COMPOUNDS AND USES THEREOF

Background

An incomplete understanding of the molecular perturbations that cause disease, as well as a limited arsenal of robust model systems, has contributed to a failure to generate successful disease- modifying therapies against common and progressive neurological disorders, such as Parkinson's Disease (PD) and Alzheimer's Disease (AD). Progress is being made on many fronts to find agents that can arrest the progress of these disorders. However, the present therapies for most, if not all, of these diseases provide very little relief. Accordingly, a need exists to develop therapies that can alter the course of neurodegenerative diseases. More generally, a need exists for better methods and compositions for the treatment of neurodegenerative diseases in order to improve the quality of the lives of those afflicted by such diseases.

Summary of the Invention

This disclosure provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula I:

Formula la

wherein B is absent or has the structure:

Formula lb Formula lc Formula Id Formula le Formula If the dashed lines represent an optional double bond;

Het is -C(0)NH- or an optionally substituted C2-C9 heteroaryl;

m is 0 or 1 ;

n is 0, 1 , or 2;

o is O, 1 , 2, 3, 4, 5, 6, 7, or 8;

p, p', r, and r' are, independently, 0 or 1 ;

X ¹ and X ² are each, independently, N or CR ⁶ ;

L ¹ is -0-, -SO2-, NR ² , optionally substituted C1 -C6 alkylene, optionally substituted C1 -C6 alkenylene, optionally substituted C1 -C6 heteroalkylene, optionally substituted C3-C7 cycloalkyi, optionally substituted C2-C9 heteroaryl, an optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heterocycle;

L ² is absent, -0-, -SO2-, NR ² , or -CR ² R ³ -; R ¹ is hydrogen, amino, hydroxy, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyi, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1 -C6 alkyl, optionally substituted C3-C7 cycloalkyl , optionally substituted C3-C7 cycloalkyl C1 -C6 alkyl, optionally substituted C2- C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1 -C6 alkyl, optionally substituted C2-C9 heterocycle, or optionally substituted C2-C9 heterocycle C1 -C6 alkyl ;

R ² and R ³ are each, independently, hydrogen, halogen, hydroxyl, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyi, or combine with the carbon to which they are attached to form a carbonyl or an optionally substituted C3-C7 cycloalkyl ;

each R ⁴ is, independently, halogen, hydroxyl, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyi , or two R ⁴ combine with the carbon two which they are attached to form a carbonyl or optionally substituted C3-C7 cycloalkyl ;

R ⁵ is optionally substituted C1 -C6 heteroalkyi, optionally substituted C1 -C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl , optionally substituted C2-C9 heterocycle, optionally substituted C6-C10 aryl C1 -C6 alkyl, optionally substituted C2-C9 heterocycle C1 -C6 alkyl, or optionally substituted C2-C9 heteroaryl C1 -C6 alkyl ; and

each R ⁶ is, independently, hydrogen, halogen, hydroxy, optionally substituted C1 -C6 heteroalkyi , or optionally substituted C1 -C6 alkyl.

In some embodiments, B is absent.

In some embodiments, B has the structure of Formula lb:

In some embodiments, X ¹ is N and X ² is CR ⁶ . In some embodiments, 0 is 0, 1 , or 2. In some embodiments, R ⁴ is halogen (e.g., fluoro), optionally substituted C1 -C6 alkyl (e.g. , methyl), or two R ⁴ combine with the carbon two which they are attached to form a carbonyl. In some embodiments, R ⁶ is hydrogen. In some embodiments, R ⁶ is halogen (e.g. , fluoro). In some embodiments, R ⁶ is optionally substituted C1 -C6 alkyl (e.g. , methyl). In some embodiments, the dashed line represents a double bond. In some embodiments, both dashed lines represent a single bond. In some embodiments, p is 1 and r is 1 . In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some

em

In some embodiments, X ¹ is CR ⁶ and X ² is N. In some embodiments, o is 0, 1 , or 2. In some embodiments, R ⁴ is halogen (e.g., fluoro), optionally substituted C1 -C6 alkyl (e.g., methyl), or two R ⁴ combine with the carbon two which they are attached to form a carbonyl. In some embodiments, R ⁶ is hydrogen. In some embodiments, R ⁶ is halogen (e.g., fluoro). In some embodiments, R ⁶ is optionally substituted C1 -C6 alkyl (e.g., methyl). In some embodiments, the dashed line represents a double bond. In some embodiments, the dashed line represents a single bond. In some embodiments, p is 1 and r is 1 . In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some embodiments, B has the structure:

In some embodiments, X ¹ is N and X ² is N. In some embodiments, o is 0, 1 , or 2. In some embodiments, R ⁴ is halogen (e.g., fluoro), optionally substituted C1 -C6 alkyl (e.g., methyl), or two R ⁴ combine with the carbon two which they are attached to form a carbonyl. In some embodiments, the dashed line represents a double bond. In some embodiments, the dashed line represents a single bond. In some embodiments, p is 1 and r is 1 . In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some embodiments, p is 1 and r is 2. In some embodiments, B has the structure:

In some embodiments, X ¹ is CR ⁶ and X ² is CR ⁶ . In some embodiments, o is 0, 1 , or 2. In some embodiments, R ⁴ is halogen (e.g., fluoro), optionally substituted C1 -C6 alkyl (e.g., methyl), or two R ⁴ combine with the carbon two which they are attached to form a carbonyl. In some embodiments, the dashed line represents a double bond. In some embodiments, the dashed line represents a single bond.

In some embodiments, p is 1 and r is 1 . In some embodiments, p is 1 and r is 0. In some embodiments, p is 0 and r is 0. In some embodiments, B has the structure:

In some embodiments, B has the structure of Formula lc:

In some embodiments, X ¹ is N and X ² is N. In some embodiments, o is 0. In some

embodiments, p, p', r, and r' are 0. In some embodiments, p and r are each 1 and p' and r' are 0. In some embodiments, B has the structure:

In some embodiments, B has the structure of Formula Id: In some embodiments, X ¹ is N and X ² is N. In some embodiments, o is 0. In some embodiments, B has the structure:

In some embodiments, B has the structure of Formula le:

In some embodiments, X ¹ is N and X ² is N. In some embodiments, o is 0. In some

embodiments, B has the structure:

In some embodiments, B has the structure of Formula If:

In some embodiments of any of the foregoing compounds, Het is -C(0)NH- or:

wherein X ³ is O or S.

In some embodiments, Het is

In some embodiments, Het is

In some embodiments, Het is

In some embodiments, Het is

In some embodiments, Het is

In some embodiments, L ² is absent. In some embodiments, L ² is -NR ² - (e.g., -NH-). In some embodiments, L ² is -0-. In some embodiments, L ² is -SO2-. In some embodiments, L ² is -CR ² R ³ -. In some embodiments, R ² and R ³ combine with the carbon to which they are attached to form a carbonyl. In some embodiments, R ² and R ³ combine with the carbon to which they are attached to form an optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl). In some embodiments, R ² and R ³ are both hydrogen. In some embodiments, R ² is hydrogen and R ³ is optionally substituted C1 -C6 alkylene (e.g., methylene).

In some embodiments, n is 0. In some embodiments, n is 1 . In some embodiments, L ¹ is -NR ² - (e.g., -NH- or -N(Et)-). In some embodiments, L ¹ is -0-. In some embodiments, L ¹ is -SO2-. In some embodiments, L ¹ is optionally substituted C1 -C6 alkylene (e.g., methylene or hydroxy-methylene). In some embodiments, L ¹ is optionally substituted C1 -C6 heteroalkylene (e.g., -NH-CH2-, -O-CH2-, -O-CH2-

CH2-, -CH2-O-CH2-, -CH2-O-, In some embodiments, L ¹

is optionally s heterocycle (e.g.

In some embodiments, R ¹ is cyano, optionally substituted C1 -C6 alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoroethyl, pentafluoro-ethyl, 2-chloro-ethyl, 1 -chloro-3-hydroxy- isopropyl, 2-methoxy-ethyl, or hexafluoro-isopropyl). In some embodiments, R ¹ is optionally substituted C6-C10 aryl (e.g., phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2-trifluoromethyl-phenyl, 3- trifluoromethyl-phenyl, 4- trifluoromethyl-phenyl, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 3- isopropyl-phenyl, 4-isopropyl-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 4-difluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 2-chloro-5-fluoro-phenyl, 2-fluoro-4-chloro-phenyl, 3-fluoro-4-chloro-phenyl, 2-bromo-4-methoxy-phenyl -trifluoromethyl-5-fluoro-phenyl, 2-trifluoromethyl-

5-chloro-phenyl, , In some embodiments, R ¹ is optionally substituted C6-C10 aryl C1 -C6 alkyl (e.g., naphthylmethyl). In some embodiments, R ¹ is optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl, cyclohexyl, 6-methoxy-cyclohexyl, 1 -cyano- cyclopropyl, bicycle[1 .1 .1 ]pentane, 1 -methyl-cyclopropyl, 1 -ethyl-cyclopropyl, 1 -fluoro-cyclopropyl, 1 - methoxy-cyclopropyl, 1 -hydroxy-cyclopropyl, -dimethyl-cyclopropyl, 2,2-difluoro-cyclopropyl,

cyclobutyl, ). In some embodiments, R ¹ is optionally substituted C3-C7 cycloalkyl C1 -C6 alkyl (cyclopropylmethyl). In some embodiments, R ¹ is

