Modulators of cystic fibrosis transmembrane conductance regulator

This application claims the benefit of U.S. Provisional Application No. 63/063,194, filed on Aug. 7, 2020, the contents of which are incorporated by reference in its entirety.

The invention relates to modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing the modulators, methods of treating cystic fibrosis and CFTR-mediated disorders using such modulators and pharmaceutical compositions, and processes for making such modulators.

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.

In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lung and accompanying microbial infections that ultimately cause death in CF patients. 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.

Sequence analysis of the CFTR 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, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. 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.

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 for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of 1480 amino acids that encode a protein which is made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.

Chloride transport takes place by the coordinated activity of ENaC (epithelial sodium channel) and CFTR present on the apical membrane and the Na + -K + -ATPase pump and Cl − channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl − channels, resulting in a vectorial transport. Arrangement of Na + /2Cl − /K + co-transporter, Na + -K + -ATPase pump and the basolateral membrane K + channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride. 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.

A number of CFTR modulators have recently been identified. These modulators can be characterized as, for example, potentiators, correctors, potentiator enhancers/co-potentiators, amplifiers, readthrough agents, and nucleic acid therapies. CFTR modulators that increase the channel gating activity of mutant and wild-type CFTR at the epithelial cell surface are known as potentiators. Correctors improve faulty protein processing and resulting trafficking to the epithelial surface. Ghelani and Schneider-Futschik (2020) ACS Pharmacol. Transl. Sci. 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 molecule CFTR 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.

One aspect of the invention provides novel compounds, including compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIe, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

For example, compounds of Formula I can be depicted as:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 ,

—CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each R 1 is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen and hydroxy), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

wherein Ring C is selected from C 6 -C 10 aryl and 5- to 10-membered heteroaryl;

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 6 -C 10 aryl; or two instances of R Z3 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.

In some embodiments, X is —O—.

In some embodiments, each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 3 -C 8 cycloalkyl, and —OR Y1 , wherein Q and R Y1 are as defined above. In some embodiments, —OR Y1 is —OH.

In some embodiments, each Q is independently selected from C 3 -C 8 cycloalkyl and C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl. In some embodiments, each Q is independently selected from:

In some embodiments, each R Y is independently selected from: hydrogen, fluorine,

In some embodiments, Ring B is selected from C 3 -C 8 cycloalkyl and phenyl optionally substituted with 1-3 groups independently selected from halogen. In some embodiments, Ring B is selected from:

In some embodiments, n is selected from 4, 5, and 6.

In some embodiments, —(Y) n — is a group selected from:

In some embodiments, each R 1 is independently selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen and hydroxy), —N(R 2 ) 2 , and —CO 2 R 2 , wherein R 2 is as defined above. In some embodiments, each R 1 is independently selected from —CF 3 , —NH 2 , —NH(CH 2 CH 3 ), CO 2 H, and CH 2 OH.

In some embodiments, each R 2 is independently selected from hydrogen and C 1 -C 6 alkyl.

In some embodiments, Z is selected from

wherein R Z1 , R Z2 , and Ring C are as defined above. In some embodiments, Z is

wherein R Z1 and R Z2 are as defined above. In some embodiments, Z is

wherein R Z1 and R Z2 are as defined above. In some embodiments, Z is

wherein R Z1 and R Z2 are as defined above. In some embodiments, Z is

wherein R Z1 and R Z2 are as defined above, and wherein (R) refers to the stereochemical designation of the central carbon atom under the Cahn-Ingold-Prelog convention. In some embodiments, Z is

wherein R Z1 and R Z2 are as defined above, and wherein (S) refers to the stereochemical designation of the central carbon atom under the Cahn-Ingold-Prelog convention.

In some embodiments, the group:

is selected from:

In some embodiments, the group:

is selected from:

In some embodiments, R Z1 is selected from hydrogen and C 1 -C 6 alkyl (optionally substituted with 1-3 groups selected from halogen). In some embodiments, R Z1 is selected from hydrogen and —CF 3 . In some embodiments, R Z1 is —CF 3 .

In some embodiments, R Z2 is hydroxy.

In some embodiments, Z is selected from:

In some embodiments, Z is

In some embodiments, Z is

In some embodiments, Z is

In some embodiments, Z is

In some embodiments, m is selected from 1 and 2.

In some embodiments, compounds of the invention are encompassed by Formula I′

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is —O—;

each Y is independently selected from —C(R Y ) 2 —, —O—, and

each R Y is independently selected from hydrogen and C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q);

Ring B is selected from C 3 -C 8 cycloalkyl groups:

each Q is independently selected from C 3 -C 8 cycloalkyl and C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl,

each R 1 is independently selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen) and —NH 2 ;

Z is

R Z1 is selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen);

R Z2 is hydroxy;

n is selected from 5 and 6; and

m is 2.

In some embodiments, each Q of Formula I′ is independently selected from:

In some embodiments, each R Y of Formula I′ is independently selected from: hydrogen,

In some embodiments, Ring B of Formula I′ is

In some embodiments, —(Y) n — of Formula I′ is a group selected from:

In some embodiments, R Z1 in Formula I′ is —CF 3 .

In some embodiments, Z in Formula I′ is

In some embodiments, Z in Formula I′ is

In some embodiments, n in Formula I′ is 5. In some embodiments, n in Formula I′ is 6.

In some embodiments, compounds of the invention are encompassed by Formula I″:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl;

n is selected from 4, 5, 6, and 7; and

m is selected from 0, 1, 2, and 3.

In some embodiments, X in Formula I″ is —O—.

In some embodiments, each Y in Formula I″ is independently selected from —C(R Y ) 2 —, —CO—, and

wherein R Y and Ring B are as defined for Formula I″.

In some embodiments, each Y in Formula I″ is —C(R Y ) 2 —, wherein R Y is as defined for Formula I″.

In some embodiments, each R Y in Formula I″ is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), and —OR Y1 , wherein R Y1 and Q are as defined for Formula I″.

In some embodiments, each R Y in Formula I″ is independently selected from: hydrogen,

wherein Q is as defined for Formula I″.

In some embodiments, each Q in Formula I″ is independently selected from:

C 3 -C 8 cycloalkyl, C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.

In some embodiments, each Q in Formula I″ is independently selected from:

In some embodiments, Ring B in Formula I″ is selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen.

In some embodiments, Ring B in Formula I″ is selected from:

In some embodiments, —(Y) n — in Formula I″ is a group selected from:

In some embodiments, each in Formula I″ is independently selected from C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen) and —N(R 2 ) 2 , wherein R 2 is as defined for Formula I″. In some embodiments, each R 1 in Formula I″ is independently selected from —CF 3 and —N(R 2 ) 2 , wherein R 2 is as defined for Formula I″.

In some embodiments, each R 2 in Formula I″ is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen). In some embodiments, each R 2 in Formula I″ is independently selected from hydrogen and C 1 -C 6 alkyl. In some embodiments, each R 2 in Formula I″ is hydrogen.

In some embodiments, Z in Formula I″ is

wherein R Z1 and R Z2 are as defined for Formula I″. In some embodiments, Z in Formula I″ is

wherein R Z1 and R Z2 are as defined for Formula I″. In some embodiments, Z in Formula I″ is

In some embodiments, R Z1 in Formula I″ is selected from C 1 -C 6 alkyl (optionally substituted with 1-3 groups selected from halogen). In some embodiments, R Z1 in Formula I″ is —CF 3 .

In some embodiments, R Z2 in Formula I″ is hydroxy.

In some embodiments, n in Formula I, I′, and/or I″ is selected from 4, 5, and 6. In some embodiments, n in Formula I, I′, and/or I″ is 5. In some embodiments, n in Formula I, I′, and/or I″ is 6.

In some embodiments, m in Formula I, I′, and/or I″ is selected from 1 and 2. In some embodiments, m in Formula I, I′, and/or I″ is 1. In some embodiments, m in Formula I, I′, and/or I″ is 2.

Another aspect of the invention provides pharmaceutical compositions comprising at least one compound chosen from the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives 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 the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, and at least one pharmaceutically acceptable carrier, optionally as part of a pharmaceutical composition comprising at least one additional component, to a subject in need thereof.

In certain embodiments, the pharmaceutical compositions of the invention comprise at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof. In some embodiments, compositions comprising at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof 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, and pharmaceutically acceptable salts and deuterated derivatives thereof.

Another aspect of the invention provides methods of treating the CFTR-mediated disease cystic fibrosis comprising administering to a patient in need thereof at least one compound chosen from the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, and optionally further administering one or more additional CFTR modulating agents selected from (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II), N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound III) or N-(2-(tert-butyl)-5-hy droxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound III-d), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane carboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV), N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound V), N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound VI), (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound VII), (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound VIII); N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound IX), and N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound X).

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:

disclosed in Journal of Cystic Fibrosis (2018), 17(5), 595-606, and:

disclosed in WO 2016/105485. In one embodiment, the additional CFTR modulating agent is ASP-11. In one embodiment, the additional CFTR modulating agent is PTI-428.

Another aspect of the invention provides methods of treating the CFTR-mediated disease cystic fibrosis comprising administering to a patient in need thereof at least one compound chosen from 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:

disclosed in United States Patent Application Publication No. 2016-0120841;

disclosed in WO 2018/065921;

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.

Another aspect of the invention provides compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, for use in any of the methods described herein.

FIG. 1 provides an X-ray power diffraction (XRPD) pattern of Compound 11 heptane solvate.

FIG. 2 provides an overlay of X-ray power diffraction (XRPD) patterns of Compound 11 heptane solvate prepared under three different drying conditions.

FIG. 3 provides a DSC analysis of Compound 11 heptane solvate.

FIG. 4 provides a 13 C solid-state NMR spectrum of Compound 11 heptane solvate.

FIG. 5 provides a 19 F solid-state NMR spectrum of Compound 11 heptane solvate.

FIG. 6 A provides a thermogravimetric analysis (TGA) curve for Compound 11 heptane solvate (Drying Condition 1). FIG. 6 B provides a thermogravimetric analysis (TGA) curve for Compound 11 heptane solvate (Drying Condition 2). FIG. 6 C provides a thermogravimetric analysis (TGA) curve for Compound 11 heptane solvate (Drying Condition 3).

“Compound II” as used herein, refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, which can be depicted with the following structure:

Compound II may be in the form of a pharmaceutically acceptable salt. Compound II and methods of making and using Compound II are disclosed in WO 2010/053471, WO 2011/119984, WO 2011/133751, WO 2011/133951, and WO 2015/160787, each incorporated herein by reference.

“Compound III” as used throughout this disclosure refers to N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide which is depicted by the structure:

Compound III may also be in the form of a pharmaceutically acceptable salt. Compound III and methods of making and using Compound III are disclosed in WO 2006/002421, WO 2007/079139, WO 2010/108162, and WO 2010/019239, each incorporated herein by reference.

In some embodiments, a deuterated derivative of Compound III (Compound III-d) is employed in the compositions and methods disclosed herein. A chemical name for Compound III-d is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, as depicted by the structure:

Compound III-d may be in the form of a pharmaceutically acceptable salt. Compound III-d and methods of making and using Compound III-d are disclosed in WO 2012/158885, WO 2014/078842, and U.S. Pat. No. 8,865,902, incorporated herein by reference.

“Compound IV” as used herein, refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yObenzoic acid, which is depicted by the chemical structure:

Compound IV may be in the form of a pharmaceutically acceptable salt. Compound IV and methods of making and using Compound IV are disclosed in WO 2007/056341, WO 2009/073757, and WO 2009/076142, incorporated herein by reference.

“Compound V” as used herein, refers to N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-tri methylpyrroli din-1-yl]pyridine-3-carboxamide, which is depicted by the chemical structure:

Compound V may be in the form of a pharmaceutically acceptable salt. Compound V and methods of making and using Compound V are disclosed in WO 2018/107100 and WO 2019/113476, incorporated herein by reference.

“Compound VI” as used herein, refers to N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is depicted by the chemical structure:

Compound VI may be in the form of a pharmaceutically acceptable salt. Compound VI and methods of making and using Compound VI are disclosed in WO 2018/064632, incorporated herein by reference.

“Compound VII” as used herein, refers to (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-p entaazatetracyclo [17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione, which is depicted by the chemical structure:

Compound VII may be in the form of a pharmaceutically acceptable salt. Compound VII and methods of making and using Compound VII are disclosed in WO 2019/152940 and United States Provisional Patent Application No. 62/886,660, incorporated herein by reference.

“Compound VIII” as used herein, refers to (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, which is depicted by the chemical structure:

Compound VIII may be in the form of a pharmaceutically acceptable salt. Compound VIII and methods of making and using Compound VIII are disclosed in PCT/US2020/026331, incorporated herein by reference.

“Compound IX” as used herein, refers to N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is depicted by the chemical structure:

Compound IX may be in the form of a pharmaceutically acceptable salt. Compound IX and methods of making and using Compound IX are disclosed in WO 2016/057572, incorporated herein by reference.

“Compound X” as used herein, refers to N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5 s obutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is depicted by the chemical structure:

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.

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.

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.

As used herein, the term “haloalkyl group” refers to an alkyl group substituted with one or more halogen atoms.

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.

As used herein, the term “haloalkoxyl group” refers to an alkoxy group substituted with one or more halogen atoms.

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 3-10 carbons). “Cycloalkyl” groups encompass monocyclic, bicyclic, tricyclic, bridged, fused, and spiro rings, including mono spiro and dispiro rings. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbomyl, and dispiro[2.0.2.1]heptane. Cycloalkyl groups may be substituted or unsubstituted.

The term “heteroaryl ring” as used herein refers to an aromatic ring comprising at least one ring atom that is a heteroatom, such as O, N, or S.

As used herein, the terms “heterocyclyl ring” and “heterocyclyl” refer to a non-aromatic hydrocarbon containing 3 to 12 atoms in a ring (such as, for example 3-10 atoms) comprising at least one ring atom that is a heteroatom, such as O, N, S, or Si. “Heterocyclyl” rings encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro rings, including mono spiro and dispiro rings.

“Substituted” indicates that at least one hydrogen of the “substituted” group is replaced by a substituent. 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.

Examples of protecting groups for nitrogen include, for example, t-butyl carbamate (Boc), benzyl (Bn), para-methoxybenzyl (PMB), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), methyl carbamate, ethyl carbamate, 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), allyl carbamate (Aloc or Alloc), formamide, acetamide, benzamide, allylamine, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. 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.

As used herein, “deuterated derivative(s)” means the same chemical structure, with one or more hydrogen atoms replaced by a deuterium atom. In some embodiments, the deuterated derivatives are compounds where one or more hydrogen atoms of an alkyl group are replaced by a deuterium atom.

As used herein, “CFTR” means cystic fibrosis transmembrane conductance regulator.

As used herein, the term “CFTR modulator” refers to a compound that increases the activity of CFTR. The increase in activity resulting from a CFTR modulator includes but is not limited to compounds that correct, potentiate, stabilize and/or amplify CFTR.

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.

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.

As used herein, the term “CFTR potentiator enhancer”, “CFTR potentiation enhancer”, and “CFTR co-potentiator” are used interchangeably and refer to a compound that enhances CFTR potentiation.

As used herein, the term “active pharmaceutical ingredient” (“API”) or “therapeutic agent” refers to a biologically active compound.

As used herein, the term “one or more additional therapeutic agent(s) comprise(s),” includes the possibility that there is only one therapeutic agent.

The terms “patient” and “subject” are used interchangeably and refer to an animal including humans.

The terms “effective dose” and “effective amount” are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in CF or a symptom of CF, or lessening the severity of CF or a symptom of CF). 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).

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.

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 pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other.

The terms “about” and “approximately”, when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. The terms “about” and “approximately” may refer to an acceptable error for a particular value as determined by one of skill in the art, which depends in part on how the values is measured or determined. 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.”

As used herein, the term “solvent” refers to any liquid in which the product is at least partially soluble (solubility of product>1 g/L).

As used herein, the term “room temperature” or “ambient temperature” means 15° C. to 30° C.

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” ( ) or “hash” ( ) bond to a stereogenic atom indicates a chiral center of known absolute stereochemistry (i.e., one stereoisomer). As 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 ( ) to a double-bonded carbon indicates a mixture of E/Z 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 (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. As used herein, a stereogenic atom that is notated with an (R) or (S) indicates the stereochemical designation of the stereogenic atom under the Cahn-Ingold-Prelog convention.

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:

As used herein, “minimal function (MF) mutations” refer to CFTR gene mutations associated with minimal CFTR function (little-to-no functioning CFTR protein) and include, for example, mutations associated with severe defects in ability of the CFTR channel to open and close, known as defective channel gating or “gating mutations”; mutations associated with severe defects in the cellular processing of CFTR and its delivery to the cell surface; mutations associated with no (or minimal) CFTR synthesis; and mutations associated with severe defects in channel conductance.

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.

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.

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.

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:

Non-limiting examples of pharmaceutically acceptable acid addition salts include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, 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 N + (C 1-4 alkyl) 4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

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 crystalline material. A solid material, comprising an amorphous compound, may be characterized by, for example, a glass transition temperature which is lower than the melting point of a pure crystalline solid. Other techniques, such as, for example, solid state NMR may also be used to characterize crystalline or amorphous forms.

As used herein, the terms “crystal form,” “crystalline form,” and “Form” interchangeably refer to a crystal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and 13 C solid state nuclear magnetic resonance ( 13 C SSNMR). Accordingly, as used herein, the terms “crystalline Form [X] of Compound I” refer to unique crystalline forms that can be identified and distinguished from other crystalline forms by one or more characterization techniques including, for example, XRPD, single crystal X-ray diffraction, and 13 C SSNMR. 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 (°2θ).

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.

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 stoichiometric or nonstoichiometric amounts. When the solvent is water, the solvate is referred to as a “hydrate.”

In some embodiments, a solid material may comprise a mixture of crystalline solids and amorphous solids. A solid material comprising an amorphous compound may also, for example, contain up to 30% of a crystalline solid. 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.

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.

As 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.

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 form(s) in a sample. In some embodiments, the solid form is “substantially pure” when it accounts for an amount by weight equal to or greater than 99% of the sum of all solid form(s) in a sample. It is also noted that the term “substantially pure” includes the descriptor “pure,” which refers to materials that are 100% pure.

As used herein, the term “XRPD” refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns disclosed herein were recorded at ambient conditions in transmission or reflection geometry using a diffractometer.

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.

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 positions (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 2θ (°2θ), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed as “a signal at . . . degrees two-theta,” “a signal at [a] two-theta value(s)of . . . ” and/or “a signal at at least . . . two-theta value(s) selected from . . . .”

A “signal” or “peak” as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum. 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.

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 (°2θ).

The repeatability of the measured angular values is in the range of ±0.2° 2θ, i.e., the angular value can be at the recited angular value +0.2 degrees two-theta, the angular value −0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value −0.2 degrees two-theta).

The terms “signal intensities” and “peak intensities” interchangeably refer to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).

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.

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 SSNMR 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.

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).

As used herein, the term “DSC” refers to the analytical method of Differential Scanning calorimetry.

As used herein, the term “onset of decomposition” refers to the intersection point of the baseline before transition and the interflection tangent.

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.

As used herein, the term “TGA” refers to the analytical method of Thermo Gravimetric (or thermogravimetric) Analysis.

In addition to compounds of Formula I, I′, and I″, pharmaceutically acceptable salts thereof, and deuterated derivatives of those compounds and salts, the invention provides compounds of Formulae I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof.

For example, in some embodiments, the compound of Formula I is selected from compounds of Formula Ia:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each R 1 is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl; and

n is selected from 4, 5, 6, and 7.

In some embodiments, X in Formula Ia is —O—.

In some embodiments, each Y in Formula Ia is independently selected from —C(R Y ) 2 —, —CO—, and

wherein R Y and Ring B are as defined for Formula Ia.

In some embodiments, each Y in Formula Ia is —C(R Y ) 2 —, wherein R Y is as defined for Formula Ia.

In some embodiments, each R Y in Formula Ia is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), and —OR Y1 , wherein Q and R Y1 are as defined for Formula Ia.

In some embodiments, each R Y in Formula Ia is independently selected from: hydrogen,

In some embodiments, each Q in Formula Ia is independently selected from:

C 3 -C 8 cycloalkyl, C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.

In some embodiments, each Q in Formula Ia is independently selected from:

In some embodiments, Ring B in Formula Ia is selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen.

In some embodiments, Ring B in Formula Ia is selected from:

In some embodiments, —(Y) n — in Formula Ia is a group selected from:

In some embodiments, each in Formula Ia is independently C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen) and —N(R 2 ) 2 , wherein R 2 is as defined for Formula Ia. In some embodiments, each R 1 in Formula Ia is independently selected from —CF 3 and —N(R 2 ) 2 , wherein R 2 is as defined for Formula Ia.

In some embodiments, each R 2 in Formula Ia is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-3 groups independently selected from halogen). In some embodiments, each R 2 in Formula Ia is independently selected from hydrogen and C 1 -C 6 alkyl. In some embodiments, each R 2 in Formula Ia is hydrogen.

In some embodiments, Z in Formula Ia is

wherein R Z1 and R Z2 are as defined for Formula Ia.

In some embodiments, R Z1 in Formula Ia is selected from C 1 -C 6 alkyl (optionally substituted with 1-3 groups selected from halogen). In some embodiments, R Z1 in Formula Ia is —CF 3 .

In some embodiments, R Z2 in Formula Ia is hydroxy.

In some embodiments, n in Formula Ia is selected from 4, 5, and 6. In some embodiments, n in Formula Ia is 6.

In some embodiments, the compound of Formula I is selected from compounds of Formulae IIa, IIb, and IIc:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each R 1 is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl; and

m is selected from 0, 1, 2, and 3.

In some embodiments, m in Formulae IIa, IIb, or IIc is selected from 1 and 2. In some embodiments, m in Formulae IIa, IIb, or IIc is 2.

In some embodiments, the compound of Formula I is selected from compounds of Formulae IId, IIe, and IIf:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH; and

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl.

In some embodiments, X in Formulae IIa, IIb, IIc, IId, IIe, or IIf is —O—.

In some embodiments, each Y in Formulae IIa, IIb, IIc, IId, IIe, or IIf is independently selected from —C(R Y ) 2 —, —CO—, and

wherein R Y and Ring B are as defined for Formulae IIa, IIb, IIc, IId, IIe, or IIf.

In some embodiments, each Y in Formulae IIa, IIb, IIc, IId, IIe, or IIf is —C(R Y ) 2 —, wherein R Y is as defined for Formulae IIa, IIb, IIc, IId, IIe, or IIf.

In some embodiments, each R Y in Formulae IIa, IIb, IIc, IId, IIe, or IIf is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), and —OR Y1 , wherein Q and R Y1 are as defined for Formulae IIa, IIb, IIc, IId, IIe, or IIf.

In some embodiments, each R Y in Formulae IIa, IIb, IIc, IId, IIe, or IIf is independently selected from: hydrogen,

wherein Q is as defined for Formulae IIa, IIb, IIc, IId, IIe, or IIf.

In some embodiments, each Q in Formulae IIa, IIb, IIc, IId, IIe, or IIf is independently selected from:

C 3 -C 8 cycloalkyl, C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.

In some embodiments, each Q in Formulae IIa, IIb, IIc, IId, IIe, or IIf is independently selected from:

In some embodiments, Ring B in Formulae IIa, IIb, IIc, IId, IIe, or IIf is selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen.

In some embodiments, Ring B in Formulae IIa, IIb, IIc, IId, IIe, or IIf is selected from:

In some embodiments, each R 1 in Formulae IIa, IIb, IIc, IId, IIe, or IIf is independently C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen) and —N(R 2 ) 2 wherein R 2 is as defined for Formulae IIa, IIb, IIc, IId, IIe, or IIf. In some embodiments, each R 1 in Formulae IIa, IIb, IIc, IId, IIe, or IIf is independently selected from —CF 3 and —N(R 2 ) 2 wherein R 2 is as defined for Formulae IIa, IIb, IIc, IId, IIe, or IIf.

In some embodiments, each R 2 in Formulae IIa, IIb, IIc, IId, IIe, or IIf is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-3 groups independently selected from halogen). In some embodiments, each R 2 in Formulae IIa, IIb, IIc, IId, IIe, or IIf is independently selected from hydrogen and C 1 -C 6 alkyl. In some embodiments, each R 2 in Formulae IIa, IIb, IIc, IId, IIe, or IIf is hydrogen.

In some embodiments, Z in Formulae IIa, IIb, IIc, IId, IIe, or IIf is

wherein R Z1 and R Z2 are as defined for Formulae IIa, IIb, IIc, IId, IIe, or IIf.

In some embodiments, R Z1 in Formulae IIa, IIb, IIc, IId, IIe, or IIf is selected from C 1 -C 6 alkyl (optionally substituted with 1-3 groups selected from halogen). In some embodiments, R Z1 in Formulae IIa, IIb, IIc, IId, IIe, or IIf is —CF 3 .

In some embodiments, R Z2 in Formulae IIa, IIb, IIc, IId, IIe, or IIf is hydroxy.

In some embodiments, the compound of Formula I is selected from compounds of Formulae IIIa, IIIb, and IIIc:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each R 1 is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl; and

m is selected from 0, 1, 2, and 3.

In some embodiments, m in Formulae IIIa, IIIb, or IIIc is selected from 1 and 2. In some embodiments, m in Formulae IIIa, IIIb, and IIIc is 2.

In some embodiments, the compound of Formula I is selected from compounds of Formulae IIId, IIIe, and IIIr

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each R 1 is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl.

In some embodiments, X in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is —O—.

In some embodiments, each Y in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is independently selected from —C(R Y ) 2 —, —CO—, and

wherein R Y and Ring B as defined for Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

In some embodiments, each Y in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is —C(R Y ) 2 —, wherein R Y is as defined for Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

In some embodiments, each R Y in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), and —OR Y1 , wherein Q and R Y1 are as defined for Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

In some embodiments, each R Y in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is independently selected from: hydrogen,

wherein Q is as defined for Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

In some embodiments, each Q in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is independently selected from:

C 3 -C 8 cycloalkyl, C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.

In some embodiments, each Q in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is independently selected from:

In some embodiments, Ring B in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen.

In some embodiments, Ring B in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is selected from:

In some embodiments, each R 1 in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is independently C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen) and —N(R 2 ) 2 , wherein R 2 is as defined for Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf. In some embodiments, each R 1 in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is independently selected from —CF 3 and —N(R 2 ) 2 , wherein R 2 is as defined for Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

In some embodiments, each R 2 in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-3 groups independently selected from halogen). In some embodiments, each R 2 in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is independently selected from hydrogen and C 1 -C 6 alkyl.

In some embodiments, each R 2 in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is hydrogen.

In some embodiments, Z in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is

wherein Z is as defined for Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

In some embodiments, R Z1 in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or Illf is selected from C 1 -C 6 alkyl (optionally substituted with 1-3 groups selected from halogen). In some embodiments, R Z1 in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is —CF 3 .

In some embodiments, R Z2 in Formulae IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is hydroxy.

In some embodiments, the compound of Formula I is selected from compounds of Formula I′″:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —CO 2 R Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen and hydroxy), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

n is selected from 4, 5, 6, 7, and 8; and

m is selected from 0, 1, 2, and 3.

In some embodiments, X in Formula I′″ is —O—.

In some embodiments, each R Y in Formula I′″ is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 3 -C 8 cycloalkyl, and —ORY 1 , wherein Q and R Y1 are as defined for Formula I′″. In some embodiments, —OR Y1 in Formula I′″ is —OH.

In some embodiments, each Q in Formula I′″ is independently selected from C 3 -C 8 cycloalkyl and C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl. In some embodiments, each Q in Formula I′″ is independently selected from:

In some embodiments, each R Y in Formula I′″ is independently selected from: hydrogen, fluorine,

In some embodiments, Ring B in Formula I′″ is selected from C 3 -C 8 cycloalkyl and phenyl optionally substituted with 1-3 groups independently selected from halogen. In some embodiments, Ring B in Formula I′″ is selected from:

In some embodiments, n in Formula I′″ is selected from 4, 5, and 6.

In some embodiments, —(Y) n — in Formula I′″ is a group selected from:

In some embodiments, each in Formula I′″ is independently selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen and hydroxy), —N(R 2 ) 2 , and —CO 2 R 2 , wherein R 2 is as defined for Formula I′″. In some embodiments, each R 1 in Formula I′″ is independently selected from —CF 3 , —NH 2 , —NH(CH 2 CH 3 ), CO 2 H, and CH 2 OH.

In some embodiments, each R 2 in Formula I′″ is independently selected from hydrogen and C 1 -C 6 alkyl.

In some embodiments, R Z1 in Formula I′″ is selected from hydrogen and C 1 -C 6 alkyl (optionally substituted with 1-6 groups selected from halogen). In some embodiments, R Z1 in Formula I′″ is —CF 3 .

In some embodiments, R Z2 in Formula I′″ is hydroxy.

In some embodiments, R Z1 in Formula I′″ is C 1 -C 6 alkyl (optionally substituted with 1-6 groups selected from halogen) and R Z2 in Formula I′″ is hydroxy. In some embodiments, R Z1 in Formula I′″ is —CF 3 and R Z2 in Formula I′″ is hydroxy.

In some embodiments, m in Formula I′″ is selected from 1 and 2.

In some embodiments, the compound of Formula I is selected from compounds of Formula IIa′:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH; and

m is selected from 0, 1, 2, and 3.

In some embodiments, m in Formula IIa′ is selected from 1 and 2. In some embodiments, m in Formula IIa′ is 2.

In some embodiments, X in Formula IIa′ is —O—.

In some embodiments, each Y in Formula IIa′ is independently selected from —C(R Y ) 2 —, —CO—, and

wherein R Y and Ring B are as defined for Formula IIa′.

In some embodiments, each Y in Formula IIa′ is —C(R Y ) 2 —, wherein R Y is as defined for Formula IIa′.

In some embodiments, each R Y in Formula IIa′ is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), and —OR Y1 , wherein Q and R Y1 are as defined for Formula IIa′.

In some embodiments, each R Y in Formula IIa′ is independently selected from: hydrogen,

wherein Q is as defined for Formula IIa′.

In some embodiments, each Q in Formula IIa′ is independently selected from:

C 3 -C 8 cycloalkyl, C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.

In some embodiments, each Q in Formula IIa′ is independently selected from:

In some embodiments, Ring B in Formula IIa′ is selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen.

In some embodiments, Ring B in Formula IIa′ is selected from:

In some embodiments, each in Formula IIa′ is independently C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen) and —N(R 2 ) 2 wherein R 2 is as defined for Formula IIa′. In some embodiments, each R 1 in Formula IIa′ is independently selected from —CF 3 and —N(R 2 ) 2 wherein R 2 is as defined for Formula IIa′.

In some embodiments, each R 2 in Formula IIa′ is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-3 groups independently selected from halogen). In some embodiments, each R 2 in Formula IIa′ is independently selected from hydrogen and C 1 -C 6 alkyl. In some embodiments, each R 2 in Formula IIa′ is hydrogen.

In some embodiments, R Z1 in Formula IIa′ is selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups selected from halogen). In some embodiments, R Z1 in Formula IIa′ is —CF 3 .

In some embodiments, R Z2 in Formula IIa′ is hydroxy.

In some embodiments, R Z1 in Formula IIa′ is C 1 -C 6 alkyl (optionally substituted with 1-6 groups selected from halogen) and R Z2 in Formula IIa′ is hydroxy. In some embodiments, R Z1 in Formula IIa′ is —CF 3 and R Z2 in Formula IIa′ is hydroxy.

In some embodiments, the compound of Formula I is selected from compounds of Formula IIIa′:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each R 1 is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH; and

m is selected from 0, 1, 2, and 3.

In some embodiments, X in Formula IIIa′ is —O—.

In some embodiments, each Y in Formula IIIa′ is independently selected

from —C(R Y ) 2 —, —CO—, and

wherein R Y and Ring B as defined for Formula IIIa′.

In some embodiments, each Y in Formula IIIa′ is —C(R Y ) 2 —, wherein R Y is as defined for Formula IIIa′.

In some embodiments, each R Y in Formula IIIa′ is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), and —OR Y1 , wherein Q and R Y1 are as defined for Formula IIIa′.

In some embodiments, each R Y in Formula IIIa′ is independently selected from: hydrogen,

wherein Q is as defined for Formula IIIa′.

In some embodiments, each Q in Formula IIIa′ is independently selected from:

C 3 -C 8 cycloalkyl, C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.

In some embodiments, each Q in Formula IIIa′ is independently selected from:

In some embodiments, Ring B in Formula IIIa′ is selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen.

In some embodiments, Ring B in Formula IIIa′ is selected from:

In some embodiments, each in Formula IIIa′ is independently C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen) and —N(R 2 ) 2 , wherein R 2 is as defined for Formula IIIa′. In some embodiments, each in Formula IIIa′ is independently selected from —CF 3 and —N(R 2 ) 2 , wherein R 2 is as defined for Formula IIIa′.

In some embodiments, each R 2 in Formula IIIa′ is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-3 groups independently selected from halogen). In some embodiments, each R 2 in Formula IIIa′ is independently selected from hydrogen and C 1 -C 6 alkyl.

In some embodiments, each R 2 in Formula IIIa′ is hydrogen.

In some embodiments, R Z1 in Formula IIIa′ is selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups selected from halogen). In some embodiments, R Z1 in Formula IIIa′ is —CF 3 .

In some embodiments, R Z2 in Formula IIIa′ is hydroxy.

In some embodiments, R Z1 in Formula IIIa′ is C 1 -C 6 alkyl (optionally substituted with 1-6 groups selected from halogen) and R Z2 in Formula IIIa′ is hydroxy. In some embodiments, R Z1 in Formula IIIa′ is —CF 3 and R Z2 in Formula IIIa′ is hydroxy.

Compounds of the invention include Compounds 1-53 and 54-77, and deuterated derivatives and pharmaceutically acceptable salts thereof.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77

Methods of Treatment

Any of the novel compounds disclosed herein, such as for example, compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, pharmaceutically acceptable salts thereof, and deuterated derivatives of such compounds and salts can act as a CFTR modulator, i.e., it modulates CFTR 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 CFTR quantity, i.e., the number of CFTR channels at the cell surface, or it may impact CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations affecting CFTR quantity include mutations that cause defective synthesis (Class I defect), mutations that cause defective processing and trafficking (Class II defect), mutations that cause reduced synthesis of CFTR (Class V defect), and mutations that reduce the surface stability of CFTR (Class VI defect). Mutations that affect CFTR function include mutations that cause defective gating (Class III defect) and mutations that cause defective conductance (Class IV defect). Some CFTR mutations exhibit characteristics of multiple classes. Certain mutations in the CFTR gene result in cystic fibrosis.

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 disclosed herein, such as for example, compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, pharmaceutically acceptable salts thereof, and/or deuterated derivatives of such compounds and salts, alone or in combination with another active ingredient, such as another CFTR modulating agent. In some embodiments, the patient has an F508del/minimal function (MF) genotype, F508de1/F508de1 genotype (homozygous for the F508de1 mutation), F508del/gating genotype, or F508del/residual function (RF) genotype. In some embodiments the patient is heterozygous and has one F508de1 mutation. In some embodiments the patient is homozygous for the N1303K mutation.

In some embodiments, 1 mg to 1000 mg of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a deuterated derivative of such compound or salt are administered daily.

In some embodiments, the patient is heterozygous and has an F508del mutation on one allele and a mutation on the other allele selected from Table 2:

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 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.

The isotope-labelled compounds and salts can be used in a number of beneficial ways. They can be suitable for medicaments and/or various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3 H)- and/or carbon-14 ( 14 C)-labelled compounds are particularly useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability. For example, deuterium ( 2 H)-labelled ones are therapeutically useful with potential therapeutic advantages over the non- 2 H-labelled compounds. In general, deuterium ( 2 H)-labelled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labelled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which could be desired. The isotope-labelled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.

In some embodiments, the isotope-labelled compounds and salts are deuterium ( 2 H)-labelled ones. In some specific embodiments, the isotope-labelled compounds and salts are deuterium ( 2 H)-labelled, wherein one or more hydrogen atoms therein have been replaced by deuterium. In chemical structures, deuterium is represented as “ 2 H” or “D.”

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.

The deuterium ( 2 H)-labelled compounds and salts can modulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of k M /k D =2−7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development , Ann. Rep. Med. Chem. 2011, 46, 403-417, which is incorporated herein by reference.

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 incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Combination Therapies

One aspect disclosed herein provides methods of treating cystic fibrosis and other CFTR-mediated diseases using any of the novel compounds disclosed herein, such as for example, compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, pharmaceutically acceptable salts thereof, and deuterated derivatives of such compounds and salts in combination with at least one additional active pharmaceutical ingredient.

