 0 H -TFA

= F3C .......õ(1"--...r.---..,,,,A.
t--1, \ µ
u I -s--; -NE ---1 Br ---0 + ' I ..-'1,, 0 )\--CF3 Step 4 . F3C-(.N 'km. Step 5 , '-r- 0 õ-IN,.._ >,0NE-1 N¨N
'`-f7''-=(" Ir---\0 3 * II 0 ..Ø..

.1.(NH N-N

EIZ III iXtU re -0.....õ---......., ..k, HN---\\
\ __ ( 0- Ni -->
\---....\_ Br Br \--, Step 6 F3C,t.., Step 7 F3C N \,... _____ > 1 N ---\ -- ..

y.--1-..?--0 Fs N¨N
>,0NH N¨Nr \ /
...--L /
C C.N.....µ\
F3C =,....N L--) Step 8 F3C '-' N
Step 9_ ,,, ...c.-- ,0 \¨CF
',:., 3 rd ...s. .0 ,NH N-N i NH2 ¨N
*
C1\2i'N1 N V._.
Step 10 F3 ),..õ'Y -----\ + F3C ,,, -1 I
F3c,,AN "1" I i -N
-,---CF J o )T NoH 3 -rj.0-¨.0c.HF'3 ,..t...--,....1 )01.F3 NH2 N-N NH2 N¨N

diastereomer pair I diastersonter pair 2 Step 1: tert-Butyl 3-vinylpyrrolidine-1.-carboxylate er, CN`
[00389] n-Butyl lithium (26.6 ml, of 2.5 M in hexanes, 66.5 mmol) was slowly added to a suspension of methyluiphenylphosphonium bromide (23.8 g, 66.625 mmol) in tetrahydrofuran (100 mL) at 0 'C. The resulting orange solution was stirred at 0 C for 5 minutes. A solution of ten-butyl 3-formylpyrrolidine-1-carboxylate (12.5 g, 62.736 mmol) in tetrahydrofuran (75 mL) was slowly added using an addition funnel keeping the reaction mixture at 0 C. After stirring for 15 minutes at 0 C, the reaction was warmed to room temperature over 2.5 hours. Again, the reaction mixture was cooled to 0 "C and was quenched with saturated aqueous ammonium chloride (200 mL) and extracted using diethyl ether (3 X 150 InL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient from 0 % to 15 % Et0Ac in heptanes giving as a clear liquid, tert-butyl 3-vinylpyrrolidine-1-carboxylate (10.18 g, 82%). IHNMR (300 MHz, Chloroform-d) 5 1.45 (s, 9H), 1.60-1.77 (m, 1H), 1.99 (dtdõ/=12,5, 6.4, 3.4 Hz, 1H), 2.69-2.85 (m, 1H), 2.96-3.12 (in, 11-1), 3.19-3.36 (m, IfI), 3.38-3.63 (m, 2E), 4.97-5.15 (m, 211), 5.76 (dt, J=17.1, 8.6 Hz, 1H) ppm. ESI-MS tri/z calc. 197.14159, found 142.2 (M-liu+1)+;
Retention time:
2.08 minutes (LC Method 13).
Step 2: 3-Vinylpyrrolidine (trifluoroacetate salt) Ic-&µN` 1-FA

[00390] Trifluoroacetic acid (47.360 g, 32 mL, 415.35 mmol) was added slowly to tert-butyl 3-vinylpyrrolidine-l-carboxylate (8 g, 40,553 mrnol) in dichlorometha.ne (32 mL) at 0 C. The mixture was stirred for 2 hours at room temperature then concentrated. Toluene (40 nil.) was added and concentrated to provide as a brown oil, 3-vinylpyrrolidine (trifluoroacetate salt) (13.3 g, 93 %). IH NMR (300 MHz, Chloroform-d) 5 8.87 (br. s., 2H), 5.81 - 5.64 (m, 1H), 5.28 - 5,09 (m, 211), 3.56 - 3.40 (m, 21-1), 3.39 -3.25 (m, 1H), 3.10 - 2.91 (m, 21:1), 2.32 - 2.16 (m, -1H), 1.96 - 1.79 (m, 1H) ppm. 19F NMR
(282 MHz, Chloroform-d) 6 -75.96 (s, 3F) ppm. EST-MS m/i calc. 97.08915, found 98.2 (MAY;
Retention time: 0.33 minutes (LC Method 0).
Step 3: 9H-Fluorein-9-ylmethyl 3-vitaylpyrrolidine-1-earboxylate , o N
N) .11TA
1003911 9H-Fluoren-9-ylmethyl carbonochloridate (550 mg, 2.126 mmol) was added to 3-vinylpyrrolidine (tritluoroacetate salt) (500 mg, 1..4206 mmol) and diisopropylethylamine (556.50 mg, 0.75 mL, 4.3058 mmol) in dichloromethane (20 mL) at room temperature. The solution was stirred for 2 days then water (20 mL) was added and extracted the mixture with DC:M (2 X 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient from 0 % to 20 % of ethyl acetate in heptanes giving as a clear oil, 9/1-fluoren-9-ylmeth2,713-vinylpyrrolidine-1-carboxylate (458 mg, 100 %). 1H -NMR (300 MHz, DMSO-d6) 6 1.54-1.75 (m, 1H), 1,84-2,04 (m, 1.H), 2.66-2.85 (m, 1H), 2.90-3.05 (m, 1H), 3.13-3.27 (m, 3.28-3.49 (m, 2H), 4.15-4.37 (m, 3II), 4.93-5.18 (m, 2H), 5.69-5,87 (in, 1H), 7.21-7.47 (m, 4H), 7.62 (d,1=7,3 Hz, 2H), 7.88 (d, J7.6 Hz, 2H) ppm. ESI-MS m/z calc. 319.15723, found 320.2 (M 1) ;
Retention time: 2.36 minutes (LC Method B).
Step 4: 911-Fluoren-9-ylmethyl 3-15-benzyloxy-545-16-bromo-3-(tert-butoxyearbonylamino)-5-(trifluoromethyl)-2-pyridy11-1,3,4-oxadiazol-2-y1]-6,6,6-trifluoro-bex-1-enyllpyrrolidine-1-earboxylate (EIZ mixture) r ) 0y NO
N Br I' ----s-e Y,O, õ-\--CF3 1\ ir 0 N¨N
b ,>oyNH NN [

Ea mixture 1003921 To a degassed solution of tert-butyl N424541-benzyloxy-1-(trifluoromethyppent-4-envi]-1,3,4-oxadiazol-2-y ]-6-bromo-5 -(trifluoromethyl)-3 pyridyllcarbamate (1.63 g, 2.5023 mmol) and 9H-fluoren-9-ylmethyl 3-vinylpyrrolidine-1-carboxylate (3.6 g, 11.271 mmol.) in 1,2-dichloroethane (8 mL) was added Grubbs catalyst, 2nd generation (129 mg, 0,1516 mmol). The resultant mixture was stirred at 40 C overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography using a gradient from 0 A) to 30 A) ethyl acetate in heptanes giving as an off-white solid, 911-fluoren-9-ylmethyl 345-benzyloxy-5-[546-bromo-3-(tert-butoxycarbonylami no)-5-(tri uoromethyl)-2-pyridy 1-1,3,4-oxadiazol-2-y111-6,6,6-trifluoro-hex-1 -enyli pyrrolidine- 1 -carboxylate (EIZ
mixture) (1.3 g, 47%). 'VAR (300 MHz, Chloroform-d) 6 1,56 (s, 91:1), 1.60-1.76 (m, 1H), 1.90-2.03 (in, 1H), 2.10-2.23 (m, ,1H), 2.28-2.55 (m, 3H), 2.65-2.85 (m, 1H), 3.01-3.14 (m, 1H), 3.29-3.43 (m, 111), 3.47-3.64 (m, 211), 4.18-4.29 (m, 111), 4,31-4,41 (m, 2:11), 4.63-4.74 (m, 1H), 4.76-4.88 (m, 1H), 5.37-5.56 (m, 2H), 7.28-7.45 (m, 7H), 7.47-7.55 (m, 2H), 7.57-7.65 (m, 2H), 7.73-7.81 (m, 2H), 9.35 (s, 1H), 10.16-10.22 (m, 1H) ppm.
'9F NAIR
(282 MHz, Chloroform-d) 5 -72.5 (br. s., 3F), -63.8 (br. s., 3F) ppm.
Retention time: 2.96 minutes (LC Method K).
Step 5: 9H-Fitioren-9-ylmethyl 3-15-benzyloxy-545-16-bromo-3-(tert-butoxyearbonylamino)-5-(trifluoromethyl)-2-pyridy11-11.,3,4-oxadiazol-2-y1]-6,6,6-trifluoro-hexyl]pyrrolidine-.1-earboxylate r>
F3C Br \\ II 0 ---CF3 _NH N¨N \ /1 b I>OyNHN¨N