_Λ OCH ₃

OH ,). In some embodiments, R ¹ is optionally substituted C2-C9 heterocycle C1 -C6 alkyl (e.g., x

) ^■

In some embodiments, R ⁵ is optionally substituted C6-C10 aryl (e.g., phenyl, 3,4-dimethoxy- phenyl, 3-methoxy-4-ethoxy-phenyl, 3,5-dimethoxy-phenyl, 3-methoxy-4-cyclopropoxy-phenyl, 3-

diments,

embodiments, R ⁵ is an optionally substituted indazole. In some embodiments, R ⁵ is optionally substituted

C2-C9 heterocycle (e.g., a nitrogen containing heterocycle such as

⁵ is optionally substituted C2-C9 heteroaryl C1 -C6 alkyl (e.g.,

In some embodiments, R ⁵ is a bicyclic heterocyle. For example, a bicyclic heterocycle such as an indazole. In some embodiments, R ⁵ is an indazole having the structure:

wherein R ^5a is hydrogen or optionally substituted C1 -C6 alkyl (e.g., methyl) and R ^5b is optionally substituted C1 -C6 alkyl (e.g., methyl or iso-propyl), optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or optionally substituted C3-C7 cycloalkyl (e.g., cyclopropyl).

In some embodiments, B has the sturucture:

In some embodiments, R ¹ is optionally substituted C1 -C6 alkyl (e.g., methyl, ethyl, iso-propyl, or tert-butyl), optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl.

In some embodiments, m is 0, n is 1 , L ¹ is -0-, and L ² is -C(O)-. In some embodiments, m is 0, n

is 0, and L ² is -C(O)-. In some embodiments, m is 0, n is 1 , L ¹ is , and L ² is -C(O)-. In some embodiments, m is 1 , n is 1 , L ¹ is H , and L ² is -C(O)-.

In some embodiments, R ⁵ is an indazole having the structure:

wherein R ^5a is hydrogen or optionally substituted C1 -C6 alkyl (e.g., methyl) and R ^5b is optionally substituted C1 -C6 alkyl (e.g., methyl or iso-propyl), optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or optionally subst B has the sturucture:

R ¹ is optionally substituted C1 -C6 alkyl (e.g., methyl, ethyl, iso-propyl, or tert-butyl), optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl; and s 0, n is 1 , L ¹ is -0-, and L ² is -C(O)-, m is 0, n is 0, and L ² is -C(0)-, m is 0, n is 1 , L ¹ is

, and L ² is -C(O)-, or m is 1 , n is 1 , L ¹ is H , and L ² is -C(O)-.

In some embodiments, m is 0, n is 1 , L ¹ is -0-, L ² is -C(O)- and R ¹ is optionally substituted C1 -C6 alkyl (e.g., methyl, ethyl, iso-propyl, or tert-butyl).

In some embodiments, m is 0, n is 0, L ² is -C(O)-, and R ¹ is optionally substituted C6-C10 aryl.

In some embodiments, m is 0, n is 1 , L ¹ is , L ² is -C(O)-, and R ¹ is optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl.

In some embodiments, m is 1 , n is 1 , L ¹ is H , L ² is -C(O)-, and R ¹ is optionally substituted C6-C10 aryl.

In some embodiments, the compound has the structure of Formula Ig:

Formula Ig

wherein Het is an optionally substituted oxadiazole;

o is O, 1 , 2, 3, 4, 5, 6, 7, or 8;

X ² is N or CR ⁶ ;

R ¹ is optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyi, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1 -C6 alkyl, optionally substituted C3-C7 cycloalkyi, optionally substituted C3-C7 cycloalkyi C1 -C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1 -C6 alkyl, optionally substituted C2-C9 heterocycle, or optionally substituted C2-C9 heterocycle C1 -C6 alkyl;

each R ⁴ is, independently, halogen, hydroxyl, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyi, or two R ⁴ combine with the carbon two which they are attached to form a carbonyl or optionally substituted C3-C7 cycloalkyi;

R ⁵ is optionally substituted C1 -C6 heteroalkyi, optionally substituted C1 -C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocycle, optionally substituted C6-C10 aryl C1 -C6 alkyl, optionally substituted C2-C9 heterocycle C1 -C6 alkyl, or optionally substituted C2-C9 heteroaryl C1 -C6 alkyl; and

each R ⁶ is, independently, hydrogen, halogen, optionally substituted C1 -C6 heteroalkyi, or optionally substituted C1 -C6 alkyl. In some embodiments, Het is

In some embodiments, Het is

In some embodiments, X ² is N or CH. In some embodiments, X ² is N. In some embodiments, X ² is CH.