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 disclosed herein, such as for example, compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, pharmaceutically acceptable salts thereof, and/or deuterated derivatives of such compounds and salts, alone or in combination with at least one additional active pharmaceutical ingredient, such as, e.g., a CFTR modulating agent.

In some embodiments, at least one additional active pharmaceutical ingredient is selected from mucolytic agents, bronchodilators, antibiotics, anti-infective agents, and anti-inflammatory agents.

In some embodiments, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levoflaxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin.

In some embodiments, the additional agent is a mucolyte. Exemplary mucolytes useful herein includes Pulmozyme®.

In some embodiments, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabuline sulfate.

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 (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.

In some embodiments, the additional agent is a nutritional agent. Exemplary nutritional agents include pancrelipase (pancreating enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation. In one embodiment, the additional nutritional agent is pancrelipase.

In some embodiments, at least one additional active pharmaceutical 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 example, ASP-11). In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR amplifier. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR readthrough agent. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy.

In some embodiments, the at least one additional active pharmaceutical ingredient is a ENaC inhibitor. In some embodiments, the at least one additional active pharmaceutical ingredient is a TMEM16A modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a GPR39 agonist.

In some embodiments, the at least one additional active pharmaceutical ingredient is chosen from (a) Compound II and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) Compound IV and pharmaceutically acceptable salts and deuterated derivatives thereof, (c) Compound V and pharmaceutically acceptable salts and deuterated derivatives thereof, (d) Compound VI and pharmaceutically acceptable salts and deuterated derivatives thereof, (e) Compound VII and pharmaceutically acceptable salts and deuterated derivatives thereof, and (f) Compound VIII and pharmaceutically acceptable salts and deuterated derivatives thereof. Thus, in some embodiments, the combination therapies provided herein comprise a compound selected from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and 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. In some embodiments, the combination therapies provided herein comprise (a) at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least one compound chosen from Compound II, Compound IV, and pharmaceutically acceptable salts and deuterated derivatives thereof, and (c) at least one compound chosen from Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof. In some embodiments, the combination therapies provided herein comprise (a) at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least one compound selected from Compound II and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one compound chosen from Compound VII and pharmaceutically acceptable salts and deuterated derivatives thereof.

In some embodiments, the combination therapies provided herein comprise (a) a compound selected from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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; 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, or Journal of Cystic Fibrosis (2018), 17(5), 595-606.

In some embodiments, the combination therapies provided herein comprise (a) a compound selected from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and Hit; Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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; and (c) at least one compound chosen from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, and PTI-801.

In some embodiments, the combination therapies provided herein comprise (a) a compound selected from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and Hit; Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (b) at least two compounds chosen from compounds disclosed in WO 2019/195739, WO 2019/200246, WO 2021/030555, WO 2021/030556, WO 2017/173274, WO 2019/010092, WO 2019/018353, 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. 2016-0120841, United States Patent Application Publication No. 2017-0101405, WO 2017/009804, WO 2018/065921, WO 2017/062581, Journal of Cystic Fibrosis (2018), 17(5), 595-606, 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. 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 al., Front. Pharmacol. 2019, 10, 3, or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888.

In some embodiments, the combination therapies provided herein comprise (a) a compound selected from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and Hit; Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and (b) at least two compounds chosen from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, and PTI-801, and pharmaceutically acceptable salts and deuterated derivatives thereof.

In some embodiments, the combination therapies provided herein comprise (a) a compound selected from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least one compound chosen from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808 (dirocaftor), GLPG1837, GLPG2451/ABBV-2451, QBW251 (icenticaftor), GLPG3067/ABBV-3067 (Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF 552 , GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5 Rx, BI 1265162, AZ5634, ARO-ENaC1001, ETD002, and DS-1039, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one pharmaceutically acceptable carrier.

In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, He, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof is administered in combination with at least one compound chosen from Compound II and pharmaceutically acceptable salts and deuterated derivatives thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf; Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof is administered in combination with at least one compound chosen from Compound IV and pharmaceutically acceptable salts and deuterated derivatives thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof is administered in combination with at least one compound chosen from Compound V and pharmaceutically acceptable salts and deuterated derivatives thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof is administered in combination with at least one compound chosen from Compound VI and pharmaceutically acceptable salts and deuterated derivatives thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof is administered in combination with at least one compound chosen from Compound VII and pharmaceutically acceptable salts and deuterated derivatives thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof is administered in combination with at least one compound chosen from Compound VIII and pharmaceutically acceptable salts and deuterated derivatives thereof.

Each of the compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and Hit; Compounds 1 to 53, Compounds 54 to 77, Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and their pharmaceutically acceptable salts and deuterated derivatives thereof, independently can be administered once daily, twice daily, or three times daily. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof is administered once daily. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and Hit; Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof is administered twice daily. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof and at least one compound chosen from Compound VIII and pharmaceutically acceptable salts thereof are administered twice daily.

In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 once daily. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof; and at least one compound chosen from Compound VII and pharmaceutically acceptable salts thereof are administered twice daily.

Compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and their pharmaceutically acceptable salts and deuterated derivatives 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.

In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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.

In some embodiments, at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof is administered in a first pharmaceutical composition; at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; and at least one compound chosen from Compound VII and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

Any suitable pharmaceutical compositions known in the art can be used for compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof. Some exemplary pharmaceutical compositions for Compound II and its pharmaceutically acceptable salts can be found in WO 2011/119984 and WO 2014/014841, incorporated herein by reference. Some exemplary pharmaceutical compositions for Compound III and its pharmaceutically acceptable salts can be found in WO 2007/134279, WO 2010/019239, WO 2011/019413, WO 2012/027731, and WO 2013/130669, and some exemplary pharmaceutical compositions for Compound III-d and its pharmaceutically acceptable salts can be found in U.S. Pat. Nos. 8,865,902, 9,181,192, 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

Another aspect of the invention provides a pharmaceutical composition comprising at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments, the invention provides pharmaceutical compositions comprising at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIa′, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 TMEM16A 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 of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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 of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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.

In some embodiments, the invention provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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.

In some embodiments, the invention provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, (b) at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.

In some embodiments, the invention provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, (b) at least one compound chosen from Compound VII and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.

In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, (b) at least one compound chosen from Compound II, Compound IV, and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.

In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, (b) at least one compound chosen from Compound II and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from Compound VII and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives 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, Journal of Cystic Fibrosis (2018), 17(5), 595-606, 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. 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 al., Front. Pharmacol. 2019, 10, 3, or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888; and (d) at least one pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least one compound chosen from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof; (c) at least one compound chosen from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, and PTI-801; and (d) at least one pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least two compounds chosen from compounds disclosed in WO 2019/195739, WO 2019/200246, WO 2021/030555, WO 2021/030556, WO 2017/173274, WO 2019/010092, WO 2019/018353, 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. 2016-0120841, United States Patent Application Publication No. 2017-0101405, WO 2017/009804, WO 2018/065921, WO 2017/062581, Journal of Cystic Fibrosis (2018), 17(5), 595-606, 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 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 al., Front. Pharmacol. 2019, 10, 3, or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888; and (c) at least one pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least two compounds chosen from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, and PTI-801, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical compositions provided herein comprise (a) a compound selected from compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least one compound chosen from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808 (dirocaftor), GLPG1837, GLPG2451/ABBV-2451, QBW251 (icenticaftor), GLPG3067/ABBV-3067 (Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF 552 , GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5 Rx, BI 1265162, AZ5634, ARO-ENaC1001, ETD002, and DS-1039, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one pharmaceutically acceptable carrier.

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.

The pharmaceutical compositions described herein are useful for treating cystic fibrosis and other CFTR-mediated diseases.

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, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, 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), alginic 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.

Compound 11 Heptane Solvate

In some embodiments, the invention provides solvated crystalline forms of Compound 11. In some embodiments, the solvated crystalline form is a heptane solvate. In some embodiments, the invention provides Compound 11 heptane solvate. FIG. 1 provides an X-ray powder diffractogram of Compound 11 heptane solvate at room temperature.

In some embodiments, Compound 11 heptane solvate is substantially pure. In some embodiments, Compound 11 heptane solvate is substantially crystalline. In some embodiments, Compound 11 heptane solvate is characterized by an X-ray powder diffractogram generated by an X-ray powder diffraction analysis with an incident beam of Cu Kα radiation. In some embodiments, Compound 11 heptane solvate has many molecules in an asymmetric unit. In some embodiments, Compound 11 heptane solvate is a physical mixture of crystal lattices. In some embodiments, Compound 11 heptane solvate has a variable amount of heptane in the crystal lattice. In some embodiments, Compound 11 heptane solvate has a stoichiometric amount of heptane in the crystal lattice. In some embodiments, Compound 11 heptane solvate has a nonstoichiometric amount of heptane in the crystal lattice.

In some embodiments, Compound 11 heptane solvate is characterized by an X-ray powder diffractogram having a signal at 5.8±0.2 degrees two-theta. In some embodiments, Compound 11 heptane solvate is characterized by an X-ray powder diffractogram having a signal at 10.1±0.2 degrees two-theta. In some embodiments, Compound 11 heptane solvate is characterized by an X-ray powder diffractogram having a signal at 11.7±0.2 degrees two-theta. In some embodiments, Compound 11 heptane solvate is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.8±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 11.7±0.2 degrees two-theta.

In some embodiments, Compound 11 heptane solvate is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.8±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 11.7±0.2 degrees two-theta, and (b) one, two, three, or four signals selected from 5.6±0.2 degrees two-theta, 18.1±0.2 degrees two-theta, 20.5±0.2 degrees two-theta, and 20.9±0.2 degrees two-theta. In some embodiments, Compound 11 heptane solvate is characterized by an X-ray powder diffractogram having signals at 5.6±0.2 degrees two-theta, 5.8±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, 11.7±0.2 degrees two-theta, 18.1±0.2 degrees two-theta, 20.5±0.2 degrees two-theta, and 20.9±0.2 degrees two-theta.

In some embodiments, Compound 11 heptane solvate is characterized by an X-ray powder diffractogram substantially similar to FIG. 1 .

In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 166.3±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 165.8±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 164.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 163.4±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 154.8±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 154.0±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 152.1±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 151.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 140.2±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 139.4±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 138.5±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 138.0±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 135.1±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 134.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 131.3±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 130.2±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 129.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 128.5±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 125.7±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 123.7±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 123.2±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 122.9±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 121.1±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 120.2±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 119.2±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 117.8±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 76.2±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 74.4±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 73.7±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 73.3±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 40.0±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 38.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 37.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 36.9±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 35.7±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 33.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 32.5±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 32.0±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 30.4±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 30.1±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 29.5±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 28.8±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 28.1±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 27.1±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 25.3±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 23.1±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 22.7±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 22.0±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 21.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 20.3±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 19.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 18.3±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 17.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 13.8±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 13.1±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with a peak at 12.5±0.2 ppm.

In some embodiments, Compound 11 heptane solvate is characterized as having a 13 C SSNMR spectrum with one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 166.3±0.2 ppm, 165.8±0.2 ppm, 164.6±0.2 ppm, 163.4±0.2 ppm, 154.8±0.2 ppm, 154.0±0.2 ppm, 152.1±0.2 degppm, 151.6±0.2 ppm, 140.2±0.2 ppm, 139.4±0.2 ppm, 138.5±0.2 ppm, 138.0±0.2 ppm, 135.1±0.2 ppm, 134.6±0.2 ppm, 131.3±0.2 ppm, 130.2±0.2 ppm, 129.6±0.2 ppm, 128.5±0.2 ppm, 125.7±0.2 ppm, 123.7±0.2 ppm, 123.2±0.2 ppm, 122.9±0.2 ppm, 121.1±0.2 ppm, 120.2±0.2 ppm, 119.2±0.2 ppm, 117.8±0.2 ppm, 76.2±0.2 ppm, 74.4±0.2 ppm, 73.7±0.2 ppm, 73.3±0.2 ppm, 40.0±0.2 ppm, 38.6±0.2 ppm, 37.6±0.2 ppm, 36.9±0.2 ppm, 35.7±0.2 ppm, 33.6±0.2 ppm, 32.5±0.2 ppm, 32.0±0.2 ppm, 30.4±0.2 ppm, 30.1±0.2 ppm, 29.5±0.2 ppm, 28.8±0.2 ppm, 28.1±0.2 ppm, 27.1±0.2 ppm, 25.3±0.2 ppm, 23.1±0.2 ppm, 22.7±0.2 ppm, 22.0±0.2 ppm, 21.6±0.2 ppm, 20.3±0.2 ppm, 19.6±0.2 ppm, 18.3±0.2 ppm, 17.6±0.2 ppm, 13.8±0.2 ppm, 13.1±0.2 ppm, and 12.5±0.2 ppm.

In some embodiments, Compound 11 heptane solvate is characterized by a 13 C SSNMR spectrum substantially similar to FIG. 3 .

In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with a peak at −63.5±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with a peak at −63.8±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with a peak at −65.1±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with a peak at −65.8±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with a peak at −66.3±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with a peak at −67.0±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with a peak at −74.0±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with a peak at −74.9±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with a peak at −76.6±0.2 ppm.

In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with one, two, or three peaks selected from −65.1±0.2 ppm, −67.0±0.2 ppm, and −76.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with one, two, three, four, or five peaks selected from −63.5±0.2 ppm, −65.1±0.2 ppm, −67.0±0.2 ppm, −74.9±0.2 ppm, and −76.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with one, two, three, four, five, or more peaks selected from −63.5±0.2 ppm, −63.8±0.2 ppm, −65.1±0.2 ppm, −65.8±0.2 ppm, −66.3±0.2 ppm, −67.0±0.2 ppm, −74.0±0.2 ppm, −74.9±0.2 ppm, and −76.6±0.2 ppm. In some embodiments, Compound 11 heptane solvate is characterized as having a 19 F SSNMR spectrum with one, two, three, four, five, or more peaks selected from −63.5±0.2 ppm, −63.8±0.2 ppm, −65.1±0.2 ppm, −65.8±0.2 ppm, −66.3±0.2 ppm, −67.0±0.2 ppm, −74.0±0.2 ppm, −74.9±0.2 ppm, −76.6±0.2 ppm, and −77.6±0.2 ppm.

In some embodiments, Compound 11 heptane solvate is characterized by a 19 F SSNMR spectrum substantially similar to FIG. 4 .

Another aspect of the invention provides a process for preparing a solvated crystalline solid form of Compound 11 comprising dissolving Compound 11 in one or more solvents to form a mixture and crystallising the compound from the mixture. In some embodiment the one or more solvents comprises heptane. In some embodiment the one or more solvents comprises heptane and dichloromethane.

Another aspect of the invention provides a method of making Compound 11 heptane solvate. In some embodiments, the method of making Compound 11 heptane solvate comprises: (i) dissolving Compound 11 in heptane and dichloromethane to form a mixture; (ii) concentrating the mixture; (iii) collecting solids from the mixture; and (iv) drying the collected solids. In some embodiments, (ii) optionally comprises swirling the mixture at room temperature. In some embodiments, (iii) optionally comprises rinsing the collected solids with cold heptane. In some embodiments, the method of making Compound 11 heptane solvate comprises dissolving Compound 11 in heptane and dichloromethane, concentrating under rotary evaporation, swirling at room temperature, filtering the solids, washing the solids with cold heptane, and drying under vacuum to provide Compound 11 heptane solvate.

Non-Limiting Exemplary Embodiments

1. A compound selected from compounds of Formula I:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo; each is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen and hydroxy), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

wherein Ring C is selected from C 6 -C 10 aryl and 5- to 10-membered heteroaryl;

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 6 -C 10 aryl; or two instances of R Z3 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:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 ; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each R 1 is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl;

n is selected from 4, 5, 6, and 7; and

m is selected from 0, 1, 2, and 3.

3. The compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1 or 2, wherein X is —O—.

4. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-3, wherein each Y is independently selected from —C(R Y ) 2 —, —CO—, and

5. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-4, wherein each R Y is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), and —OR Y1 .

6. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-5, wherein each R Y is independently selected from: hydrogen,

7. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-6, wherein each Q is independently selected from:

C 3 -C 8 cycloalkyl, C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.

8. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-7, wherein each Q is independently selected from:

9. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-8, wherein Ring B is selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen.

10. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-9, wherein Ring B is selected from:

11. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-10, wherein —(Y) n — is a group selected from:

12. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-11, wherein each Y is —C(R Y ) 2 —.

13. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-12, wherein each R 1 is independently selected from —CF 3 and —N(R 2 ) 2 .

14. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-13, wherein each R 2 is independently selected from hydrogen and C 1 -C 6 alkyl.

15. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-14, wherein each R 2 is hydrogen.

16. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-15, wherein Z is

17. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-16, wherein R Z1 is selected from C 1 -C 6 alkyl (optionally substituted with 1-3 groups selected from halogen).

18. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-17, wherein R Z1 is —CF 3 .

19. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-18, wherein R Z2 is hydroxy.

20. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-19, wherein n is selected from 4, 5, and 6.

21. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-20, wherein n is 6.

22. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-21, wherein m is selected from 1 and 2.

23. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1-22, wherein m is 2.

24. A compound selected from compounds of Formula Ia:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl; and

n is selected from 4, 5, 6, and 7.

25. The compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 24, wherein X is —O—.

26. The compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 24 or 25, wherein each Y is independently selected from —C(R Y ) 2 —, —CO—, and

27. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-26, wherein each R Y is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), and —OR Y1 .

28. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-27, wherein each R Y is independently selected from: hydrogen,

29. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-28, wherein each Q is independently selected from:

C 3 -C 8 cycloalkyl, C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.

30. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-29, wherein each Q is independently selected from:

31. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-30, wherein Ring B is selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen.

32. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-31, wherein Ring B is selected from:

33. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-32, wherein —(Y) n — is a group selected from:

34. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-33, wherein each Y is —C(R Y ) 2 —.

35. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-34, wherein each R 1 is independently selected from —CF 3 and —N(R 2 ) 2 .

36. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-35, wherein each R 2 is independently selected from hydrogen and C 1 -C 6 alkyl.

37. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-36, wherein each R 2 is hydrogen.

38. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-37, wherein Z is

39. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-38, wherein R Z1 is selected from C 1 -C 6 alkyl (optionally substituted with 1-3 groups selected from halogen).

40. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-39, wherein R Z1 is —CF 3 .

41. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-40, wherein R Z2 is hydroxy.

42. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-41, wherein n is selected from 4, 5, and 6.

43. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24-42, wherein n is 6.

44. A compound selected from compounds of Formulae IIa, IIb, and IIc:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each R 1 is independently selected from halogen, —CF 3 , —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups selected from halogen and hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl; and

m is selected from 0, 1, 2, and 3.

45. The compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 44, wherein m is selected from 1 and 2.

46. The compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 44 or 45, wherein m is 2.

47. A compound selected from compounds of Formulae IId, IIe, and IIf:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each R 1 is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH; and

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl.

48. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-47, wherein X is —O—.

49. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-48, wherein each Y is independently selected from —C(R Y ) 2 —, —CO—, and

50. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-49, wherein each R Y is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), and —OR Y1 .

51. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-50, wherein each R Y is independently selected from: hydrogen,

52. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-51, wherein each Q is independently selected from:

C 3 -C 8 cycloalkyl, C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.

53. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-52, wherein each Q is independently selected from:

54. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-53, wherein Ring B is selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen.

55. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-54, wherein Ring B is selected from:

56. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-55, wherein each Y is —C(R Y ) 2 —.

57. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-56, wherein each R 1 is independently selected from —CF 3 and —N(R 2 ) 2 .

58. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-57, wherein each R 2 is independently selected from hydrogen and C 1 -C 6 alkyl.

59. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-58, wherein each R 2 is hydrogen.

60. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-59, wherein Z is

61. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-60, wherein R Z1 is selected from C 1 -C 6 alkyl (optionally substituted with 1-3 groups selected from halogen).

62. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-61, wherein R Z1 is —CF 3 .

63. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 44-62, wherein R Z2 is hydroxy.

64. A compound selected from compounds of Formulae IIIa, IIIb, and IIIc:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each R 1 is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl; and

m is selected from 0, 1, 2, and 3.

65. The compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 64, wherein m is selected from 1 and 2.

66. The compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 64 or 65, wherein m is 2.

67. A compound selected from compounds of Formulae IIId, IIIe, and IIIf:

and deuterated derivatives and pharmaceutically acceptable salts thereof, wherein:

X is selected from —O—, —S—, —SO—, and —SO 2 —;

each Y is independently selected from —C(R Y ) 2 —, —O—, —CO—, and

each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 6 -C 10 aryl, 5- to 10-membered heteroaryl, —OR Y1 , —CO 2 R Y1 , —COR Y1 , —CON(R Y1 ) 2 , and —NR Y1 —; or two instances of R Y on the same atom are taken together to form a ring selected from C 3 -C 8 cycloalkyl and 3- to 6-membered heterocyclyl; or two instances of R Y , one of which is on one atom and the second of which is on an adjacent atom, are taken together to form a pi bond;

each R Y1 is independently selected from hydrogen and C 1 -C 6 alkyl, or two instances of R Y1 bonded to the same nitrogen taken together form a 3- to 6-membered heterocyclyl;

Ring B is selected from:

C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl);

each Q is independently selected from:

C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from:

halogen, oxo, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from halogen and —OCF 3 ), and C 3 -C 8 cycloalkyl,

C 3 -C 8 cycloalkyl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen, —NH 2 , and —NHCOMe), C 1 -C 6 alkoxy, C 6 -C 10 aryl (optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl), and C 3 -C 8 cycloalkyl,

C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:

halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen and hydroxy), C 1 -C 6 alkoxy optionally substituted with 1-4 groups independently selected from:

halogen, C 3 -C 8 cycloalkyl (optionally substituted with CF 3 ),

C 3 -C 8 cycloalkyl (optionally substituted with 1-3 groups independently selected from halogen, CF 3 , OCF 3 , and C 1 -C 6 alkyl), and C 6 -C 10 aryl,

5- to 10-membered heteroaryl optionally substituted with 1-3 groups independently selected from:

halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from halogen), C 3 -C 8 cycloalkyl (optionally substituted with 1-3 CF 3 groups), and 3- to 10-membered heterocyclyl,

3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from:

C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C 3 -C 8 cycloalkyl), and oxo;

each is independently selected from halogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), —OR 2 , —N(R 2 ) 2 , —CO 2 R 2 , —CO—N(R 2 ) 2 , —CN, phenyl, benzyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, —SO 2 R 2 , —SR 2 , —SOR 2 , —PO(OR 2 ) 2 , and —PO(R 2 ) 2 ;

each R 2 is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen), and C 6 -C 10 aryl (optionally substituted with C 1 -C 6 alkoxy, which is optionally substituted with 1-6 groups independently selected from halogen);

Z is selected from

R Z1 is selected from hydrogen, —CN, C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen or 1-3 hydroxy), 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl;

R Z2 is selected from hydrogen, halogen, and hydroxy, or R Z1 and R Z2 taken together form a group selected from oxo and ═N—OH;

each R Z3 is independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and C 6 -C 10 aryl; or two instances of R Z3 are taken together to form a 3- to 6-membered heterocyclyl.

68. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-67, wherein X is —O—.

69. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-68, wherein each Y is independently selected from —C(R Y ) 2 —, —CO—, and

70. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-69, wherein each R Y is independently selected from hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), and —OR Y1 .

71. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-70, wherein each R Y is independently selected from: hydrogen,

72. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-71, wherein each Q is independently selected from:

C 3 -C 8 cycloalkyl, C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.

73. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-72, wherein each Q is independently selected from:

74. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-73, wherein Ring B is selected from C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen.

75. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-74, wherein Ring B is selected from:

76. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-75, wherein each Y is —C(R Y ) 2 —.

77. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-76, wherein each R 1 is independently selected from —CF 3 and —N(R 2 ) 2 .

78. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-77, wherein each R 2 is independently selected from hydrogen and C 1 -C 6 alkyl.

79. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-78, wherein each R 2 is hydrogen.

80. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-79, wherein Z is

81. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-80, wherein R Z1 is selected from C 1 -C 6 alkyl (optionally substituted with 1-3 groups selected from halogen).

82. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-81, wherein R Z1 is —CF 3 .

83. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 64-82, wherein R Z2 is hydroxy.

84. The compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1, wherein X is —O—.

85. The compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1 or 84, wherein each R Y is independently selected from hydrogen, halogen, C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q), C 3 -C 8 cycloalkyl, and —OR Y1 .

86. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1, 84, and 85, wherein —OR Y1 is —OH.

87. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-86, wherein each Q is independently selected from:

C 3 -C 8 cycloalkyl, C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl.

88. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-87, wherein each Q is independently selected from:

89. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-88, wherein each R Y is independently selected from: hydrogen, fluorine,

90. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-89, wherein Ring B is selected from C 3 -C 8 cycloalkyl and phenyl optionally substituted with 1-3 groups independently selected from halogen.

91. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-90, wherein Ring B is selected from:

92. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-91, wherein n is selected from 4, 5, and 6.

93. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-92, wherein —(Y) n — is a group selected from:

94. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-93, wherein each R 1 is independently selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen and hydroxy), —N(R 2 ) 2 , and —CO 2 R 2 .

95. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 85-94, wherein each R 2 is independently selected from hydrogen and C 1 -C 6 alkyl.

96. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-95, wherein each R 1 is independently selected from —CF 3 , —NH 2 , —NH(CH 2 CH 3 ), CO 2 H, and CH 2 OH.

97. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-96, wherein Z is selected from

98. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-97, wherein the group:

is selected from:

99. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-98, wherein the group:

is selected from:

100. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-99, wherein R Z1 is selected from hydrogen and C 1 -C 6 alkyl (optionally substituted with 1-3 groups selected from halogen).

101. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-100, wherein R Z1 is selected from hydrogen and —CF 3 .

102. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-101, wherein R Z2 is hydroxy.

103. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-102, wherein Z is selected from:

104. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 and 84-103, wherein m is selected from 1 and 2.

105. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1, 2, and 84-104, wherein:

X is —O—;

each Y is independently selected from —C(R Y ) 2 —, —O—, and

each R Y is independently selected from hydrogen and C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxy and Q);

Ring B is selected from C 3 -C 8 cycloalkyl groups:

each Q is independently selected from: C 3 -C 8 cycloalkyl and C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkyl,

each R 1 is independently selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen) and —NH 2 ;

Z is

R Z1 is selected from C 1 -C 6 alkyl (optionally substituted with 1-6 groups independently selected from halogen);

R Z2 is hydroxy;

n is selected from 5 and 6; and

m is 2.

106. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1, 2, and 84-105, wherein each Q is independently selected from:

107. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1, 2, and 84-106, wherein each R Y is independently selected from: hydrogen,

108. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1, 2, and 84-107, wherein Ring B is

109. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1, 2, and 84-108, wherein —(Y) n — is a group selected from:

110. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1, 2, and 84-109, wherein R Z1 is —CF 3 .

111. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1, 2, and 84-110, wherein n is 5.

112. The compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1, 2, and 84-110, wherein n is 6.

113. A compound selected from compounds of Table 12, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

114. A compound selected from compounds of Table 13, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

115. A compound according to Embodiment 113, wherein the compound is selected from:

Comp. No. Structure 5 11 14 36 37 47 49 50 52

deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing.

116. A compound according to Embodiment 114, wherein the compound is selected from:

Comp. No. Structure 59 61 63 64

deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing.

117. A pharmaceutical composition comprising a compound, deuterated derivative, or pharmaceutically acceptable salt of any one of Embodiments 1-116 and a pharmaceutically acceptable carrier.

118. The pharmaceutical composition according to Embodiment 117, further comprising one or more additional therapeutic agent(s).

119. The pharmaceutical composition according to Embodiment 118, wherein the one or more additional therapeutic agent(s) comprise(s) a compound with CFTR modulating activity or a salt or deuterated derivative thereof.

120. The pharmaceutical composition according to Embodiment 118 or 119, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR corrector.

121. The pharmaceutical composition according to any one of Embodiments 118-120, wherein the one or more additional therapeutic agent(s) comprise(s) (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II):

122. The pharmaceutical composition according to any one of Embodiments 118-121, wherein the one or more additional therapeutic agent(s) comprise(s) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV):

123. The pharmaceutical composition according to any one of Embodiments 118-122, wherein the one or more additional therapeutic agent(s) comprise(s) N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound V):

124. The pharmaceutical composition according to any one of Embodiments 118-123, wherein the one or more additional therapeutic agent(s) comprise(s) N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound VI):

125. The pharmaceutical composition according to any one of Embodiments 118-124, wherein the one or more additional therapeutic agent(s) comprise(s) (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound VII):

126. The pharmaceutical composition according to any one of Embodiments 118-125, wherein the one or more additional therapeutic agent(s) comprise(s) (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound VIII):

127. The pharmaceutical composition according to any one of Embodiments 118-126, 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, and PTI-801.

128. The pharmaceutical composition according to any one of Embodiments 118-127, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR potentiator enhancer.

129. The pharmaceutical composition according to any one of Embodiments 118-128, wherein the one or more additional thereapeutic agent(s) comprise(s) ASP-11.

130. A method of treating cystic fibrosis, comprising administering an effective amount of the compound, salt, or deuterated derivative according to any one of Embodiments 1-116 or the pharmaceutical composition according to any one of Embodiments 117-129 to a patient in need thereof.

131. The method according to Embodiment 130, further comprising administering one or more additional therapeutic agent(s).

132. The method according to Embodiment 131, wherein the one or more additional therapeutic agent(s) comprise(s) a compound with CFTR modulating activity or a salt or deuterated derivative thereof.

133. The method according to Embodiment 131 or 132, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR corrector.

134. The method according to any one of Embodiments 131-133, wherein the one or more additional therapeutic agent(s) comprise(s) (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound II):

135. The method according to any one of Embodiments 131-134, wherein the one or more additional therapeutic agent(s) comprise(s) 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound IV):

136. The method according to any one of Embodiments 131-135, wherein the one or more additional therapeutic agent(s) comprise(s) N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound V):

137. The method according to any one of Embodiments 131-136, wherein the one or more additional therapeutic agent(s) comprise(s)N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl) cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound VI):

138. The method according to any one of Embodiments 131-137, wherein the one or more additional therapeutic agent(s) comprise(s) (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound VII):

139. The method according to any one of Embodiments 131-138, wherein the one or more additional therapeutic agent(s) comprise(s) (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ 6 thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound VIII):

140. The method according to any one of Embodiments 131-139, wherein the one or more additional thereapeutic 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, and PTI-801.

141. The method according to any one of Embodiments 131-140, wherein the one or more additional therapeutic agent(s) comprise(s) a CFTR potentiator enhancer.

142. The method according to any one of Embodiments 131-141, wherein the one or more additional thereapeutic agent(s) comprise(s) ASP-11.

143. The compound, deuterated derivative, or pharmaceutically acceptable salt of any one of Embodiments 1-116 or the pharmaceutical composition according to any one of Embodiments 117-129 for use in the treatment of cystic fibrosis.

144. Use of the compound, deuterated derivative, or pharmaceutically acceptable salt of any one of Embodiments 1-117 in the manufacture of a medicament for the treatment of cystic fibrosis.

145. Use of the pharmaceutical composition according to any one of Embodiments 117-129 in the manufacture of a medicament for the treatment of cystic fibrosis.

146. Substantially crystalline Compound 11 heptane solvate (i.e., wherein less than 15% of Compound 11 is in amorphous form, wherein less than 10% of Compound 11 is in amorphous form, wherein less than 5% of Compound 11 is in amorphous form).

147. The Compound 11 according to Embodiment 146, wherein Compound 11 is 100% crystalline heptane solvate.

148. The crystalline Compound 11 heptane solvate according to Embodiment 146 or 147, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.8±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 11.7±0.2 degrees two-theta.

149. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-148, characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected selected from 5.8±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 11.7±0.2 degrees two-theta, and (b) one, two, three, or four signals selected from 5.6±0.2 degrees two-theta, 18.1±0.2 degrees two-theta, 20.5±0.2 degrees two-theta, and 20.9±0.2 degrees two-theta.

150. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-149, characterized by an X-ray powder diffractogram having signals at 5.6±0.2 degrees two-theta, 5.8±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, 11.7±0.2 degrees two-theta, 18.1±0.2 degrees.

151. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-150, characterized by an X-ray powder diffractogram substantially similar to FIG. 1 .

152. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-151, characterized by a 13 C ssNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 166.3±0.2 ppm, 165.8±0.2 ppm, 164.6±0.2 ppm, 163.4±0.2 ppm, 154.8±0.2 ppm, 154.0±0.2 ppm, 152.1±0.2 ppm, 151.6±0.2 ppm, 140.2±0.2 ppm, 139.4±0.2 ppm, 138.5±0.2 ppm, 138.0±0.2 ppm, 135.1±0.2 ppm, 134.6±0.2 ppm, 131.3±0.2 ppm, 130.2±0.2 ppm, 129.6±0.2 ppm, 128.5±0.2 ppm, 125.7±0.2 ppm, 123.7±0.2 ppm, 123.2±0.2 ppm, 122.9±0.2 ppm, 121.1±0.2 ppm, 120.2±0.2 ppm, 119.2±0.2 ppm, 117.8±0.2 ppm, 76.2±0.2 ppm, 74.4±0.2 ppm, 73.7±0.2 ppm, 73.3±0.2 ppm, 40.0±0.2 ppm, 38.6±0.2 ppm, 37.6±0.2 ppm, 36.9±0.2 ppm, 35.7±0.2 ppm, 33.6±0.2 ppm, 32.5±0.2 ppm, 32.0±0.2 ppm, 30.4±0.2 ppm, 30.1±0.2 ppm, 29.5±0.2 ppm, 28.8±0.2 ppm, 28.1±0.2 ppm, 27.1±0.2 ppm, 25.3±0.2 ppm, 23.1±0.2 ppm, 22.7±0.2 ppm, 22.0±0.2 ppm, 21.6±0.2 ppm, 20.3±0.2 ppm, 19.6±0.2 ppm, 18.3±0.2 ppm, 17.6±0.2 ppm, 13.8±0.2 ppm, 13.1±0.2 ppm, and 12.5±0.2 ppm.

153. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-152, characterized by a 13 C SSNMR spectrum substantially similar to FIG. 3 .

154. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-153, characterized as having a 19 F SSNMR spectrum with one, two, three, four, five, or more peaks selected from −63.5±0.2 ppm, −63.8±0.2 ppm, −65.1±0.2 ppm, −65.8±0.2 ppm, −66.3±0.2 ppm, −67.0±0.2 ppm, −74.0±0.2 ppm, −74.9±0.2 ppm, and −76.6±0.2 ppm.

155. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-154, characterized as having a 19 F SSNMR spectrum with one, two, three, four, five, or more peaks selected from −63.5±0.2 ppm, −63.8±0.2 ppm, −65.1±0.2 ppm, −65.8±0.2 ppm, −66.3±0.2 ppm, −67.0±0.2 ppm, −74.0±0.2 ppm, −74.9±0.2 ppm, −76.6±0.2 ppm, and −77.6±0.2 ppm.

156. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-155, characterized as having a 19 F SSNMR spectrum with a peak at −67.0±0.2 ppm.

157. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-156, characterized as having a 19 F SSNMR spectrum with a peak at −65.1±0.2 ppm.

158. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-157, characterized as having a 19 F SSNMR spectrum with a peak at −76.6±0.2 ppm.

159. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-158, characterized as having a 19 F SSNMR spectrum with a peak at −63.5±0.2 ppm.

160. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-159, characterized as having a 19 F SSNMR spectrum with a peak at −74.9±0.2 ppm.

161. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-160, characterized as having a 19 F SSNMR spectrum with at least one peak selected from −65.1±0.2 ppm, −67.0±0.2 ppm, and −76.6±0.2 ppm.

162. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-161, characterized as having a 19 F SSNMR spectrum with peaks at −65.1±0.2 ppm, −67.0±0.2 ppm, and −76.6±0.2 ppm.

163. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-162, characterized as having a 19 F SSNMR spectrum with at least one peak selected from −63.5±0.2 ppm, −65.1±0.2 ppm, −67.0±0.2 ppm, −74.9±0.2 ppm, and −76.6±0.2 ppm.

164. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-163, characterized as having a 19 F SSNMR spectrum with peaks at −63.5±0.2 ppm, −65.1±0.2 ppm, −67.0±0.2 ppm, −74.9±0.2 ppm, and −76.6±0.2 ppm.

165. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-164, characterized by a 19 F SSNMR spectrum substantially similar to FIG. 4 .