E/Z

miKture [00393] To a nitrogen degassed solution of 9H-fluoren-9-ylmethyl 345-benzyloxy-[6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)-2-pyridyli-1,3,4-oxadiazol-2-y11-6,6,6-trifluoro-hex-1-enyllpyrrolidine-1-carboxylate (EIZ mixture) (205 tng, 0,2175 mmol) in ethyl acetate (16 mL) was added palladium on carbon (46 mg, 0.0216 mmol) and the reaction was stirred for 2 h under a hydrogen balloon at room temperature.
The reaction mixture was filtered over Celite, washed with ethyl acetate and the filtrate was evaporated to give as an amber gum., 9H-fluoren-9-ylmethyl 345-benzyloxy-54546-bri.Dmo-3-(tert-butoxycarbonylarnino)-5-(trifluoromethyl)-2-pyridy11-1,3,4-oxadiazol-2-yll-6,6,6-trifluoro-h.exylipyrrolidine-1-carboxylate (190 mg, 92 %). 'II NMR
(300 MHz, Chloroform-d) 6 1.34-1.46 (m, 4H), 1.56 (s, 911), 1.91-2.18 (m, 3H), 2.25-2.50 (in, 3111), 2.85-2.99 (m, 1H), 3.25-3.40 (m, 1H), 3.44-3.66 (m, 3H), 4.18-4.29 (m, 1H), 4.30-4.41 (m, 2H), 4.63-4.74 (m, 1F1), 4.75-4.85 (m, 1H), 7.26-7.44 (m, 7I1), 7.46-7.54 (m, 2111), 7.56-7.65 (m, 2H), 7.72-7.80 (in, 2H), 9.34 (s, 1H), 10.19 (br. 5., 1H) ppm.
PT NMR (282 MHz, Chloroform-d) 6 -72.5 (br. s., 3F), -63.8 (br. s., 3F) ppm. Retention time: 2.97 minutes (LC Method K).
Step 6: tert-Butyl N-1245-11-benzyloxy-5-pyrrolidin-3-y1-1-(triftuoromethyl)penty11-1,3,4-oxadiazol-2-34]-6-bromo-5-(trifluoromethyl)-3-pyridyllearbamate cr-----1 9 1-171õD

F3C,,,iIN ---I -------------------- . F3CN ----, ,r,--.--1,,,,;(0.7A-CF3 -..f.:1-0...)\a-CF3 ,>,,oy NH N---'4 0..r.NH N-N L., ---,-;":
[00394] Piperidine (172.20 mg, 0.2 mL, 2.0224 mmol) was added to 911-fluoren-9-ylmethyl 345-benzyloxy-54516-bromo-3-(tert-butoxycarbonyiamino)-5-(trifluorornethyl)-2-pyridyli-1,3,4-oxadiazol-2-y11-6,6,6-trifluoro-hexyl]pyrrolidine-1-carboxylate (75 mg, 0,0794 minol) in Ti-IF (5 mL) and the mixture was stirred overnight at room temperature then concentrated under reduced pressure. The residue was purified by reverse phase (C18 column) chromatography using a gradient from 5 % to 70 (.)/0 to 100 (.)/0 of methanol in water containing 0.1 % formic acid giving as a clear oil, tert-butyl N4245-[1-benzyloxy-5-pyrrolidin-3-y1-1-(trifluoromethyppentyl]-1,3,4-oxadiazol-2-y1]-6-bromo-5-(trifluoromethyl)-3-pyridyncarbamate (27 mg, 43 %). IF1 NMR (300 MHz, Chloroform-d) 8 1.31-1.47 (m, 4H), 1.49-1.71 (in, 10H), 1.96-2.25 (m, 4H), 2.26-2.44 (in, 2H), 2.62-2.74 (m, 1.11), 3.07-3.19 (m, 1F1), 3.22-3.42 (in, 2H), 4.64-4.73 (m, 1H), 4.74-4.83 (m, 1H), 7.29-7.44 (m, 3H), 7.44-7.53 (in, 2H), 8.42 (br. s, 1H), 9.35 (s, 1H), 10.18 (s, 1H) ppm. 19F
NMR. (282 MHz, Chloroform-d) 6 -72.5 (br. s., 3F), -63.8 (s, 3F) ppm. ESI-MS
m/z calc.
721.16986, found 722.2 (M+1)'; Retention time: 2.01 minutes (LC Method K).

Step 7: tert-Butyl N-110-(benzyloxy)-10,18-his(trifluoromethyl)-20-oxa-2,12,13,19-tetraazatetracyclo[13.3.1.12,5.111,141henieosa-1,(18),1,1,13,15(1.9),16-pentaen-16-Acarbamate HQ
Br FsCs, .YCC),r¨OCF3 >r0,ior KI-4 a =
1003951 DIPEA (51.940 mg, 0.07 mL, 0.4019 mmol) was added to tert-butyl benzyloxy-5-pyn-olidin-3-y1-1-(trifluoromethyppentyl]-13,4-oxadiazol-2-01-6-bromo-5-(trifluoromethyl)-3-pyridyllcarbamate (32 mg, 0.0443 mmol) in acetonitrile (7 mL) and the mixture was heated at 80 (i.; overnight, The mixture was poured in saturated sodium bicarbonate solution (50 inL) and extracted with ethyl acetate (3 X 50 mt.), The organic phases were combined, washed with brine (50 mL), dried on anhydrous sodium sulfate;
filtered and concentrated, 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, tent-butyl N-[10-(benzyl oxy)-10,18-bis(tri fluorom ethyl)-20-oxa-2,12,13,19-tetraazatetracyclo[13.3.1.12,5.111 ,14]henicosa-1(18),11,13,15(19),16-pentaen-ylicarbamate (23 mg, 79 %). NMR
(300MHz, Chloroforrn-d): 6 9.03-9.32 (m, 1H), 8.90-9.01 (m, 1H), 7.19-7.30 (in, 5H), 4.61-4.83 (m, 2E1), 4.44-4.59 (m, 4.10-4.19 (m, 1H), 3.28-3.51 (m, 2H), 3.09-3.26 (m, 114), 2.52-2.68 (m, 1.H), 2.20-2.38 (m, 1H), 1.93-2.17 (m, 3H), 1.73-1.92 (m, 1111), 1.39-1.60 (m, 9H), 1.22-1.37 (m, 414) ppm. 19F
NMR (282 MHz, Chloroform-d) 6 -60.41 (5, 1.5F), -60.90 (s, 1.5F), -74.03 (s, 1.5F), -74.94 (br. s., 1.5F) ppm. :ESI-MS m/z calc. 641.24365, found 642.2 0,1 1r;
Retention time: 3.14 minutes (LC Method 0).