166. The crystalline Compound 11 heptane solvate according to any one of Embodiments 146-165, prepared by a process comprising dissolving Compound 11 in heptane and dichloromethane, concentrating under rotary evaporation, swirling at room temperature, filtering the solids, washing the solids with cold heptane, and drying under vacuum to provide Compound 11 heptane solvate.

167. A method of preparing the crystalline Compound 11 heptane solvate according to any one of Embodiments 146-166, prepared by a process comprising dissolving Compound 11 in heptane and dichloromethane, concentrating under rotary evaporation, swirling at room temperature, filtering the solids, washing the solids with cold heptane, and drying under vacuum to provide Compound 11 heptane solvate.

168. The pharmaceutical composition according to any one of Embodiments 118-126, wherein the one or more additional therapeutic agent(s) comprise(s) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808 (dirocaftor), GLPG1837, GLPG2451/ABBV-2451, QBW251 (icenticaftor), GLPG3067/ABBV-3067 (Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF 552 , GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5 Rx, BI 1265162, AZ5634, ARO-ENaC1001, ETD002, and DS-1039.

169. The method according to any one of Embodiments 131-139, wherein the one or more additional thereapeutic agent(s) comprise(s) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN23765, ARN23766, PTI-801, FDL-176, PTI-808 (dirocaftor), GLPG1837, GLPG2451/ABBV-2451, QBW251 (icenticaftor), GLPG3067/ABBV-3067 (Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, amiloride, ETD001, CF 552 , GS-9411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5 Rx, BI 1265162, AZ5634, ARO-ENaC1001, ETD002, and DS-1039.

170. Substantially crystalline Compound 6 (free form) (i.e., wherein less than 15% of

Compound 6 is in amorphous form, wherein less than 10% of Compound 6 is in amorphous form, wherein less than 5% of Compound 6 is in amorphous form).

171. The Compound 6 (free form) according to Embodiment 170, wherein Compound 6 is 100% crystalline Compound 6 (free form).

172. The crystalline Compound 6 (free form) according to Embodiment 170 or 171, characterized by a monoclinic crystal system, a P21 space group, and unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with Cu K α radiation (λ=1.5478 Å) of:

a  9.6 ± 0.1 Å α 90° b 13.6 ± 0.1 Å β 105.3° ± 0.1° c 13.8 ± 0.1 Å γ 90°

173. Substantially crystalline Compound 19 (free form) (i.e., wherein less than 15% of Compound 19 is in amorphous form, wherein less than 10% of Compound 19 is in amorphous form, wherein less than 5% of Compound 19 is in amorphous form).

174. The Compound 19 (free form) according to Embodiment 173, wherein Compound 19 is 100% crystalline Compound 19 (free form).

175. The crystalline Compound 19 (free form) according to Embodiment 173 or 174, characterized by a tetragonal crystal system, a P4 1 2 1 2 space group, and unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with Mo K α radiation (λ=0.71073 Å) of:

a  9.8 ± 0.1 Å α 90° b  9.8 ± 0.1 Å β 90° c 37.1 ± 0.1 Å γ 90°

176. Substantially crystalline Compound 20 (free form) (i.e., wherein less than 15% of Compound 20 is in amorphous form, wherein less than 10% of Compound 20 is in amorphous form, wherein less than 5% of Compound 20 is in amorphous form).

177. The Compound 20 (free form) according to Embodiment 176, wherein Compound 20 is 100% crystalline Compound 20 (free form).

178. The crystalline Compound 20 (free form) according to Embodiment 176 or 177, characterized by an orthorhombic crystal system, a P2 1 2 1 2 1 space group, and unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with Mo K α radiation (λ=0.71073 Å) of:

General Experimental Procedures

ACN: Acetonitrile

AcOH: Acetic acid

BCl 3 : Boron trichloride

Boc anhydride ((Boc) 2 O): Di-tert-butyl dicarbonate

CDCl 3 : Chloroform-d

CDI: 1,1′-Carbonyldiimidazole

CD 3 OD: Methyl-d 3 alcohol-d

CH 2 Cl 2 : Dichloromethane

CH 3 CN: Acetonitrile

CO 2 : Carbon dioxide

Cs 2 CO 3 : Cesium carbonate

CuBr 2 : Copper(II) bromide

CuI: Copper(I)iodide

DCE: 1,2-Dichloroethane

DCM: Dichloromethane

DDQ: 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

DI: Deionized

DIAD: Diisopropyl azodicarboxylate

DIEA: DIPEA; N,N-Diisopropylethylamine

DMAP: 4-Dimethylaminopyridine

DMF: N,N-Dimethylformamide

DMSO: Dimethyl sulfoxide

DMSO-d 6 : Dimethyl sulfoxide-d 6

EA: Ethyl acetate

ELSD: Evaporative light scattering detector

Et 2 O: Diethyl ether

EtOAc: Ethyl acetate

EtOH: Ethanol

ESI-MS: Electrospray ionization mass spectrometry

Grubbs 1 st Generation catalyst: Dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II)

Grubbs 2 nd Generation catalyst: [1,3-Bis(2,4,6-trimethylphenypimidazolidin-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium

H 2 : Hydrogen

HATU: N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide

HCl: Hydrochloric acid

HFIP: Hexafluoroisopropanol

Hoveyda-Grubbs 2 nd Generation catalyst: Dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II)

HPLC: High performance liquid chromatography

IPA: Isopropanol

IPAC: Isopropyl acetate

iPrOH: Isopropanol

KHSO 4 : Potassium bisulfate

LC: Liquid chromatography

LCMS: Liquid chromatography mass spectrometry

LDA: Lithium diisopropylamide

LiOH: Lithium hydroxide

MeCN: Acetonitrile

MeTHF or 2-MeTHF: 2-Methyltetrahydrofuran

MeOH: Methanol

MTBE: Methyl tert-butyl ether

MgSO 4 : Magnesium sulfate

n-BuLi: n-Butyllithium

NaBH 4 : Sodium borohydride

NaHCO 3 : Sodium bicarbonate

NaHMDS: Sodium bis(trimethylsilyl)amide

NaOH: Sodium hydroxide

Na 2 S 2 O 3 : Sodium thiosulfate

Na 2 SO 4 : Sodium sulfate

NBS: N-Bromosuccinimide

NMP: N-Methyl-2-pyrrolidone

NMR: Nuclear magnetic resonance

Pd/C: Palladium on carbon

Pd(OAc) 2 : Palladium(II) acetate

rt: Room temperature

SFC: Supercritical fluid chromatography

Silica Cat Pd: Palladium on Silica

SilicaMetS: Silica Supported Metal Scavenger

SiO 2 : Silica gel

T 3 P: 1-Propanephosphonic anhydride

TBAI: Tetrabutylammonium iodide

TEA: Triethylamine

TFA: Trifluoroacetic acid

THF: Tetrahydrofuran

UPLC: Ultra Performance Liquid Chromatography

Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

XPhos Pd G3: (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1 1 -biphenyl)]palladium(II) methanesulfonate

Zhan catalyst-1B: Dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II)

General Methods

Reagents and starting materials were obtained by commercial sources unless otherwise stated and were used without purification.

Proton and carbon NMR spectra were acquired on either a Bruker Biospin DRX 400 MHz FTNMR spectrometer operating at a 1 H and 13 C resonant frequency of 400 and 100 MHz respectively, or on a 300 MHz NMR spectrometer. One dimensional proton and carbon spectra were acquired using a broadband observe (BBFO) probe with 20 Hz sample rotation at 0.1834 and 0.9083 Hz/Pt digital resolution respectively. All proton and carbon spectra were acquired with temperature control at 30° C. using standard, previously published pulse sequences and routine processing parameters.

NMR (1D & 2D) spectra were also recorded on a Bruker AVNEO 400 MHz spectrometer operating at 400 MHz and 100 MHz respectively equipped with a 5 mm multinuclear Iprobe.

NMR spectra were also recorded on a Varian Mercury NMR instrument at 300 MHz for 1 H using a 45 degree pulse angle, a spectral width of 4800 Hz and 28860 points of acquisition. FID were zero-filled to 32 k points and a line broadening of 0.3 Hz was applied before Fourier transform. 19 F NMR spectra were recorded at 282 MHz using a 30 degree pulse angle, a spectral width of 100 kHz and 59202 points were acquired. FID were zero-filled to 64 k points and a line broadening of 0.5 Hz was applied before Fourier transform.

NMR spectra were also recorded on a Bruker Avance III HD NMR instrument at 400 MHz for 1 H using a 30 degree pulse angle, a spectral width of 8000 Hz and 128 k points of acquisition. FID were zero-filled to 256 k points and a line broadening of 0.3 Hz was applied before fourrier transform. 19 F NMR spectra were recorded at 377 MHz using a 30 deg pulse angle, a spectral width of 89286 Hz and 128 k points were acquired. FID were zero-filled to 256 k points and a line broadening of 0.3 Hz was applied before Fourier transform.

NMR spectra were also recorded on a Bruker AC 250 MHz instrument equipped with a: 5 mm QNP(H1/C13/F19/P31) probe (type: 250-SB, s #23055/0020) or on a Varian 500 MHz instrument equipped with a ID PFG, 5 mm, 50-202/500 MHz probe (model/part #99337300).

Unless stated to the contrary in the following examples, final purity of compounds was determined by reversed phase UPLC using an Acquity UPLC BEH Cls column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 3.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C. Final purity was calculated by averaging the area under the curve (AUC) of two UV traces (220 nm, 254 nm). Low-resolution mass spectra were reported as [M+1] + species obtained using a single quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source capable of achieving a mass accuracy of 0.1 Da and a minimum resolution of 1000 (no units on resolution) across the detection range.

Solid-state NMR (SSNMR) spectra were recorded on a Bruker-Biospin 400 MHz wide-bore spectrometer equipped with Bruker-Biospin 4 mm HFX probe. Samples were packed into 4 mm ZrO2 rotors and spun under Magic Angle Spinning (MAS) condition with spinning speed typically set to 12.5 kHz. The proton relaxation time was measured using 1 H MAS T 1 saturation recovery relaxation experiment in order to set up proper recycle delay of the 13 C cross-polarization (CP) MAS experiment. The fluorine relaxation time was measured using 19 F MAS T 1 saturation recovery relaxation experiment in order to set up proper recycle delay of the 19 F MAS experiment. The CP contact time of carbon CPMAS experiment was set to 2 ms. A CP proton pulse with linear ramp (from 50% to 100%) was employed. The carbon Hartmann-Hahn match was optimized on external reference sample (glycine). Both carbon and fluorine spectra were recorded with proton decoupling using TPPM15 decoupling sequence with the field strength of approximately 100 kHz.

General Synthetic Schemes

Another aspect of the disclosure provides methods for making compounds of Formulae I, I′, I″, I′″, Ia, IIa, IIa′, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc, IIId, IIIe, and IIIf, Compounds 1 to 53, Compounds 54 to 77, and pharmaceutically acceptable salts of any of those compounds, deuterated derivatives of any of the foregoing, 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 1 refers to processes for preparing an intermediate compound of Formula S1-7 from a compound of Formula S1-1. Alk is selected from C 1 -C 6 linear or branched alkyl groups. X 1 is selected from halogens such as Cl, I, or Br. Y and R Y are as defined for Formula I above.

Any suitable conditions for a Grignard addition can be used to react a compound of Formula S1-1 with a compound of Formula S1-2 to form a compound of Formula S1-3. For example, the Grignard addition of a compound of Formula 51-1 with a compound of Formula S1-2 may be performed in Et 2 O at −78° C., followed by addition of 1 N aqueous HCl to yield a compound of Formula S1-3. Conversion of a compound of Formula S1-3 to a compound of Formula S1-4 may be accomplished by any suitable benzylation procedure. Conversion of an ester of Formula S1-4 to a carboxylic acid of Formula S1-5 may be accomplished by any suitable hydrolysis conditions. For example, conversion of a carboxylic acid of Formula S1-5 to a compound of Formula S1-6 may be accomplished by reacting a compound of Formula S1-5 with HATU and Et 3 N in DMF, followed by addition of tert-butyl N-aminocarbamate. Any suitable hydrolysis conditions may be used to convert a carbamate of Formula S1-6 to a hydrazide of Formula S1-7. For example, a compound of Formula S1-7 may be obtained by reacting a compound of Formula S1-6 with HCl in CH 2 Cl 2 at ambient temperature.

Scheme 2 refers to processes for preparing an intermediate compound of Formula S2-3 from a compound of Formula S2-1. R A1 is selected from —X—(Y) 2-4 -C(R Y )═C(R Y ) 2 , —OH, —OPG (wherein PG is a suitable protecting group), and halogen. R 1 , m, X, Y, and R Y are as defined for Formula I above.

Any suitable conditions to form an amide bond can be used to produce a compound of Formula S2-2 from a compound of Formula S2-1 and a compound of Formula S1-7. For example, a compound of Formula S2-1 can be reacted with CDI in acetonitrile and DMF, followed by addition of a compound of Formula S1-7, to yield a compound of Formula S2-2. A compound of Formula S2-2 can be converted to a compound of Formula S2-3 using any conditions suitable for oxadiazole formation. For example, a compound of Formula S2-2 can be reacted with DIPEA in acetonitrile, followed by addition of p-toluenesulfonyl chloride, to yield an oxadiazole of Formula S2-3.

Scheme 3 refers to processes for preparing a compound of Formula S3-8 from a compound of Formula S3-1. Alk is selected from C 1 -C 6 linear or branched alkyl groups. LG is selected from halogens and oxygen-based leaving groups such as OTf. R 1 , m, Y and R Y are as defined for Formula I above.

The reaction of a compound of Formula S3-1 with a compound of Formula S3-2 to yield a compound of Formula S3-3 may be accomplished by any suitable aromatic substitution conditions. For example, a compound of Formula S3-2 may be reacted with sodium hydride in DMF, followed by addition to a compound of Formula S3-1, to yield a compound of Formula S3-3. Conversion of an ester of Formula S3-3 to a carboxylic acid of Formula S3-4 may be accomplished by any suitable hydrolysis conditions. A compound of Formula S3-5 may be prepared from a compound of Formula S3-4 and a compound of Formula S1-7 using any suitable amide bond formation conditions. A compound of Formula S3-5 can be converted to a compound of Formula S3-6 using any conditions suitable for oxadiazole formation. For example, a compound of Formula S3-5 can be reacted with methoxycarbonyl-(triethylammonio)sulfonyl-azanide in THF to yield an oxadiazole of Formula S3-6. Macrocyclization of a compound of Formula S3-6 may be accomplished by any suitable ring-closing metathesis conditions. For example, a compound of Formula S3-6 may be reacted in the presence of [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2-isopropoxy-5-nitro-phenyl)methylene]ruthenium in DCE to yield a macrocycle of Formula S3-7 as a mixture of E/Z isomers (as denoted by the bond). Conversion of an unsaturated compound of Formula S3-7 to a macrocycle of Formula S3-8 can be accomplished using any suitable procedure for olefin reduction and benzyl deprotection.

Scheme 4 refers to processes for preparing a compound of Formula S4-4 from a compound of Formula S4-1. LG is selected from halogens, hydroxy, and oxygen-based leaving groups such as OTf. R 1 , m, Y and R Y are as defined for Formula I above.

The reaction of a compound of Formula S4-1 with a compound of Formula S3-2 to yield a compound of Formula S4-2 may be accomplished by any suitable aromatic substitution conditions or Mitsunobu conditions. For example, a compound of Formula S4-1 may be reacted an alcohol of Formula S3-2 with cesium carbonate and iodocopper in DMSO. Macrocyclization of a compound of Formula S4-2 may be accomplished by any suitable ring-closing metathesis conditions. For example, a compound of Formula S4-2 may be reacted in the presence of Grubbs 2 nd generation catalyst in DCE to yield a macrocycle of Formula S4-3 as a mixture of E/Z isomers (as denoted by the bond). Conversion of an unsaturated compound of Formula S4-3 to a macrocycle of Formula S4-4 can be accomplished using any suitable procedure for olefin reduction and benzyl deprotection.

Scheme 5 refers to processes for preparing a compound of Formula S5-3, a compound of Formula S5-6, and a compound of Formula S5-7 from a compound of Formula S5-1. R 1 , m, and Y are as defined for Formula I above.

The conversion of a compound of Formula S5-1 to a deuterated compound of Formula S5-2 may be accomplished by any suitable catalytic deuteration conditions. For example, a compound of Formula S5-1 may be reacted with 10% palladium on carbon in CD 3 OD under a deuterium gas atmosphere to yield a compound of Formula S5-2. Conversion of a benzyl-protected compound of Formula S5-2 to a free alcohol of Formula S5-3 may be accomplished by any suitable deprotection conditions.

Conversion of an unsaturated compound of Formula S5-1 to an alcohol of Formula S5-4 may be accomplished by any suitable hydroboration/oxidation conditions. For example, a compound of Formula S5-1 may be reacted with borane dimethylsulfide complex in THF, followed by quenching with aqueous NaOH and a subsequent addition of hydrogen peroxide to yield an alcohol of Formula S5-4 as a mixture of regioisomers. Debenzylation of a compound of Formula S5-4 to yield a compound of Formula S5-5 may be accomplished using any suitable benzyl deprotection conditions. Conversion of a compound of Formula S5-5 to a compound Formula S5-7 may be accomplished by any suitable oxidation conditions. For example, a compound of Formula S5-5 may be reacted with NaHCO 3 and Dess-Martin periodinane in CH 2 Cl 2 to yield a compound of Formula S5-7.

In an alternative route, conversion of a compound of Formula S5-4 to a compound of Formula S5-6 may be accomplished by any suitable oxidation conditions. For example, a compound of Formula S5-4 may be reacted with Dess-Martin periodinane in CH 2 Cl 2 to yield a compound of Formula S5-6. Debenzylation of a compound of Formula S5-6 to yield a compound of Formula S5-7 may be accomplished using any suitable benzyl deprotection conditions.

Scheme 6 refers to processes for preparing a compound of Formula S6-5 from a compound of Formula S6-1. LG is selected from halogens and oxygen-based leaving groups such as OTf. R 1 , m, Y, and R Y are as defined for Formula I above.

The conversion of a compound of Formula S6-1 and a compound of Formula S6-2 to a compound of Formula S6-3 may be accomplished by any suitable aromatic substitution conditions. For example, a compound of Formula S6-1 may be reacted with a compound of Formula S6-2 and DMSO. Macrocyclization of a compound of Formula S6-3 may be accomplished by any suitable ring-closing metathesis conditions. For example, a compound of Formula S6-3 may be reacted in the presence of benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-ruthenium;tricyclohexylphosphane in DCE to yield a macrocycle of Formula S6-4 as a mixture of E/Z isomers (as denoted by the bond). Conversion of an unsaturated compound of Formula S6-4 to a macrocycle of Formula S6-5 can be accomplished using any suitable procedure for olefin reduction and benzyl deprotection.

Scheme 7 refers to processes for preparation of a compound of Formula S7-6 from a compound of Formula S7-1. R 1 , m, Y, and R Y are as defined for Formula I above. LG is selected from halogens and oxygen-based leaving groups such as OTf.

Reaction of a compound of Formula S7-1 with a compound of Formula S7-2 to form a compound of Formula S7-3 can be accomplished by any suitable lithiation procedure. For example, the reaction of a compound of Formula S7-1 with a compound of Formula S7-2 may be performed in ether at −78° C. with n-BuLi to form a compound of Formula S7-3. Conversion of a compound of Formula S7-3 to a compound of Formula S7-4 may be accomplished by any suitable ring-closing metathesis procedure. For example, the ring-closing metathesis reaction of the compound of Formula S7-3 may be accomplished in the presence of benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-ruthenium;tricyclohexylphosphane in DCE to yield a compound of Formula S7-4 as a mixture of E/Z isomers (as denoted by the bond). Conversion of a compound of Formula S7-4 to a compound of Formula S7-5 may be accomplished by any suitable procedure for olefin reduction and benzyl deprotection. Conversion of a compound of Formula S7-5 to a compound of Formula S7-6 may be accomplished by any suitable procedure for oxidizing a thioether to a sulfoxide.

Scheme 8 refers to processes for preparing a compound of Formula S8-8 from a compound of Formula S8-1. Alk is selected from C 1 -C 6 linear or branched alkyl groups. LG is selected from oxygen-based leaving groups such as OTf and halogens such Cl, I, and Br. R 1 m, Y, R Y , and Ring B are as defined for Formula I above.

Any suitable conditions for synthesizing an aryl ether from an alcohol and an aryl halide can be used to react a compound of Formula S8-1 with a compound of Formula S8-2 to yield a compound of Formula S8-3. Any suitable conditions for condensation of a hydrazide with a carboxylic acid can be used to react a compound of Formula S8-3 with a compound of Formula S8-4 to form a compound of Formula S8-5. Any suitable conditions for oxadiazole formation from a hydrazide can be used to convert a compound of Formula S8-5 to a compound of Formula S8-6. Conversion of a compound of Formula S8-6 to a compound of Formula S8-7 may be accomplished by any suitable ring-closing metathesis procedure. For example, the ring-closing metathesis reaction of the compound of Formula S8-6 may be accomplished in the presence of benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-ruthenium;tricyclohexylphosphane in DCE to yield a compound of Formula S8-7 as a mixture of E/Z isomers (as denoted by the bond). Conversion of a compound of Formula S8-7 to a compound of Formula S8-8 may be accomplished by any suitable procedure for olefin reduction and benzyl deprotection.

Scheme 9 refers to processes for preparing a compound of Formula S9-6 and a compound of Formula S9-7 from a compound of Formula S9-1. R 1 , m, Y, R Y , and Ring B are as defined for Formula I above. LG is selected from oxygen-based leaving groups such as OTf and halogens such Cl, I, and Br. L x is selected from halogens such as Cl, I, or Br.

Any suitable conditions for synthesizing an aryl ether from an alcohol and an aryl halide can be used to react a compound of Formula S9-1 with a compound of Formula S9-2 to form a compound of Formula S9-3. Conversion of a compound of Formula S9-3 to a compound of Formula S9-4 and/or a compound of Formula S9-5 may be accomplished by any suitable cross-coupling procedure. For example, the macrocyclization reaction of the compound of Formula S9-3 may be accomplished in the presence of palladium (II) acetate, tris-o-tolylphosphane, and triethylamine in acetonitrile to yield the compound of Formula S9-4 and/or the compound of Formula S9-5. Conversion of a compound of Formula S9-4 to a compound of Formula S9-6 and conversion of a compound of Formula S9-5 to a compound of Formula S9-7 may be accomplished by any suitable procedure olefin reduction and benzyl deprotection.

Scheme 10 refers to processes for preparing a compound of Formula S10-6 from a compound of Formula S10-1. R 1 , m, Y, R Y , and Ring B are as defined for Formula I above. L x is selected from halogens such as Cl, I, or Br.

Reaction of a compound of Formula S10-1 with a compound of Formula S10-2 to yield a compound of Formula S10-3 may be accomplished using any suitable oxadiazole formation procedure. For example, a compound of Formula S10-1 may be reacted with a compound of Formula S10-2 and (isocyanoimino)triphenylphosphorane to yield a compound of Formula S10-3. Conversion of a compound of Formula S10-3 to a compound of Formula S10-4 may be accomplished by any suitable cross-coupling procedure. For example, the macrocyclization reaction of the compound of Formula S10-3 may be accomplished in the presence of palladium (II) acetate, tris-o-tolylphosphane, and triethylamine in acetonitrile to yield a compound of Formula S10-4 as a mixture of E/Z isomers (as denoted by the bond). Conversion of a compound of Formula S10-4 to a compound of Formula S10-5 may be accomplished by any suitable procedure for reducing olefins.

Procedures for the Synthesis of Common Intermediates

Intermediate 1: Preparation of Methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate

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-dichloroethane (300 mL) at 0° C. Trifluoroacetic anhydride (107.70 g, 72 mL, 507.65 mmol) was then added over 30 minutes at a temperature of −10° C., with cooling bath (CO 2 /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 mL). The mixture was diluted with dichloromethane (300 mL) and then layers were separated. The aqueous phase was extracted with dichloromethane (2×200 mL). The combined organic phase was washed with water (2×300 mL) and brine (1×200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (47.6 g, 90%) as light yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.89 (s, 1H), 8.02-7.90 (m, 1H), 7.86-7.72 (m, 1H), 3.89 (s, 3H) ppm. 19 F NMR (282 MHz, DMSO-d 6 ) δ −62.00 (s, 3F) ppm. ESI-MS m/z calc. 221.02998, found 222.1 (M+1) + ; Retention time: 1.24 minutes. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

Trifluoroacetic anhydride (291.62 g, 193 mL, 1.3885 mol) was added drop-wise to a mixture of methyl 1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (51.058 g, 230.66 mmol) in DMF (305 mL) at 0° 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° C. 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 over high vacuum to afford methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (45.24 g, 86%) as white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.90 (d, J=7.2 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 4.02 (s, 3H) ppm. 19 F NMR (282 MHz, DMSO-d 6 ) δ −66.39 (s, 3F) ppm. ESI-MS m/z calc. 221.03, found 222.1 (M+1) + ; Retention time: 1.43 minutes. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

To an ice-cooled solution of methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (33.04 g, 149.41 mmol) in sulfuric acid (200 mL of 18.4 M, 3.6800 mol) was added nitric acid (13 mL of 15.8 M, 205.40 mmol) dropwise. After 5 min, the ice bath was removed, and the reaction mixture was stirred at 38° C. overnight. The reaction was not completed, nitric acid (3 mL 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 into 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 mL). The solid was dried overnight under high vacuum to give methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (39.49 g, 99%) as white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 3.95 (s, 3H) ppm. 19 F NMR (282 MHz, DMSO-d 6 ) δ −64.56 (s, 3F) ppm. ESI-MS m/z calc. 266.0151, found 267.1 (M+1) + ; Retention time: 1.64 minutes. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

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 (2×200 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-(trifluoromethyl)pyridine-2-carboxylate (5.45 g, 50%) as a yellow solid. 1 H NMR (300 MHz, CDCl 3 ) δ 8.75 (s, 1H), 4.07 (s, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −64.12 (s, 3F) ppm. ESI-MS m/z calc. 283.9812, found 285.0 (M+1) + ; Retention time: 1.95 minutes. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

Intermediate 2: Preparation of 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid

A mixture of methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-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 1-L separatory funnel with 2-methyl THF and extracted. The layers were separated and the organic layer was then washed with water (150 mL), brine (150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid (29.61 g, 96%) as off-white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.45 (s, 1H) ppm. 19 F NMR (282 MHz, DMSO-d 6 ) δ −64.53 (s, 3F) ppm. ESI-MS m/z calc. 251.9994, found 253.0 (M+1) + ; Retention time: 0.79 minutes. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

Intermediate 3: Preparation of 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid

To a solution of methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (1.14 g, 4.006 mmol) in THF (48.51 mL) and water (24.26 mL) at 0° C. was added lithium hydroxide monohydrate (201.7 mg, 4.807 mmol). The reaction was allowed to warm to room temperature then stirred for 2 hours. The solution was acidified to pH ˜2-3 by the addition of 1 N HCl, then extracted with EtOAc. The organic phase was washed with water and brine, then dried over sodium sulfate, filtered and concentrated to afford, as a clear syrup, 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid (1.05 g, 97%). ESI-MS m/z calc. 269.9655, found 271.0 (M+1) + ; Retention time: 0.37 minutes determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 1-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Intermediate 4: Preparation of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyppyridine-2-carboxylate

A mixture of methyl 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate (47.3 g, 197.43 mmol), diphenylmethanimine (47 g, 259.33 mmol), Xantphos (9.07 g, 15.675 mmol), and cesium carbonate (131 g, 402.06 mmol) in dioxane (800 mL) was degassed with bubbling nitrogen for 30 minutes. Pd(OAc) 2 (3.52 g, 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 EtOAc and solvents were evaporated under reduced pressure to give methyl 3-(benzhydrylideneamino)-5-(trifluoromethyl)pyridine-2-carboxylate (90 g, 84%) as yellow solid. ESI-MS m/z calc. 384.10855, found 385.1 (M+1) + ; Retention time: 2.24 minutes. LCMS Method: Kinetex C 18 4.6×50 mm 2.6 μM, 2.0 mL/min, 95% H 2 O (0.1% formic acid)+5% acetonitrile (0.1% formic acid) to 95% acetonitrile (0.1% formic acid) gradient (2.0 min) then held at 95% acetonitrile (0.1% formic acid) for 1.0 min.

To a suspension of methyl 3-(benzhydrylideneamino)-5-(trifluoromethyl)pyridine-2-carboxylate (65 g, 124.30 mmol) in methanol (200 mL) was added HCl (3 M in methanol) (146 mL of 3 M, 438.00 mmol). The mixture was stirred at room temperature for 1.5 hour then the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (2 L) and dichloromethane (500 mL). The organic phase was washed with 5% aqueous sodium bicarbonate solution (3×500 mL) and brine (2×500 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was triturated with heptanes (2×50 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. 1 H NMR (300 MHz, CDCl 3 ) δ 8.24 (s, 1H), 7.28 (s, 1H), 5.98 (br. s, 2H), 4.00 (s, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −63.23 (s, 3F) ppm. ESI-MS m/z calc. 220.046, found 221.1 (M+1) + ; Retention time: 1.62 minutes. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

To a solution of methyl 3-amino-5-(trifluoromethyl)pyridine-2-carboxylate (18.75 g, 80.91 mmol) in acetonitrile (300 mL) at 0° C. was added portion wise N-bromosuccinimide (18.7 g, 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 (3×200 mL) which were back extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (3×200 mL), brine (200 mL), dried over sodium sulfate and concentrated in vacuo to provide methyl 3-amino-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (25.46 g, 98%). 1 1-INMR (300 MHz, CDCl 3 ) δ 3.93-4.03 (m, 3H), 6.01 (br. s., 2H), 7.37 (s, 1H) ppm. 19 F NMR (282 MHz, CDCl 3 ) ppm −64.2 (s, 3F). ESI-MS m/z calc. 297.9565, found 299.0 (M+1) + ; Retention time: 2.55 minutes. LCMS Method: Kinetex C 18 4.6×50 mm 2.6 μM. Temp: 45° C., Flow: 2.0 mL/min, Run Time: 6 min. Mobile Phase: Initial 95% H 2 O (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 held at 95% acetonitrile (0.1% formic acid) for 2.0 min.

A mixture of methyl 3-amino-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (5 g, 15.549 mmol), (Boc) 2 O (11 g, 11.579 mL, 50.402 mmol), DMAP (310 mg, 2.5375 mmol) and CH 2 Cl 2 (150 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purification by silica gel chromatography (0-15% ethyl acetate in heptane) provided methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (6.73 g, 87%) as light yellow solid. 1 H NMR (300 MHz, CDCl 3 ) δ 1.42 (s, 18H), 3.96 (s, 3H), 7.85 (s, 1H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −63.9 (s, 3F) ppm. ESI-MS m/z calc. 498.06134, Retention time: 2.34 minutes. LCMS Method: Kinetex C 18 4.6×50 mm 2.6 μM. Temp: 45° C., Flow: 2.0 mL/min, Run Time: 3 min. Mobile Phase: Initial 95% H 2 O (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 held at 95% acetonitrile (0.1% formic acid) for 1.0 min.

Intermediate 5: Preparation of 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid

To a mixture of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyppyridine-2-carboxylate (247 g, 494.7 mmol) in THF (1.0 L) was added a solution of LiOH (47.2 g, 1.971 mol) in water (500 mL). The mixture was stirred at ambient temperature for 18 h affording a yellow slurry. The mixture was cooled with an ice-bath and slowly acidified with HCl (1000 mL of 2 M, 2.000 mol) keeping the reaction temperature <15° C. The mixture was diluted with heptane (1.5 L), mixed and the organic phase separated. The aqueous phase was extracted with heptane (500 mL). The combined organic phases were washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. The crude oil was dissolved in heptane (600 mL), seeded and stirred at ambient temperature for 18 h affording a thick slurry. The slurry was diluted with cold heptane (500 mL) and the precipitate collected using a medium frit. The filter cake was washed with cold heptane and air dried for 1 h, then in vacuo at 45° C. for 48 h to afford 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (158.3 g, 83%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 9.01 (s, 1H), 1.50 (s, 9H) ppm. ESI-MS m/z calc. 383.99326, found 384.9 (M+1) + ; Retention time: 2.55 minutes. LCMS Method Detail: Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Intermediate 6: Preparation of methyl 3-amino-6-bromo-5-fluoro-pyridine-2-carboxylate

In an autoclave (600 mL) was added 2-bromo-5-fluoro-pyridin-3-amine (22 g, 115.18 mmol), methanol (250 mL), triethylamine (23.232 g, 32 mL, 229.59 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.1 g, 2.8700 mmol). The autoclave was purged with nitrogen, then with carbon monoxide. The mixture was heated to 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). Water (200 mL) and sodium carbonate (15 g) were added and the mixture was vigorously stirred for 20 minutes. The layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to provide methyl 3-amino-5-fluoro-pyridine-2-carboxylate (14.4 g, 53%) as brown solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (s, 1H), 6.72 (d, J=9.8 Hz, 1H), 5.94 (br. s, 2H), 3.96 (s, 3H) ppm. ESI-MS m/z calc. 170.04915, found 171.1 (M+1) + ; Retention time: 1.35 minutes. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

To a solution of methyl 3-amino-5-fluoro-pyridine-2-carboxylate (2.03 g, 11.931 mmol) in acetonitrile (40 mL), Ar-bromosucciMmicle (2.34 g, 13.147 mmol) was added portion-wise. After stirring at room temperature for 2 h, the reaction mixture was diluted with EtOAc (150 mL), washed with a saturated aqueous NaHCO 3 (150 mL) and brine (150 mL), then dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel chromatography (20% to 60% ethyl acetate in heptanes) provided methyl 3-amino-6-bromo-5-fluoro-pyridine-2-carboxylate (2.9 g, 98%) as white solid. 1 H NMR (300 MHz, CDCl 3 ) δ 6.80 (d, J=8.5 Hz, 1H), 5.98 (br. s., 2H), 4.22-3.72 (m, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −105.70 (d, J=9.2 Hz, 1F) ppm. ESI-MS m/z calc. 247.9597, found 248.9 (M+1) + ; Retention time: 1.73 minutes. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

Intermediate 7: Preparation of 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride salt)

To a solution of ethyl 3,3,3-trifluoro-2-oxo-propanoate (25.15 g, 147.87 mmol) in Et 2 O (270 mL) at −78° C. was added bromo(but-3-enyl)magnesium in THF (190 mL of 0.817 M, 155.23 mmol) dropwise over a period of 1.5 h (inner temperature −72° C. to −76° C.). 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 HCl (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 EtOAc (2×150 mL). The combined organic phase was washed with 5% aqueous NaHCO 3 (50 mL) and brine (20 mL), dried with Na 2 SO 4 . The mixture was filtered and concentrated, and co-evaporated with THF (2×40 mL) to give ethyl 2-hydroxy-2-(trifluoromethyl)hex-5-enoate (37.44 g, 96%) as colorless oil. 1 H NMR (300 MHz, CDCl 3 ) δ 5.77 (ddt, J=17.0, 10.4, 6.4 Hz, 1H), 5.15-4.93 (m, 2H), 4.49-4.28 (m, 2H), 3.88 (s, 1H), 2.35-2.19 (m, 1H), 2.17-1.89 (m, 3H), 1.34 (t, J=7.0 Hz, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −78.74 (s, 3F) ppm.

To a solution of ethyl 2-hydroxy-2-(trifluoromethyl)hex-5-enoate (24.29 g, 87.6% purity, 94.070 mmol) in DMF (120 mL) at 0° C. was added NaH (60% in mineral oil, 5.64 g, 141.01 mmol) portion-wise. The mixture was stirred at 0° C. 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. NH 4 Cl (3 g, 0.6 eq) was added. The mixture was stirred for 10 min. 30 mL of EtOAc was added, then ice-water was added (400 g). The mixture was extracted with CH 2 Cl 2 and the combined organic layers were concentrated. Purification by silica gel chromatography (0-20% CH 2 Cl 2 in heptanes) provided ethyl 2-benzyloxy-2-(trifluoromethyl)hex-5-enoate (26.05 g, 88%) as pink oil. 1 H NMR (300 MHz, CDCl 3 ) δ 1.34 (t, J=7.2 Hz, 3H), 2.00-2.19 (m, 3H), 2.22-2.38 (m, 1H), 4.33 (q, J=7.2 Hz, 2H), 4.64 (d, J=10.6 Hz, 1H), 4.84 (d, J=10.9 Hz, 1H), 4.91-5.11 (m, 2H), 5.62-5.90 (m, 1H), 7.36 (s, 5H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −70.5 (s, 3F) ppm. ESI-MS m/z calc. 316.12863, found 317.1 (M+1) + ; Retention time: 2.47 minutes. LCMS Method: Kinetex C 18 4.6×50 mm 2.6 μM. Temp: 45° C., Flow: 2.0 mL/min, Run Time: 3 min. Mobile Phase: Initial 95% H 2 O (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 held at 95% acetonitrile (0.1% formic acid) for 1.0 min.

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-(trifluoromethyl)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 (1×100 mL). The aqueous solution was acidified to pH=2 with aqueous 3N solution of HCl. The carboxylic acid was extracted with dichloromethane (3×100 mL) and dried over sodium sulfate. The solution was filtered and concentrated to give 2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid (22.57 g, 97%) as pale yellow oil. 1 H NMR (300 MHz, DMSO-d 6 ) δ 14.31 (br. s., 1H), 7.55-7.20 (m, 5H), 5.93-5.70 (m, 1H), 5.17-4.91 (m, 2H), 4.85-4.68 (m, 1H), 4.67-4.55 (m, 1H), 2.32-1.94 (m, 4H) ppm. 19 F NMR (282 MHz, DMSO-d 6 ) δ −70.29 (s, 3F) ppm. ESI-MS m/z calc. 288.09732, found 287.1 (M−1); Retention time: 3.1 minutes. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 6 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

To a solution of 2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid (21.92 g, 92.4% purity, 70.263 mmol) in DMF (130 mL) was added HATU (37.2 g, 97.836 mmol) and Et 3 N (15 g, 148.24 mmol). The mixture was stirred for 10 minutes then tert-butyl N-aminocarbamate (12.2 g, 92.312 mmol) was added. The mixture was stirred at 25° C. overnight and at 40° C. for 1 h. The mixture was diluted with ice-water (500 g) and extracted with CH 2 Cl 2 . The organic layer dried over anhydrous sodium sulfate and was concentrated. Purification by silica gel chromatography (0-30% EtOAc in heptanes) provided tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamate (26.08 g, 92%) as white solid. 1 H NMR (300 MHz, CDCl 3 ) δ 1.46 (s, 9H), 2.10-2.31 (m, 3H), 2.34-2.51 (m, 1H), 4.60-4.72 (m, 1H), 4.73-4.86 (m, 1H), 4.95-5.19 (m, 2H), 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, 1H) ppm. 19 F NMR (282 MHz, CDCl 3 ) ppm −73.6 (s, 3F) ppm.

To a solution of tert-butyl N-[[2-benzyloxy-2-(trifluoromethyphex-5-enoyl]amino]carbamate (43.12 g, 107.2 mmol) in CH 2 Cl 2 (200 mL) was added HCl (100 mL of 4 M, 400.0 mmol) and the mixture was stirred at ambient temperature for 7 h. The solvent was removed in vacuo, the residue stripped 2 times from heptane and the resultant solid was dried in vacuo using a high vac for 20 h giving 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (Hydrochloride salt) (35 g, 96%). 1 H NMR (400 MHz, Chloroform-d) δ 9.92 (s, 2H), 7.41-7.31 (m, 2H), 7.30-7.24 (m, 2H), 7.24-7.16 (m, 1H), 5.72-5.57 (m, 1H), 5.02-4.87 (m, 2H), 4.71 (d, J=10.9 Hz, 1H), 4.62 (d, J=11.0 Hz, 1H), 3.70 (s, 2H), 2.34-1.85 (m, 4H) ppm. ESI-MS m/z calc. 302.1242, found 303.2 (M+1) + ; Retention time: 1.5 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Intermediate 8: Preparation of [6-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-nitro-3-(trifluoromethyl)-2-pyridyl]trifluoromethanesulfonate

Step 1: N′-[2-Benzyloxy-2-(trifluoromethyl)hex-5-enoyl]-6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide

To a solution of 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid (29.92 g, 102.66 mmol) in acetonitrile (300 mL) and DMF (60 mL) was added CDI (17.48 g, 107.80 mmol). The mixture was stirred for 0.5 h at room temperature, then 2-benzyloxy-2-(trifluoromethyl)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 mL) and 2-Me THF (400 mL). The mixture was extracted with 2-Me THF (3×400 mL). The combined organic layer was washed with 0.5 N aqueous solution of HCl (3×300 mL), brine (3×250 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated by evaporation under reduced pressure. It was then solubilized twice in dichloromethane (2×300 mL) and the volatiles were removed by evaporation under reduced pressure to provide N′-[2-benzyloxy-2-(trifluoromethyphex-5-enoyl]-6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide (58.5 g, 94%) as brown foam residue. ESI-MS m/z calc. 536.11304, found 537.2 (M+1) + . Retention time: 2.03 minutes; LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

Step 2: [6-[5-[1-Benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-nitro-3-(trifluoromethyl)-2-pyridyl]trifluoromethanesulfonate

To a 0° C. solution of N′-[2-benzyloxy-2-(trifluoromethyphex-5-enoyl]-6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide (9.76 g, 16.922 mmol) in dichloromethane (190 mL) was added DIPEA (8.0136 g, 10.8 mL, 62.004 mmol) followed by trifluoromethylsulfonyl trifluoromethanesulfonate (12.410 g, 7.4 mL, 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 HCl, and EtOAc (300 mL). The organic layer was separated, and the aqueous phase extracted with ethyl acetate (2×150 mL). The combined organic layer was washed again with ice-cold HCl 1.0 N aqueous solution (60 mL) and brine (3×40 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-10% EtOAc in heptanes) provided [6-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-nitro-3-(trifluoromethyl)-2-pyridyl]trifluoromethanesulfonate (5.334 g, 40%) as an orange oil. 1 H NMR (300 MHz, CDCl 3 ) δ 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, J=10.9 Hz, 1H), 2.60-2.16 (m, 4H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −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. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 6 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

Intermediate 9: Preparation of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate

Step 1: tert-Butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate

To a mixture of 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-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 EtOAc (2.2 L) at ambient temperature was added pyridine (200 mL, 2.473 mol) which afforded a precipitate. To the mixture was added 1-propanephosphonic anhydride (500 g of 50% w/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 EtOAc (1 L). The combined organic phases washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. After half of the solvent was removed, the organic phase was washed 2 times with aqueous HCl (1000 mL of 1 M, 1.000 mol). The organic phase was dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was slurried in warm heptane (2.5 L) and MTBE (0.25 L) and the mixture stirred at ambient temperature for 12 h affording a light yellow slurry. The slurry was filtered, and the resultant filter cake was washed 2 times with 1 L 10% MTBE/heptane. The off-white solid was air dried for 2 h, then in vacuo at 40° C. for 20 h giving tert-butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyphex-5-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (379.9 g, 91%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.09 (s, 1H), 10.92 (s, 1H), 10.35 (s, 1H), 9.15 (s, 1H), 7.50 (d, J=7.4 Hz, 2H), 7.36 (dt, J=24.4, 7.2 Hz, 3H), 5.87 (ddt, J=16.0, 10.4, 5.2 Hz, 1H), 5.09 (d, J=16.9 Hz, 1H), 5.02 (d, J=10.1 Hz, 1H), 4.84 (q, J=11.4 Hz, 2H), 2.35-2.12 (m, 4H), 1.49 (s, 9H) ppm. ESI-MS m/z calc. 668.1069, found 670.9 (M+1) + ; Retention time: 3.5 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 5.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate

tert-Butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyphex-5-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (102 g, 150.8 mmol) was dissolved in anhydrous acetonitrile (1000 mL) and DIPEA (92 mL, 528.2 mmol) was added. The resultant orange solution was heated to 70° C. (internal temp) making a clear 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 mL 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 mmol) in 700 mL water, then 400 mL saturated NaHCO 3 , then 300 mL brine. The organic layer was then dried over anhydrous MgSO 4 and concentrated under reduced pressure. The material was purified using silica gel chromatography using a gradient of 15% to 50% of 8% EtOAc in hexanes (B) and Hexanes (A) to provide tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (91.7 g, 93%). 1 H NMR (400 MHz, Chloroform-d) δ 10.18 (s, 1H), 9.35 (s, 1H), 7.55-7.47 (m, 2H), 7.45-7.37 (m, 2H), 7.36-7.28 (m, 1H), 5.83-5.68 (m, 1H), 5.10-4.93 (m, 2H), 4.82 (d, J=10.5 Hz, 1H), 4.69 (d, J=10.5 Hz, 1H), 2.59-2.13 (m, 4H), 1.56 (s, 9H) ppm. ESI-MS m/z calc. 650.0963, found 651.0 (M+1) + ; Retention time: 3.81 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Intermediate 10: Preparation of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

Step 1: tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

Into a solution of ter t-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (30 g, 41.910 mmol) in MTBE (300 mL) was added DIEA (6.6780 g, 9 mL, 51.670 mmol), DMAP (0.28 g, 2.2919 mmol) and Boc 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% EtOAc in hexanes) provided tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (28.68 g, 87%) as white solid. 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.89 (s, 1H), 7.51 (d, J=7.4 Hz, 2H), 7.43 (t, J=7.5 Hz, 2H), 7.35 (t, J=7.3 Hz, 1H), 5.96-5.76 (m, 1H), 5.11 (d, J=17.2 Hz, 1H), 5.01 (d, J=10.1 Hz, 1H), 4.73 (d, J=10.7 Hz, 1H), 4.66 (d, J=10.6 Hz, 1H), 2.65-2.51 (m, 2H), 2.36-2.17 (m, 2H), 1.27 (d, J=23.5 Hz, 18H) ppm.

Intermediate 11: Preparation of 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride salt)

To a solution of ethyl 3,3,3-trifluoro-2-oxo-propanoate (30 g, 176.38 mmol) in diethyl ether (300 mL) at −78° C. was added allyl(bromo)magnesium (185 mL of 1 M, 185.00 mmol) 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 warmed to about 10° C. over a period of 1 h and added to a mixture of 1 N aqueous HCl (210 mL) and crushed ice (400 g) (pH 4). The mixture was extracted with EtOAc, washed with 5% aqueous NaHCO 3 , brine and dried over anhydrous Na 2 SO 4 . The mixture was filtered, concentrated and co-evaporated with hexane to give ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate (42.2 g, 90%) as light yellow oil. 1 H NMR (300 MHz, CDCl 3 ) δ 1.33 (t, J=7.1 Hz, 3H), 2.60-2.79 (m, 2H), 3.84 (br. s., 1H), 4.24-4.48 (m, 2H), 5.09-5.33 (m, 2H), 5.59-5.82 (m, 1H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −78.5 (s, 3F) ppm.

To a solution of ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate (18.56 g, 83.105 mmol) in DMF (100 mL) was added NaH (5.3 g, 60% w/w, 132.51 mmol) at 0° 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 mL) and extracted with ethyl acetate (3×300 mL) before being washed with brine (500 mL) and dried over sodium sulfate. Purification by silica gel chromatography (20 to 60% DCM in hexanes) provided ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate (22.01 g, 70%) as colorless oil. 1 H NMR (250 MHz, CDCl 3 ) δ 7.55-7.25 (m, 5H), 6.00-5.80 (m, 1H), 5.30-5.10 (m, 2H), 4.86 (d, J=10.5 Hz, 1H), 4.68 (d, J=10.5 Hz, 1H), 4.33 (q, J=7.0 Hz, 2H), 2.81 (d, J=7.0 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H) ppm. ESI-MS m/z calc. 302.113, found 303.5 (M+1) + ; Retention time: 4.14 minutes. LCMS Method: Merck Millipore Chromolith SpeedROD C 18 column (50×4.6 mm) and a dual gradient run from 5-100% mobile phase B over 6 minutes. Mobile phase A=water (0.1% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.1% CF 3 CO 2 H).

Into a solution of ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate (28.99 g, 95.902 mmol) in methanol (150 mL) was added a solution of NaOH (7.6714 g, 191.80 mmol) in water (50 mL). The reaction mixture was stirred at 40° 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 HCl to pH 1 and extracted with diethyl ether (3×200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to furnish 2-benzyloxy-2-(trifluoromethyl)pent-4-enoic acid (28.04 g, 99%) as a light yellow liquid. 1 H NMR (250 MHz, CDCl 3 ) δ 7.55-7.28 (m, 5H), 5.97-5.69 (m, 1H), 5.33-5.17 (m, 2H), 4.95-4.66 (m, 2H), 2.91 (d, J=7.1 Hz, 2H) ppm.

To a solution of 2-benzyloxy-2-(trifluoromethyl)pent-4-enoic acid (300 g, 1.094 mol) in DMF (2 L) was added HATU (530 g, 1.394 mol) and DIEA (400 mL, 2.296 mol) and the mixture was stirred at ambient temperature for 10 min. To the mixture was added tert-butyl N-aminocarbamate (152 g, 1.150 mol) and the mixture stirred at ambient temperature for 36 h. The reaction was quenched with cold water (4 L) and the mixture extracted 2× with EtOAc (2 L). The organic phase was washed brine, dried over MgSO 4 , filtered and concentrated in vacuo. Purification by silica gel chromatography (0-40% EtOAc/hexanes) provided tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate (386.49 g, 91%) as an oil which slowly crystallized to an off-white solid. 1 H NMR (400 MHz, DMSO) δ 10.00 (d, J=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, J=17.1 Hz, 1H), 5.17 (d, J=10.1 Hz, 1H), 4.77 (s, 2H), 2.96 (qd, J=15.4, 6.8 Hz, 2H), 1.39 (d, J=17.3 Hz, 9H) ppm. ESI-MS m/z calc. 388.16098, found 389.0 (M+1) + ; Retention time: 2.51 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

To a solution of tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate (98.5 g, 240.94 mmol) in DCM (400 mL) was added HCl in dioxane (200 mL of 4 M, 800.00 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and co-evaporated with DCM and hexanes to give 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride salt) (81.15 g, 97%) as an off white solid. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.07 (s, 1H), 7.70-7.16 (m, 5H), 5.87-5.61 (m, 1H), 5.45-5.09 (m, 2H), 4.79 (s, 2H), 3.6-3.4 (m, 2H), 3.23-3.07 (m, 1H), 3.04-2.87 (m, 1H) ppm. ESI-MS m/z calc. 288.10855, found 289.2 (M+1) + ; Retention time: 2.0 minutes. LCMS Method: Waters Cortex 2.7u C 18 (3.0 mm×50 mm), 55° C.; flow: 1.2 mL/min; mobile phase: 100% water with 0.1% trifluoroacetic acid then 100% acetonitrile with 0.1% trifluoroacetic acid, gradient of 5% to 100% B over 4 min, with equilibration at 100% B for 0.5 min, then 5% B over 1.5 min.

Intermediate 12: Preparation of [6-[5-[1-Benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-nitro-3-(trifluoromethyl)-2-pyridyl]trifluoromethanesulfonate

Step 1: N′-[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide

To a solution of 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid (8.5 g, 29.165 mmol) in acetonitrile (90 mL) and DMF (18 mL) was added CDI (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 THF (400 mL). The mixture was extracted with 2-methyl tetrahydrofuran (3×400 mL). The combined organic layer was washed with 0.5 N aqueous solution of HCl (3×300 mL), brine (3×250 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. It was then solubilized twice in dichloromethane (2×300 mL) and the volatiles were removed under reduced pressure giving N′-[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide (14.7 g, 75%) as yellow solid. ESI-MS m/z calc. 522.0974, found 523.1 (M+1) + ; Retention time: 2.08 minutes. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

Step 2: [6-[5-[1-Benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-nitro-3-(trifluoromethyl)-2-pyridyl] trifluoromethanesulfonate

Trifluoromethylsulfonyl trifluoromethanesulfonate (14.758 g, 8.8 mL, 52.308 mmol) was added to N′-[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide (14.7 g, 20.712 mmol) and DIPEA (9.79 g, 13.2 mL, 75.783 mmol) in dichloromethane (175 mL) at 0° C. The ice-cold bath was removed after 20 min and the reaction was stirred at room temperature for 2.5 h. The mixture was transferred to a separatory funnel with ice-cold aqueous 1.0 N solution of HCl (180 mL), and EtOAc (500 mL). The organic layer was separated, and the aqueous phase extracted with ethyl acetate (2×120 mL). The combined organic layer was washed again with ice-cold HCl 1.0 N aqueous solution (120 mL) and brine (3×120 mL), dried over anhydrous Na 2 SO 4 , 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-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-nitro-3-(trifluoromethyl)-2-pyridyl]trifluoromethanesulfonate (5.425 g, 40%) as an orange viscous oil. 1 H NMR (300 MHz, CDCl 3 ) δ 8.65 (s, 1H), 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, J=10.6 Hz, 1H), 3.21-3.05 (m, 2H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −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. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 6 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

Intermediate 13: Preparation of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate

Step 1: tert-Butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate

To a mixture of 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (53 g, 137.6 mmol) and 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride salt) (55 g, 169.4 mmol) in EtOAc (500 mL) at ambient temperature was added pyridine (44 mL, 544.0 mmol). To the mixture was added 1-propanephosphonic anhydride (111 g of 50% w/w, 174.4 mmol) and the reaction mixture stirred at ambient temperature for 12 h. The reaction was quenched with slow addition of NaOH (35 g of 50% w/w, 437.5 mmol) in water (500 mL) and the mixture stirred for 15 min. The organic phase was separated, and the aqueous phase extracted with EtOAc (500 mL). The combined organic phases washed with HCl (250 mL of 1 M, 250.0 mmol), brine, dried over MgSO 4 , filtered and concentrated in vacuo. Purification by silica gel chromatography (0-20% EtOAc/hexanes) provided tert-butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (66 g, 73%) as pale pink solid. 1 H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 10.91 (s, 1H), 10.40 (s, 1H), 9.16 (s, 1H), 7.47 (d, J=6.9 Hz, 2H), 7.42-7.29 (m, 3H), 5.91 (ddt, J=17.1, 10.6, 7.1 Hz, 1H), 5.37 (dd, J=17.2, 1.9 Hz, 1H), 5.22 (dd, J=10.4, 1.8 Hz, 1H), 4.85 (d, J=2.1 Hz, 2H), 3.20-2.91 (m, 2H), 1.50 (s, 9H) ppm. ESI-MS m/z calc. 654.09125, found 657.0 (M+1) + ; Retention time: 3.49 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate

A solution of tert-butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (2.15 g, 3.2641 mmol) and DIPEA (1.12 g, 1.5 mL, 8.6117 mmol) in acetonitrile (43 mL) was heated at 50° C., thenp-toluenesulfonyl chloride (765 mg, 4.0127 mmol) was added portion wise at 50° C. Resultant mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled, then basified with a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% to 10% of ethyl acetate in heptanes) afforded tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (1.7 g, 80%) as yellow viscous oil. 1 H NMR (300 MHz, CDCl 3 ) δ 10.18 (br. s, 1H), 9.33 (br. s, 1H), 7.53-7.27 (m, 5H), 6.00-5.83 (m, 1H), 5.32-5.13 (m, 2H), 4.86-4.76 (m, 1H), 4.73-4.64 (m, 1H), 3.27-3.11 (m, 2H), 1.55 (s, 9H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −63.78 (s, 3F), −72.93 (s, 3F) ppm. No ionization by regular ESI method was observed, but ionization was observed using an APCI method: (M−C 4 H 8 +1) ++ =580.8. ESI-MS m/z calc. 636.0807, Retention time: 2.7 minutes; LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 4 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

Intermediate 14: Preparation of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate

Step 1: tert-Butyl N-[2-[[[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate

The racemic tert-butyl N-[2-[[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (24.5 g, 37.38 mmol) was purified by preparative chiral SFC by 500 μL injections of a 32 mg/mL solution onto a ChiralPak IC (250×21.2 mm), 5 μm column eluted at 40° C. at 70 mL/min with 8% MeOH (20 mM NH 3 ) and 92% CO 2 . First eluting enantiomer-1 (Peak 1 at retention time=4.17 min) to provided tert-butyl N-[2-[[[(2S)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (11.73 g, 96%). 1 H NMR (400 MHz, Chloroform-d) δ 10.59 (s, 1H), 9.83 (s, 1H), 9.28 (s, 1H), 9.02 (d, J=29.6 Hz, 1H), 7.48-7.33 (m, 5H), 5.96-5.77 (m, 1H), 5.41 (d, J=1.6 Hz, 1H), 5.36-5.29 (m, 1H), 4.86 (s, 2H), 3.19 (dd, J=15.5, 5.9 Hz, 1H), 3.03 (dd, J=15.5, 7.8 Hz, 1H), 1.53 (s, 9H) ppm; 19 F NMR (376 MHz, Chloroform-d) δ −63.89, −73.76 ppm. ESI-MS m/z calc. 654.09125, found 655.3 (M+1) + ; Retention time: 0.53 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

The later eluting enantiomer 2 (Peak 2 at retention time=6.63 min) provided tert-butyl N-[2-[[[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (11.62 g, 95%). 1 H NMR (400 MHz, Chloroform-d) δ 10.59 (s, 1H), 9.74 (s, 1H), 9.28 (s, 1H), 9.06 (s, 1H), 7.39 (d, J=4.4 Hz, 5H), 6.02-5.79 (m, 1H), 5.44-5.36 (m, 1H), 5.34 (dd, J=10.3, 1.3 Hz, 1H), 4.91-4.81 (m, 2H), 3.19 (dd, J=15.4, 5.8 Hz, 1H), 3.03 (dd, J=15.5, 7.8 Hz, 1H), 1.53 (s, 9H) ppm; 19 F NMR (376 MHz, Chloroform-d) δ −63.89, −73.76 ppm. ESI-MS m/z calc. 654.09125, found 657.2 (M+1) + ; Retention time: 0.53 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate

tert-Butyl N-[2-[[[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (enantiomer 2) (24.97 g, 38.10 mmol) was dissolved in anhydrous acetonitrile (200 mL) under nitrogen, making a clear yellow solution. DIPEA (19.91 mL, 114.3 mmol) was added, and the solution turned orange. The solution was heated to 70° C., then p-toluenesulfonyl chloride (7.99 g, 41.91 mmol) was added in 3 portions at 30 min intervals and heated for about 3 h. The reaction mixture was cooled to room temperature and evaporated majority of the acetonitrile at 45° C. Added 145 mL MTBE, followed by a solution of citric acid (11.0 g, 57.25 mmol) in 250 mL water, stirred, then added 73 mL hexanes. Separated the layers and water layer extracted with MTBE. Combined the organic layers dried over MgSO 4 , concentrated in vacuo at 45° C. Purification by silica gel chromatography (15% to 80% of hexanes (as solvent A) in 10% EtOAc/hexanes (as solvent B)) provided tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (20.47 g, 84%). 1 H NMR (400 MHz, Chloroform-d) δ 10.18 (s, 1H), 9.34 (s, 1H), 7.48 (d, J=7.1 Hz, 2H), 7.39 (t, J=7.5 Hz, 2H), 7.31 (t, J=7.3 Hz, 1H), 6.00-5.81 (m, 1H), 5.25 (d, J=17.1, 1.6 Hz, 1H), 5.20 (d, J=10.1, 1.5 Hz, 1H), 4.82 (d, J=10.6 Hz, 1H), 4.70 (d, J=10.6 Hz, 1H), 3.30-3.09 (m, 2H), 1.56 (s, 9H) ppm. ESI-MS m/z calc. 636.0807, found 637.3 (M+1) + ; Retention time: 3.81 minutes. LCMS Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Intermediate 15: Preparation of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

Step 1: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

To a stirring solution of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (5.52 g, 7.485 mmol) in DMSO (35.86 mL) at room temperature was added cesium acetate (1.437 g, 7.486 mmol) and the mixture was capped and heated under nitrogen atmosphere at 80° C. overnight. Cooled to room temperature and diluted with saturated aqueous NH 4 Cl then extracted with EtOAc (2×). Combined the organic fractions, dried over MgSO 4 , filtered and concentrated to a yellow oil. Purification by silica gel chromatography (100% hexanes to 100% EtOAc) giving as a white solid, tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (1.8 g, 36%). ESI-MS m/z calc. 674.2175, found 575.2 (M-Boc) + . Retention time: 0.45 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Intermediate 16: Preparation of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

Step 1: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

di-tert-Butyl dicarbonate (208 mg, 0.9530 mmol) and triethylamine (400 μL, 2.870 mmol) were added to a solution of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (500 mg, 0.7531 mmol) dissolved in dioxane (5 mL) followed by DMAP (14 mg, 0.1146 mmol). The reaction mixture was stirred for 3 hours at room temperature. The mixture was concentrated to half of its volume and water was added. Extracted with ethyl acetate and combined organics washed with brine. The organics were separated, dried over sodium sulfate, and evaporated. Purification by silica gel chromatography (0 to 50% EtOAc in hexanes) provided tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (487 mg, 88%) as white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.90 (s, 1H), 7.49 (d, J=7.5 Hz, 2H), 7.42 (t, J=7.4 Hz, 2H), 7.35 (t, J=7.3 Hz, 1H), 5.93 (dq, J=17.1, 7.6 Hz, 1H), 5.38 (d, J=17.0 Hz, 1H), 5.25 (d, J=10.2 Hz, 1H), 4.78 (d, J=10.6 Hz, 1H), 4.65 (d, J=10.6 Hz, 1H), 2.50 (p, J=1.8 Hz, 2H), 1.27 (d, J=21.4 Hz, 18H) ppm. ESI-MS m/z calc. 736.1331, found 739.2 (M+1) + ; Retention time: 1.66 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 50-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Intermediate 17: Preparation of (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid

Step-1: (2R)-2-Benzyloxy-2-(trifluoromethyl)hex-5-enoic acid; (R)-4-quinolyl-[(2S,4S)-5-vinylquinuclidin-2-yl]methanol

To a N 2 purged jacketed reactor set to 20° C. was added isopropyl acetate (IPAC, 100 L, 0.173 M, 20 Vols), followed by previously melted 2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid (5.00 kg, 17.345 mol) and cinchonidine (2.553 kg, 8.67 mol) made into a slurry with minor amount of the reaction solvent. The reactor was set to ramp internal temperature to 80° C. over 1 hour, with solids going in solution upon heating to set temperature, then the solution was held at temperature for at least 10 minutes, then cooled to 70° C. held and seeded with chiral salt (50 g, 1.0% by wt). The mixture was stirred for 10 minutes, then ramped to 20° C. internal temperature over 4 hours, then held overnight at 20° C. The mixture was filtered, cake washed with isopropyl acetate (10.0 L, 2.0 vols) and dried under vacuum. The cake was then dried in vacuo (50° C., vacuum) to afford 4.7 kg of salt. The resulting solid salt was returned to the reactor by making a slurry with a portion of isopropyl acetate (94 L, 20 vol based on current salt wt), and pumped into reactor and stirred. The mixture was then heated to 80° C. internal, stirred hot slurry for at least 10 minutes, then ramped to 20° C. over 4-6 h, then stirred overnight at 20° C. The material was then filtered and cake washed with isopropyl acetate (9.4 L, 2.0 vol), pulled dry, cake scooped out and dried in vacuo (50° C., vacuum) to afford 3.1 kg of solid. The solid (3.1 kg) and isopropyl acetate (62 L, 20 vol based on salt solid wt) was slurried and added to a reactor, stirred under N 2 purge and heated to 80° C. and held at temperature at least 10 minutes, then ramped to 20° C. over 4-6 hours, then stirred overnight. The mixture was filtered, cake washed with isopropyl acetate (6.2 L, 2 vol), pulled dry, scooped out and dried in vacuo (50° C., vac) to afford 2.25 kg of solid salt. The solid (2.25 kg) and isopropyl acetate (45 L, 20 vol based on salt solid wt) was slurried and added to a reactor, stirred under N 2 purge and heated to 80° C., held at temperature at least 10 minutes, then ramped to 20° C. over 4-6 hours, then stirred overnight. The mixture was filtered, cake washed with isopropyl acetate (4.5 L, 2 vol), pulled dry, scooped out and dried in vacuo (50° C. to afford (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid;(R)-4-quinolyl-[(2S,4S)-5-vinylquinuclidin-2-yl]methanol (1.886 kg, >98.0% ee) as off-white to tan solid. Chiral purity was determined by Agilent 1200 HPLC instrument using Phenomenex Lux i-Amylose-3 column (3 μm, 150×4.6 mm) and a dual, isocratic gradient run 30% to 70% mobile phase B over 20.0 minutes. Mobile phase A=H 2 O (0.1% CF 3 CO 2 H). Mobile phase B=MeOH (0.1% CF 3 CO 2 H). Flow rate=1.0 mL/min, injection volume=2 μL, and column temperature=30° C., sample concentration: 1 mg/mL in 60% acetonitrile/40% water.

A suspension of (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid; (R)-4-quinolyl-[(2S,4S)-5-vinylquinuclidin-2-yl]methanol (50 g, 87.931 mmol) in ethyl acetate (500.00 mL) was treated with an aqueous solution of hydrochloric acid (200 mL of 1 M, 200.00 mmol). After stirring 15 minutes at room temperature, the two phases were separated. The aqueous phase was extracted twice with ethyl acetate (200 mL). The combined organic layer was washed with 1 N HCl (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The material was dried over high vacuum overnight to give (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid (26.18 g, 96%) as pale brown oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.46-7.31 (m, 5H), 5.88-5.73 (m, 1H), 5.15-4.99 (m, 2H), 4.88 (d, J=10.3 Hz, 1H), 4.70 (d, J=10.3 Hz, 1H), 2.37-2.12 (m, 4H) ppm. 19 F NMR (377 MHz, CDCl 3 ) δ −71.63 (br s, 3F) ppm. ESI-MS m/z calc. 288.0973, found 287.0 (M−1) − ; Retention time: 2.15 minutes. LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in H 2 O (0.1% formic acid) 1.2 mL/min.

Intermediate 18: Preparation of (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide

To a solution of (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoic acid (365 g, 1.266 mol) in DMF (2 L) was added HATU (612 g, 1.610 mol) and DIEA (450 mL, 2.584 mol) and the mixture was stirred at ambient temperature for 10 min. To the mixture was added tert-butyl N-aminocarbamate (200 g, 1.513 mol) (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 EtOAc (2 L) and washed with brine. The organic phase was dried over MgSO 4 , filtered and concentrated in vacuo. The oil was diluted with EtOAc (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% EtOAc/hexanes) provided tert-butyl N-[[(2R)-2-benzyloxy-2-(trifluoromethyphex-5-enoyl]amino]carbamate (464 g, 91%, combined with product from crystallization). ESI-MS m/z calc. 402.17664, found 303.0 (M+1-Boc) + ; Retention time: 2.68 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350) and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

To a solution of tert-butyl N-[[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamate (464 g, 1.153 mol) in DCM (1.25 L) and was added HCl (925 mL of 4 M, 3.700 mol) and the mixture stirred at ambient temperature for 20 h. The mixture was concentrated in vacuo removing most of the DCM. The mixture was diluted with isopropyl acetate (1 L) and basified to pH=6 with NaOH (140 g of 50 w/w, 1.750 mol) in 1 L of ice water. The organic phase was separated and washed with 1 L of brine and the combined aqueous phases were extracted with isopropyl acetate (1 L). The combined organic phases were dried over MgSO 4 , filtered and concentrated in vacuo affording a dark yellow oil of (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (358 g, quant.). 1 H NMR (400 MHz, CDCl 3 ) δ 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 (dd, J=10.5, 1.5 Hz, 1H), 4.61 (d, J=10.5 Hz, 1H), 3.78 (s, 2H), 2.43 (ddd, J=14.3, 11.0, 5.9 Hz, 1H), 2.26-1.95 (m, 3H) ppm. ESI-MS m/z calc. 302.1242, found 303.0 (M+1) + ; Retention time: 2.0 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Intermediate 19: Preparation of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate

Step 1: tert-Butyl N-[2-[[[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate

To a mixture of 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (304 g, 789.3 mmol) and (2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (270 g, 893.2 mmol) in EtOAc (2.25 L) at ambient temperature was added DIEA (425 mL, 2.440 mol). To the mixture was slowly added T 3 P (622 g of 50% w/w, 977.4 mmol) using an ice-water bath to keep the temperature <35° C. (temperature rose to 34° C.) and the reaction mixture was stirred at ambient temperature for 18 h. Added additional DIEA (100 mL, 574.1 mmol) and T 3 P (95 g, 298.6 mmol) and stirred at ambient temperature for 2 days. Starting material was still observed and an additional T 3 P (252 g, 792 mmol) was added and stirred for 5 days. The reaction was quenched with the slow addition of water (2.5 L) and the mixture stirred for 30 min. The organic phase was separated, and the aqueous phase extracted with EtOAc (2 L). The combined organic phases were washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was dissolved in MTBE (300 mL) and diluted with heptane (3 L), the mixture stirred at ambient temperature for 12 h affording a light yellow slurry. The slurry was filtered, and the resultant solid was air dried for 2 h, then in vacuo at 40° C. for 48 h. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0-20% EtOAc/hexanes) and combined with material obtained from crystallization providing tert-butyl N-[2-[[[(2R)-2-benzyloxy-2-(trifluoromethyphex-5-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (433 g, 82%). 1 H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 10.91 (s, 1H), 10.32 (s, 1H), 9.15 (s, 1H), 7.53-7.45 (m, 2H), 7.45-7.28 (m, 3H), 5.87 (ddt, J=17.0, 10.2, 5.1 Hz, 1H), 5.09 (dq, J=17.1, 1.3 Hz, 1H), 5.02 (dd, J=10.3, 1.9 Hz, 1H), 4.84 (q, J=11.3 Hz, 2H), 2.37-2.13 (m, 4H), 1.49 (s, 9H) ppm. ESI-MS m/z calc. 668.1069, found 669.0 (M+1) + ; Retention time: 3.55 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate

To a solution of tert-butyl N-[2-[[[(2R)-2-benzyloxy-2-(trifluoromethyphex-5-enoyl]amino]carbamoyl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (240 g, 358.5 mmol) in anhydrous acetonitrile (1.5 L) under nitrogen was added DIEA (230 mL, 1.320 mol) and the orange solution heated to 70° C. To the mixture was added p-toluenesulfonyl chloride (80.5 g, 422.2 mmol) in 3 equal portions over 1 h. The mixture was stirred at 70° C. for 9 h then additional p-toluenesulfonyl chloride (6.5 g, 34.09 mmol) was added. The mixture was stirred for a total of 24 h then allowed to cool to ambient temperature. Acetonitrile was removed in vacuo affording a dark orange oil which was diluted with EtOAc (1.5 L) and water (1.5 L). The organic phase was separated and washed with 500 mL of 1M HCl, 500 mL of brine, dried over MgSO 4 , filtered and concentrated in vacuo. Purification by silica gel chromatography (0-20% EtOAc/hexanes) provided tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (200 g, 86%). 1 H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 9.10 (s, 1H), 7.55-7.48 (m, 2H), 7.47-7.28 (m, 3H), 5.87 (ddt, J=16.7, 10.2, 6.4 Hz, 1H), 5.11 (dt, J=17.2, 1.7 Hz, 1H), 5.01 (dt, J=10.2, 1.5 Hz, 1H), 4.74 (d, J=10.6 Hz, 1H), 4.65 (d, J=10.6 Hz, 1H), 2.55-2.42 (m, 2H), 2.30 (qd, J=11.3, 10.3, 6.9 Hz, 2H), 1.52 (s, 9H) ppm. ESI-MS m/z calc. 650.0963, found 650.0 (M+1) + ; Retention time: 3.78 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Intermediate 20: Preparation of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

Step 1: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

To a solution of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (222 g, 340.8 mmol) in MTBE (1.333 L) was added DIPEA (65.3 mL, 374.9 mmol) followed DMAP (2.09 g, 17.11 mmol). Added a solution of di-tert-butyl dicarbonate (111.6 g, 511.3 mmol) in MTBE (250 mL) over approx. 8 minutes, and the resulting mixture was stirred for additional 30 min. Added 1 L of water and separated the layers. The organic layer was washed with KHSO 4 (886 mL of 0.5 M, 443.0 mmol), 300 mL brine, dried with MgSO 4 and most (>95%) of the MTBE was evaporated by rotary evaporation at 45° C., leaving a thick oil. Added 1.125 L of heptane, 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 tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (240.8 g, 94%). 1 H NMR (400 MHz, Chloroform-d) δ 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, J=10.4 Hz, 1H), 4.64 (d, J=10.4 Hz, 1H), 2.57-2.26 (m, 3H), 2.26-2.12 (m, 1H), 1.41 (s, 18H) ppm. ESI-MS m/z calc. 750.14874, found 751.1 (M+1) + ; Retention time: 3.76 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 and column temperature=60° C.