Step 8: 10-(Benzyloxy)-10,18-bis(trifluoromethyl)-20-oxa-2,1.2,13,19-tetraazatetracyclo[1.3.3.1.12,5.111,141heniensa-1,(18),1,1,13,15(1.9),16-pentaen-16-amine N
FõC "--\
00F3 Tr-Y

[00396] TFA (1.4800g. 1 ml.., 12.98 rnmol) was added to tert-butyl N410-(benzy1oxy)-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-ylicarbamate (60 mg, 0.0935 mmol) in DCM (2 at room temperature, and the mixture was stirred for 2 h. The mixture was poured in saturated sodium bicarbonate solution (20 triL) and extracted with DCM (3 X 10 ml..). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated giving as a green-yellow-gum, 10-(ben.z,y1oxy)-10,18-bis(trifitiorotriethy1)-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 (36 mg, 71 %). 111, NMR. (300 MHz, Chloroform-d) 8 7.34 (s, 1H), 7.29- 7.13 (m, 511), 5.51 - 5.06 (m, 21:1), 4.85 -4.72 (m, 11-0, 4.71 -4.60 Om 1H), 4.59 - 4.43 (m, 11-), 3.53 -327 (m, 1H), 3.25 -2.84 (m, 2H), 2.70 -2.50 (tri, 1H), 2.43 -2.21 (m, 1H), 2.14 - 1.91 (m, 311), 1.66- 1.28 (m, 6H) ppm. 191F -NMR (282 MHz, Chloroform-d): 8 -62.15 to -60,08 (m, 3F), -75.57 to -73.50 (m, 3F) ppm. ESI-MS niviz calc. 541.1912, found 542.1 (M+1)+;
Retention time: 2.65 minutes (11,C, Method 0), Step 9: 16-Amino-10,18-bis(trifluoromethyl)-20-oxa-2,12913,19-tetraazatetracyclo[1.3.3.1.12,5.111j41heniensa-1,(19),1,1,13,15,17-pentaen-10-ol i\\\
Fac ocF, N

eF
-\\ OH 3 [00397] To a nitrogen degassed solution of 10-(benzyloxy)-1.0,18-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 mle) was added SiliaCat Pd (120 mg, 0.24 mmol/g, 0.0288 mmol) and the reaction was stirred for 2 days under a hydrogen balloon at room temperature. The reaction mixture was filtered over Celite, washed with methanol and the filtrate was evaporated. The 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-bi s(tri fluorom ethyl)-20-oxa-2,12,13,19-tetraazatetracyclo [13.3.1.12,5 ,111,14]h enicosa-1(19),11,13,15,17-pentaen-10-ol (17 mg, 48%). 1H NMR (300 MHz, DI\ASO-d6) 6 7.70 -7.64 (m, 1.11), 7.60 - 7.54 (m, 1H), 6.52 (br. s, 114), 6.36 (br. s, 1H), 4.49 - 4.32 (m, 4.19 -4.04 (m, 1H), 3.04 - 2.83 (m, 2H), 2.21 - 1.82 (m, 5H), 1.65 - 1.25 (m, 6H) ppm. 19F
NMR, (282 MHz, DMSO-d6) 6 -59.86 (br. s., 1..5F), -60.32 (br, s., 1.5F), -77,43 (br. s., 1.5F), -78.51 (hr. s., 1.5F) ppm. ESI-MS trtez calc. 451.1443, found 452.2 (1\4+1r;
Retention time: 3.52 minutes (LC Method C).
Step 10: 16-Amino-10,18-bis(trilluoromethyl)-20-oxa-2,12,13,19-tetraazatetracyclo113.3.1.12,5.111,141henicosa-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[13.3,1.12,5.111,141henicosa-1(19)41,13,15,17-pentaen-10-ol (diastereomer pair 2) (Compound 9) ON' N N
N

r`i H2 N-N NI-I2 N-N NH2 N--N
diastereamer pair I diastereoener pair 2 1003981 16-Amino- I 0,18-bis(trift uorom ethyl)-20-oxa-2,12,13,19-tetraazatetracyclo[13.3.1.12,5.111,14]henicosa-1(19),11,13,15,17-pentaen-10-ol (14 mg, 0.03102 minol), a racemic mixture of 4 stereoisomers, was purified by reverse phase preparative chromatography using a C18 column and a gradient from 30 % to 65 %

acetonitrile in water containing 5 mM hydrochloric acid for 30 min giving two separate pairs of diastereomers:
1003991 The first pair of diastereomers to elute was isolated as 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) (5.6 mg, 78 %). ESI-MS
calc.
451.1443, found 452.0 (M+1)'; Retention time: 1..58 minutes (LC Method A).

1004001 The second pair of diastereorners to elute was isolated as 16-amino-10,18-bi s(trifl u orom ethyl)-20-oxa-2,12,13,19-tetraazamracyclo [13 .3.1.12,5.11 L
1 4]henicosa-1(19),11,13,15,17-pentaen-10-ol (diastereomer pair 2) (1.7 mg, 24 %). ESI-MS
nili calc.
451,1443, found 452.0 (INI-t1r; Retention time: 1.62 minutes (LC Method A).
Example 7: Preparation of (6E,12R)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo115.3.1.12,5.012,161cloeosa4(21),2,4,6,17,19-hexaen-20-amine (Compound 10) N
N
Step 1 Step 2 Oy-ko--0F3 ---------------------N¨N' I %\ il OHN¨N
a Ea mixture ______________ /
Step 3 OyNH
N¨N NH2 N-N

Step 1: tell-Butyl N-1(12R)-6-hydroxy-6,18-bis(triflooromethyl)-22-oxa-3,4,16,21-tetrazatetraeyelo[1.5.3.1.12,5.012,16]docosa-1(20),2,4,17(21),18-pentaen-20-yilearbamate N
F2Cylkõ
I ---------------------------------- N
\o--CF3 ---------------------------OH
N¨N
.0 NH N¨N
"z=r-õ
Ea mixture [00401] Into a solution of tert-b N-[(12S)-6-benzyloxy-6,18-bis(ttifluorometh.y1)-22-oxa-3,4,16,21-tetrazatetracycio[l 5.3.1.1.2,5.012,16]docosa-1(20),2,4,9,17(21),18-hexaen-20-Acarbamate (KZ mixture) (6.87g. 10.090 mmol) in MeOli (150 rnL) in a.
hydrogenation vessel was added 10 % Pd/C (2.7 g, 2.5371 nirnol), The 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 Me014 (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[15.3.1.12,5.012,161docosa-1(20),2,4,17(21),18-pentaen-20-ylicarbarnate (5.71 g, 95 %). ESI-MS in/z calc. 565.2124, found 566.5 (M-4-1)+, Retention time: 3.92 minutes. This material was used in the subsequent step without further purification (LC
Method G-).
Step 2: tert-Butyl .N-1(6E,12.R)-6,18-bis(trit1uoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo115.3.1.12,5.012,161cloeosa4(21),2,4,6,17,1.9-hexaen-20-yllearbarnate F3e, Fsc -1 CF3- o 0 N¨N sx0y.N1-1 N¨N

1004021 tert-Butyl N-[(12R)-6-hydroxy-6,18-bis(tritluoromethyl)-22-oxa-3,4,1.6,21-tetrazatetracyc1 415.3.1 .12,5.012,16]docosa-1(20),2,4,17(21.),18-pentaen-20-ylicarba.mate (14 mg, 0.02476 rnmol) was dissolved in pyridine (1.5 mL) and to the solution was slowly added POC:13 (105 L, 1.1.26 mmol). The mixture was sealed and heated at 50 C
for 20 h.
The reaction mixture was then cooled to room temperature and diluted with methanol then filtered. The resulting material was purified by reverse-phase preparative chromatography utilizing a C18 column eluting with 50 % to 99 % acetonitrile in water (+ 5 ntM HC1) using a 15 minute am to afford as a yellow solid, tert-butyl N-[(6.E,12/)-6,1.8-bis(trifluoromethy1)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012, 6]docosa-1(21),2,4,6,17,19-hexaen-20-yl]carba.mate (6.4 mg, 47 %). 111 MIR (500 MHz, DMSO-d6) 6 9.13 (s, 1H), 8.69 (s, 1H), 7.41 (t, ,/ 9.1 Hz, -1H), 4.26 (q, 8.7 Hz, 1H), 3.59 (q, 8.6, 8.2 Hz, 1H), 3.50 ¨ 3.40 (m, 1H), 3.04 (dõ! = 12.4 Hz, 1H), 2.44 (t, ¨12.7 Hz, 1H), 2.26 ¨ 2.17 (in, 1H), 2.13 ¨2.08 (m, -1H), 1.99 (s, -1H), 1.78 (tõ/ 11.1 Hz, 2H), 1.70 (d, 11.6 Hz, 1H), 1.63¨ 1.56 (m, 1H), 1.51 (s, 9H), 1.48 (s, 1H), 1.25 (s, 1H), 1.18 ¨
1.08 (Tn, 1H) ppm, ESI-MS rez calc. 547,2018, found 548.1 (M-I-1)+; Retention time: 1.84 minutes (LC Method M).