Intermediate 21: Preparation of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

Step 1: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (280 g, 372.6 mmol) was dissolved in DMSO (1.82 L) (yellow solution) and treated with cesium acetate (215 g, 1.120 mol) under stirring at room temperature. The yellow suspension was heated at 80° C. for 5 h. The reaction mixture was cooled to room temperature and added to a stirred cold emulsion of water (5.5 L) with 1 kg ammonium chloride dissolved in it and a 1:1 mixture of MTBE and heptane (2 L) (in 20 L). The phases were separated and the organic phase washed water (3×3 L) and with brine (1×2.5 L). The organic phase was dried with MgSO 4 , filtered and concentrated under reduced pressure. The resultant yellow solution was diluted with heptane (˜1 L) and seeded with tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate and stirred on the rotavap at 100 mbar pressure at room temperature for 1.5 h. The solid mass was stirred mechanically for 2 h at room temperature, resultant thick fine suspension was filtered, washed with dry ice cold heptane and dried under vacuum at 45° C. with a nitrogen bleed for 16 h to give tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxy carbonyl-carbamate (220 g, 85%) as an off white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.28 (s, 1H), 8.43 (s, 1H), 7.58-7.26 (m, 5H), 5.85 (ddt, J=16.8, 10.3, 6.5 Hz, 1H), 5.10 (dq, J=17.2, 1.6 Hz, 1H), 5.01 (dq, J=10.2, 1.3 Hz, 1H), 4.76 (d, J=11.0 Hz, 1H), 4.65 (d, J=11.0 Hz, 1H), 2.55 (dd, J=9.6, 5.2 Hz, 2H), 2.23 (td, J=13.2, 10.0, 5.7 Hz, 2H), 1.27 (d, J=3.8 Hz, 18H) ppm. ESI-MS m/z calc. 688.23315, found 689.0 (M+1) + ; Retention time: 3.32 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Intermediate 22: Preparation of (2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide

tert-Butyl N[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate (386.49 g, 995.1 mmol) was dissolved in DCM (1.25 L) and toluene (250 mL) and treated with HCl (750 mL 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 EtOAc (2 L). The mixture was treated with NaOH (600 mL of 2 M, 1.200 mol) and stirred at ambient temperature for 10 min. The organic phase was separated, washed with 1 L of brine, dried over MgSO 4 , filtered and concentrated in vacuo and used directly in the ensuing step (trace toluene present), 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (286 g, 100%). 1 H NMR (400 MHz, DMSO) δ 9.34 (s, 1H), 7.40-7.22 (m, 5H), 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/z calc. 288.10855, found 289.0 (M+1) + ; Retention time: 1.32 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Racemic 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (5.0 g, 17.35 mmol) was separated by chiral SFC using a ChiralPak IG column (250×21.2 mm; 5 μm) at 40° C. using a mobile phase 7% MeOH (plus 20 mM NH 3 ), 93% CO 2 at a 70 mL/min flow and concentration of the sample was 111 mg/mL in methanol (no modifier), injection volume=160 μL with an outlet pressure of 136 bar, detection wavelength of 210 nm providing as the second eluting enantiomer, (2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (1.7 g, 68%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.31 (s, 1H), 7.48-7.39 (m, 2H), 7.39-7.25 (m, 3H), 5.77-5.62 (m, 1H), 5.28 (dq, J=17.1, 1.6 Hz, 1H), 5.15 (dq, J=10.2, 1.5 Hz, 1H), 4.73 (s, 2H), 4.51 (s, 2H), 3.00 (dd, J=15.3, 7.5 Hz, 1H), 2.91 (dd, J=15.3, 6.4 Hz, 1H) ppm. ESI-MS m/z calc. 288.10855, found 289.2 (M+1) + ; Retention time: 1.28 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 30-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Intermediate 23: Preparation of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]carbamate

Step 1: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]carbamate

To a solution of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (1.089 g, 1.449 mmol) in DMSO (13.61 mL) was added (2S)-pent-4-en-2-ol (745.5 μL, 7.244 mmol), cesium carbonate (1.496 g, 4.591 mmol) and iodocopper (63.93 mg, 0.3357 mmol) and the reaction mixture was heated at 80° C. for 1 h. The reaction mixture poured into saturated aqueous NH 4 Cl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO 4 ), filtered and concentrated to an orange oil which was dissolved in THF (10.89 mL) and formic acid (10.89 mL, 288.7 mmol) was added, stirred 20 min then added formic acid (10.93 mL, 289.7 mmol) and stirred for 45 min. The reaction was quenched by slowly adding to saturated aqueous NaHCO 3 (vigorous gas evolution was observed) and EtOAc in a separatory funnel bringing the aqueous layer eventually to pH ˜2-3. The aqueous layer was removed and the EtOAc layer was washed with saturated aqueous NaHCO 3 (still vigorous gas evolution) then dried over MgSO 4 , filtered and concentrated to a yellow syrup which was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% EtOAc giving several products including tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]carbamate in an impure form. This impure material was further purified by chromatography on a 275 g reverse phase C 18 column eluting with 50-100% acetonitrile/water giving as a clear syrup, tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]carbamate (126 mg, 15%). ESI-MS m/z calc. 588.1807, found 589.2 (M+1) + ; Retention time: 0.51 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Example 1: Preparation of 6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-6-ol, Compound 1

A mixture of methyl 6-oxo-5-(trifluoromethyl)-1H-pyridine-2-carboxylate (21.15 g, 95.64 mmol), POBr3 (41.14 g, 143.5 mmol) and DMF (350 mg, 4.788 mmol) in toluene (200 mL) was heated at 110° C. overnight. The mixture was cooled to 0° C. and poured on crushed ice (200 g). The mixture was neutralized to pH=7 with KHCO 3 (100 g, 10.5 eq) at <2° C. and extracted with EtOAc (2×200 mL). The combined organic layers were washed with 5% aqueous NaHCO 3 (100 mL) and brine (100 mL) and dried with Na 2 SO 4 . The mixture was filtered, and the solvent was removed by evaporation. The residue was triturated with heptanes/EtOAc (20:1) to give 22.92 g of pure product. The filtrate was concentrated to give 4.02 g, which was purified by flash chromatography (heptanes/EtOAc 0-30%) to give an additional 3.32 g of product. The two crops were combined to give methyl 6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (26.24 g, 96%) as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ 4.04 (s, 3H), 8.05-8.30 (m, 2H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −63.8 (s, 3F) ppm. ESI-MS m/z calc. 282.9456, found 284.0 (M+1) + ; Retention time: 4.04 minutes. LCMS Method: Symmetry, 4.6×75 mm 3.5 μm. Temp: 45° C., Flow: 2.0 mL/min, run time: 8 min. Mobile Phase: Initial 95% H 2 O (0.1% formic acid) and 5% CH 3 CN (0.1% formic acid) linear gradient to 95% CH 3 CN (0.1% formic acid) for 6.0 min then held at 95% CH 3 CN (0.1% formic acid) for 2.0 min.

To a solution of methyl 6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (10.5 g, 36.968 mmol) in THF (100 mL) was added a solution of lithium hydroxide monohydrate (1.8 g, 42.894 mmol) in water (70 mL). This mixture was stirred 45 min at room temperature. The THF was evaporated in vacuo. Water (60 mL) was added to the remaining aqueous solution and the pH was adjusted to 3-4 by addition of 3 N hydrochloric acid (T<5° C.) leading to precipitation of the desired product. The solid was recovered by filtration and dried in-vacuo to give 6-bromo-5-(trifluoromethyl)pyridine-2-carboxylic acid (9.46 g, 95%) as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ 8.18-8.28 (m, 1H), 8.28-8.39 (m, 1H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −63.8 (s, 3F) ppm. ESI-MS m/z calc. 268.92993, found 270.0 (M+1) + ; Retention time: 2.08 minutes; LCMS Method: Kinetex C 18 4.6×50 mm 2.6 μM. Temp: 45° C., Flow: 2.0 mL/min, Run Time: 6 min. Mobile Phase: Initial 95% H 2 O (0.1% formic acid) and 5% CH 3 CN (0.1% formic acid) linear gradient to 95% CH 3 CN (0.1% formic acid) for 4.0 min then held at 95% CH 3 CN (0.1% formic acid) for 2.0 min.

To a solution of pent-4-en-1-ol (1.5 mL, 14.79 mmol) in DMF (12 mL) was added sodium hydride (1.05 g of 60% w/w, 26.25 mmol) and the reaction mixture was stirred at room temperature for 0.5 h. The mixture was cooled to 0° C. and 6-bromo-5-(trifluoromethyl)pyridine-2-carboxylic acid (2 g, 7.407 mmol) in DMF (12 mL) was added. The reaction mixture was warmed to room temperature and stirred for another 2 h. The mixture was carefully quenched with water (2 mL). The solvent was removed in vacuo and the reaction mixture was diluted with MeOH and filtered. The filtrate was evaporated and purified by reverse phase chromatography on C 18 column using a gradient elution of 20%-70% water/acetonitrile and a flow rate of 80 mL/min over 20 min to afford 6-pent-4-enoxy-5-(trifluoromethyl)pyridine-2-carboxylic acid (1.73 g, 85%). ESI-MS m/z calc. 275.07693, found 274.0 (M−1) + ; Retention time: 0.83 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 15-98% mobile phase B over 1.5 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

Step 4: N′-[2-Benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-pent-4-enoxy-5-(trifluoromethyl)pyridine-2-carbohydrazide

To a stirred solution of 6-pent-4-enoxy-5-(trifluoromethyl)pyridine-2-carboxylic acid (427.6 mg, 1.540 mmol) and HATU (761.2 mg, 2.002 mmol) in DMF (5 mL) was added DIPEA (697.4 μL, 4.004 mmol) (exotherm). After 5 min, 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride salt) (500 mg, 1.540 mmol) was added in one portion and the mixture was stirred for 30 min. The reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (3×15 mL) and the combined extracts were washed with brine then dried (MgSO 4 ). The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (10% to 33%) to afford N′-[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-pent-4-enoxy-5-(trifluoromethyl)pyridine-2-carbohydrazide (725 mg, 86%) as colorless gum. 1 H NMR (400 MHz, Chloroform-d) δ 9.71 (s, 1H), 9.16 (s, 1H), 7.96 (d, J=7.7 Hz, 1H), 7.77-7.70 (m, 1H), 7.38-7.26 (m, 5H), 5.88-5.72 (m, 2H), 5.36-5.22 (m, 2H), 5.05-4.90 (m, 2H), 4.85-4.73 (m, 2H), 4.40 (t, J=6.2 Hz, 2H), 3.11 (dd, J=15.5, 5.9 Hz, 1H), 2.96 (dd, J=15.5, 7.8 Hz, 1H), 2.25-2.13 (m, 2H), 1.87 (dt, J=7.9, 6.3 Hz, 2H) ppm. ESI-MS m/z calc. 545.1749, found 546.21 (M+1) + ; Retention time: 1.12 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 15-98% mobile phase B over 1.5 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

Step 5: 2-[1-Benzyloxy-1-(trifluoromethyl)but-3-enyl]-5-[6-pent-4-enoxy-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole

To a degassed solution of N′-[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-pent-4-enoxy-5-(trifluoromethyppyridine-2-carbohydrazide (100 mg, 0.1818 mmol) in THF (2 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (130 mg, 0.5455 mmol) in one portion. The resulting solution was heated in a sealed vial at 80° C. for 2 hours, solvent was evaporated then diluted the residue with ethyl acetate (10 mL), washed with 2N NaOH solution and 0.5 N HCl, brine, then dried (MgSO 4 ), filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (5% to 26%, 8 column volumes) which afforded 2-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-5-[6-pent-4-enoxy-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole (76 mg, 79%) as an oil. 1 H NMR (400 MHz, Chloroform-d) δ 8.07-8.03 (m, 1H), 7.84 (dd, J=7.8, 0.8 Hz, 1H), 7.43-7.29 (m, 5H), 6.06-5.80 (m, 2H), 5.34-5.20 (m, 2H), 5.13-5.00 (m, 2H), 4.85 (d, J=10.8 Hz, 1H), 4.65 (d, J=10.9 Hz, 1H), 4.56 (t, J=6.3 Hz, 2H), 3.30-3.21 (m, 2H), 2.33-2.22 (m, 2H), 2.02-1.91 (m, 2H) ppm. ESI-MS m/z calc. 527.16437, found 528.21 (M+1) + ; Retention time: 1.23 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 15-98% mobile phase B over 1.5 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

Step 6: 6-Benzyloxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaene (E/Z Mixture)

To a degassed stirred solution of 2-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-5-[6-pent-4-enoxy-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole (265 mg, 0.5024 mmol) in DCE (21 mL) was added [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2-isopropoxy-5-nitro-phenyl)methylene]ruthenium (68 mg, 0.1012 mmol), resultant mixture was purged with nitrogen and heated at 80° C. for 16 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (5% to 40%, 12 column volumes) which afforded 6-benzyloxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaene (E/Z mixture) (35 mg, 14%) as an oil and followed by dimeric side-product (85 mg) as white solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (dd, J=7.7, 0.8 Hz, 1H), 7.86-7.79 (m, 1H), 7.28 (d, J=2.4 Hz, 4H), 7.23-7.16 (m, 1H), 6.13-5.99 (m, 1H), 5.90-5.77 (m, 1H), 4.91 (d, J=11.6 Hz, 1H), 4.79-4.46 (m, 3H), 3.18 (dd, J=14.6, 5.3 Hz, 1H), 2.81 (dd, J=14.5, 8.9 Hz, 1H), 2.24-1.90 (m, 4H) ppm. ESI-MS m/z calc. 499.13306, found 500.2 (M+1) + ; Retention time: 1.17 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 15-98% mobile phase B over 1.5 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

Step 7: 6,15-bis(Trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-6-ol, Compound 1

To a solution of 6-benzyloxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaene (E/Z mixture) (30 mg, 0.06007 mmol) in MeOH (3 mL) was added Silica Cat Pd (70 mg of 0.2 mmol/g, 0.01400 mmol) and stirred for 16 hours under hydrogen balloon. The mixture was diluted with ethyl acetate, filtered through a pad of Celite eluting with ethyl acetate and DCM then concentrated. The residue was purified by silica gel chromatography eluted with a gradient of ethyl acetate in hexanes (5% to 40%, 15 column volumes) followed by lyophilization using acetonitrile and water which afforded racemic 6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-6-ol (17.5 mg, 70%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.08 (dd, J=7.7, 0.8 Hz, 1H), 7.85 (dd, J=7.7, 0.8 Hz, 1H), 4.69-4.60 (m, 1H), 4.54-4.42 (m, 1H), 3.94 (d, J=1.3 Hz, 1H), 2.52-1.34 (m, 10H) ppm. ESI-MS m/z calc. 411.10175, found 411.54 (M+1) + ; Retention time: 3.7 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 5-85% mobile phase B over 6.0 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

Example 2: Preparation of 6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-6-ol (enantiomer 1), Compound 2, and 6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-6-ol (enantiomer 2), Compound 3

Step 1: 6,15-bis(Trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-6-ol (enantiomer 1), Compound 2, and 6,15-bis(Trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-6-ol (enantiomer 2), Compound 3

Racemic 6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-6-ol (9.5 mg, 0.02310 mmol) was separated by SFC using isocratic 3% methanol over 30 min on a Lux2 10×250 mm column to provide two single enantiomers. The first enantiomer to elute, 3.6 mg of 6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-6-ol (enantiomer 1), was enantiomerically pure however LCMS of this compound showed a polar impurity. This material was re-purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (5% to 40%, 15 column volumes) affording 6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-6-ol (enantiomer 1) (2.7 mg, 54%), chiral purity, >99.9%. ESI-MS m/z calc. 411.10175, found 412.21 (M+1) + ; Retention time: 3.76 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 5-85% mobile phase B over 6.0 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid). The second enantiomer to elute from the SFC separation was 6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-6-ol (3.3 mg, 69%), chiral purity, >99.9%, ESI-MS m/z calc. 411.10175, found 412.2 (M+1) + ; Retention time: 0.96 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 15-98% mobile phase B over 1.5 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

Example 3: Preparation of 17-Amino-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (racemic), Compound 4

To methyl 3-amino-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (approximately 2.5 g, 8.36 mmol) and CuBr 2 (approximately 2.801 g, 12.54 mmol) in acetonitrile (60.90 mL) at room temperature was added tert-butyl nitrite (approximately 1.293 g, 1.491 mL, 12.54 mmol) dropwise and the reaction was stirred at room temperature for 16 h in a closed atmosphere. Complete consumption of the SM was observed. The reaction was diluted with saturated aqueous NH 4 Cl and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure. The crude residue, methyl 3,6-dibromo-5-(trifluoromethyl)pyridine-2-carboxylate (1.6 g, 53%) was used in the next reaction without further purification.

To a solution of methyl 3,6-dibromo-5-(trifluoromethyl)pyridine-2-carboxylate (1 g, 2.755 mmol) in THF (10 mL) was added a solution of lithium hydroxide monohydrate (2 mL of 1.7 M, 3.400 mmol) in water (2.8 mL). This mixture was stirred room temperature for 15 hours, concentrated by rotary evaporation, acidified with aqueous 2 N HCl and extracted with methylene chloride (3×15 mL). The combined extracts were passed through a phase separator and concentrated to afford 3,6-dibromo-5-(trifluoromethyl)pyridine-2-carboxylic acid (920 mg, 93%) as a brown solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H) ppm. ESI-MS m/z calc. 346.84042, found 347.91 (M+1) + ; Retention time: 0.51 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 15-98% mobile phase B over 1.5 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

To a stirred suspension of sodium hydride (310 mg of 60% w/w, 7.751 mmol) in DMF (6 mL) was added pent-4-en-1-ol (550 μL, 5.421 mmol) in DMF (2 mL) stirred at room temperature for 0.5 h. The mixture was cooled to 0° C., 3,6-dibromo-5-(trifluoromethyl)pyridine-2-carboxylic acid (920 mg, 2.566 mmol) in DMF (6 mL) was added, the reaction mixture was warmed to room temperature and stirred for a further 2 h. The mixture was carefully quenched with water (10 mL). Aqueous basic solution was washed with hexanes and ether (1:1), acidified with aqueous 2 N HCl, extracted with ether (3×20 mL) and combined extracts were washed with brine, dried (MgSO 4 ) and concentrated. Purification by column chromatography afforded still impure 3-bromo-6-pent-4-enoxy-5-(trifluoromethyl)pyridine-2-carboxylic acid (600 mg, 66%) as an oil which was used as such in the next step without further purification. ESI-MS m/z calc. 352.98743, found 354.01 (M+1) + ; Retention time: 0.86 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 15-98% mobile phase B over 1.5 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

Step 4: N′-[2-Benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-3-bromo-6-pent-4-enoxy-5-(trifluoromethyl)pyridine-2-carbohydrazide

To a stirred solution of 3-bromo-6-pent-4-enoxy-5-(trifluoromethyl)pyridine-2-carboxylic acid (640 mg, 1.807 mmol) and HATU (885 mg, 2.328 mmol) in DMF (6 mL) was added DIPEA (1.1 mL, 6.315 mmol) (exotherm). After 5 min, 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride salt) (600 mg, 1.791 mmol) was added in one portion and the mixture was stirred for 16 h. The reaction mixture was diluted with water (25 mL), extracted with ethyl acetate (3×25 mL) and combined extracts were washed with brine and dried (MgSO 4 ) then filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (5% to 29%, 10 column volumes) to afford N′-[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-3-bromo-6-pent-4-enoxy-5-(trifluoromethyl)pyridine-2-carbohydrazide (340 mg, 26%) as colorless gum. 1 H NMR (400 MHz, Chloroform-d) δ 9.81 (s, 1H), 9.31 (s, 1H), 8.14 (s, 1H), 7.40-7.35 (m, 5H), 5.88-5.75 (m, 2H), 5.38-5.26 (m, 2H), 5.07-4.95 (m, 2H), 4.83 (s, 2H), 4.43 (t, J=5.9 Hz, 2H), 3.20-2.97 (m, 2H), 2.28-2.19 (m, 2H), 1.96-1.87 (m, 2H) ppm. ESI-MS m/z calc. 623.08545, found 624.13 (M+1) + ; Retention time: 1.1 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 15-98% mobile phase B over 1.5 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

Step 5: 2-[1-Benzyloxy-1-(trifluoromethyl)but-3-enyl]-5-[3-bromo-6-pent-4-enoxy-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole

To a degassed solution of N′-[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-3-bromo-6-pent-4-enoxy-5-(trifluoromethyppyridine-2-carbohydrazide (340 mg, 0.4609 mmol) in THF (6 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (330 mg, 1.385 mmol) in one portion. Resultant solution was heated in a sealed vial at 80° C. for 2 hours. The mixture was quenched with 2 N NaOH (˜1.5 mL) and water (5 mL), most of the solvent was evaporated then diluted with ethyl acetate (20 mL). The organic solution was washed with 0.5 N HCl, brine, dried (MgSO 4 ), filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (0% to 12%, 12 column volumes) affording 2-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-5-[3-bromo-6-pent-4-enoxy-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole (240 mg, 86%) as an oil. 1 H NMR (400 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.39-7.27 (m, 5H), 6.00-5.88 (m, 1H), 5.86-5.75 (m, 1H), 5.29-5.21 (m, 1H), 5.21-5.16 (m, 1H), 5.06-4.95 (m, 2H), 4.84 (d, J=10.8 Hz, 1H), 4.63 (d, J=10.8 Hz, 1H), 4.44 (t, J=6.3 Hz, 2H), 3.20 (t, J=6.0 Hz, 2H), 2.20 (q, J=7.2 Hz, 2H), 1.93-1.84 (m, 2H) ppm. ESI-MS m/z calc. 605.0749, found 607.12 (M+1) + ; Retention time: 1.22 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 15-98% mobile phase B over 1.5 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

Step 6: 6-Benzyloxy-17-bromo-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaene (E/Z Mixture)

To a degassed stirred solution of 2-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-5-[3-bromo-6-pent-4-enoxy-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole (247 mg, 0.4074 mmol) in DCE (20 mL) was added [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2-isopropoxy-5-nitro-phenyl)methylene]ruthenium (50 mg, 0.07445 mmol) and the resulting mixture was purged with nitrogen and heated at 80° C. for 30 min. SiliaMetS (150 mg) was added, stirred for 30 min, filtered and rinsed with DCM then concentrated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (0% to 20%, 15 column volumes) to afford 6-benzyloxy-17-bromo-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaene (E/Z mixture) (100 mg, 42%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.17 (brs, 1H), 7.25-7.24 (m, 2H), 7.24-7.23 (m, 2H), 7.18-7.12 (m, 1H), 5.88-5.80 (m, 2H), 4.88 (d, J=11.6 Hz, 1H), 4.69-4.57 (m, 1H), 4.53 (d, J=11.6 Hz, 1H), 4.50-4.41 (m, 1H), 3.12 (dd, J=14.4, 4.3 Hz, 1H), 2.72 (dd, J=14.6, 8.0 Hz, 1H), 2.19-1.83 (m, 4H) ppm. ESI-MS m/z calc. 577.0436, found 579.97 (M+1) + ; Retention time: 1.16 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 15-98% mobile phase B over 1.5 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

Step 7: 6-Benzyloxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaen-17-amine (E/Z Mixture)

To a degassed mixture of 6-benzyloxy-17-bromo-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaene (E/Z mixture) (35 mg, 0.06052 mmol), Xantphos (4 mg, 0.006913 mmol), diphenylmethanimine (14 μL) and cesium carbonate (40 mg, 0.1228 mmol) in dioxane (700 μL) was added Pd(OAc) 2 (1.8 mg, 0.008017 mmol). Degassed using vacuum/nitrogen and heated in a sealed vial at 100° C. for 2.5 hours, cooled to room temperature, diluted with water (2 mL), extracted with ethyl acetate (4×5 mL) and combined extracts were dried (MgSO 4 ), filtered and concentrated to afford the intermediate N-[6-benzyloxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaen-17-yl]-1,1-diphenyl-methanimine intermediate as a yellow liquid. ESI-MS m/z calc. 678.20654, found 678.38 (M+1) + ; Retention time: 2.16 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 50-100% mobile phase B over 3.0 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid). To a stirred solution of the crude N-[6-benzyloxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaen-17-yl]-1,1-diphenyl-methanimine (E/Z mixture) (60 mg, 129%) in THF (2 mL) was added HCl (2 mL of 2 M, 4.000 mmol) at room temperature, stirred for 10 min, concentrated by rotary evaporation, diluted with water (1 mL), extracted with methylene chloride (3×5 mL) and the combined extracts were dried (MgSO 4 ), filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (10% to 40%, 9 column volumes) which afforded 6-benzyloxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaen-17-amine (E/Z mixture) (24 mg, 77%) as a brown solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.40 (brs, 1H), 7.27-7.22 (m, 4H), 7.20-7.14 (m, 1H), 6.09-5.98 (m, 1H), 5.78 (dt, J=14.9, 7.0 Hz, 1H), 5.32 (s, 2H), 4.86 (d, J=11.5 Hz, 1H), 4.56 (d, J=11.5 Hz, 1H), 4.53-4.32 (m, 2H), 3.14 (dd, J=14.6, 5.4 Hz, 1H), 2.78 (dd, J=14.5, 8.7 Hz, 1H), 2.18-1.84 (m, 4H) ppm. ESI-MS m/z calc. 514.144, found 515.15 (M+1) + ; Retention time: 1.14 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 15-98% mobile phase B over 1.5 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

Step 8: 17-Amino-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 4

To a solution of 6-benzyloxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaen-17-amine (E/Z mixture) (22 mg, 0.04277 mmol) in MeOH (3 mL) was added SiliaCat Pd (49 mg, 0.1944 mmol), stirred for 2 hours under hydrogen balloon then added an additional amount of SiliaCat Pd (20 mg of 0.2 mmol/g, 0.004000 mmol). Stirred for 2 hours and then the mixture was heated at 50° C. for 2 hours. The reaction was diluted with ethyl acetate, filtered through a pad of Celite eluting with ethyl acetate then concentrated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (10% to 50%, 15 column volumes) followed by lyophilization using acetonitrile and water which afforded 17-amino-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (14.5 mg, 77%) as a light yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.36 (s, 1H), 5.18 (brs, 2H), 4.44-4.24 (m, 2H), 3.48 (brs, 1H), 2.35-2.11 (m, 2H), 2.09-1.94 (m, 1H), 1.92-1.69 (m, 1H), 1.67-1.33 (m, 6H) ppm. ESI-MS m/z calc. 426.11267, found 427.29 (M+1) + ; Retention time: 3.83 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC HSS T3 column made by Waters, and a dual gradient run from 5-85% mobile phase B over 6.0 minutes. Mobile phase A=water (with formic acid). Mobile phase B=acetonitrile (with formic acid).

Example 4: Preparation of (6R)-17-amino-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 5

Step 1: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]carbamate

To a stirring solution of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (10 g, 15.69 mmol) in DMSO (64.97 mL) at room temperature was added cesium acetate (3.012 g, 15.69 mmol) and the mixture was capped and heated under nitrogen atmosphere to 80° C. and stirred for 160 min. Reaction was stopped as it was progressing to the undesired N-acetyl product. Diluted the reaction mixture with water and extracted with EtOAc. Washed the organic layer with saturated aqueous NaHCO 3 (1×), saturated aqueous NH 4 Cl (1×) and brine (1×), then dried (MgSO 4 ), filtered and concentrated to a residue which was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% EtOAc. Mixed fractions were combined, concentrated and purified by C 18 reverse phase chromatography using a gradient run from 50%-99% mobile phase B over 15.0 minutes (mobile phase A=H 2 O (5 mM HCl), mobile phase B=acetonitrile. Isolated tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]carbamate (297.7 mg, 3%) as a minor product which was used directly in the ensuing step.

Step 2: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-pent-4-enoxy-5-(trifluoromethyl)-3-pyridyl]carbamate

To a solution of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]carbamate (295 mg, 0.5135 mmol) and pent-4-en-1-ol (78.14 μL, 0.7702 mmol) in toluene (6.21 mL) was added triphenylphosphine (178.4 μL, 0.7700 mmol). After stirring at room temperature for 1 min, DIAD (161.8 μL, 0.8218 mmol) was added and the mixture was stirred at room temperature for 5 minutes. Diluted the reaction mixture with EtOAc then washed with saturated aqueous NaHCO 3 (1×), saturated aqueous NH 4 Cl (1×) and brine (1×) then dried over MgSO 4 , filtered and concentrated to a yellow oil which was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% EtOAc giving as a clear, slightly yellow syrup, tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-pent-4-enoxy-5-(trifluoromethyl)-3-pyridyl]carbamate (271.9 mg, 82%). ESI-MS m/z calc. 642.22766, found 643.3 (M+1) + ; Retention time: 0.83 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: tert-Butyl N-[(6R)-6-benzyloxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaen-17-yl]carbamate (E/Z Mixture)

To a two neck flask bubbling in nitrogen added tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-pent-4-enoxy-5-(trifluoromethyl)-3-pyridyl]carbamate (271.9 mg, 0.4231 mmol) in DCE (62.54 mL) and heated to 60° C. Then added via syringe, Zhan catalyst-1B (77.63 mg, 0.1058 mmol) in dichloroethane (1 mL), heated reaction to 60° C. and stirred while bubbling nitrogen through the solution. Added dichloroethane intermittently as the reaction progressed to maintain volume. After 80 min, added Zhan catalyst-1B (46.56 mg, 0.06345 mmol) and continued stirring at 60° C. for 160 min. Allowed the reaction mixture to cool to room temperature then added 2-sulfanylpyridine-3-carboxylic acid (26.26 mg, 0.1692 mmol) and stirred for 5 min. Concentrated the reaction mixture by rotary evaporation then purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% EtOAc giving as a yellow solid, tert-butyl N-[(6R)-6-benzyloxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaen-17-yl]carbamate (E/Z mixture) (169 mg, 65%). ESI-MS m/z calc. 614.1964, found 615.2 (M+1) + ; Retention time: 0.75 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 4: tert-Butyl N-[(6R)-6-hydroxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-17-yl]carbamate

To a solution of tert-butyl N-[(6R)-6-benzyloxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,8,14(18),15-hexaen-17-yl]carbamate (E/Z mixture) (167 mg, 0.2717 mmol) in AcOH (5.566 mL) was added Pd/C (88.83 mg of 10% w/w, 0.08347 mmol) and hydrogen gas was bubbled through the stirring mixture for 15 minutes then the reaction was sealed and capped with a hydrogen balloon and stirred for 2.5 h. Added palladium (28.91 mg of 10% w/w, 0.02717 mmol), stirred for 1 h then purged the flask with nitrogen and filtered over Celite eluting with EtOAc. The filtrate was concentrated then purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% EtOAc giving as a white foam, tert-butyl N-[(6R)-6-hydroxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-17-yl]carbamate (143 mg, 100%). ESI-MS m/z calc. 526.1651, found 527.2 (M+1) + ; Retention time: 0.52 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 5: (6R)-17-Amino-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 5

To a stirring solution of tert-butyl N-[(6R)-6-hydroxy-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-17-yl]carbamate (143 mg, 0.2716 mmol) in DCM (1.43 mL) was added TFA (522.9 μL, 6.787 mmol) and the resulting mixture was stirred at room temperature for 2 h then concentrated by rotary evaporation to a yellow residue which was dissolved in EtOAc and washed with saturated aqueous NaHCO 3 (1×), dried (MgSO 4 ), filtered and concentrated to a pale yellow residue. This material was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% EtOAc giving as a pale yellow solid, (6R)-17-amino-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (88.7 mg, 76%). 1 H NMR (400 MHz, DMSO) δ 7.80-7.76 (m, 1H), 7.55 (s, 1H), 6.37 (s, 2H), 4.44-4.27 (m, 2H), 2.20 (q, J=7.2 Hz, 1H), 2.10 (dd, J=14.7, 7.1 Hz, 1H), 2.06-1.96 (m, 1H), 1.80 (dd, J=11.3, 5.8 Hz, 1H), 1.69-1.53 (m, 4H), 1.42 (d, J=7.2 Hz, 2H) ppm. ESI-MS m/z calc. 426.11267, found 427.4 (M+1) + ; Retention time: 1.86 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Example 5: Preparation of (6S)-17-amino-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 6

Step 1: (6S)-17-Amino-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 6

Racemic 17-amino-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (32.6 mg, 0.07647 mmol) was separated by preparative SFC using a LUX-4 (25 cm×2.1 cm, 5 μM) column using methanol as solvent to give as the second enantiomer to elute, (6S)-17-amino-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (11.8 mg, 72%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.78 (s, 1H), 7.61 (s, 1H), 6.39 (s, 2H), 4.35 (s, 2H), 2.18 (s, 1H), 2.08 (d, J=39.0 Hz, 2H), 1.82 (s, 1H), 1.64 (s, 4H), 1.42 (s, 2H) ppm. ESI-MS m/z calc. 426.11267, found 427.0 (M+1) + ; Retention time: 1.86 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Single crystals of crystalline Compound 6 (neat form) were grown by vapor diffusion of pentane into a solution of Compound 6 in 1,2-dicholorethane. X-ray diffraction data were acquired at 100 K on a Bruker diffractometer equipped with Cu K + radiation (λ=1.5478 Å) and a CCD detector. The structure was solved and refined using SHELX programs (Sheldrick, G. M., Acta Cryst., (2008) A64, 112-122). The results are summarized in Table 3 below.

Example 6: Preparation of 17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (hydrochloride salt) (diastereomer pair 1), Compound 7, and 17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (hydrochloride salt) (diastereomer pair 2), Compound 8

To a solution of methyl 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate (25 g, 102.26 mmol) in dichloromethane (250 mL) cooled to 0° C. was added urea hydrogen peroxide (34 g, 361.43 mmol) followed by the slow addition of trifluoroacetic anhydride (72.528 g, 48 mL, 345.32 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then poured into ice-water (200 mL) and adjusted to pH=7-8 with 25% aqueous sodium hydroxide solution. The mixture was diluted with dichloromethane (100 mL) and then the layers were separated. The aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic phases were washed with brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 3-chloro-1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (24.5 g, 94%) as a white solid which was used directly in the ensuing step. 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.00 (s, 1H), 8.25 (s, 1H), 3.97 (s, 3H) ppm. 19 F NMR (282 MHz, DMSO-d 6 ) δ −61.75 (br. s., 3F) ppm. ESI-MS m/z calc. 254.99101, found 256.0 (M+1) + ; Retention time: 1.66 minutes; LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in water (0.1% formic acid) 1.2 mL/min.

Methyl 3-chloro-1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (18.52 g, 72.463 mmol) was added in portions to phosphoryl trichloride (121.73 g, 74 mL, 793.90 mmol) at 0° C. and the resulting mixture was stirred at 50° C. overnight. Removal of the solvent in vacuo gave a black oil which was dissolved in ethyl acetate (200 mL) and carefully neutralized with a saturated aqueous solution of sodium carbonate until pH ˜8. The mixture was extracted with ethyl acetate (2×500 mL) and the combined organic phases were washed with brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The black oil was purified by flash chromatography on silica gel, eluting with a gradient from 0% to 20% ethyl acetate in heptanes to afford methyl 3,6-dichloro-5-(trifluoromethyl)pyridine-2-carboxylate (16.43 g, 83%) as a light yellow oil. 1 H NMR (300 MHz, CDCl 3 ) δ 8.13 (s, 1H), 4.04 (d, J=1.8 Hz, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) ppm −64.2 (s, 3F) ppm. ESI-MS m/z calc. 272.95712, found 274.0 (M+1) + ; Retention time: 2.02 minutes; LCMS Method: Kinetex C 18 4.6×50 mm 2.6 μM. Temp: 45° C., Flow: 2.0 mL/min, Run Time: 3 min. Mobile Phase: Initial 95% H 2 O (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 held at 95% acetonitrile (0.1% formic acid) for 1.0 min.

A mixture of methyl 3,6-dichloro-5-(trifluoromethyl)pyridine-2-carboxylate (14.63 g, 52.428 mmol) in THF (150 mL) and water (150 mL) was treated with lithium hydroxide monohydrate (4.5 g, 107.24 mmol) added portion-wise and the mixture was stirred vigorously at room temperature for 1.5 h. The crude reaction mixture was transferred to a 2 L separatory funnel with 5% citric acid (400 mL) and ethyl acetate (800 mL) and the layers were separated. The aqueous phase was extracted further with ethyl acetate (2×200 mL). The combined organic layers were then washed with water (120 mL), brine (2×120 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3,6-dichloro-5-(trifluoromethyl)pyridine-2-carboxylic acid (12.58 g, 92%) as a pale pink solid which was used directly in the ensuing step. 1 H NMR (300 MHz, DMSO-d 6 ) δ 14.64 (br. s, 1H), 8.68 (s, 1H) ppm. 19 F NMR (282 MHz, DMSO-d 6 ) δ −62.62 (s, 3F) ppm. ESI-MS m/z calc. 258.94147, found 257.9 (M+1) + ; Retention time: 1.51 minutes; LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in water (0.1% formic acid) 1.2 mL/min.

Step 4: N′-[2-Benzyloxy-2-(trifluoromethyl)hex-5-enoyl]-3,6-dichloro-5-(trifluoromethyl)pyridine-2-carbohydrazide

To a solution of 3,6-dichloro-5-(trifluoromethyl)pyridine-2-carboxylic acid (8.5 g, 32.693 mmol) in DMF (80 mL) was added triethylamine (10.890 g, 15 mL, 107.62 mmol) and HATU (15 g, 39.450 mmol). The mixture was stirred for 10 min, then 2-benzyloxy-2-(trifluoromethyl)hex-5-enehydrazide (hydrochloride salt) (11.51 g, 33.978 mmol) was added. The mixture was stirred at room temperature for 18 h, then poured into ice-cold water (200 g) and extracted with ethyl acetate (2×220 mL). The combined organic layers were washed with aqueous saturated sodium bicarbonate solution (2×80 mL), water (1×80 mL) and brine (2×80 mL). The organic layer was concentrated by evaporation under reduced pressure to give a dark yellow oil residue (19.2 g) that was combined with dichloromethane (100 mL) and pre-adsorbed on silica gel. Flash chromatography on silica gel (220 g column, crude dry loaded on 50 g of silica gel) using a gradient from 0% to 20% EtOAc in heptanes afforded N′-[2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]-3,6-dichloro-5-(trifluoromethyl)pyridine-2-carbohydrazide (11.37 g, 60%) as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ 9.18 (br. s, 1H), 8.17 (s, 1H), 7.49-7.32 (m, 5H), 5.95-5.75 (m, 1H), 5.18-5.01 (m, 2H), 4.86 (d, J=10.3 Hz, 1H), 4.73 (d, J=10.6 Hz, 1H), 2.55-2.38 (m, 1H), 2.36-2.16 (m, 3H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −64.15 (s, 3F), −73.62 (s, 3F) ppm. ESI-MS m/z calc. 543.0551, found 544.1 (M+1) + ; Retention time: 2.25 minutes; LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in water (0.1% formic acid) 1.2 mL/min.

Step 5: 2-[1-Benzyloxy-1-(trifluoromethyl)pent-4-enyl]-5-[3,6-dichloro-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole

To a solution of N′-[2-benzyloxy-2-(trifluoromethyphex-5-enoyl]-3,6-dichloro-5-(trifluoromethyl)pyridine-2-carbohydrazide (10.37 g, 17.891 mmol) and N,N-diisopropylethylamine (6.5378 g, 8.9 mL, 50.079 mmol) in acetonitrile (240 mL) at 50° C. was added p-toluenesulfonyl chloride (4.15 g, 21.768 mmol) portion-wise. The mixture was stirred at 70° C. Upon completion (1 h), the reaction mixture was concentrated. The residue was dissolved in dichloromethane and washed with 5% aqueous sodium bicarbonate (20 mL), dried with anhydrous sodium sulfate. Flash chromatography on silica gel (40 g column, gradient from 0% to 15% EtOAc in heptanes) afforded 2-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-5-[3,6-dichloro-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole (8.1 g) as a white solid, containing residual p-toluenesulfonyl chloride. A 1.9 g fraction was dissolved in dichloromethane (40 mL) and added ammonium hydroxide (2.5 mL, 28-30% NH 3 basis) under stirring. The mixture was stirred at room temperature for 1 h, then transferred to a separatory funnel with ethyl acetate (160 mL) and separated. The organic layer was further washed with water (2×30 mL) and brine (30 mL), dried over anhydrous sodium sulfate and filtered. The volatiles of the filtrate were removed by evaporation under reduced pressure. The residue was dry loaded on silica gel (50 g) and purified by silica gel chromatography (80 g column) using a gradient from 0% to 10% EtOAc in heptanes giving 2-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-5-[3,6-dichloro-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole (1.7 g, 18%) as a white solid. The remaining 6.2 g fraction from the initial silica gel column was dissolved in dichloromethane (60 mL) and added ammonium hydroxide (5.0 mL, 28.0-30.0% NH 3 basis) under stirring. The mixture was stirred at room temperature for 1 h, then transferred to a separatory funnel with dichloromethane (100 mL) and separated. The organic layer was washed with water (2×30 mL) and brine (30 mL), dried over anhydrous sodium sulfate then filtered. The volatiles of the filtrate were removed by evaporation under reduced pressure. The residue was dry loaded on silica gel (50 g) and purified by silica gel chromatography on a 120 g column using a gradient from 0% to 10% ethyl acetate in heptanes giving 2-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-5-[3,6-dichloro-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole (5.87 g, 62%) as a white solid, calculated overall yield of product from both columns was 80%. 1 H NMR (300 MHz, CDCl 3 ) δ 8.25 (s, 1H), 7.53-7.28 (m, 5H), 5.87-5.68 (m, 1H), 5.13-4.94 (m, 2H), 4.85 (d, J=10.6 Hz, 1H), 4.66 (d, J=10.9 Hz, 1H), 2.61-2.15 (m, 4H) ppm. 19 F NMR (282 MHz, CDCl 3 ) δ −64.11 (s, 3F), −72.85 (s, 3F) ppm. ESI-MS m/z calc. 525.04456, found 526.1 (M+1) + ; Retention time: 2.42 minutes; LCMS Method: Kinetex Polar C 18 3.0×50 mm 2.6 μm, 3 min, 5-95% acetonitrile in water (0.1% formic acid) 1.2 mL/min.

Step 6: 2-[1-Benzyloxy-1-(trifluoromethyl)pent-4-enyl]-5-[3-chloro-6-(1-methylbut-3-enoxy)-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole

To a solution of 2-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-5-[3,6-dichloro-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole (1 g, 1.900 mmol) in DMSO (10 mL) was added pent-4-en-2-ol (502 mg, 5.828 mmol), Cs 2 CO 3 (3.2 g, 9.821 mmol) and iodocopper (215 mg, 1.129 mmol) then the mixture was heated at 60° C. for 6 h. The reaction mixture was poured onto crushed ice and the resultant pasty material was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated. The resultant brown residue was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 50% EtOAc in hexanes to afford 2-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-5-[3-chloro-6-(1-methylbut-3-enoxy)-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole (427 mg, 39%). ESI-MS m/z calc. 575.14105, found 567.1 (M+1) + ; Retention time: 0.79 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 30-99% mobile phase B over 2.9 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 7: tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-(1-methylbut-3-enoxy)-5-(trifluoromethyl)-3-pyridyl]carbamate

To a nitrogen degassed solution of 2-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-5-[3-chloro-6-(1-methylbut-3-enoxy)-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole (425 mg, 0.7379 mmol) in dioxane (5 mL), was added tert-butyl carbamate (262 mg, 2.237 mmol), XPhos Pd G3 (8.6 mg, 0.01016 mmol), palladium (II) acetate (4.2 mg, 0.01871 mmol) and Cs 2 CO 3 (375 mg, 1.151 mmol) and heated the mixture in a sealed vial at 100° C. overnight. Cooled to room temperature, diluted with water (8 mL), extracted with ethyl acetate (3×70 mL) then combined extracts were washed with brine (15 mL), dried (sodium sulfate), filtered and concentrated. The resultant brown residue was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 100% EtOAc to afford tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-(1-methylbut-3-enoxy)-5-(trifluoromethyl)-3-pyridyl]carbamate (152 mg, 31%) as a mixture of diastereomers. ESI-MS m/z calc. 656.24335, found 657.4 (M+1) + ; Retention time: 0.78 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 8: tert-Butyl N-[6-b enzyloxy-12-methyl-6,15-bis (trifluo romethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z mixture)

To a degassed solution of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-(1-methylbut-3-enoxy)-5-(trifluoromethyl)-3-pyridyl]carbamate (150 mg, 0.2284 mmol) in DCE (50 mL) was added dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (Zhan catalyst-1B, 50 mg, 0.06221 mmol) and the reaction was heated at 70° C. overnight while continuously bubbling nitrogen into the solution with a gas outlet. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. Diluted with 1:4 EtOAc/hexanes and filtered through Celite. The filtrate was concentrated and the resultant brown residue was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 30% EtOAc in hexanes to afford tert-butyl N-[6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z mixture) (52 mg, 36%) as a yellow oil. ESI-MS m/z calc. 628.21204, found 629.3 (M+1) + ; Retention time: 0.73 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 9: tert-Butyl N-[6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate

Combined tert-butyl N-[6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z mixture) (52 mg, 0.08273 mmol), Pd/C (47 mg of 10% w/w, 0.04416 mmol), and AcOH (1 mL) in a Parr pressure vessel and sealed. Subjected to vacuum and backfilled with nitrogen gas three times then subjected to vacuum. Filled the vessel with hydrogen gas at 150 psi then stirred the mixture for 15 h. Subjected to vacuum and backfilled with nitrogen gas three times then diluted with ethyl acetate and filtered over Celite. The filtrate was concentrated and purified by reverse phase HPLC-MS using a gradient from 30% to 99% acetonitrile in water (+5 mM HCl) over 15.0 minutes to afford tert-butyl N-[6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate (12.7 mg, 28%) as light brown solid. ESI-MS m/z calc. 540.1807, found 541.2 (M+1) + ; Retention time: 2.07 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 50-99% mobile phase B over 2.9 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 10: 17-Amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (hydrochloride salt) (diastereomer pair 1), Compound 7, and 17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (hydrochloride salt) (diastereomer pair 2), Compound 8

To a solution of tert-butyl N-[6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate (12 mg, 0.02220 mmol) was added TFA (100 μL, 1.298 mmol) and dichloromethane (300 μL) (pre made solution of 1:4 TFA/dichloromethane) and the reaction was stirred at room temperature for about 1 h. Solvents were removed and dissolved in DMSO (1 mL) and the residue was purified by reverse phase HPLC-MS using a gradient from 1% to 99% acetonitrile in water (+5 mM HCl) over 15.0 minutes to afford as a light brown solid and the first eluting diastereomer pair, 17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (hydrochloride salt) (diastereomer pair 1) (2.1 mg, 38%). ESI-MS m/z calc. 440.1283, found 441.16 (M+1) + ; Retention time: 1.46 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 30-99% mobile phase B over 2.9 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C. The second eluting diastereomer pair, isolated as a light brown solid, was 17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (hydrochloride salt) (diastereomer pair 2) (3.6 mg, 67%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.76 (s, 1H), 7.63 (s, 1H), 6.36 (s, 2H), 4.77-4.65 (m, 1H), 2.55 (dd, J=8.8, 4.4 Hz, 1H), 2.17 (t, J=12.2 Hz, 1H), 2.09 (ddd, J=14.2, 10.5, 6.9 Hz, 1H), 1.68 (s, 1H), 1.59 (d, J=7.9 Hz, 2H), 1.48 (d, J=6.6 Hz, 3H), 1.33 (d, J=6.3 Hz, 3H), 1.14 (q, J=9.0, 8.0 Hz, 1H) ppm. ESI-MS m/z calc. 440.1283, found 441.2 (M+1) + ; Retention time: 1.51 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 30-99% mobile phase B over 2.9 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Example 7: Preparation of (6R)-17-amino-13,13-dioxo-6,15-bis(trifluoromethyl)-19-oxa-13λ 6 -thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 1), Compound 9, and (6S)-17-amino-13,13-dioxo-6,15-bis(trifluoromethyl)-19-oxa-13λ 6 -thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (enantiomer 2), Compound 10

Step 1: tert-Butyl N-[2-[5-[1-benzyloxy-t-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-but-3-enylsulfonyl-5-(trifluoromethyl)-3-pyridyl]carbamate

A mixture of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (545 mg, 0.84 mmol), but-3-ene-1-sulfinate (sodium salt) (351 mg, 2.47 mmol), and CuI (472 mg, 2.48 mmol) in DMSO (5 mL) was heated at 100° C. for 3 h, then diluted with ether and water, the mixture filtered, the layers partitioned and the organic layer washed with water, brine, dried (MgSO 4 ) and evaporated. The residue was purified by silica gel chromatography (24 g SiO 2 , 0-20% EtOAc in hexanes over 15 min) to provide tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-but-3-enylsulfonyl-5-(trifluoromethyl)-3-pyridyl]carbamate (327 mg, 57%). 1 H NMR (400 MHz, Chloroform-d) δ 10.36 (s, 1H), 9.57 (s, 1H), 7.42-7.28 (m, 5H), 5.75 (tdt, J=17.0, 10.2, 6.5 Hz, 2H), 5.06 (dt, J=17.1, 1.4 Hz, 2H), 5.01 (d, J=10.2 Hz, 2H), 4.84 (d, J=10.9 Hz, 1H), 4.66 (d, J=10.8 Hz, 1H), 3.69 (hept, J=7.0 Hz, 2H), 2.65-2.58 (m, 2H), 2.56-2.31 (m, 2H), 2.30-2.18 (m, 1H), 1.59 (s, 9H), 1.55-1.51 (m, 1H)ppm. 19 F NMR (376 MHz, Chloroform-d) δ −58.48, −72.86 ppm. ESI-MS m/z calc. 690.1947, found 691.2 (M+1) + ; Retention time: 0.89 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 1-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-[6-(benzyloxy)-13,13-dioxo-6,15-bis(trifluoromethyl)-19-oxa-13λ 6 -thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z Mixture)

A solution of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-but-3-enylsulfonyl-5-(trifluoromethyl)-3-pyridyl]carbamate (300 mg, 0.4344 mmol) in 5 mL DCE was added dropwise over 5 min to a solution of benzylidene-[1,3-bis(2,4,6-trimethylphenypimidazolidin-2-ylidene]-dichloro-ruthenium;tricyclohexylphosphane (55 mg, 0.06478 mmol) in DCE (42 mL) heated at 70° C. with constant N 2 bubbling for 1 h. The solvent was evaporated and the residue purified by silica gel chromatography (24 g SiO 2 , 0-20% EtOAc in hexane over 15 min) to provide tert-butyl N-[6-(benzyloxy)-13,13-dioxo-6,15-bi s (trifluoromethyl)-19-oxa-13λ 6 -thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1 (18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z mixture) (157 mg, 55%). 1 H NMR (400 MHz, Chloroform-d) δ 10.05 (s, 1H), 9.54 (s, 1H), 7.36-7.20 (m, 5H), 5.67 (q, J=8.3, 7.8 Hz, 1H), 5.48 (q, J=9.1, 8.7 Hz, 1H), 4.90 (s, 2H), 3.65 (ddd, J=14.6, 12.6, 4.4 Hz, 1H), 3.58-3.47 (m, 1H), 3.06-2.84 (m, 2H), 2.60-2.34 (m, 2H), 2.23 (t, J=10.5 Hz, 1H), 2.12-2.06 (m, 1H), 1.58 (d, J=2.9 Hz, 9H)ppm. 19 F NMR (376 MHz, Chloroform-d) δ −58.72, −74.24 ppm. ESI-MS m/z calc. 662.1634, found 663.2 (M+1) + ; Retention time: 0.85 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 1-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: tert-Butyl N-[6-hydroxy-13,13-dioxo-6,15-bis(trifluoromethyl)-19-oxa-13λ 6 -thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate

A mixture of tert-butyl N-[6-(benzyloxy)-13,13-dioxo-6,15-bis(trifluoromethyl)-19-oxa-13λ 6 -thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z mixture) (154 mg, 0.232 mmol), and Pd/C (74 mg of 10% w/w, 0.070 mmol) in AcOH (1.5 mL) was stirred at room temperature under 180 psi H 2 in a stainless steel pressure vessel for 15 h. Then the mixture was filtered and the filtrate evaporated to provide the target tert-butyl N-[6-hydroxy-13,13-dioxo-6,15-bis(trifluoromethyl)-19-oxa-13λ 6 -thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate (136 mg, 96%), ESI-MS m/z calc. 574.1321, found 575.1 (M+1) + ; Retention time: 0.72 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 1-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 4: (6R)-17-Amino-6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa-13λ 6 -thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaene-13,13-dione (enantiomer 1), Compound 9, and (6S)-17-amino-6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa-13λ 6 -thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaene-13,13-dione (enantiomer 2), Compound 10

A mixture of tert-butyl N-[6-hydroxy-13,13-dioxo-6,15-bis(trifluoromethyl)-19-oxa-13λ 6 -thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate (134 mg, 0.22 mmol), TFA (2 mL), triisopropylsilane (67 μL, 0.33 mmol) and water (100 μL) was stirred at room temperature for 30 min and then solvent evaporated. The residue was co-evaporated from acetonitrile (2×). The residue, dissolved into 2 mL acetonitrile, was subjected to preparative SFC with 330 μL injections through a preparative SFC eluting a gradient of 5 mM NH 3 in methanol to CO 2 (5-15% over 10 min) though a 21.2×250 mm AD column, 5 μm particle giving the first eluent (6R)-17-amino-6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa-13λ 6 -thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaene-13,13-dione (enantiomer 1) (38 mg, 37%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.93 (s, 1H), 7.66 (s, 3H, D 2 O exchanged), 3.77-3.64 (m, 1H), 3.61-3.49 (m, 1H), 2.21 (t, J=12.1 Hz, 2H), 2.08 (d, J=15.0 Hz, 1H), 1.92 (dd, J=12.5, 7.2 Hz, 1H), 1.56 (m, 6H) ppm; 19 F NMR (376 MHz, DMSO-d 6 ) δ −57.96, −78.11 ppm. ESI-MS m/z calc. 474.07965, found 475.0 (M+1) + ; Retention time: 1.16 minutes. Final purity was determined by reversed phase HPLC-MS using an Onyx Monolithic C 18 column (50×4.6 mm) sold by Phenomenex (pn: CH0-7644), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=12 mL/min, injection volume=50 μL, and column temperature=25° C. UV/vis λ max 231, 277, 356 nm.

Further elution provided the second eluent (6S)-17-amino-6-hydroxy-6,15-bis(trifluoromethyl)-19-oxa-13λ 6 -thia-3,4,18-tri azatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaene-13,13-dione (enantiomer 2) (36 mg, 35%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.93 (s, 1H), 7.66 (s, 3H, D 2 O exchanged), 3.77-3.63 (m, 1H), 3.56 (td, J=14.9, 13.7, 4.1 Hz, 1H), 2.21 (t, J=11.9 Hz, 2H), 2.08 (dd, J=14.1, 8.0 Hz, 1H), 1.97-1.84 (m, 1H), 1.56 (m, 6H) ppm; 19 F NMR (376 MHz, DMSO-d 6 ) δ −57.96, −78.11. ESI-MS m/z calc. 474.07965, found 475.0 (M+1) + ; Retention time: 1.16 minutes. Final purity was determined by reversed phase HPLC-MS using an Onyx Monolithic C 18 column (50×4.6 mm) sold by Phenomenex (pn: CH0-7644), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=12 mL/min, injection volume=50 ut, and column temperature=25° C.

Example 8: Preparation of (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 11

Step 1: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-[(1R)-1-methylbut-3-enoxy]-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

Dissolved tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (159.3 g, 231.3 mmol) and triphenylphosphine (72.9 g, 277.9 mmol) in toluene (1 L), then added (2S)-pent-4-en-2-ol (28.7 mL, 278.9 mmol). Heated this mixture to 45° C., then added DIAD (58.3 mL, 296.1 mmol) (exotherm) slowly over 40 min. For the next approximately 2 h, the mixture was cooled to room temperature. During this cooling period, after the first 10 minutes, triphenylphosphine (6.07 g, 23.14 mmol) was added. After a further 1 h, additional triphenylphosphine (3.04 g, 11.59 mmol) was added. After a further 23 min, DIAD (2.24 mL, 11.57 mmol) was added. After the ˜2 h cooling to room temperature period, the mixture was cooled to 15° C., and seed crystals of DIAD-triphenylphosphine oxide complex were added which caused precipitation to occur, then added 1000 mL heptane. Stored the mixture at −20° C. for 3 days. Filtered out and discarded the precipitate and concentrated the filtrate to give a red residue/oil. Dissolved the residue in 613 mL heptane at 45° C., then cooled to 0° C., seeded with DIAD-triphenylphosphine oxide complex, stirred at 0° C. for 30 min, then filtered the solution. The filtrate was concentrated to a smaller volume, then loaded onto a 1.5 kg silica gel column (column volume=2400 mL, flow rate=600 mL/min). Ran a gradient of 1% to 6% EtOAc in hexanes over 32 minutes (8 column volumes), then held at 6% EtOAc in hexanes until the product finished eluting which gave tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-[(1R)-1-methylbut-3-enoxy]-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (163.5 g, 93%). 1 H NMR (400 MHz, Chloroform-d) δ 7.82 (s, 1H), 7.43-7.27 (m, 5H), 5.88-5.69 (m, 2H), 5.35 (h, J=6.2 Hz, 1H), 5.16-4.94 (m, 4H), 4.81 (d, J=10.7 Hz, 1H), 4.63 (d, J=10.7 Hz, 1H), 2.58-2.15 (m, 6H), 1.42 (s, 18H), 1.36 (d, J=6.2 Hz, 3H) ppm. ESI-MS m/z calc. 756.2958, found 757.3 (M+1) + ; Retention time: 4.0 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-[(6R,12R)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]-N-tert-butoxycarbonyl-carbamate (E/Z Mixture)

The following reaction was run, split equally between two, 12 L reaction flasks run in parallel. Mechanical stirring was employed, and reactions were subjected to a constant nitrogen gas purge using a course porosity gas dispersion tube. To each flask was added tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-[(1R)-1-methylbut-3-enoxy]-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (54 g, 71.36 mmol in each flask) dissolved in DCE (8 L in each flask) and both flasks were strongly purged with nitrogen at room temperature. Both flasks were heated to 62° C. and Grubbs 1 st Generation Catalyst (9 g, 10.94 mmol in each flask) was added to each reaction and stirred at 400 rpm while setting an internal temperature control to 75° C. with strong nitrogen purging (both reactions reached 75° C. after approximately 20 min). After 5 h 15 min, the internal temperature control was set to 45° C. After approximately 2 h, 2-sulfanylpyridine-3-carboxylic acid (11 g, 70.89 mmol in each flask) was added to each flask followed by triethylamine (10 mL, 71.75 mmol in each flask). On completion of addition, the nitrogen purge was turned off and both reaction flasks were stirred at 45° C. open to air overnight. The reactions were then removed from heat and 130 g of silica gel was added to each reaction and each was stirred at room temperature. After approximately 2 h, the green mixtures were combined and filtered over Celite then concentrated by rotary evaporation at 43° C. The obtained residue was dissolved in dichloromethane/heptane 1:1 (400 mL) and the formed orange solid was removed by filtration. The greenish mother liquor was evaporated to give 115.5 g of a green foam. Dissolved this material in 500 mL of 1:1 dichloromethane/hexanes then loaded onto a 3 kg silica gel column (column volume=4800 mL, flow rate=900 mL/min). Ran a gradient of 2% to 9% EtOAc in hexanes over 43 minutes (8 column volumes), then ran at 9% EtOAc until the product finished eluting giving 77.8 g of impure product. This material was co-evaporated with methanol (˜500 mL) then diluted with methanol (200 mL) to give 234.5 g of a methanolic solution, which was halved and each half was purified by reverse phase chromatography (3.8 kg C 18 column, column volume=3300 mL, flow rate=375 mL/min, loaded as solution in methanol). Ran the column at 55% acetonitrile for 5 minutes (0.5 column volumes), then at a gradient of 55% to 100% acetonitrile in water over 170 minutes (19-20 column volumes), then held at 100% acetonitrile until the product and impurities finished eluting. Clean product fractions from both columns were combined and concentrated by rotary evaporation then transferred with ethanol into 5 L flask, evaporated and carefully dried (becomes a foam) to give as a mixture of olefin isomers, tert-butyl N-[(6R,12R)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]-N-tert-butoxycarbonyl-carbamate (E/Z mixture) (55.5 g, 53%). ESI-MS m/z calc. 728.26447, found 729.0 (M+1) + ; Retention time: 3.82 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: tert-Butyl N-[(6R,12R)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate

tert-Butyl N-[(6R,12R)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]-N-tert-butoxycarbonyl-carbamate (E/Z mixture) (11.7 g, 16.06 mmol) was dissolved in stirring ethanol (230 mL) and cycled the flask 3 times vacuum/nitrogen and treated with 10% Pd/C (50% water wet, 2.2 g of 5% w/w, 1.034 mmol). The mixture was cycled 3 times between vacuum/nitrogen and 3 times between vacuum/hydrogen. The mixture was then stirred strongly under hydrogen (balloon) for 7.5 h. The catalyst was removed by filtration, replaced with fresh 10% Pd/C (50% water wet, 2.2 g of 5% w/w, 1.034 mmol) and stirred vigorously under hydrogen (balloon) overnight. Then, the catalyst was removed again by filtration, the filtrate evaporated and the residue (11.3 g, 1 g set aside) was dissolved in ethanol (230 mL) charged with fresh 10% Pd/C (50% water wet, 2.2 g of 5% w/w, 1.034 mmol) and stirred vigorously under hydrogen (balloon) for 6 h, recharged again with fresh 10% Pd/C (50% water wet, 2.2 g of 5% w/w, 1.034 mmol) and stirred vigorously under hydrogen (balloon) overnight. The catalyst was removed by filtration and the filtrate was evaporated (10 g of residue obtained). This crude material (10 g+1 g set aside above) was purified by silica gel chromatography (330 g column, liquid load in dichloromethane) with a linear gradient of 0% to 15% ethyl acetate in hexane until the product eluted followed by 15% to 100% ethyl acetate in hexane to giving, as a colorless foam, tert-butyl N-[(6R,12R)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate (9.1 g, 78%). ESI-MS m/z calc. 730.2801, found 731.0 (M+1) + ; Retention time: 3.89 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 4: (6R,12R)-17-Amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 11

tert-Butyl N-[(6R,12R)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate (8.6 g, 11.77 mmol) was dissolved in ethanol (172 mL) then the flask was cycled 3 times between vacuum/nitrogen. Treated the mixture with 10% Pd/C (50% water wet, 1.8 g of 5% w/w, 0.8457 mmol) then cycled 3 times between vacuum/nitrogen and 3 times between vacuum/hydrogen and then stirred vigorously under hydrogen (balloon) at room temperature for 18 h. The mixture was cycled 3 times between vacuum/nitrogen, filtered over Celite washing with ethanol and then the filtrate was evaporated to give 7.3 g of tert-butyl N-tert-butoxycarbonyl-N-[(6R,12R)-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate an off-white solid. This material was dissolved in dichloromethane (69 mL), cooled in an ice bath under nitrogen and slowly treated with TFA (23 mL, 298.5 mmol). The solution was stirred in the ice bath for 5 min and then at room temperature for 1 h. The pale-yellow solution was diluted with heptane (˜100 mL) and evaporated to give a yellow solid mass. The residue was diluted again with heptane (˜100-200 mL) and dichloromethane was added under warming until a yellow solution was obtained. Most of the dichloromethane was removed by rotary evaporation (35° C. water bath, 100 mbar pressure) to give a fine yellow suspension. The suspension was swirled for ˜1 h at room temperature, filtered washing the solid with dry ice chilled heptane and then dried over 3 days under vacuum with a nitrogen leak at 50° C. to give as a pale yellow solid, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (4.68 g, 90%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.77 (s, 1H), 7.55 (s, 1H), 6.34 (s, 2H), 4.90-4.70 (m, 1H), 2.47 (dd, J=7.8, 5.5 Hz, 1H), 2.29 (t, J=11.2 Hz, 1H), 2.11 (ddd, J=14.4, 8.7, 6.1 Hz, 1H), 1.73 (dt, J=12.7, 7.6 Hz, 2H), 1.59-1.38 (m, 4H), 1.35 (d, J=6.3 Hz, 3H), 1.18 (ddt, J=12.4, 9.6, 6.2 Hz, 1H) ppm. 1 H NMR (400 MHz, Chloroform-d) δ 7.42 (d, J=0.8 Hz, 1H), 5.20 (s, 2H), 4.75 (dtt, J=12.6, 6.3, 3.2 Hz, 1H), 3.98 (s, 1H), 2.68 (dtd, J=12.9, 7.6, 2.3 Hz, 1H), 2.38-2.18 (m, 2H), 2.03 (d, J=7.9 Hz, 1H), 1.75-1.46 (m, 5H), 1.41 (d, J=6.3 Hz, 3H), 1.35-1.27 (m, 1H) ppm. 19 F NMR (376 MHz, Chloroform-d) δ −63.95, −77.34 ppm. ESI-MS m/z calc. 440.1283, found 441.0 (M+1) + ; Retention time: 2.87 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

A. X-Ray Powder Diffraction

The X-ray powder diffraction (XRPD) diffractogram of the product of Step 4, Compound 11 heptane solvate, was acquired at room temperature in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 Å). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 40°2θ with a step size of 0.0131303° and 49 s per step.

The XRPD diffractogram for Compound 11 heptane solvate is provided in FIG. 1 , and the XRPD data are summarized below in Table 4.

XRPD diffractograms for Compound 11 heptane solvate samples prepared under three different drying conditions are provided in FIG. 2 . The XRPD diffractograms were 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 45 kV and 40 mA. Pixel 1d detector was used with anti-scatter slit P8. The Divergence optics is Bragg Brentano High Definition (BBHD) with a 10 mm mask, ⅛ divergence slit, and ½ 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.

Under Drying Condition 1, Compound 11 heptane solvate was dried over the weekend under house vacuum with a nitrogen leak at 50° C. Under Drying Condition 2, Compound 11 heptane solvate was dried over the weekend at 40-45° C. Under Drying Condition 3, Compound 11 heptane solvate was dried for 4 days under house vacuum with a nitrogen bleed at 40-45° C.

The XRPD diffractograms for Compound 11 heptane solvate samples prepared under Drying Condition 1, Drying Condition 2, and Drying Condition 3 are provided in FIG. 2 , and the XRPD data are summarized below in Tables 5, 6, and 7. In FIG. 2 , the top curve corresponds to Drying Condition 2, the middle curve corresponds to Drying Condition 1, and the bottom curve corresponds to Drying Condition 3. Each curve is substantially similar to each other and to the XRPD of FIG. 1 .

B. Differential Scanning Calorimetry Analysis

The melting point of the product of Step 4, Compound 11 heptane solvate, was measured using the TA Instruments Q2000 DSC.

The DSC thermogram for Compound 11 heptane solvate is provided in FIG. 2 . The thermogram for Compound 11 heptane solvate shows an endotherm at ˜93.45° C. and recrystallization at ˜103° C.

C. Solid-State 13 C NMR

The 13 C SSNMR of the product of Step 4, Compound 11 heptane solvate, was acquired using the procedure described in the General Methods. The 13 C SSNMR spectrum for Compound 11 heptane solvate Form is provided in FIG. 3 , and the data are summarized below in Table 8.

D. Solid-State 19 F NMR

The 19 F SSNMR of the product of Step 4, Compound 11 heptane solvate, was acquired using the procedure described in the General Methods. The 19 F SSNMR spectrum for Compound 11 heptane solvate is provided in FIG. 4 , and the data are summarized below in Table 9.

E. Thermogravimetric Analysis (TGA)

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. TGA data were collected on a Mettler Toledo TGA/DSC 3+ STARe System.

The TGA curve for Compound 11 heptane solvate prepared under Drying Condition 1 is provided in FIG. 6 A . The TGA curve for Compound 11 heptane solvate prepared under Drying Condition 2 is provided in FIG. 6 B . The TGA curve for Compound 11 heptane solvate prepared under Drying Condition 3 is provided in FIG. 6 C . Each of the curves in FIGS. 6 A, 6 B, and 6 C are substantially similar to each other.