Step 3: (6E,12R)-6,18-Bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyc1o[1.5.3.1.12,5.012,161doeosa-1(21),2,4,6,17,19-hexaen-20-amine (Compound 10) k F3Ck,N `-i )K-LCF3 I ft 0 1, NiK" CF3 >,0NH N-N NH2 K1-4 1004031 To a solution of tert-butylN-1(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-ylicarbamate (17 mg, 0.03105 mmol) in DC141(0.50 mil) was slowly added TFA
(0.4 miõ
5.192 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was purified by silica gel chromatography using DCM (15 mL) providing (6E,12R)-6,18-bis(trifluoromethy1)-22-oxa-3,4,16,21-tetraazatetracycl o[15.3.1.12,5.012,16]docosa-1(2 1),2,4,6,17,19-hexaen-20-amine (11 mg, 78 %). 'H NNIR (400 MHz, Chioroform-d) 6 7.43 (s, 1H), 7.16 - 6.96 (m, 1,H), 4.59 (bs, 21-1), 4,24 (qõ/ ¨ 7,8 Hz, in), 3.40 (t, J = 9.1 Hz, 1.11), 3.00 (qd, J ¨
11,5, 4.2 Hz, 111), 2.67 -2.39 (m, 1H), 2.23 (dtdõ,/ 12.5, 6.4, 3.1 Hz, in), 2.07 (cid, J¨ 12.4, 6.1 Hz, 1H), 1.96 (dq, J = 13.3, 4.8, 4.4 Hz, 211), 1.81 - 1.66 (in, 311), 1.64 - 1,48 (in., 211), 1.26 (s, 111), 1.15 (td,J 12.1, 6.0 Hz, 1,11). ES1-MS mtz calc. 447.14938, found 448.1 (M-1-1)%
Retention time: 0.43 minutes (LC Method M).
Example 8: Preparation of (12R)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo115.3.1.12,5.012,161dorosa-1(21),2,4,17,19-pentaen-20-amine (enantiomer 1) (Compound 11) and (12R)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo115.3.1.12,5.012,161docosa-1(21),2,4,17,19-pentaen-20-amine (enantiomer 2) (Compound 12) N Step 1 F3C Step 2 I I 1,, 0 N
=->_,O,ir NH N-N N-N

n enantiomer I antiomer 2 Step 1: tert-Butyl N-1(12R)-6,18-bis(trifluoromethy1)-22-oxa-3,4,16,21-tetrauzatetracyclo[15.3.1.12,5.012,161docosa-421),2,4,17,19-pentaen-20-yl]carbamate \

.0, CF3 _____________________________________________ r -CF3 N--N N--N
-o 1004041 To a solution of tert-butyl 3V-[(6E,12R)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16idocosa-1(21),2,4,6,17,19-hexaen-20-yl]carbamate (17 mg, 0.03105 minol) in Me011 (2 ral.:) was added Pt02 (1.7 mg, 0.007486 mrnol). The flask was sealed by a rubber septum. All air was evacuated and filled by nitrogen gas 3 times. Finally, all nitrogen gas was removed, and the flask was connected to a hydrogen balloon. The reaction was stirred for 90 minutes, filtered through Celite and concentrated to give tert-buty1N-[(1210-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetrauatetracycl o[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-penta.en-20-y I
icarbamate (14 mg, 82 %). ESI-MS calc.
549.21747, found 550.2 (1\4+1).'; Retention time: 0.88 minutes (LC Method M).
Step 2: (12R)-6,18-bis(trifluoromethy1)-22-oxa-34,16,21-tetraazatetracyclo115.11.12,5.012,161doeosa-1(21.),2,4,17,19-pentaen-20-amine (enantiomer 1) (Compound 11) and (12R)-6,18-bis(trifluoromethy1)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16jdocosa-1(21),24,17,19-pentaen-20-amine (enantiorner 2) (Compound 12) N
F3c F3C F3CN
0 0 µs1 )2JCF3 w?. cF,3 -\.co cF3 NH2 N--N NH, N--N
0 emantlomer 1 enantiomer 2 1004051 To a solution of tert-butyl N-[(12R)-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-ylicarbarnate (18 mg, 0.03276 mmol) in DCM (2 mt.) was added TFA. (1 mt., 12.98 minol) at room temperature. The mixture was stirred for 45 minutes and concentrated. The residue, dissolved into 1 inL methanol, was subjected to preparative chiral SFC with 70 }IL
injections through a preparative ChiralCel ODAD column (10 X 250 mm, 5 iirn particle) eluting with 14 % Me011 in CO2 giving two single enantiomers:

1004061 The first enantiomer to elute was isolated as (12R)-6,18-bis(trifluoromethy1)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen.-20-amine (enantiomer 1) (4.2 mg, 56 %). IH NMR (400 MHz, Chloroform-d) 6 7.43 (s, 1H), 3.99 (d, I - 8.4 Hz, 111), 3.82 (ddd, 1 - 11.9, 8.1, 3.0 HZ, 11-1), 3.61 (t, J
= 8.5 Hz, itI), 3.55 (bs, 2H), 3.43 (t, zzz 9.3 Hz, 1H), 2.55 (t, I zzz 11.4 Hz, 1H), 2.39 (qõI -zzz 12.6 Hz, 1H), 2.17 (dtdõ! = 12.3, 6.3, 3.5 Hz, 1H), 1.98 (ddt, I -- 9.8, 6.8, 3.5 Hz, 2H), 1.88 - 1.75 (rn, 1.11), 1.57 (m, zzz: 28,4, 17,2, 6.4 Hz, 7H), 0.89 (q, I zzz 9.9, 9.2 Hz, 1H) ppm. ES1-MS
mtz cale. 449.16504, found 450.1 (MH-1) ; Retention time: 10.21 minutes (LC
Method P).
[00407] The second enantiorner to elute was isolated as (12R.)-6,18-bis(triftuoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-20-amine (enantiomer 2) (5.0 mg, 65 %). 1-1-1NNIR (400 MHz, Chloroform-d) 6 7.42 (s, 1.11), 4,16 (q, I -zz= 8.7, 8,2 Hz, 1E1), 4.00 (td,1 -zzz 8.4, 4.4 Hz, Hi), 3.63 (qõ:/ zzz: 8.5 Hz, I H), 3.40 (t, 1= 9.3 Hz, 1H), 2.78 (hs, 2H), 2.45 -2.37 (m, 1H), 2.23-2.1 (m, 3H), 2.03 - 1.92 (m, IR), 1.86 - 1.72 (m, 3H), 1.71 - 1.57 (m, 2R), 1.52-1.45 (m, 3H), 1,04 -0.98 (m, 1R) pprn. ESI-MS /wiz ca1e. 449.16504, found 450.1 (M 1)'; Retention time: 10.03 minutes (1-C Method P).
Example 9: Preparation of (6R,12R)-20-(methylamino)-6,18-bis(trilluoromethyl)-oxa-3,4,16,21-tetraazatetraeyelo[15.:3,1.12,5.012,16[doeosa-1(21),2,4,17,19-pentaen-6-ol (Compound 13) Step 1.. F3C....,A,N
.0 kCF3 % OH w\ OH