Example 9: Preparation of (6S,12R)-17-amino-12-methyl-6,15-b is (trifluo romethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (hydrochloride salt), Compound 12

Step 1: tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-[(1R)-1-methylbut-3-enoxy]-5-(trifluoromethyl)-3-pyridyl]carbamate

To a solution of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (500 mg, 0.6653 mmol) in DMSO (5 mL) was added (2R)-pent-4-en-2-ol (350 μL, 3.401 mmol), cesium carbonate (751 mg, 2.305 mmol) and iodocopper (31 mg, 0.1628 mmol) and the reaction mixture was heated at 100° C. for 6 h in an oil bath. The reaction mixture was poured onto crushed ice and extracted with ethyl acetate and washed with brine. The organics were separated, dried over sodium sulfate, filtered and evaporated. The resultant brown residue was purified by silica gel chromatography using a shallow gradient 100% hexanes to 50% EtOAc in hexanes to afford as light brown viscous oil, tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-[(1R)-1-methylbut-3-enoxy]-5-(trifluoromethyl)-3-pyridyl]carbamate (120 mg, 27%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.71 (s, 1H), 8.86 (s, 1H), 7.46-7.28 (m, 5H), 5.91-5.72 (m, 2H), 5.24 (qt, J=6.1, 3.1 Hz, 1H), 5.16-4.97 (m, 4H), 4.75 (d, J=11.0 Hz, 1H), 4.66 (d, J=11.0 Hz, 1H), 2.50-2.40 (m, 4H), 2.32 (d, J=8.1 Hz, 2H), 1.49 (s, 9H), 1.32 (d, J=6.2 Hz, 3H) ppm. ESI-MS m/z calc. 656.24335, found 657.3 (M+1) + ; Retention time: 0.84 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-[(12R)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z Mixture)

To a degassed solution of [1,3-bis(2,4,6-trimethylphenypimidazolidin-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium (32 mg, 0.05107 mmol) (Grubbs 2nd generation catalyst) in DCE (50 mL) was added a degassed solution of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-[(1R)-1-methylbut-3-enoxy]-5-(trifluoromethyl)-3-pyridyl]carbamate (150 mg, 0.2284 mmol) in DCE (50 mL) slowly dropwise under a stream of nitrogen flow bubbling through the solution over 30 min and the reaction mixture was then heated at 50° C. for 5 h. The reaction was stopped, and the solvents were removed by rotary evaporation. The resultant brown residue was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 30% EtOAc in hexanes to afford as a mixture of olefin isomers, tert-butyl N-[(12R)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z mixture) (102 mg, 36%) which co-eluted with some unreacted starting material. ESI-MS m/z calc. 628.21204, found 629.2 (M+1) + ; Retention time: 0.36 minutes. This material was used directly in the ensuing step. ESI-MS m/z calc. 628.21204, found 629.2 (M+1) + ; Retention time: 0.36 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: tert-Butyl N-[(12R)-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate

To a solution of tert-butyl N-[(12R)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z mixture) (102 mg, 0.08114 mmol) in AcOH (5 mL) was added 10% w/w Pd/C (54 mg, 0.05074 mmol) in a 250 mL flask equipped with a hydrogen balloon using a 3-way adaptor. Subjected the flask to vacuum and backfilled with nitrogen gas three times then subjected to vacuum. Filled the vessel with hydrogen gas and the mixture was stirred at room temperature for 15 h. Subjected the vessel to vacuum and backfilled with nitrogen gas three times then diluted with ethyl acetate and filtered over Celite. The filtrate was concentrated to afford tert-butyl N-[(12R)-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate (120 mg, 96%) which was used directly in the ensuing step. ESI-MS m/z calc. 540.1807, found 541.2 (M+1) + ; Retention time: 0.57 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 4: (6S,12R)-17-Amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (hydrochloride salt), Compound 12

To a solution of tert-butyl N-[(12R)-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate (120 mg, 0.2220 mmol) was added TFA (500 mL, 6.490 mol) and dichloromethane (1.5 mL) (pre made solution of 1:4 TFA/dichloromethane) and the reaction was stirred at room temperature for about 1 h. The solvents were removed by evaporation and the residue was dissolved in DMSO (1 mL) and purified by reverse phase HPLC using a gradient run from 40% to 85% acetonitrile in water (+5 mM HCl) over 30.0 minutes to afford as a light brown solid and the second diastereomer to elute, (6S,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (hydrochloride salt) (14.7 mg, 28%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.78 (s, 1H), 4.72 (ddt, J=11.5, 7.7, 3.8 Hz, 1H), 2.61-2.52 (m, 1H), 2.24-2.03 (m, 2H), 1.68 (s, 1H), 1.59 (h, J=7.5, 6.4 Hz, 2H), 1.54-1.38 (m, 3H), 1.34 (d, J=6.3 Hz, 3H), 1.21-1.10 (m, 1H) ppm. ESI-MS m/z calc. 440.1283, found 441.1 (M+1) + ; Retention time: 2.87 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Example 10: Preparation of (6S,12S)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (hydrochloride salt), Compound 13

Step 1: tert-Butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-[(1S)-1-methylbut-3-enoxy]-5-(trifluo romethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate

To a solution of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (800 mg, 1.065 mmol) in DMSO (10 mL) was added (2S)-pent-4-en-2-ol (550 μL, 5.345 mmol), cesium carbonate (1.1 g, 3.376 mmol) and iodocopper (47 mg, 0.2468 mmol) and the reaction mixture was heated at 80° C. for 3 h. The reaction mixture was poured onto crushed ice and extracted with ethyl acetate and the organic phase was washed with brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The resultant brown residue was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 30% EtOAc in hexanes to afford tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-1(1S)-1-methylbut-3-enoxyl-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (303 mg, 38%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.41-7.30 (m, 5H), 5.90-5.75 (m, 2H), 5.43 (qt, J=7.7, 3.9 Hz, 1H), 5.12-4.98 (m, 4H), 4.81 (d, J=11.1 Hz, 1H), 4.68 (d, J=11.0 Hz, 1H), 2.60-2.47 (m, 4H), 2.39-2.26 (m, 2H), 1.38-1.26 (m, 21H) ppm. ESI-MS m/z calc. 756.2958, found 757.47 (M+1) + ; Retention time: 0.78 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-[(12S)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z Mixture)

To a degassed solution of [1,3-bis(2,4,6-trimethylphenypimidazolidin-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium (43 mg, 0.06862 mmol) (Grubbs 2nd generation catalyst) in DCE (50 mL) was added a degassed solution of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-[(1S)-1-methylbut-3-enoxy]-5-(trifluoromethyl)-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (200 mg, 0.2643 mmol) in DCE (50 mL) slowly dropwise under a stream of nitrogen flow bubbling through the solution over 30 min and on completion of addition the reaction mixture was heated at 50° C. for 5 h. The reaction was stopped, and the solvents removed by rotary evaporation. The resultant brown residue was purified by silica gel chromatography using a shallow gradient from 100% hexanes to 30% EtOAc in hexanes to afford as a mixture of olefin isomers, tert-butyl N-[(12S)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z mixture) (150 mg, 45%) along with some unreacted starting material which co-eluted with the product. This material was used directly in the ensuing step without further purification. ESI-MS m/z calc. 628.21204, found 629.3 (M+1) + ; Retention time: 0.7 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: (6S,12S)-17-Amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (hydrochloride salt), Compound 13

To a solution of tert-butyl N-[(12S)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z mixture) (150 mg, 0.2386 mmol) in AcOH (5 mL) was added 10% w/w Pd/C (78 mg, 0.07329 mmol) in a 250 mL flask equipped with a hydrogen balloon using a 3-way adaptor. Subjected to vacuum and backfilled with nitrogen gas three times then subjected to vacuum. Filled the vessel with hydrogen gas and the mixture was stirred at room temperature for 15 h. Subjected to vacuum and backfilled with nitrogen gas three times then diluted with ethyl acetate and filtered over Celite. The filtrate was concentrated to afford 125 mg of tert-butyl N-[(12S)-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate as a mixture of diastereomers. This material was dissolved in a 1:3 mixture of a premixed solution of TFA (500 μL, 6.490 mmol) and dichloromethane (1.5 mL) and the mixture was stirred for 30 min at room temperature. The solvent was removed by rotary evaporation and the resulting residue was purified by reverse phase HPLC using a gradient from 40% to 85% acetonitrile in water (+5 mM HCl) over 30.0 minutes to afford as a light brown solid and the first enantiomer to elute, (6S,12S)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (hydrochloride salt) (20.6 mg, 36%). 1 H NMR (400 MHz, Chloroform-d) δ 7.42 (s, 1H), 4.75 (ddt, J=10.6, 6.7, 3.4 Hz, 1H), 4.06-3.76 (m, 1H), 2.76-2.63 (m, 1H), 2.28 (t, J=7.6 Hz, 2H), 2.01 (d, J=5.7 Hz, 1H), 1.61 (m, 4H), 1.50 (dd, J=12.0, 6.5 Hz, 1H), 1.41 (d, J=6.3 Hz, 3H), 1.33-1.26 (m, 1H), 0.89 (m, 1H) ppm. ESI-MS m/z calc. 440.1283, found 441.1 (M+1) + ; Retention time: 2.82 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Example 11: Preparation of (6R,12S)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 14

Step 1: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-[(1S)-1-methylbut-3-enoxy]-5-(trifluoromethyl)-3-pyridyl]carbamate

To a solution of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-hydroxy-5-(trifluoromethyl)-3-pyridyl]carbamate (417.3 mg, 0.7091 mmol) and (2R)-pent-4-en-2-ol (109.5 μL, 1.064 mmol) in toluene (8.784 mL) was added triphenylphosphine (246.6 μL, 1.064 mmol). After stirring at room temperature for 1 min, DIAD (223.5 μL, 1.135 mmol) was added and the mixture was stirred at room temperature for 5 min. Diluted the reaction mixture with EtOAc then washed with saturated aqueous sodium bicarbonate (1×), saturated aqueous NH 4 Cl (1×) and brine (1×) then dried over magnesium sulfate, filtered and concentrated to a yellow oil which was purified by silica gel chromatography using a gradient from 100% hexanes to 100% EtOAc giving as a clear, slightly yellow syrup, tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-[(1S)-1-methylbut-3-enoxy]-5-(trifluoromethyl)-3-pyridyl]carbamate (433.8 mg, 93%). 1 H NMR (400 MHz, Chloroform-d) δ 9.81 (s, 1H), 9.16 (s, 1H), 7.42-7.37 (m, 2H), 7.36-7.28 (m, 3H), 5.90-5.72 (m, 2H), 5.26 (q, J=6.1 Hz, 1H), 5.13-4.97 (m, 4H), 4.83 (d, J=10.8 Hz, 1H), 4.68 (d, J=10.9 Hz, 1H), 2.51 (m, 2H), 2.46-2.36 (m, 3H), 2.27 (d, J=11.2 Hz, 1H), 1.55 (s, 9H), 1.36 (d, J=6.2 Hz, 3H) ppm. ESI-MS m/z calc. 656.24335, found 657.3 (M+1) + ; Retention time: 0.86 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-[(6R,12S)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z Mixture)

To a degassed solution of [1,3-bis(2,4,6-trimethylphenypimidazolidin-2-ylidene]-dichloro-[(2-isopropoxyphenyOmethylene]ruthenium (378.2 mg, 0.6036 mmol) (Hoveyda Grubbs 2nd Gen catalyst) in toluene (229 mL) stirring at 100° C. with a reflux condenser and nitrogen bubbling through the solution was added a degassed solution of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-[(1S)-1-methylbut-3-enoxy]-5-(trifluoromethyl)-3-pyridyl]carbamate (1.5269 g, 2.325 mmol) in toluene (229 mL) slowly dropwise under a stream of nitrogen flow bubbling through the solution over 10 min and the reaction mixture was heated at 100° C. for 60 min. The mixture was removed from the heating bath and 2-sulfanylpyridine-3-carboxylic acid (180.5 mg, 1.163 mmol) was added. The resulting mixture was stirred for 10 min then concentrated by rotary evaporation to a residue which was chromatographed on a 275 g reverse phase C 18 column eluting with a gradient from 50% to 100% acetonitrile in water giving as an off-white/yellow foam, tert-butyl N-[(6R,12S)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z mixture) (324.3 mg, 22%). ESI-MS m/z calc. 628.21204, found 629.2 (M+1) + ; Retention time: 0.82 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: tert-Butyl N-[(6R,12S)-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate

To a solution of tert-butyl N-[(6R,12S)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z mixture) (324.3 mg, 0.5159 mmol) in AcOH (10.81 mL) was added 10% w/w Pd/C (168.7 mg, 0.1585 mmol, 50% water wet) and hydrogen gas was bubbled through the stirring mixture for 15 minutes then the reaction was sealed and capped with a hydrogen balloon and stirred for 16 h. Added 10% w/w Pd/C (54.9 mg, 0.05159 mmol, 50% water wet), stirred for 1 h then purged the flask with nitrogen and filtered over Celite eluting with EtOAc. The filtrate was concentrated then purified by silica gel chromatography using a gradient from 100% hexanes to 100% EtOAc giving as a white foam, tert-butyl N-[(6R,12S)-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate (216 mg, 77%). ESI-MS m/z calc. 540.1807, found 541.2 (M+1) + ; Retention time: 0.61 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 4: (6R,12S)-17-Amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 14

To a stirring solution of tert-butyl N-[(6R,12S)-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate (216 mg, 0.3997 mmol) in dichloromethane (2.16 mL) was added TFA (769.6 μL, 9.989 mmol) and the resulting mixture was stirred at room temperature for 1 h then concentrated by rotary evaporation to a yellow residue. The residue was chromatographed on a 100 g reverse phase C 18 column eluting with a gradient from 50% to 100% acetonitrile in water giving as a pale yellow solid, (6R,12S)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (177.1 mg, 100%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.76 (s, 1H), 7.59 (s, 1H), 6.36 (s, 2H), 4.73 (dq, J=6.4, 3.1, 2.4 Hz, 1H), 2.56 (d, J=5.5 Hz, 1H), 2.22-2.04 (m, 2H), 1.74-1.64 (m, 1H), 1.59 (d, J=7.9 Hz, 2H), 1.54-1.43 (m, 3H), 1.34 (d, J=6.3 Hz, 3H), 1.22-1.10 (m, 1H) ppm. ESI-MS m/z calc. 440.1283, found 441.1 (M+1) + ; Retention time: 2.02 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Example 12: Preparation of 16-amino-12,12-dioxo-6,14-bis(trifluoromethyl)-18-oxa-12λ 6 -thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (enantiomer 1), Compound 15 and 16-amino-12,12-dioxo-6,14-bis(trifluoromethyl)-18-oxa-12λ 6 -thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (enantiomer 2), Compound 16

Step 1: tert-Butyl N-[2-[5-[1-benzyloxy-t-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-but-3-enylsulfonyl-5-(trifluoromethyl)-3-pyridyl]carbamate

A mixture of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (225 mg, 0.3530 mmol), but-3-ene-1-sulfinate (sodium salt) (150 mg, 1.055 mmol), and iodocopper (202 mg, 1.061 mmol) in DMSO (2.2 mL) was heated at 100° C. for 3 h, then diluted with ether and water, filtered through Celite, the layers partitioned and the organic layer washed with water, brine, dried (MgSO 4 ) and evaporated. Purification by silica gel chromatography (0-20% EtOAc in hexanes) provided tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-but-3-enylsulfonyl-5-(trifluoromethyl)-3-pyridyl]carbamate (99 mg, 41%). 1 H NMR (400 MHz, Chloroform-d) δ 10.36 (s, 1H), 9.56 (s, 1H), 7.41-7.28 (m, 5H), 5.91 (dt, J=17.0, 8.5 Hz, 1H), 5.74 (ddt, J=16.8, 10.2, 6.5 Hz, 1H), 5.32-5.17 (m, 2H), 5.10-5.04 (m, 1H), 5.02 (dq, J=10.2, 1.3 Hz, 1H), 4.83 (d, J=10.9 Hz, 1H), 4.67 (d, J=10.9 Hz, 1H), 3.80-3.60 (m, 2H), 3.29-3.14 (m, 2H), 2.65-2.56 (m, 2H), 1.54 (s, 9H) ppm; 19 F NMR (376 MHz, Chloroform-d) δ −58.49, −73.15 ppm. ESI-MS m/z calc. 676.179, found 677.2 (M+1) + ; Retention time: 0.87 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 1-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-[6-benzyloxy-12,12-dioxo-6,14-bis(trifluoromethyl)-18-oxa-12λ 6 -thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(16),2,4,8,13(17),14-hexaen-16-yl]carbamate (E/Z Mixture)

In a 3-neck round bottom flask, a solution of tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-but-3-enylsulfonyl-5-(trifluoromethyl)-3-pyridyl]carbamate (206 mg, 0.3045 mmol) in DCE (10 mL) was slowly added dropwise from an addition funnel over 45 min to a solution of dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (34 mg, 0.04634 mmol) in DCE (25 mL) heated at 70° C. with N 2 bubbling through the solution. The mixture was stirred at 70° C. with N 2 bubbling a further 90 min and then the solvent was evaporated. Purification by silica gel chromatography (0-20% EtOAc in hexanes) provided tert-butyl N-[6-benzyloxy-12,12-dioxo-6,14-bis (trifluoromethyl)-18-oxa-12λ 6 -thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(16),2,4,8,13(17),14-hexaen-16-yl]carbamate (E/Z mixture) (92 mg, 44%). 1 H NMR (400 MHz, Chloroform-d) δ 9.46 (s, 1H), 9.42 (s, 1H), 7.37-7.27 (m, 2H), 7.25-7.16 (m, 3H), 5.88-5.64 (m, 2H), 4.92 (d, J=11.6 Hz, 1H), 4.54 (d, J=11.6 Hz, 1H), 4.13-3.98 (m, 1H), 3.59 (dt, J=15.6, 5.9 Hz, 1H), 3.12 (dd, J=14.6, 4.8 Hz, 1H), 2.87-2.76 (m, 2H), 2.69-2.62 (m, 1H), 1.58 (s, 9H) ppm; 19 F NMR (376 MHz, Chloroform-d) δ −58.84, −74.24 ppm; UV/vis λ max 233, 268, 322 nm. ESI-MS m/z calc. 648.1477, found 649.1 (M+1) + ; Retention time: 0.83 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 1-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: tert-Butyl N-[6-hydroxy-12,12-dioxo-6,14-bis(trifluoromethyl)-18-oxa-12λ 6 -thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(16),2,4,13(17),14-pentaen-16-yl]carbamate

A mixture of tert-butyl N-[6-benzyloxy-12,12-dioxo-6,14-bis(trifluoromethyl)-18-oxa-12λ 6 -thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(16),2,4,8,13(17),14-hexaen-16-yl]carbamate (E/Z mixture) (90 mg, 0.1304 mmol) and Pd/C (42 mg of 10% w/w, 0.03947 mmol) in AcOH (850 μL) was stirred at room temperature under 180 psi H 2 in a stainless steel pressure vessel for 36 h. Then the mixture was filtered and the filtrate was evaporated to provide ter t-butyl N-[6-hydroxy-12,12-dioxo-6,14-bis(trifluoromethyl)-18-oxa-12λ 6 -thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(16),2,4,13(17),14-pentaen-16-yl]carbamate (81 mg, 102%). ESI-MS m/z calc. 560.1164, found 561.2 (M+1) + ; Retention time: 0.69 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 1-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.; UV/vis λ max 233, 268, 323 nm.

Step 4: 16-Amino-12,12-dioxo-6,14-bis(trifluoromethyl)-18-oxa-12λ 6 -thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (enantiomer 1) and 16-amino-12,12-dioxo-6,14-bis(trifluoromethyl)-18-oxa-12λ 6 -thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (enantiomer 2)

tert-Butyl N-[6-hydroxy-12,12-dioxo-6,14-bis(trifluoromethyl)-18-oxa-12λ 6 -thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(16),2,4,13(17),14-pentaen-16-yl]carbamate (81 mg, 0.13 mmol) was dissolved into TFA (1.27 mL), water (68 μL) and triisopropylsilane (40 μL, 0.1953 mmol), and stirred at room temperature for 15 min, then solvents evaporated. The residue was subjected to chiral separation by SFC chromatography using a ChiralPak AD (250×21.2 mm column, 5 μm particle size) with 5% to 30% methanol (5 mM NH 3 )/and carbon dioxide mobile phase at 10 mL/min over 10.0 min (injection volume=330 μL of 25 mg/mL solution in methanol) giving as the first enantiomer to elute 16-amino-12,12-dioxo-6,14-bis(trifluoromethyl)-18-oxa-12λ 6 -thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (16 mg, 27%) as a white crystalline solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.84 (s, 1H), 7.66 (s, 1H, D 2 O exchanged), 7.39 (s, 2H, D 2 O exchanged), 3.87-3.69 (m, 1H), 3.57-3.41 (m, 1H), 2.30-2.02 (m, 4H), 1.70 (m, 2H), 1.58-1.45 (m, 2H) ppm; 19 F NMR (376 MHz, DMSO-d 6 ) δ −58.27, −77.73; UV/vis λ max 230, 275, 353 nm. ESI-MS m/z calc. 460.064, found 461.0 (M+1) + ; Retention time: 1.04 minutes. Final purity was determined by reversed phase HPLC-MS using an Onyx Monolithic C 18 column (50×4.6 mm) sold by Phenomenex (pn: CH0-7644), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=12 mL/min, injection volume=50 μL, and column temperature=25° C.

The second enantiomer to elute was 16-amino-12,12-dioxo-6,14-bis(trifluoromethyl)-18-oxa-12λ 6 -thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (14.4 mg, 24%) as a white crystalline solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.84 (s, 1H), 7.66 (s, 1H, D 2 O exchanged), 7.39 (s, 2H, D 2 O exchanged), 3.84-3.70 (m, 1H), 3.55-3.43 (m, 1H), 2.31-2.00 (m, 4H), 1.70 (s, 2H), 1.56-1.45 (m, 2H) ppm; 19 F NMR (376 MHz, DMSO-d 6 ) δ −58.27, −77.73 ppm; UV/vis λ max 230, 275, 353 nm. ESI-MS m/z calc. 460.064, found 460.9 (M+1) + ; Retention time: 1.04 minutes. Final purity was determined by reversed phase HPLC-MS using an Onyx Monolithic C 18 column (50×4.6 mm) sold by Phenomenex (pn: CH0-7644), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=12 mL/min, injection volume=50 μL, and column temperature=25° C.

Example 13: Preparation of 21-amino-6,19-bis(trifluoromethyl)-17,23-dioxa-3,4,22-triazatetracyclo[16.3.1.12,5.011,16]tricosa-1(22),2,4,11(16),12,14,18,20-octaen-6-ol (hydrochloride salt), Compound 17

Step 1: Methyl 6-(2-allylphenoxy)-3-[bis(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)pyridine-2-carboxylate

To a solution of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (1.2 g, 2.403 mmol) in DMSO (12 mL) was added 2-allylphenol (380 μL, 2.911 mmol), cesium carbonate (2.43 g, 7.458 mmol) and iodocopper (100 mg, 0.5251 mmol) and the reaction mixture was heated at 100° C. for 30 min in an oil bath. LCMS shows completion of the reaction. The reaction mixture was poured on crushed ice and extracted with ethyl acetate and washed with brine. The organics were separated, dried over sodium sulfate, and evaporated. The resultant brown residue was purified by silica gel column chromatography using a gradient of 100% hexanes to 100% EtOAc to afford methyl 6-(2-allylphenoxy)-3-[bis(tert-butoxycarbonyl)amino]-5-(trifluoromethyppyridine-2-carboxylate (612 mg, 46%). 1 H NMR (400 MHz, Chloroform-d) δ 7.85 (s, 1H), 7.30-7.25 (m, 2H), 7.20 (t, J=7.6 Hz, 2H), 5.88 (ddt, J=16.8, 10.1, 6.6 Hz, 1H), 5.02-4.94 (m, 2H), 3.79 (s, 3H), 3.32 (d, J=6.7 Hz, 2H), 1.42 (s, 18H) ppm; ESI-MS m/z calc. 552.2083, found 453.1 (M+1) + ; Retention time: 0.75 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 30-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: 6-(2-Allylphenoxy)-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid

To a solution of methyl 6-(2-allylphenoxy)-34bis(tert-butoxycarbonyl)aminol-5-(trifluoromethyl)pyridine-2-carboxylate (612 mg, 1.108 mmol) in THF (8 mL), MeOH (8 mL), and water (8 mL) was added LiOH (86 mg, 3.591 mmol). The mixture was stirred at room temperature for 30 min.

THF and methanol were removed under reduced pressure and then 10 mL HCl (10%) was carefully added to pH ˜6 and the product was extracted by EtOAc (2×50 mL). The organic phases were combined, washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and placed under high vacuum for 12 hours to afford as a yellow solid 6-(2-allylphenoxy)-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (482 mg, 99%). ESI-MS m/z calc. 438.14026, found 439.13 (M+1) + ; Retention time: 0.69 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 30-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: tert-Butyl N-[6-(2-allylphenoxy)-2-[[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-5-(trifluoromethyl)-3-pyridyl]carbamate

To a solution of 6-(2-allylphenoxy)-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (394.8 mg, 0.9006 mmol) and 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (312.5 mg, 1.084 mmol) in DMF (5 mL) was added DIEA (527.0 μL, 3.026 mmol), followed by HATU (526.6 mg, 1.385 mmol). The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with water and extracted with ethyl acetate. The organic phases combined and dried over MgSO 4 , filtered, and concentrated in vacuo. The resultant brown residue was purified by silica gel column chromatography using a gradient of 100% hexanes to 30% EtOAc-hexanes to afford tert-butyl N-[6-(2-allylphenoxy)-2-[[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-5-(trifluoromethyl)-3-pyridyl]carbamate (543 mg, 85%). ESI-MS m/z calc. 708.2383, found 808.0 (M+1) + ; Retention time: 0.7 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 4: tert-Butyl N-[6-(2-allylphenoxy)-2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyl]carbamate

To a solution of tert-butyl N-[6-(2-allylphenoxy)-2-[[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamoyl]-5-(trifluoromethyl)-3-pyridyl]carbamate (630 mg, 0.8890 mmol) in acetonitrile (75 mL) was added DIEA (500 μL, 2.871 mmol) and was heated to 70° C., then 4-methylbenzenesulfonyl chloride (255 mg, 1.338 mmol) was added in 3 portions (85 mg each portion in 10 min intervals). The resulted mixture was heated at 70° C. for 16 hours. The reaction mixture was cooled and quenched with saturated solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo. The resultant brown residue was purified by silica gel column chromatography using a gradient from 100% hexanes to 30% EtOAc to afford tert-butyl N-[6-(2-allylphenoxy)-2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyl]carbamate (336 mg, 55%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.99 (s, 1H), 7.35-7.29 (m, 4H), 7.25 (m, 5H), 5.90-5.72 (m, 2H), 5.23-5.10 (m, 2H), 4.96-4.87 (m, 2H), 4.66 (d, J=10.9 Hz, 1H), 4.52 (d, J=10.9 Hz, 1H), 3.29 (dd, J=11.3, 6.8 Hz, 2H), 3.10 (d, J=7.1 Hz, 2H), 1.49 (s, 9H) ppm. ESI-MS m/z calc. 690.22766, found 691.3 (M+1) + ; Retention time: 0.81 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 5: tert-Butyl N-[6-(benzyloxy)-6,19-bis(trifluoromethyl)-17,23-dioxa-3,4,22-triazatetracyclo[16.3.1.12,5.011,16]tricosa-1(22),2,4,8,11(16),12,14,18,20-nonaen-21-yl]carbamate (E/Z Mixture)

To a degassed solution of benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-ruthenium;tricyclohexylphosphane (6 mg, 0.007067 mmol) (Grubbs-2nd Gen catalyst) in DCE (30 mL) was added degassed solution of tert-butyl N-[6-(2-allylphenoxy)-2-[5-[1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyl]carbamate (212 mg, 0.3070 mmol) in DCE (30 mL) slowly dropwise under a stream of N 2 flow bubbling through the solution over 30 min and the reaction mixture was heated at 50° C. for 5 h. The temperature was increased to 70° C. and the reaction mixture was heated overnight. The reaction was stopped, and the solvents removed in vacuo. The resultant brown residue was purified by silica gel column chromatography using a shallow gradient of 100% hexanes to 30% EtOAc-hexanes to afford tert-butyl N-[6-(benzyloxy)-6,19-bis(trifluoromethyl)-17,23-dioxa-3,4,22-triazatetracyclo[16.3.1.12,5.011,16]tricosa-1(22),2,4,8,11(16),12,14,18,20-nonaen-21-yl]carbamate (E/Z mixture) (126 mg, 62%). ESI-MS m/z calc. 662.1964, found 663.19 (M+1) + ; Retention time: 0.74 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 6: tert-Butyl N-[6-hydroxy-6,19-bis(trifluoromethyl)-17,23-dioxa-3,4,22-triazatetracyclo[16.3.1.12,5.011,16]tricosa-1(22),2,4,11(16),12,14,18,20-octaen-21-yl]carbamate

To a solution of a 1:1 isomeric mixture of tert-butyl N-[6-(benzyloxy)-6,19-bis(trifluoromethyl)-17,23-dioxa-3,4,22-triazatetracyclo[16.3.1.12,5.011,16]tricosa-1(22),2,4,8,11(16),12,14,18,20-nonaen-21-yl]carbamate (E/Z mixture) (120 mg, 0.1811 mmol) and tert-butyl N-[6-(2-allylphenoxy)-2-[5-[1-hydroxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyl]carbamate (120 mg, 0.1998 mmol) in AcOH (5 mL) was added Pd/C (42 mg of 10% w/w, 0.03947 mmol) in a round-bottomed flask equipped with a H 2 balloon using a 3-way adaptor. Subjected to vacuum and backfilled with nitrogen gas three times then subjected to vacuum. Filled the flask with hydrogen gas then stirred the mixture for 15 hours. Subjected to vacuum and backfilled with nitrogen gas three times then diluted with ethyl acetate and filtered over Celite. Filtrate was concentrated and dried under high vacuum. The resultant brown residue was purified by silica gel column chromatography using a shallow gradient of 100% hexanes to 30% EtOAc-hexanes to afford tert-butyl N-[6-hydroxy-6,19-bis(trifluoromethyl)-17,23-dioxa-3,4,22-triazatetracyclo[16.3.1.12,5.011,16]tricosa-1(22),2,4,11(16),12,14,18,20-octaen-21-yl]carbamate (14.2 mg, 27%); ESI-MS m/z calc. 574.1651, found 575.2 (M+1) + ; Retention time: 1.31 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 50-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 7: 21-Amino-6,19-bis(trifluoromethyl)-17,23-dioxa-3,4,22-triazatetracyclo[16.3.1.12,5.011,16]tricosa-1(22),2,4,11(16),12,14,18,20-octaen-6-ol (hydrochloride salt), Compound 17

To a solution of tert-butyl N-[6-hydroxy-6,19-bis(trifluoromethyl)-17,23-dioxa-3,4,22-triazatetracyclo[16.3.1.12,5.011,16]tricosa-1(22),2,4,11(16),12,14,18,20-octaen-21-yl]carbamate (13 mg, 0.02263 mmol) was added TFA (100 μL, 1.298 mmol) and DCM (400 μL) (pre made solution of 1:4 TFA-DCM) and the reaction was stirred at room temperature for about 1 h. LCMS shows the completion of reaction. Solvents were removed and dissolved in DMSO (1 mL) and the residue was purified by a reverse phase HPLC-MS method using a dual gradient run from 50-99% mobile phase B over 15.0 minutes (mobile phase A=H 2 O (5 mM HCl); mobile phase B=CH 3 CN) to afford 21-amino-6,19-bis(trifluoromethyl)-17,23-dioxa-3,4,22-triazatetracyclo[16.3.1.12,5.011,16]tricosa-1(22),2,4,11(16),12,14,18,20-octaen-6-ol (Hydrochloride salt) (2.6 mg, 22%) as an off-white amorphous solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.49 (s, 1H), 7.35-7.33 (m, 1H), 7.21-7.14 (m, 3H), 5.36 (s, 2H), 3.63 (s, 1H), 3.06-2.89 (m, 2H), 2.29 (m, 1H), 2.22-2.14 (m, 1H), 2.13-2.05 (m, 2H), 1.92 (d, J=5.2 Hz, 2H) ppm. ESI-MS m/z calc. 474.11267, found 475.13 (M+1) + ; Retention time: 2.76 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=CH 3 CN (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Example 14: Preparation of (15R)-20-amino-8-fluoro-15-methyl-6,18-bis(trifluoromethyl)-16,23-dioxa-3,4,21-triazatetracyclo[15.3.1.12,5.17,11]tricosa-1(21),2,4,7(22),8,10,17,19-octaen-6-ol (diastereomer pair), Compound 18

Step 1: 3-[bis(tert-Butoxycarbonyl)amino]-6-[(1R)-1-methylbut-3-enoxy]-5-(trifluoromethyl)pyridine-2-carboxylic acid

To a solution of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (500 mg, 1.001 mmol) in DMSO (2 mL) was added (2R)-pent-4-en-2-ol (160 μL, 1.555 mmol), cesium carbonate (504 mg, 1.547 mmol) and iodocopper (47 mg, 0.2468 mmol) and the reaction mixture was heated at 100° C. for 3 h. The reaction mixture was cooled to RT and poured on crushed ice and extracted with ethyl acetate and washed with brine. The organics were separated, dried over sodium sulfate, and evaporated. The resultant brown residue was purified by silica gel column chromatography using 100% hexanes to 30% EtOAc-hexanes to afford 3-[bis(tert-butoxycarbonyl)amino]-6-[(1R)-1-methylbut-3-enoxy]-5-(trifluoromethyl)pyridine-2-carboxylic acid (64 mg, 26%). 1 H NMR (400 MHz, Chloroform-d) δ 10.17 (s, 1H), 7.63 (s, 1H), 5.73 (ddt, J=17.2, 10.2, 7.1 Hz, 1H), 5.20 (p, J=6.4 Hz, 1H), 5.17-5.07 (m, 2H), 2.48 (dt, J=13.5, 6.6 Hz, 1H), 2.37 (dt, J=14.1, 6.9 Hz, 1H), 1.45 (d, J=3.0 Hz, 18H), 1.34 (d, J=6.3 Hz, 3H) ppm. ESI-MS m/z calc. 490.1927, found 391.2 (M-Boc) + . Retention time: 0.5 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 30-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[6-[(1R)-1-methylbut-3-enoxy]-2-[5-[2,2,2-trifluoro-1-(2-fluoro-5-iodo-phenyl)-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyl]carbamate

To a pre-heated at 50° C. stirred solution of 3-[bis(tert-butoxycarbonyl)amino]-6-[(1R)-1-methylbut-3-enoxy]-5-(trifluoromethyl)pyridine-2-carboxylic acid (120 mg, 0.2447 mmol) and 2,2,2-trifluoro-1-(2-fluoro-5-iodo-phenyl)ethanone (121 mg, 0.3805 mmol) in DMF (2 mL) was added (isocyanoimino)triphenylphosphorane (113 mg, 0.3738 mmol) at once. The mixture was stirred at room temperature overnight then it was diluted with EtOAc (50 mL), washed with water and brine consecutively, then dried over sodium sulfate and filtered. The filtrate was concentrated to dryness. The resultant brown residue was purified by silica gel column chromatography using 100% hexanes to 50% EtOAc-hexanes to provide a light brown viscous oil, tert-butyl N-tert-butoxycarbonyl-N-[6-[(1R)-1-methylbut-3-enoxy]-2-[5-[2,2,2-trifluoro-1-(2-fluoro-5-iodo-phenyl)-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyl]carbamate (103 mg, 51%). 1 H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J=2.2 Hz, 1H), 7.81 (s, 1H), 7.76 (ddd, J=8.6, 4.6, 2.2 Hz, 1H), 6.83 (ddd, J=10.4, 8.7, 1.2 Hz, 1H), 5.79 (ddtd, J=17.4, 10.9, 7.1, 4.0 Hz, 1H), 5.38 (hept, J=6.2 Hz, 1H), 5.14-5.01 (m, 2H), 4.84 (d, J=3.9 Hz, 1H), 2.53 (dtd, J=13.7, 6.7, 2.9 Hz, 1H), 2.42 (dt, J=13.7, 6.7 Hz, 1H), 1.66 (s, 3H), 1.38 (dd, J=4.1, 2.1 Hz, 18H) ppm. ESI-MS m/z calc. 832.12036, found 733.1 (M-Boc) + . Retention time: 0.79 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 30-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: tert-Butyl N-[(15R)-8-fluoro-6-hydroxy-15-methyl-6,18-bis(trifluoromethyl)-16,23-dioxa-3,4,21-triazatetracyclo[15.3.1.12,5.17,11]tricosa-1(21),2,4,7(22),8,10,12,17,19-nonaen-20-yl]carbamate (E/Z mixture)

To a stirred solution of tert-butyl N-tert-butoxycarbonyl-N-[6-[(1R)-1-methylbut-3-enoxy]-2-[5-[2,2,2-trifluoro-1-(2-fluoro-5-iodo-phenyl)-1-hydroxy-ethyl]-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)-3-pyridyl]carbamate (100 mg, 0.1201 mmol) in acetonitrile (10 mL) was added Palladium (II) acetate (8 mg, 0.03563 mmol) followed by tris-o-tolylphosphane (21 mg, 0.06900 mmol) and triethylamine (60 μL, 0.4305 mmol) and the solution was bubbled with N 2 for 1 min then heated by microwave irradiation at 120° C. for 0.5 h. The mixture was cooled to room temperature then diluted with EtOAc and washed with saturated aqueous NH 4 Cl (1×) and brine (1×) then dried over sodium sulfate, filtered and concentrated to a yellow oil. The resulting material was dissolved in DMSO, filtered and purified using a reverse phase HPLC-MS method using a Luna C 18 column (75×30 mm, 5 μm particle size) sold by Phenomenex (pn: 00C-4252-U0-AX), and a dual gradient run from 50-99% mobile phase B over 15.0 minutes (mobile phase A=H 2 O (5 mM HCl), mobile phase B=acetonitrile, flow rate=50 mL/min, injection volume=950 μL and column temperature=25° C. giving a yellow solid, tert-butyl N-[(15R)-8-fluoro-6-hydroxy-15-methyl-6,18-bis(trifluoromethyl)-16,23-dioxa-3,4,21-triazatetracyclo[15.3.1.12,5.17,1 l]tricosa-1(21),2,4,7(22),8,10,12,17,19-nonaen-20-yl]carbamate (E/Z mixture) (21 mg, 29%). ESI-MS m/z calc. 604.15564, found 605.03 (M+1) + ; Retention time: 0.55 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 4: (15R)-20-Amino-8-fluoro-15-methyl-6,18-bis(trifluoromethyl)-16,23-dioxa-3,4,21-triazatetracyclo[15.3.1.12,5.17,11]tricosa-1(21),2,4,7(22),8,10,17,19-octaen-6-ol (diastereomer pair), Compound 18

Part 1: To a solution of tert-butyl N-[(15R)-8-fluoro-6-hydroxy-15-methyl-6,18-bis(trifluoromethyl)-16,23-dioxa-3,4,21-triazatetracyclo[15.3.1.12,5.17,11]tricosa-1(21),2,4,7(22),8,10,12,17,19-nonaen-20-yl]carbamate (E/Z mixture) (20 mg, 0.03309 mmol) in ethanol (2 mL) was added Pd/C (18 mg of 10% w/w, 0.01691 mmol) in a round bottom flask equipped with a H 2 balloon using a 3-way adaptor. The mixture was subjected to vacuum and backfilled with nitrogen gas three times then subjected to vacuum. The flask was filled with hydrogen gas then stirred the mixture for 15 hours. The mixture was subjected to vacuum and backfilled with nitrogen gas three times then diluted with ethyl acetate and filtered over Celite. The filtrate was concentrated and dried under high vacuum.