Step 1: (6R,12R)-20-(Methylamino)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.:3,1.12,5.012,16[doeosa-1(242,4,17,19-pentaen-6-ol (Compound 13) N
Pd [00408] To a solution of (6R,12R)-20-amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[l 5.3.1.12,5.012,16]docosa-1(21),2,4,17,19-penta.en-6-ol (30 mg, 0.06446 mmol) in DNIF (0.6 mL) at room temperature was added [bis(trimethylsilyparnino]sodium (142 uL of 1 M, 0.142 mrnol) and then iodomethane (71 p.L of 1 M, 0.071 tumor) in THF. The mixture was stirred at room temperature for 1 h. The reaction was diluted with ether and washed with aqueous 1 M NH4C1. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by silica gel chromatography using a gradient from 10 % to 35 % Et0Ae in hexanes (12 g column) giving as an orange solid, (6R,12R)-20-(methylamino)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[l 5.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaen-6-ol (13.3 mg, 43 %). 1H NMR (400 MHz, DMSO-d6) 6 7.61 (s, 1H), 7.51 (s, 1H), 6.31 (q, J=
5.4 Hz, 1H), 3,91 (qõ/ 8,3 Hz, 1E1), 3.54 (q,./ zzz 8.7 Hz, 1H), 3.32 - 3.24 (m, 1H), 2.97 (d, ¨ 4.9 Hz, 3H), 2.29 (t, 13.0 Hz, 1H), 2.14 (s, 1H), 2.02- 1.89 (m, 3H), 1.85 - 1.68 (m, 114), 1,51 (d, J ¨ 24.3 Hz, 7H), 0.84 (d, 1¨ 12.2 Hz, 1H) ppm. 19F NNIR (376 MHz, DMSO-d6) 6 -55.43, -79.24 ppm. ES1-MS tn/z calc. 479.1756, found 480.1 (M+1.)+;
Retention time: 1,94 minutes (LC Method Q).
Example 10: Preparation of (6R,12R)-20-(ethylamino)-6,18-bis(trilluoromethyl)-oxa-3,4,16921-tetraazatetracyclo115.3.1.1.2,50012,161docosa-1.(21),2,4,17,19-pentaen-6-ol ((Iompound 14) Step I F3C---LN

r-sil 3 w.\ if OH
NH2 N¨N N¨N
Step 1: (6R,12R)-20-(Ethylamino)-6,18-bisttrifluoromethy1)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3,1.12,5.012,161docosa-1(21),2,4,17,19-pentaen-6-ol (Compound 14) CAN., `/7---V, 3 NH2 N¨N
1004091 To a solution of (6R,121?)-20-amino-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetra.cyclo[15.3.1.12,5.012,16idocosa-i(21),2,4,17,19-pentaen-6-ol (30 mg, 0.06446 mmol) in DMF (0.6 mL) at room temperature was added [bis(trimethylsily1)amino]sodium (142 p.11, of 1 M, 0.142 mmol) and then bromoetliane (71 pi, of 1 M, 0,071 mmol) in THE The mixture was stirred at room temperature for 1 h, diluted with ether and washed with aqueous 1 M NRIC1 and the organic layer dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient from 10 % to 35 % Et0Ac in hexanes (1.2 g column) giving as an orange solid, (6R,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-penta.en-6-ol (18,4 mg, 58 %). NUR
(400 MHz, DMSO-d6) 6 7.60 (s, 1H), 7.55 (s, 1E1), 6.23 (t, J ---- 5.7 Hz, 114), 3.98 - 3.85 (m, 1H), 3.54 (qõ/ = 8.6 Hz, 1H), 3.37 (m, 3H), 2.29 4, I = 13.7 Hz, 1H), 2.14 (m, 1,11), 2.03 - 1.88 (m, 21-1), 1.83 - 1.70 (m, 1H), 1.65 - 1.36 (m, 8H), 1.22 (t, 1 7.0 Hz, 3H), 0.84 (s, 1H) ppm. PT NNIR (376 MHz, DMSO-d6) 6 -55.40, -79.25 ppm. ESI-MS

m./z calc. 493.19125, found 494.1 (M-+-1)+; Retention time: 2.03 minutes (LC
Method Q) .
Example 11: Preparation of (6S,12R)-20-(methylamino)-6,18-his(trifluoromethyl)-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,16]docosa-1(21),2,4,17,19-pentaeta-6-ol (Compound 15) N`

C Step I
j 0 eF y-1 õ\,0y1,70CHF3 Step 1: (6S,12R)-20-(Methylamino)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo115.11.1.2,5.012,161docosa-1(21),2,4,17,19-pentaen-6-ol (Compound 15) N
CF

1004101 To a solution of (6S,12R)-20-amino-6,18-bis(trifluoromethy0-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,1.6]docosa-1(21),2,4,17,19-pentaen-6-ol (30 mg, 0.06446 mmol) in DMF (0.6 mL) at room temperature was added [bis(trimethylsily1)aminolsodium (142 piL of 1 M, 0.142 mmol) and then iodomethane (71 fit of I M, 0.071 mmol) in TI-IF. The mixture was stirred at room temperature for 1 h, diluted with ether and washed with aqueous 1 M INTh,CI and the organic layer was dried (iMgSO4), filtered and evaporated. The residue was purified by silica gel chromatography using a gradient from 10 % to 35 % Et0Ac in hexanes (12 g column) giving as a yellow solid, (65`,12/)-20-(methylamino)-6,18-bis(nifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[15.3.1.12,5.012,161docosa-1(21),2,4,17,19-pentaen-6-ol (15.5 mg, 50 %). -MAR
(400 MHz, DMSO-d6) 6 7.57 (s, IH), 7.51 (s, 1111), 6.33 (qõ./ = 5.0 Hz, 1H), 4.03 (q, I - 7.3, 6.8 Hz, 1H), 3.55 (q, 1- 8.6 Hz, 111), 3.31 -3.22 (m, 1H), 2.97 (d, 1 -4.9 Hz, 3H), 2.44 - 2.25 (m, 1H), 2.17 (d, I = 7.3 Hz, 1H), 2.05 (q, J 8.5 Hz, 1111), 1.93 (s, Ill), 182- 1.62 (m, 4H), 1.49 (ddd, 1=340, 18.0, 7,7 Hz, 5H), 0.97 - 0.83 (m, 114) ppm. 19F NMR (376 MHz, DMSO-d6) 6 -55.57, -76,40 ppm. ES1-MS cafe.
479.1756, found 480.2 (M+1)% Retention time: 1.93 minutes (LC Method Q).
Example 12: Preparation of (6S,12R)-20-(ethylamino)-6,18-bis(trifluoromethyl)-oxa-3,4,16,21.-tetraazatetraeyelo[15.3.1.12,5.012,11.61docosa-1(21),2,4,17,19-pentaen-6-ol (Compound 16) , N INN
Step I
f--- 3 Step 1: (6S,12R)-20-(Ethylamino)-6,18-bis(triflooromethyl)-22-oxa-3,4,16,21-tetraazatetracyclo[1.5.3.1.12,5.012,16jdoeosa-1(21),2,4,17919-pentaen-6-ol (Compound 16) C-)NN'oN

eF
3 -oil 3 [00411] To (6S,12R)-20-amino-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 (30 mg, 0.06446 mrnol) in DMF (0.6 triL) at room. temperature was added [bis(trimethylsilyparnino]sodium (142 uL of 1 M, 0.142 mmol) and then bromoethane (T1 pi: of 1 M, 0.071 minor) in THF. The mixture was stirred at room temperature for 1 h. then diluted with ether and aqueous 1 M NE14C1. Separated the layers and the organic layer was dried (IVIgSO4), filtered and evaporated. The residue was purified by silica gel chromatography (12 g column) using a gradient from 10 % to 35 % Et0Ae in h.exanes which provided as a yellow solid, (6S,12R)-20-(ethylarnino)-6,18-bis(trifluoromethyl)-22-oxa-3,4,16,21-tetraazatetracycl.o [15,3.1.12,5.01.2,16] docosa.-1(21),2,4,17,19-pentaen -6-01 (16.6 mg, 52 %). -MAR
(400 MHz, DMSO-d6) d 7.55 (s, 2H), 6.24 (tõI 5.7 Hz, 1H), 4.03 (q, 1 - 8.7 Hz, 111), 3.55 (q, 1 - 9.0, 8.5 Hz, 1H), 3.21-3.40 (m, 31-1), 2.44 - 2.26 (m, 1H), 2.18 (t, I = 7.2 Hz, 1H), 2.03 (tdõ ./ = 13.8, 12.6, 7.4 Hz, 1H), 1.94 (d, J = 11.7 Hz, 1H), 1.72 (dci, J ¨ 21.7, 13.1, 11.4 Hz, 3H), 1.47 (ddt, I ¨ 41.4, 15.4, 9.5 Hz, 6H), 1.24 (t, 1 ¨ 7.1 Hz, 3H), 0.91 (td, J ¨ 11.8, 6.0 Hz, 111), 19F NNIR (376 MHz, DMSO-d6) d -55.55, -76.42. ESI-MS m/z calc. 493.19125, found 494.1 (M+1)+; Retention time:
2.02 minutes (LC Method Q).
Example 13: Preparation of 19-amino-6,17-bis(ttilluoromethyl)-21-oxa-3,4,15,20-tetraazatetracyclo1143.1.12,5.011,151henicosa-1(20),2,4,16,18-pentaen-6-ol (diastereomer pair 1) (Compound 17) and 19-amino-6,17-bis(trilluoromethyl)-21-oxa-3,4,15,20-tetraazatetraeyelo114.3.1.12,5.011,151henieosa-1(20),2A16,18-pentaen-6-01 (diastereomer pair 2) (Compound 18) 1,,1"
F3C, õõ)., F3C -1,.....,N
l-III ' N1-1(0 + Step 2 --* .// Step 1 F3C =-t-,,N
, Step 3 11..,., ____________ 'N,------"' 1 >'o y `0 >,..0N,T.z a i\ cc.....
r\ 0 N Ii N 5-F3C r YLN H Cii' 'fCF3 Step 4 -------------------------------- ..- .-1..
; ' N

-.1.5-..."_.,i(OAC F3 Step 5 >0 NH 0 .,.._ 1 y 0,__NH N¨N
r n .....õ,,,.;, N N
F3C,_,.--Ls. N \
Step 6 F3C--1,-, -\.. F3C
/ 0 CF -' ,,,i,--= , 3 II ,J, ' 0 .--cF.3 4- I 03\---CF3 -.. .õ.0,_,NH ' ..,1 11 ',..,...,-,, NH N¨N -... Oy NH IN1-34 diastereemer pair 1 diastereomer per 2 Step 7 Step 8 CI ¨
N N`
F3C,....,-;L::.--\,...1 y 1 ././ 0NA-- CF3 F3CN
il J.c\,0 iykl 0¨CHF3 NH2 N¨N NH2 N¨N
diastereemer pair 1 diastereomer pair 2 Step 1: Methyl 3-ibis(tert-hutoxycarhony1)aminol-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-1-y1)pyridine-2-carboxylate Br F3C;L'N

0 .N >
0 r 0lT

1004121 In a 250-mL sealed vessel, 2-vinylpyrrolidine (879 mg, 9.047 mmol), IAEA
(4.75 mL, 27.27 mmol) and methyl 34bis(tert-butoxycarbonypaminoi-6-bromo-5-(tritluoromethyl)pyridine-2-carboxylate (2.5 g, 5.007 mmol) were combined in acetonitrile (28 mL) and the mixture was heated at 80 C for 18 hours. The reaction mixture was cooled to ambient temperature and the solvent removed in vacua The residue was diluted with Et0Ac (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 c/'/0 ethyl acetate in hexanes giving as a tan solid, methyl 3-[bis(tert-butoxycarbonypaminori-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-1-y1)pyridine-2-carboxylate (1.93 g, 75 %). -NMI?, (400 MHz, DMSO-d6) 8 8.04 (s, 1H), 5.74 (dd.dõ./ = 16.7, 10.3, 6.1 Hz, 1H), 5.16 - 5.06 (m, 1H), 5.03 - 4.90 (m, 2H), 3.79 (s, 3H), 3.65 (p j ---- 8.6 Hz, 114), 3.43 (t, J 8.3 Hz, 1H), 2.14 11,9, 6.5 Hz, I H), 2.02 - 1.92 (m, 1H), 1.90 - 1.78 (m, 1H), 1.71 (ddt, 1 11.9, 9.2, 7.0 Hz, 1H), 1.35 (s, 18H) ppm. ES1-MS nui calc. 515.2243, found 516.2 (M:-F1); Retention time: 1,79 minutes (1_,C. Method .1).
Step 2: 3-(tert-Butoxycarbotaylamino)-5-(trifluoromethy1)-6-(2-vinylpyrrolidin-yl)pyridine-2-carboxylic acid 0,1 N`
OH

rs, [004131 To a solution of methyl 3-[bis(tert-butoxycarbonyl)aminoi-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-111)ppidine-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 mixture was stirred at 60 C for 4 h. Tiff and methanol were removed by evaporation, then 30 mL of 10 % aqueous HCI was added and extracted with Et0A.c (2 X 50 mL). The organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
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-(ieri-butoxy carbonyl amino)-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-1-yppyridine-2-carboxylic acid (1.35 g, 90%). 1HNMR (400 MHz, DMS046) 6 13.46 (s, 1H), 9.69 (s, 1H), 8.64 (s, I El), 5.71 (Mil, J zzz: 16,9, 10,2, 6,5 Hz, I El), 5.18 (ddd, Jzzz: 17.1, 2.1, 1.1 Hz, 1H), 5.00 - 4.88 (m, 2H), 3.61 (q,1 8.5 Hz, 1H), 3.29 (s, 1H), 2.12 (dtdõ! =
11.2, 6.5, 3.7 Hz, 111), 1.93 (dtd, I - 1.3.3, 6.7, 3.2 Hz, 1H), 1.85 - 1.75 (m, 111), L73 - 1,62 (m, 1H), 1.47 (s, 9H) ppm. ES1-MS rtilz calc. 401.15625, found 402.2 (M+1)+;
Retention time:
1.72 minutes (LC Method A).
Step 3: tert-Butyl N42-11[2.-benzyloxy-2-(trifluoromethy1)hev-5-enoyllaminolcarbamoyli-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-1-y1)-3-pyridyl]carbatuate J

;. N + H2N HN
'CF
.HCI H T
I Ii >J0y NH 0 õ.00 [004141 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 DI A (2.25 mL, 12.92 mmol) followed by HATU (1.7 g, 4.471 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 1.0 % citric acid solution followed by brine. 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 70 % ethyl acetate in hexanes giving as a yellow solid, tert-butyl N-12-11[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]aminoricarbamoyli-5-(trifluoromethy1)-6-(2-vinylpyrrolidin-1-y1)-3-pyridyl]carbamate (1.75 g, 79 %). ESI-MS
m/z calc. 685.2699, found 686.2 (WO', Retention time: 2.3 minutes (LC Method J).
Step 4: tert-,Buty111424541-benzyloxy-1-(tritluoromethyl)pent-4-enyll-1,3,4-oxadiazol-2-y11-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-1-y1)-3-pyridyllcarbamate N
Jc.
1--cF3 y 0 õay,. r. N-N
0=8 [00415] A solution of teri-butyl N42-[[[2-benzyloxy-2-(trifluoromethyphex-5-enoyl]amino]carbamoyli-5-(trifluoromethyl)-6-(2-vinylpyrrolidin-1.-y1)-3-pyridylicarbamate (1.75 g, 2.552 mmol) and DIE, A (1.55 triL, 8.899 mmol) in acetonitrile (40 ml...) was heated to 50 C, then p-toluenesulfonyl chloride (760 mg, 3.986 mmol) was added in 3 portions. 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 mil) 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-A-5-(trifluoromethyl)-6-(2-vinylm,Trolidin-1-y1)-3-pyridylicarbamate (1.69 g, 99 %). 11-1 NAIR (400 MHz, DMSO-d6) 6 9.49 (s, 1H), 8.65 (s, 1H), 7,45 ¨
7.31 (m, 5H), 5.86 (m, --NA, 16,7, 10,1, 6,4 Hz, 1E1), 5.64 (m, J 17.1, 10.2, 6.9, 5.0 Hz, 1H), 5.22¨ 5.12 (m, -1H), 5.12 ¨4.94 (m, 2H), 4.90 (dddd, J= 19.0, 10.2, 1.9, 0.8 Hz, 1H), 4.83 4,70 (m., 2H), 4.65 (ddõI zzz 11.0, 6.9 Hz, 1.11), 3.65 (q, J 8,5 Hz, 1H), 3.39 (tõI
8.7 Hz, 1H), 2.57 (m, 15.7, 10.8, 5.7 Hz, -1H), 2.48 --2.37 (m, 1H), 2.35 ¨2.20 (m, 21-1), 2.10 (dt, ¨ 11.6, 5.8 Hz, 111), 2.03 ¨ 1.93 (in, 1H), 1.85-1.75 (m., 11:1), 1.75 ¨ 1.65 (m, 1H), 1.46 (s, 9H) ppm. ES1-MS m/z calc. 667.25934, found 668.2 (11,1.+1.)'; Retention time: 2.23 minutes (IC Method M), DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