Part 2: The material from Step 1 was dissolved in TFA (100 μL, 1.298 mmol) and DCM (400 μL) (pre-made solution of 1: 4 TFA-DCM) and the reaction was stirred at room temperature for about 1 h. Solvents were removed and dissolved in DMSO (1 mL) and the residue was purified by a reverse phase HPLC-MS method using a dual gradient run from 30-99% mobile phase B over 15.0 minutes using a mobile phase A=H 2 O (5 mM HCl) and a mobile phase B=acetonitrile to afford (15R)-20-amino-8-fluoro-15-methyl-6,18-bis(trifluoromethyl)-16,23-dioxa-3,4,21-triazatetracyclo[15.3.1.12,5.17,11]tricosa-1(21),2,4,7(22),8,10,17,19-octaen-6-ol (2 mg, 12%) as diastereomeric mixture. ESI-MS m/z calc. 506.1189, found 507.1 (M+1) + ; Retention time: 2.93 minutes; Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 4.5 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Example 15: Preparation of (6R,13S)-17-Amino-13-oxido-6,15-bis(trifluoromethyl)-19-oxa-13-thionia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 19, and (6R,13R)-17-amino-13-oxido-6,15-bis(trifluoromethyl)-19-oxa-13-thionia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 20

Step 1: (6R,13S)-17-Amino-13-oxido-6,15-bis(trifluoromethyl)-19-oxa-13-thionia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 19, and (6R,13R)-17-amino-13-oxido-6,15-bis(trifluoromethyl)-19-oxa-13-thionia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 20

To a solution of (6R)-17-amino-6,15-bis(trifluoromethyl)-19-oxa-13-thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (56 mg, 0.127 mmol) in EtOAc (1.5 mL) cooled by ice bath was added 3-chlorobenzenecarboperoxoic acid (802 μL of 0.11 M, 0.088 mmol) as a solution in EtOAc and the mixture stirred at 0° C. for 15 min. Then 3-chlorobenzenecarboperoxoic acid (227 μL of 0.11 M, 0.025 mmol) as a solution in EtOAc was added and the mixture was stirred at 0° C. for 15 additional minutes. Then more 3-chlorobenzenecarboperoxoic acid (85 μL of 0.11 M, 0.0094 mmol) as a solution in EtOAc was added and the mixture stirred at 0° C. for 15 min. Then the mixture was diluted with EtOAc (30 mL) and MeOH (1 mL) and washed with 5% Na 2 S 2 O 3 , 1 M NaHCO 3 , dried (MgSO 4 ) and evaporated. The residue was purified by silica gel chromatography (12 g SiO 2 , 10-50% of a solution (10% MeOH in EtOAc) to hexanes over 20 min) eluted first 2.3 mgs (4%) of recovered starting material (6R)-17-amino-6,15-bis(trifluoromethyl)-19-oxa-13-thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol. Continued elution provided (6R,13R)-17-amino-13-oxido-6,15-bis(trifluoromethyl)-19-oxa-13-thionia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (2.6 mg, 4%). Continued elution provided (6R,13S)-17-amino-13-oxido-6,15-bis(trifluoromethyl)-19-oxa-13-thionia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and then a mixture of (6R,13S)-17-amino-13-oxido-6,15-bis(trifluoromethyl)-19-oxa-13-thionia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and (6R,13R)-17-amino-13-oxido-6,15-bis(trifluoromethyl)-19-oxa-13-thionia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol.

The mixture of (6R,13S)-17-amino-13-oxido-6,15-bis(trifluoromethyl)-19-oxa-13-thionia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and (6R,13R)-17-amino-13-oxido-6,15-bis(trifluoromethyl)-19-oxa-13-thionia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol was dissolved in 1:1 MeOH/acetonitrile and subjected to preparative HPLC eluting with 30-70% acetonitrile vs 5 mM HCl in water at 50 mL/min over 14 min through a Luna 5 μM C 18 100μ 75×30 mm column to provide the first eluent as a white solid (6R,13R)-17-amino-13-oxido-6,15-bis(trifluoromethyl)-19-oxa-13-thionia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (18 mg, 31%): 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.82 (s, 1H), 3.80 (td, J=12.5, 5.1 Hz, 1H), 3.15 (td, J=12.4, 3.8 Hz, 1H), 2.37 (td, J=13.0, 11.5, 3.3 Hz, 1H), 2.29-2.17 (m, 1H), 2.09-1.97 (m, 1H), 1.95-1.84 (m, 1H), 1.83-1.65 (m, 4H), 1.59 (t, J=8.6 Hz, 2H) ppm; 19 F NMR (376 MHz, Methanol-d 4 ) δ −60.52, −80.84 ppm; ESI-MS m/z calc. 458.08472, found 459.1 (M+1) + ; Retention time: 0.94 minutes. Final purity was determined by reversed phase HPLC-MS using an Onyx Monolithic C 18 column (50×4.6 mm) sold by Phenomenex (pn: CH0-7644), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=12 mL/min, injection volume=50 μL, and column temperature=25° C. Continued elution provided second eluent (6R,13S)-17-amino-13-oxido-6,15-bis(trifluoromethyl)-19-oxa-13-thionia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (19 mg, 33%): 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.81 (s, 1H), 3.75 (td, J=12.7, 4.0 Hz, 1H), 3.28-3.17 (m, 1H), 2.48-2.27 (m, 3H), 2.25-2.11 (m, 1H), 1.72 (dddd, J=32.5, 20.0, 13.7, 8.0 Hz, 6H) ppm; 19 F NMR (376 MHz, Methanol-d 4 ) δ −60.41, −80.81; ESI-MS m/z calc. 458.08472, found 459.0 (M+1) + ; Retention time: 1.09 minutes. Final purity was determined by reversed phase HPLC-MS using an Onyx Monolithic C 18 column (50×4.6 mm) sold by Phenomenex (pn: CH0-7644), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=12 mL/min, injection volume=50 μL, and column temperature=25° C.

Compound 19 (15 mg) was dissolved in 0.45 mL of methanol. The solution was allowed to sit at room temperature for 2 hours. Cubes with slightly opaque faces formed.

Single crystals of crystalline Compound 19 (neat form) were grown by slow cooling a methanol solution from 80° C. to 25° C. X-ray diffraction data were acquired at 100 K on a Bruker diffractometer equipped with Mo K α radiation (λ=0.71073 Å) and a CCD detector. The structure was solved and refined using SHELX programs (Sheldrick, G. M., Acta Cryst., (2008) A64, 112-122). The results are summarized in Table 10 below.

Compound 20 (10 mg) was dissolved in 0.3 mL of methanol. The solution was heated, then cooled to room temperature over 2 hours. Clear rectangular prisms were obtained.

Single crystals crystalline Compound 20 (neat form) were grown by slow cooling of a methanol solution. X-ray diffraction data were acquired at 100 K on a Bruker diffractometer equipped with Mo K α radiation (λ=0.71073 Å) and a CCD detector. The structure was solved and refined using SHELX programs (Sheldrick, G. M., Acta Cryst., (2008) A64, 112-122) and results are summarized in Table 11 below.

Example 16: (6R)-17-Amino-6,15-bis(trifluoromethyl)-19-oxa-13-thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 21

A mixture of 1-methyl-4-sulfidosulfonyl-benzene (potassium salt) (2000 mg, 8.836 mmol), and 4-iodobut-1-ene (913 μL, 8.026 mmol) in DMF (20 mL) was stirred at 60° C. for 30 min, then diluted with ether and washed with water (2×) and brine, dried (MgSO 4 ) and evaporated. The residue was purified by silica gel chromatography (0-15% EtOAc in hexanes over 15 min) to provide 1-but-3-enylsulfanylsulfonyl-4-methyl-benzene (1.516 g, 78%). 1 H NMR (400 MHz, Chloroform-d) δ 7.87-7.78 (m, 2H), 7.35 (d, J=8.0 Hz, 2H), 5.68 (ddt, J=17.0, 10.4, 6.7 Hz, 1H), 5.06-4.98 (m, 2H), 3.05 (t, J=7.3 Hz, 2H), 2.46 (s, 3H), 2.40-2.29 (m, 2H) ppm. ESI-MS m/z calc. 242.04352, Retention time: 0.6 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 1-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-but-3-enylsulfanyl-5-(trifluoromethyl)-3-pyridyl]carbamate

To tert-butyl N-[2-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (57 mg, 0.08750 mmol) in ether (1.15 mL) at −78° C. was added n-BuLi (76 μL of 2.5 M, 0.1900 mmol) as a solution in hexanes and the mixture stirred at −78° C. for 15 min, then a solution of 1-but-3-enylsulfanylsulfonyl-4-methyl-benzene (28 mg, 0.1155 mmol) in ether (285 μL) was added dropwise. The mixture was stirred at −78° C. for 15 min and at 0° C. for 15 min. The mixture was diluted with 1 M NH 4 Cl in water and ether then partitioned. The organic layer was separated and washed with 1 M NaHCO 3 , dried (MgSO 4 ) and evaporated. The residue was purified by silica gel chromatography (0-10% EtOAc in hexanes over 15 min) provided tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-but-3-enylsulfanyl-5-(trifluoromethyl)-3-pyridyl]carbamate (33 mg, 57%). 1 H NMR (400 MHz, Chloroform-d) δ 9.95 (s, 1H), 9.18 (s, 1H), 7.45-7.28 (m, 5H), 5.94-5.65 (m, 2H), 5.13-4.97 (m, 4H), 4.84 (d, J=10.8 Hz, 1H), 4.68 (d, J=10.9 Hz, 1H), 3.36-3.27 (m, 2H), 2.62-2.16 (m, 6H), 1.56 (s, 9H) ppm; 19 F NMR (376 MHz, Chloroform-d) δ −63.55, −72.90 ppm. ESI-MS m/z calc. 658.20483, found 659.3 (M+1) + ; Retention time: 2.09 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 50-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: tert-Butyl N-[(6R)-6-benzyloxy-6,15-bis(trifluoromethyl)-19-oxa-13-thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]carbamate (E/Z Mixture)

A solution of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-6-but-3-enylsulfanyl-5-(trifluoromethyl)-3-pyridyl]carbamate (209 mg, 0.3173 mmol) in DCE (15 mL) was dropwise added to a 80° C. preheated solution of benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-ruthenium;tricyclohexylphosphane (40 mg, 0.04712 mmol) in DCE (15 mL) and the resulting mixture heated at 80° C. for 45 min. Then the solvent was evaporated. The residue was purified by silica gel chromatography (0-5% EtOAc in hexanes over 15 min) to provide tert-butyl N-[(6R)-6-benzyloxy-6,15-bis(trifluoromethyl)-19-oxa-13-thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,9,14(18),15-hexaen-17-yl]carbamate (E/Z mixture) (158 mg, 79%). ESI-MS m/z calc. 630.1735, found 631.2 (M+1) + ; Retention time: 0.67 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 4: tert-Butyl N-[(6R)-6-benzyloxy-6,15-bis(trifluoromethyl)-19-oxa-13-thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]carbamate

A mixture of tert-butyl N-[(6R)-6-benzyloxy-6,15-bis(trifluoromethyl)-19-oxa-13-thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,9,14(18),15-hexaen-17-yl]carbamate (E/Z mixture) (158 mg, 0.2506 mmol) and Pd/C (50 mg of 10% w/w, 0.04698 mmol) in EtOAc (800 μL) and MeOH (800 μL) was stirred at room temperature under 200 psi H 2 in a stainless steel pressure vessel for 23 h. Then the mixture was filtered and the filtrate evaporated to provide tert-butyl N-[(6R)-6-benzyloxy-6,15-bis(trifluoromethyl)-19-oxa-13-thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-17-yl]carbamate (160 mg, 100%). 1 H NMR (400 MHz, Chloroform-d) δ 9.70 (s, 1H), 9.14 (s, 1H), 7.33-7.22 (m, 5H), 4.86 (d, J=11.2 Hz, 1H), 4.79 (d, J=11.2 Hz, 1H), 3.06 (ddt, J=13.8, 9.5, 4.8 Hz, 2H), 2.44 (dt, J=15.8, 8.5 Hz, 1H), 2.27 (dt, J=14.5, 7.0 Hz, 1H), 2.04 (s, 1H), 1.97-1.84 (m, 1H), 1.78 (dq, J=13.7, 6.7 Hz, 2H), 1.64 (dt, J=12.8, 6.7 Hz, 1H), 1.59-1.51 (m, 13H) ppm; 19 F NMR (376 MHz, Chloroform-d) δ −63.64, −74.38 ppm. ESI-MS m/z calc. 632.1892, found 633.3 (M+1) + ; Retention time: 0.7 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 5: (6R)-17-Amino-6,15-bis(trifluoromethyl)-19-oxa-13-thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, Compound 21

To a solution of tert-butyl N-[(6R)-6-benzyloxy-6,15-bis(trifluoromethyl)-19-oxa-13-thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(17),2,4,14(18),15-pentaen-17-yl]carbamate (57 mg, 0.090 mmol) in DCM (2 mL) at 0° C. was added BCl 3 (2 mL of 1 M, 2.00 mmol) as a solution in DCM and the mixture stirred at room temperature for 22 h. Then the mixture was evaporated, and the residue dissolved in EtOAc (70 mL) and methanol (0.5 mL) and washed with 1 M NaHCO 3 , brine, dried (MgSO 4 ) and evaporated. The residue was purified by silica gel chromatography (0-25% EtOAc in hexanes over 15 min) to provide (6R)-17-amino-6,15-bis(trifluoromethyl)-19-oxa-13-thia-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (61 mg, 62%). 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.62 (s, 1H), 3.16 (ddd, J=13.7, 12.1, 4.2 Hz, 1H), 2.97 (td, J=13.2, 4.1 Hz, 1H), 2.35 (ddd, J=14.4, 11.2, 3.3 Hz, 1H), 2.20 (dddt, J=19.8, 14.3, 10.6, 5.1 Hz, 2H), 1.83-1.50 (m, 7H) ppm; 19 F NMR (376 MHz, Methanol-d 4 ) δ −64.96, −80.84 ppm. ESI-MS m/z calc. 442.0898, found 443.0 (M+1) + ; Retention time: 1.61 minutes. Final purity was determined by reversed phase HPLC-MS using an Onyx Monolithic C 18 column (50×4.6 mm) sold by Phenomenex (pn: CH0-7644), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=12 mL/min, injection volume=50 μL, and column temperature=25° C.

Example 17: (6R)-16-amino-6,14-bis(trifluoromethyl)-18-oxa-12-thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol, Compound 22

Step 1: tert-Butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-but-3-enylsulfanyl-5-(trifluoromethyl)-3-pyridyl]carbamate

To tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-bromo-5-(trifluoromethyl)-3-pyridyl]carbamate (96 mg, 0.1506 mmol) in ether (1.8 mL) at −78° C. was added n-BuLi (130 μL, of 2.5 M, 0.3250 mmol) as a solution in hexanes, then a solution of 1-but-3-enylsulfanylsulfonyl-4-methyl-benzene (48 mg, 0.1981 mmol) in ether (500 μL) was added dropwise. The mixture was stirred at −78° C. for 15 min and at 0° C. for 15 min. The mixture was diluted with 1 M NH 4 Cl in water and ether then partitioned. The organic layer was separated and washed with 1 M NaHCO 3 , dried (MgSO 4 ) and evaporated. The residue was purified by silica gel chromatography (0-5% EtOAc in hexanes over 15 min) to provide tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-but-3-enylsulfanyl-5-(trifluoromethyl)-3-pyridyl]carbamate (42 mg, 43%). 1 H NMR (400 MHz, Chloroform-d) δ 9.94 (s, 1H), 9.17 (s, 1H), 7.40-7.28 (m, 5H), 6.09-5.76 (m, 2H), 5.25 (dd, J=17.0, 1.5 Hz, 1H), 5.22-5.18 (m, 1H), 5.07 (dd, J=17.2, 1.7 Hz, 1H), 5.01 (dd, J=10.2, 1.6 Hz, 1H), 4.83 (d, J=10.9 Hz, 1H), 4.68 (d, J=10.8 Hz, 1H), 3.31 (td, J=7.1, 2.8 Hz, 2H), 3.21 (t, J=6.4 Hz, 2H), 2.48 (q, J=7.0 Hz, 2H), 1.56 (s, 9H) ppm; 19 F NMR (376 MHz, Chloroform-d) δ −63.56, −73.16 ppm. ESI-MS m/z calc. 644.1892, found 645.2 (M+1) + ; Retention time: 0.7 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: tert-Butyl N-[(6R)-6-benzyloxy-6,14-bis(trifluoromethyl)-18-oxa-12-thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,8,13,15-hexaen-16-yl]carbamate (E/Z Mixture)

A solution of tert-butyl N-[2-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-6-but-3-enylsulfanyl-5-(trifluoromethyl)-3-pyridyl]carbamate (140 mg, 0.2172 mmol) in toluene (10 mL) was added dropwise to a 120° C. preheated solution of 1,3-bis(o-tolyl)-4,5-dihydroimidazole;dichloro-[(2-isopropoxyphenyl)methylene]ruthenium (19 mg, 0.03330 mmol) in toluene (10 mL) and the mixture heated at 120° C. for 45 min. Then more 1,3-bis(o-tolyl)-4,5-dihydroimidazole;dichloro-[(2-isopropoxyphenyl)methylene]ruthenium (12 mg, 0.02103 mmol) was added and heating continued at 120° C. for 55 min and this process was carried out one more time precisely. Then more 1,3-bis(o-tolyl)-4,5-dihydroimidazole;dichloro-[(2-isopropoxyphenyl)methylene]ruthenium (2.7 mg, 0.004733 mmol) was added and heating at 120° C. continued for 60 min and this process was carried out two more times precisely. The solvent was evaporated and the residue purified by silica gel chromatography (12 g SiO 2 , 0-30% of a solution of 10% EtOAc in hexanes from 100% hexanes over 20 min) to provide tert-butyl N-[(6R)-6-benzyloxy-6,14-bis(trifluoromethyl)-18-oxa-12-thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(16),2,4,8,13(17),14-hexaen-16-yl]carbamate (E/Z mixture) (20 mg, 13%). ESI-MS m/z calc. 616.1579, found 617.1 (M+1) + ; Retention time: 0.62 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: tert-Butyl N-[(6R)-6-benzyloxy-6,14-bis(trifluoromethyl)-18-oxa-12-thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-16-yl]carbamate

A mixture of tert-butyl N-[(6R)-6-benzyloxy-6,14-bis(trifluoromethyl)-18-oxa-12-thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(16),2,4,8,13(17),14-hexaen-16-yl]carbamate (E/Z mixture) (24 mg, 0.03309 mmol), and palladium on carbon (11 mg of 10% w/w, 0.01034 mmol) in EtOAc (300 μL) and MeOH (300 μL) was stirred at room temperature under 200 psi H 2 for 40 h, filtered and solvent evaporated. The residue was purified by silica gel chromatography (0-30% of a solution of 10% EtOAc in hexanes from 100% hexanes over 18 min) to provide tert-butyl N-[(6R)-6-benzyloxy-6,14-bis(trifluoromethyl)-18-oxa-12-thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(16),2,4,13(17),14-pentaen-16-yl]carbamate (16 mg, 78%). ESI-MS m/z calc. 618.1735, found 619.2 (M+1) + ; Retention time: 0.64 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 4: (6R)-16-Amino-6,14-bis(trifluoromethyl)-18-oxa-12-thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol, Compound 22

To a solution of tert-butyl N-[(6R)-6-benzyloxy-6,14-bis(trifluoromethyl)-18-oxa-12-thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(16),2,4,13(17),14-pentaen-16-yl]carbamate (16 mg, 0.02587 mmol) in DCM (160 μL) at 0° C. was added BCl 3 (520 μL of 1 M, 0.5200 mmol) as a solution in DCM and the mixture stirred at room temperature for 24 h. Then the mixture was evaporated and the residue dissolved in EtOAc (20 mL) and methanol (2 mL) and washed with 1 M NaHCO 3 , brine, dried (MgSO 4 ) and evaporated. The residue was purified by silica gel chromatography (5-25% EtOAc in hexanes over 15 min) to provide (6R)-16-amino-6,14-bis(trifluoromethyl)-18-oxa-12-thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (4.5 mg, 41%). 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.47 (s, 1H), 3.05 (td, J=13.1, 4.3 Hz, 1H), 2.87 (td, J=13.6, 13.1, 4.5 Hz, 1H), 2.25-2.00 (m, 3H), 1.91-1.84 (m, 1H), 1.79 (dq, J=10.9, 6.3, 5.9 Hz, 2H), 1.50 (p, J=5.5 Hz, 2H) ppm; 19 F NMR (376 MHz, Methanol-d 4 ) δ −64.87, −80.28 ppm. ESI-MS m/z calc. 428.07416, found 429.0 (M+1) + ; Retention time: 1.49 minutes. Final purity was determined by reversed phase HPLC-MS using an Onyx Monolithic C 18 column (50×4.6 mm) sold by Phenomenex (pn: CH0-7644), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=12 mL/min, injection volume=50 μL, and column temperature=25° C.

Example 18: Preparation of (6R)-16-amino-12-oxido-6,14-bis(trifluoromethyl)-18-oxa-12-thionia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (enantiomer 1), Compound 23, and (6R)-16-amino-12-oxido-6,14-bis(trifluoromethyl)-18-oxa-12-thionia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (enantiomer 2), Compound 24

Step 1: (6R)-16-Amino-12-oxido-6,14-bis(trifluoromethyl)-18-oxa-12-thionia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (enantiomer 1), Compound 23, and (6R)-16-amino-12-oxido-6,14-bis(trifluoromethyl)-18-oxa-12-thionia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (enantiomer 2), Compound 24

To a solution of (6R)-16-amino-6,14-bis(trifluoromethyl)-18-oxa-12-thia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (3.7 mg, 0.0086 mmol) in EtOAc (222.0 μL) cooled by ice bath was added 3-chlorobenzenecarboperoxoic acid (44 μL of 0.11 M, 0.0048 mmol) as a solution in EtOAc and the mixture stirred at 0° C. for 15 min. Then 3-chlorobenzenecarboperoxoic acid (20 μL of 0.11 M, 0.0022 mmol) as a solution in EtOAc was added and the mixture stirred at 0° C. for 15 additional minutes. Then more 3-chlorobenzenecarboperoxoic acid (8 μL of 0.11 M, 0.00088 mmol) as a solution in EtOAc was added with the mixture stirred at 0° C. for 15 min. Then the mixture was diluted with EtOAc (30 mL) and MeOH (1 mL) and washed with 5% Na 2 S 2 O 3 , 1 M NaHCO 3 , dried (MgSO 4 ) and evaporated. The mixture residue was dissolved into 1:1 MeOH/acetonitrile and subjected to preparative HPLC eluting with 30-99% acetonitrile vs 5 mM HCl in water at 50 mL/min over 14 min through a Luna 5 μM C 18 100 Å 75×30 mm column to provide first eluting isomer as a white solid (6R)-16-amino-12-oxido-6,14-bis(trifluoromethyl)-18-oxa-12-thionia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (enantiomer 1) (2 mg, 52%). 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.77 (s, 1H), 3.83 (ddd, J=13.1, 11.3, 5.5 Hz, 1H), 3.06 (ddd, J=13.2, 11.1, 3.8 Hz, 1H), 2.38 (dt, J=15.3, 7.8 Hz, 2H), 2.14-2.04 (m, 1H), 2.01-1.87 (m, 3H), 1.85-1.67 (m, 2H) ppm; 19 F NMR (376 MHz, Methanol-d 4 ) δ −60.67, −80.30 ppm. ESI-MS m/z calc. 444.0691, found 445.0 (M+1) + ; Retention time: 1.0 minutes. Final purity was determined by reversed phase HPLC-MS using an Onyx Monolithic C 18 column (50×4.6 mm) sold by Phenomenex (pn: CH0-7644), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=12 mL/min, injection volume=50 μL, and column temperature=25° C.

Continued elution provided as a white solid (6R)-16-amino-12-oxido-6,14-bis(trifluoromethyl)-18-oxa-12-thionia-3,4,17-triazatricyclo[11.3.1.12,5]octadeca-1(17),2,4,13,15-pentaen-6-ol (enantiomer 2) (1.6 mg, 42%). 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.76 (s, 1H), 3.64 (td, J=12.5, 5.0 Hz, 1H), 3.22 (dd, J=13.1, 3.8 Hz, 1H), 2.43 (dp, J=9.1, 6.4, 4.3 Hz, 1H), 2.28 (t, J=7.2 Hz, 2H), 2.09-1.87 (m, 2H), 1.75 (ddt, J=34.2, 7.8, 3.7 Hz, 3H) ppm; 19 F NMR (376 MHz, Methanol-d 4 ) δ −60.71, −80.20 ppm. ESI-MS m/z calc. 444.0691, found 445.0 (M+1) + ; Retention time: 0.81 minutes. Final purity was determined by reversed phase HPLC-MS using an Onyx Monolithic C 18 column (50×4.6 mm) sold by Phenomenex (pn: CH0-7644), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=12 mL/min, injection volume=50 μL, and column temperature=25° C.

Example 19: Preparation of (6R,12R)-17-amino-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-10-one (hydrochloride salt), Compound 25, and (6R,12R)-17-amino-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-9-one (hydrochloride salt), Compound 26

Step 1: tert-Butyl N-[(6R,12R)-6-benzyloxy-9-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate and tert-butyl N-[(6R,12R)-6-benzyloxy-10-hydroxy-12-methyl-6,15-bis (trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate (mixture of regioisomeric diastereomers)

To a solution of tert-butyl N-[(6R,12R)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaen-17-yl]-N-tert-butoxycarbonyl-carbamate (E/Z mixture) (190 mg, 0.2607 mmol) in THF (3 mL) at 0° C. was added dropwise borane dimethylsulfide complex (200 μL of 2 M, 0.4000 mmol) and let the resulting mixture stir for 15 min at 0° C. Allowed the reaction warm to room temperature and stirred for 1 h. Added additional borane dimethylsulfide complex (200 μL of 2 M, 0.4000 mmol) and stirred at room temperature for an additional 30 minutes. Cooled the reaction to 0° C. before quenching with aqueous NaOH (1.5 mL of 1 M, 1.500 mmol) followed by the addition of hydrogen peroxide (600 μL of 30% w/v, 5.292 mmol). Allowed the resulting mixture stir for 30 min at room temperature then the mixture was extracted with ethyl acetate (2×80 mL). The organic layers were combined, washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated. The crude residue was then purified by silica gel chromatography (80 gram column) using a gradient from 100% hexanes to 100% ethyl acetate to collect as a 1:1 inseparable mixture of regioisomeric diastereomers, tert-butyl N-[(6R,12R)-6-benzyloxy-9-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate and tert-butyl N-[(6R,12R)-6-benzyloxy-10-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate (mixture of regioisomeric diastereomers) (128 mg, 66%). ESI-MS m/z calc. 746.275, found 747.4 (M+1) + ; Retention time: 1.89 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 30-99% mobile phase B over 2.9 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 and column temperature=60° C.

Step 2: tert-Butyl N-[(6R,12R)-6-benzyloxy-12-methyl-9-oxo-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate and tert-butyl N-[(6R,12R)-6-benzyloxy-12-methyl-10-oxo-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate

To a solution of a 1:1 mixture of regioisomeric diastereomers, tert-butyl N-[(6R,12R)-6-benzyloxy-9-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate and tert-butyl N-[(6R,12R)-6-benzyloxy-10-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate (mixture of regioisomeric diastereomers) (106 mg, 0.142 mmol) in dichloromethane (2 mL) was added Dess-Martin Periodinane (92 mg, 0.2169 mmol) at 0° C. and the mixture was stirred for 1 h allowing the reaction to warm up to room temperature. The reaction was diluted with ether (10 mL) and filtered through Celite. The filtrate was washed with saturated aqueous sodium bicarbonate and with brine, dried over sodium sulfate, filtered and concentrated. The resulting material was dissolved in 2 mL of DMSO, filtered and the filtrate was purified by reverse phase HPLC using a gradient from 50% to 99% acetonitrile in water (+5 mM HCl) giving as an inseparable ˜1:1 mixture of regioisomers, tert-butyl N-[(6R,12R)-6-benzyloxy-12-methyl-9-oxo-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate and tert-butyl N-[(6R,12R)-6-benzyloxy-12-methyl-10-oxo-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate (44 mg, 42%). ESI-MS m/z calc. 744.2594, found 645.2 (M-Boc+1) + ; Retention time: 2.05 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 30-99% mobile phase B over 2.9 minutes. Mobile phase A=water (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: (6R,12R)-17-Amino-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-10-one, Compound 25, and (6R,12R)-17-amino-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-9-one, Compound 26

To a solution of a 1:1 mixture of regioisomers, tert-butyl N-[(6R,12R)-6-benzyloxy-12-methyl-9-oxo-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate and tert-butyl N-[(6R,12R)-6-benzyloxy-12-methyl-10-oxo-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate (34 mg, 0.0457 mmol) in ethanol (5 mL) was added Pd/C (116 mg of 10% w/w, 0.1090 mmol) in a flask equipped with a hydrogen balloon using a 3-way adaptor. The material was subjected to vacuum and backfilled with nitrogen gas three times then subjected to vacuum. The flask was filled with hydrogen gas then stirred the mixture for 15 h. The vessel was subjected to vacuum and backfilled with nitrogen gas three times then diluted with ethyl acetate and filtered over Celite. The filtrate was concentrated and dried under reduced pressure. The resulting residue was dissolved in TFA (1.5 mL, 19.47 mmol) and dichloromethane (4.5 mL) (pre-made solution of 1:3 TFA/dichloromethane) and the reaction was stirred at room temperature for about 1 h. The solvents were removed by rotary evaporation and the residue was dissolved in DMSO (1 mL) then purified by reverse phase HPLC using a gradient from 30% to 99% acetonitrile in water (+5 mM HCl) to afford the first eluting regioisomer (based on H NMR AB pattern of —O CH (CH3)—CH2—CO) as (6R,12R)-17-amino-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-10-one (Hydrochloride salt) (2.3 mg, 41%). 1 H NMR (400 MHz, Chloroform-d) δ 7.61 (s, 1H), 6.92 (dq, J=16.0, 6.9 Hz, 1H), 6.13 (dq, J=15.8, 1.7 Hz, 1H), 2.67 (t, J=6.7 Hz, 2H), 2.46 (ddd, J=15.1, 10.2, 5.7 Hz, 1H), 2.13 (ddd, J=14.7, 10.3, 5.0 Hz, 1H), 1.90 (dd, J=6.9, 1.6 Hz, 3H), 1.83 (dd, J=10.4, 4.8 Hz, 2H), 1.71-1.42 (m, 2H) ppm. ESI-MS m/z calc. 454.10757, found 455.1 (M+1) + ; Retention time: 1.34 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C. and the later eluting regioisomer as (6R,12R)-17-amino-6-hydroxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-9-one (Hydrochloride salt) (3.0 mg, 54%). 1 H NMR (400 MHz, Chloroform-d) δ 7.41 (s, 1H), 6.27 (s, 1H), 5.42-5.35 (m, 1H), 2.99 (ddd, J=18.3, 11.2, 2.1 Hz, 1H), 2.89-2.80 (m, 1H), 2.79-2.63 (m, 2H), 2.52 (ddd, J=18.1, 7.2, 2.2 Hz, 1H), 2.35-2.26 (m, 1H), 2.13-2.01 (m, 1H), 1.99-1.89 (m, 1H), 1.42 (d, J=6.4 Hz, 3H) ppm. ESI-MS m/z calc. 454.10757, found 455.0 (M+1) + ; Retention time: 1.7 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.2 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Example 20: Preparation of 20-amino-6,18-bis(trifluoromethyl)-16,23-dioxa-3,4,21-triazatetracyclo[15.3.1.12,5.111,15]tricosa-1(21),2,4,11(22),12,14,17,19-octaen-6-ol (enantiomer 1), Compound 27, 20-amino-6,18-bis(trifluoromethyl)-16,23-dioxa-3,4,21-triazatetracyclo[15.3.1.12,5.111,15]tricosa-1(21),2,4,11(22),12,14,17,19-octaen-6-ol (enantiomer 2), Compound 28, 19-amino-9-methyl-6,17-bis(trifluoromethyl)-15,22-dioxa-3,4,20-triazatetracyclo[14.3.1.12,5.110,14]docosa-1(20),2,4,10(21),11,13,16,18-octaen-6-ol (diastereomer pair 1), Compound 29, and 19-amino-9-methyl-6,17-bis(trifluoromethyl)-15,22-dioxa-3,4,20-triazatetracyclo[14.3.1.12,5.110,14]docosa-1(20),2,4,10(21),11,13,16,18-octaen-6-ol (diastereomer pair 2), Compound 30

Step 1: 2-[1-Benzyloxy-1-(trifluoromethyl)pent-4-enyl]-5-[6-(3-iodophenoxy)-3-nitro-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole

The reagent 3-iodophenol (30 mg, 0.1364 mmol) was added to a mixture of [6-[5-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-1,3,4-oxadiazol-2-yl]-5-nitro-3-(trifluoromethyl)-2-pyridyl] trifluoromethanesulfonate (69 mg, 0.1061 mmol) and Cs 2 CO 3 (35 mg, 0.1074 mmol) in DMF (1.4 mL) and was stirred at 0° C. for 1 h and then at room temperature for 2 h. The mixture was diluted with ether, washed with water (2×), brine, dried (MgSO 4 ) and evaporated. The residue was purified by silica gel chromatography (12 g SiO 2 , 0-10% EtOAc in hexanes over 20 min) to provide 2-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-5-[6-(3-iodophenoxy)-3-nitro-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole (51 mg, 67%). 1 H NMR (400 MHz, Chloroform-d) δ 8.76 (s, 1H), 7.67-7.56 (m, 2H), 7.40-7.28 (m, 5H), 7.23 (ddd, J=8.3, 2.3, 1.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 5.71 (ddt, J=16.7, 10.1, 6.3 Hz, 1H), 5.00 (dd, J=17.1, 1.6 Hz, 1H), 4.94 (dd, J=10.3, 1.6 Hz, 1H), 4.77 (d, J=10.6 Hz, 1H), 4.61 (d, J=10.6 Hz, 1H), 2.55-2.25 (m, 3H), 2.24-2.11 (m, 1H) ppm; 19 F NMR (376 MHz, Chloroform-d) 6-64.07, −73.02 ppm. ESI-MS m/z calc. 720.03046, found 721.0 (M+1) + ; Retention time: 0.56 minutes. Final purity was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 2: (9E)-6-(Benzyloxy)-20-nitro-6,18-bis(trifluoromethyl)-16,23-dioxa-3,4,21-triazatetracyclo[15.3.1.12,5.111,15]tricosa-1(21),2,4,9,11(22),12,14,17,19-nonaene and 6-(benzyloxy)-9-methylidene-19-nitro-6,17-bis(trifluoromethyl)-15,22-dioxa-3,4,20-triazatetracyclo[14.3.1.12,5.110,14]docosa-1(20),2,4,10(21),11,13,16,18-octaene (Inseparable Mixture of Isomers)

A mixture of 2-[1-benzyloxy-1-(trifluoromethyl)pent-4-enyl]-5-[6-(3-iodophenoxy)-3-nitro-5-(trifluoromethyl)-2-pyridyl]-1,3,4-oxadiazole (126 mg, 0.1749 mmol), palladium (II) acetate (10 mg, 0.04454 mmol), tris-o-tolylphosphane (27 mg, 0.08871 mmol) and triethylamine (51 μL, 0.3659 mmol) in acetonitrile (6.3 mL) was bubbled with N 2 for 1 min then heated at 100° C. for 1 h. The mixture was diluted with ether and washed with 1 M NH 4 Cl, 1 M NaHCO 3 , brine then dried (MgSO 4 ) and evaporated. The residue was purified by silica gel chromatography (24 g SiO 2 , 0-50% of a solution (20% EtOAc in hexanes) to hexanes over 20 min) to provide as a 2:1 inseparable mixture of isomers, (9E)-6-(benzyloxy)-20-nitro-6,18-bis(trifluoromethyl)-16,23-dioxa-3,4,21-triazatetracyclo[15.3.1.12,5.111,15]tricosa-1(21),2,4,9,11(22),12,14,17,19-nonaene (69 mg, 66% purity, 44%). ESI-MS m/z calc. 592.11816, found 593.1 (M+1) + ; Retention time: 0.55 minutes and 6-(benzyloxy)-9-methylidene-19-nitro-6,17-bis(trifluoromethyl)-15,22-dioxa-3,4,20-triazatetracyclo[14.3.1.12,5.110,14]docosa-1(20),2,4,10(21),11,13,16,18-octaene (69 mg, 33% purity, 22%). ESI-MS m/z calc. 592.11816, found 593.1 (M+1) + ; Retention time: 0.54 minutes. Final purities were determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 50-99% mobile phase B over 1.0 minutes. Mobile phase A=H 2 O (0.05% CF 3 CO 2 H). Mobile phase B=acetonitrile (0.035% CF 3 CO 2 H). Flow rate=1.5 mL/min, injection volume=1.5 μL, and column temperature=60° C.

Step 3: 20-Amino-6,18-bis(trifluoromethyl)-16,23-dioxa-3,4,21-triazatetracyclo[15.3.1.12,5.111,15]tricosa-1(21),2,4,11(22),12,14,17,19-octaen-6-ol (enantiomer 1), Compound 27, 20-amino-6,18-bis(trifluoromethyl)-16,23-dioxa-3,4,21-triazatetracyclo[15.3.1.12,5.111,15]tricosa-1(21),2,4,11(22),12,14,17,19-octaen-6-ol (enantiomer 2), Compound 28, 19-amino-9-methyl-6,17-bis(trifluoromethyl)-15,22-dioxa-3,4,20-triazatetracyclo[14.3.1.12,5.110,14]docosa-1(20),2,4,10(21),11,13,16,18-octaen-6-ol (diastereomer pair 1), Compound 29, and 19-amino-9-methyl-6,17-bis(trifluoromethyl)-15,22-dioxa-3,4,20-triazatetracyclo[14.3.1.12,5.110,14]docosa-1(20),2,4,10(21),11,13,16,18-octaen-