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Claims (87)

1. A compound selected from compounds of Formula I:
and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:
X is selected from -N(Rx1)- and Ring A is a 4- to 6-membered heterocyclyl optionally substituted with 1-3 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, -0Rx2, and -N(Rx2)2), and C3-C8 cycloalkyl;
each Rx2 is independently selected from II and C1-C6 alkyl;
each Y is independently selected from -C(RY)2-, -0-, -CO-, -NR"-, and wherein each RYN is independently selected from H, CI-C4 alkyl, and CO2R"1, wherein each RYN1 is independently selected from C1-C4 alkyl and C3-C6 cycloalkyl;
each RY is independently selected from hydrogen, hydroxy, halogen, CI-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, Ci-C6 alkoxy, and Q), C3-C8 cycloalkyl, C6-Cio aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, -ORY1, -CO2R", -CORY1, -CON(R")2, and -N(RY1)2;
or two 14" on the same atom are taken together to form a ring selected from C3-C8 cycloalkyl and 3- to 7-membered heterocyclyl; or two WI, 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 WI is independently selected frorn hydrogen and C i-C6 alkyl, or two RY1 bonded 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 Cl-C6 alkoxy), ^ C3-C8 cycloalkyl, = 5- to 10-membered beteroaryl, and = 3- 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 frorn:
o halogen, O MO, O C6-Clo aryl (optionally substituted with 1-3 groups independently selected from halogen and -0CF3), and o C3-C8 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, and -NHCOMe), o Cl-C6 alkoxy, o C6-C10 aryl (optionally substituted with 1-3 groups independently selected from C1-C6 alkyl), and o C3-Cg cycloalkyl, ^ C6-Clo aryl optionally substituted with 1-3 groups independently selected.
from:
o halogen, o CN, o CI-Cs alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), o CI-C6 alkoxy optionally substituted with 1-4 groups independently selected from:
= halogen, = C3-C8 cycloalkyl (optionally substituted with CF3), o C3-Cg cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF3, OCF3, and Ci-C6 alkyl), and o 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-C8 cycloalkyl (optionally substituted with 1-3 CF3 groups), and o 3- to 10-membered heterocyclyl, = 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:
o Ci-Cs alkyl (optionally substituted with 1-3 groups independently selected from oxo and C3-C8 cycloalkyl), and o oxo;
each WI is independently selected from. halogen, CI-Cs fluoroalkyl, C1-Cs alkyl (optionally substituted with a group selected from hydroxy, Cs-Cio aryl, and 5-to 6-membered heteroaryl), -0R2, -N(R2)2, -0O2R2, -CO-N(R2)2, -CN, C3-C8 cycloalkyl, Cs-Cio aryl, 5- to 6-membered heteroaryl (optionally substituted with 1-3 groups independently selected from C1-C6 alkyl), 3- to 6-membered heterocyclyl, -B(0R2)2, -S02R2, -SR2, -SOR2, -PO(0R2)2, and -PO(R2)2;
each R2 is independently selected from hydrogen, Ci-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), CI-Cs fluoroalkyl, and Cs-Cis aryl (optionally substituted with 1-3 groups independently selected from CI-Cs fluoroalkyl and CI-Cs fluoroalkoxy);

Z is selected from wherein Ring C is selected from C6-Ci0 aryl and 5- to 10-membered heteroaryl;
WI is selected from hydrogen, C1-C6 alkyl (optionally substituted with 1-3 hydroxy), C1-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-Clo aryl, and 5- to 6-membered heteroaryl;
1z2 is selected frorn hydrogen, halogen, hydroxy, INH, NH(CO)(Ci-C6 alkyl), and C1-C6 alkoxy (optionally substituted with 1-3 groups independently selected from (73-Cio cycloalkyl), or RP and Rz2 taken together form a group selected from oxo and -A-OH;
each Rz3 is independently selected frorn hydroxy, CI-C6 alkoxy, C4-C6 alkyl, and C6-Cio aryl; or two R" are taken together to forrn a 3- to 6-membered.
heterocyclyl;
n is selected frorn 4, 5, 6, 7, and 8; and m is selected frorn 0, 1., 2, and 3,
2. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein X is -N(Rx1)-.
3. The cornpound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein X is
4. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein X is selected from:
5. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein:
each R Y is independently selected from hydrogen, hydroxy, halogen, ci-c6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy, C1-C6 alkoxy, and Q), (23-(78 cycloalkyl, C6-C10 aryl (optionally substituted with 1-3 groups independently selected from halogen), 5- to 10-membered heteroaryl, -CO2RY1, and -CON(R Y1)2;
or two RY on the same atom are taken together to form a ring selected from C3-Cs cycloalkyl and 3- to 7-membered heterocyclyl;
or two le, 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 lel is independently selected from hydrogen and C1-C6 alkyl, or two RY1 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 le is independently selected from:

hydrogen, hydroxy, 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 Ci-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 Ci-C6 alkoxy) and pyridyl.
12. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 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 n 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:

15. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 14, wherein each W is independently selected from halogen, CI-Có fluoroalky!, C1-C6 alkyl (optionally substituted wi.th a group selected from Cs-Cm aryl), -0R2, -N(R2)2, -CO-N(R2)2, -CN, alkoxy, C3-C8 cycloalkyl, C6-C10 aryl, 5- to 6-membered heteroaryl (optionally substituted with I -3 groups independently selected from C1-C6 alkyl), 3- to 6-membered heterocyclyl, -B(0102, -SO2R2, -SR2, -SOR2, and -PO(R2),.
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-Cio aryl (optionally substituted with 1-3 groups independently selected from Cl-C6 fluoroalkoxy).
17. The cornpound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 16, wherein each R1 is independently selected from -Br, -CF3, -N112, -CH3, -CH(CH3)2, -CN, -NH(CH3), -NH(CH2CH3), -CONH2, PO(CH3)2, B(OF1)2, phenyl, pyridyl, tetrahydropyranyl, tetrahvdrofuranyl, cyclopropyl, cyclohexyl, imidazolyl,
18, The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 17, wherein Z is selected from ; wherein Ring C is selected from C6-C10 aryl.
19. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 18, wherein the group:
is selected from:
20. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 19, wherein the group:

21. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 20, wherein Rzl is selected from hydrogen, Cl-C6 alkyl (optionally substituted with 1-3 hydroxy), Ci-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C6-Cio 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 R22 is selected from hydrogen, halogen, hydroxy, and Ci-C6 alkoxy (optionally substituted with 1-3 groups independently selected from C3-C1.0 cycloalkyl).
23. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 22, wherein:
WI is selected from hydrogen, Ci-C6 alkyl (optionally substituted with 1-3 hydroxy), CI-C6 fluoroalkyl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl, and C6-Cio aryl; and Rz2 is selected from hydrogen, halogen, and hydroxy;
or Rzl and Rz2 taken together form a group selected from oxo and =N-OH.
24. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 23, wherein:
Rzl is selected from hydrogen, CH3, CF3, CH2OH, phenyl, cyclopropyl, and tetrahydropyranyl; and R72 is selected from hydrogen, halogen, and hydroxy;
or Rzl and Rz2 taken together form a group selected from oxo and :::N-OH.
25. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 24, wherein R72 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:

27. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 26, wherein m is 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:
30. A pharmaceutical composifion 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).
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 phaimaceuti cal 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) comprise(s) (R)-1-(2,2-difluorobenzo[d][1,3idioxo1-5-0)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hy droxy-2-m ethylpropan do1-5-yi)cyclopropan ecarboxami de (Compound II):
35. The pharmaceutical composition according to any one of claims 31 to 34, wherein the one or more additional therapeutic agent(s) comprise(s) 3464142,2-dif1uorobenzo[d][1,3idioxol-5-yl)cyclopropanecarboxamido)-3-methylpyri yObenzoic acid (Compound W):
36. The pharmaceutical composition according to any one of claims 31 to 35, wherein the one or more additional therapeutic agent(s) comprise(s) dimethylpyrazol-4-yi)sulfonyl-643-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-y11-2-[(4S)-2,2,4-trimethy1pyrro1idin-1-y1ipyridine-3-carboxamide (Compound V):

37. The pharmaceutical composition according to any one of claims 31 to 36, wherein the one or more additional therapeutic agent(s) comprise(s) N-(henzenesu1fony1)-6-[34211-(trif1uoromethy1) cyclopropyllethoxy]pyrazol-1-y1]-2-[(4S)-2,2,4-trimethvlpyrrolidin-l-yl]pyridine-3-carhoxamide (Compound Vt):
38. The pharmaceutical composition according to any one of clairns 31 to 37, Nvherein the one or more additional therapeutic agent(s) comprise(s) (148)-84342-dispiro[2Ø2.1]heptan-7-y1lethoxy)-1H-pyrazol-1-y111-12,12-dimethy1-26-thia-3,9J 1,18,23-pentaazatetracyclo [17.3.1.111,14.05,101tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound Vti):
39. The pharmaceutical composition according to any one of claims 31 to 38, wherein the one or more additional therapeufic agent(s) comprise(s) (11R)-6-(2,6-dimethylpheny1)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-y1}-9-oxa-2X6-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 VEM:

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, FUL-169, ARN5562, ARN21586, ARN22081, 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 N-(5-hydroxy-2,4-di-tert-buty1-pheny1)-4-oxo-1H-quinoline-3-carboxamide (Compound and N-(2-(tert-buty1)-5-hydroxy-4-(2-(methyl-d3)propan-2-y1-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound III-4
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, G1PG1837, G1PG2451/ABBV-2451 (Icenticaftor), GLPG3067/ABBV-3067 (Navocaftor), and ABBV-191.
46, The phannaceuti cal composition according to any one of claims 31 to 45, wherein the one or more additional therapeutic agent(s) comprise(s) a C.FTR amplifier.
47. The pharmaceutical composition accordMg 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) comprise(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 phannaceuti cal 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 accordMg 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 clairns 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, ETD001, 0552, CiS-9411, GS-5737, P-1037 (VX-371), .P-1055 (VX-551), AZD5634, SPX-101, loms-ENaC-2.5 Rx, BI 1265162, AZ5634, and A1O-ENaC1001.
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 INIEM16A
rn odul ator.
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) compri se(s) a GM39 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 treafing cystic fibrosis, comprising administering an effective amount of the compound, salt, or deuterated derivative according to any one of claims 1 to 29 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, frther 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 CFIR 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) (R)-1-(2,2-difluorobenzo[d][1,3idioxol-5-y l)-N-( I -(2,3-di by droxypropyl)-6-11 uoro-2-(1-hy droxy-2-methylpropan-2-y1)-1H-indol-5-ypcyclopropanecarboxamide (Compound
63. The method according to any one of claims 59 to 62, wherein the one or more additional therapeutic agent(s) comprise(s) 3464142,2-di ft uorobenzo[d] [1,3idi oxo1-5-yl)cy ci opropanecarboxam ido)-3-m ethylpyri din-2-yl)henzoic acid (Compound IV):

64. The method according to any one of claims 59 to 63, wherein the one or more additional therapeutic agent(s) comprise(s) N-(1,3-dimethylpyrazo1-4-ypsulfony1-643-(3,3,3-trifluoro-2,2-dimethy1-propoxy)pyrazo1-1-yi]-2-[(45)-2,2,4-trirnethylpyrrolidin-1-yllpyridine-3-carboxamide (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) N-(henzenesulfon.y1)-6434241-(trifluoromethyl) cyc1opropy1iethoxy]pyrazo1-1-y11-244S)-2,2,4-trirnethylpyrrolidin-1-ylipyridine-3-earboxamide (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) (14,5)-843-(2-{dispiro[2Ø2.1Theptan-7-yllethoxy)-1H-pyrazol-1-y11-12,12-dimethy1-22.6-thia-3,9,11,18,23-pentaazatetracyclo [17.3. 1.111,14.05,10itetraeosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound VII):
67. The method according to any one of claims 59 to 66, wherein the one or more additional therapeutic agent(s) comprise(s) (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropy1)-12-{ spiro[2.3]hexan-5-y1}-9-oxa-2X6-thia-3,5,12,19-tetraazatricyclo[12.3.1 .14,81]nonadeca-1.(17),4(19),5,7,14( 8),15-hexaene-2,2,1.3-trione (Compound VIM:
68. 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 PT1-428, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, ABBV-2851, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, and PT1-801,
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 rnore 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 CFIR potentiator.
72, The method according to any one of clainls 59 to 71, wherein the one or rnore additional therapeutic agent(s) comprise(s) a compound selected from N-(5-hydroxy-2,4-di-ieri-butyl-phenyl)-4-oxo-1/1-quinoline-3-carboxamid.e (Compound and N-(2-(tert-buty 0-5-hydroxy-4-(2-(methy -d3)propan.--2--yl-i, 1,1,3,3,3-d6)pheny1)-4-oxo-1,4-dihydr0quino1ine-3-carboxamide (Compound in-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, PT I-808, GLPG1837, (ìLPG2451./ABB V-245 I (lcenti caftoi), GLPG3067/ABBV-3067 (Navocaftor), and ABBV-191.
74, The method according to any one of claim.s 59 to 73, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR arnplifier.
75. The method according to any one of claims 59 to 74, wherein the one or more additional therapeutic agent(s) comprise(s) PT1-428.
76. The method according to any one of clairns 59 to 75, wherein the one or more additional therapeufic agent(s) comprise(s) a C,FTR 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 clairns 59 to 77, wherein the one or more additional therapeutic agent(s) comprise(s) a nucleic acid therapy.
79. The rnethod according to any one of claims 59 to 78, wherein the one or rnore additional therapeutic agent(s) comprise(s) at least one agent selected from 1VI1T5005, Lunar-CF, and RCT223.
80. The method according to any one of clairns 59 to 79, wherein the one or more additional therapeutic agent(s) cornprise(s) an ENaC inhibitor.
81. The rnethod according to any one of claims 59 to 80, wherein the one or more additional therapeutic agent(s) cornprise(s) arnilori de, ETD001, CF552, GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5 Rx, B1 1265162, AZ5634, and ARO-ENaC1001.
82. The rnethod according to any one of claims 59 to 81, wherein the one or more additional therapeutic agent(s) comprise(s) a IMEM16A 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.
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 A.gonist.
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 cornposition according to any one of clairns 30 to 57 for use in the treatment of cystic fibrosis.
87. Use of the compound, salt, or deuterated derivative of any one of clairns 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.
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WO2023224931A1 (en) * 2022-05-16 2023-11-23 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
WO2023224924A1 (en) 2022-05-16 2023-11-23 Vertex Pharmaceuticals Incorporated Solid forms of a macrocyclic compounds as cftr modulators and their preparation
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WO2024056798A1 (en) 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Macrocyclic cftr modulators
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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