In some embodiments, R ¹ is optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyi, or optionally substituted C6-C10 aryl.

In some embodiments, R ⁵ is optionally substituted C6-C10 aryl or optionally substituted C2-C9 heteroaryl (e.g., bicyclic heteroaryl such as an indazole). In some embodiments, R ⁵ has the structure:

wherein R ^5a is hydrogen or optionally substituted C1 -C6 alkyl (e.g., methyl) and R ^5b is optionally substituted C1 -C6 alkyl (e.g., methyl or iso-propyl), optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or optionally substituted C3-C7 cycloalkyi (e.g., cyclopropyl). In some embodiments, R ^5a is hydrogen.

In some embodiments, Het is ; 0 is 0; X ² is N or CH; R ¹ is optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyi (e.g., C1 -C6 alkoxy or C1 -C6 alkylamino), or optionally substituted C6-C10 aryl ; and R ⁵ has the structure:

wherein R ^5b is optionally substituted C1 -C6 alkyl (e.g., methyl or iso-propyl), optionally substituted C2-C9 heterocyclyl (e.g., oxetane), or optionally substituted C3-C7 cycloalkyi (e.g., cyclopropyl).

In some embodiments the compound has the structure of Formula I:

Formula I

wherein Het is an optionally substituted optionally substituted C2-C9 heteroaryl;

m is 0 or 1 ;

n is 0, 1 , or 2;

o is O, 1 , 2, 3, 4, 5, 6, 7, or 8; X ¹ and X ² are each, independently, N or CR ⁶ ;

L ¹ is optionally substituted C1 -C6 alkylene, optionally substituted C1 -C6 alkenylene, optionally substituted C1 -C6 heteroalkylene, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C9 heteroaryl, or optionally substituted C2-C9 heterocycle;

R ¹ is optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyi, optionally substituted C6-C10 aryl, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C9 heteroaryl, or optionally substituted C2-C9 heterocycle;

R ² and R ³ are each, independently, hydrogen, optionally substituted C1 -C6 alkyl, or combine with the carbon to which they are attached to form a carbonyl;

each R ⁴ is, independently, halogen, hydroxyl, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyi, or two R ⁴ combine with the carbon two which they are attached to form a carbonyl ;

R ⁵ is optionally substituted C6-C10 aryl or optionally substituted C2-C9 heteroaryl; and

each R ⁶ is, independently, hydrogen or optionally substituted C1 -C6 alkyl.

In some embodiments of any of the foregoing compounds, R ² and R ³ combine with the carbon to which they are attached to form a carbonyl. In some embodiments of any of the foregoing compounds, R ² and R ³ are both hydrogen.

In some embodiments of any of the foregoing compounds, Het is:

wherein X ³ is O or S.

In some embodiments, the compound has the structure of Formula II or Ma:

Formula II Formula Ma

In some embodiments of any of the foregoing compounds, X ³ is O. In some embodiments of any of the foregoing compounds, X ³ is S.

In some embodiments of any of the foregoing compounds, X ¹ is N and X ² is CR ⁶ . In some embodiments of any of the foregoing compounds, X ¹ is N and X ² is N. In some embodiments of any of the foregoing compounds, X ¹ is CR ⁶ and X ² is N. In some embodiments of any of the foregoing compounds, R ⁶ is hydrogen.

In some embodiments of any of the foregoing compounds, R ⁵ is optionally substituted C6-C10 aryl. For example, in some embodiments, R ⁵ is a C6-C10 aryl substituted with 1 , 2, 3, or 4 substituents independently selected from C1 -C6 alkyl (e.g., methyl), halogen (e.g., fluoro, chloro, or bromo), C1 -C6 alkoxy (e.g., methoxy or ethoxy), nitrile, or two substituents combine to form a 5 or 6-membered heterocycle (e.g., 2,2-difluoro-1 ,3-benzodioxole). In some embodiments of any of the foregoing compounds, R ⁵ is phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3,4-dimethyl-phenyl, 2- methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,4-dimethoxy-phenyl, 2-fluoro-phenyl, 3- fluoro - phenyl, 4- fluoro -phenyl, 3,4-di fluoro -phenyl, 3,4-dichloro-phenyl, 3-methoxy-4-ethoxy-phenyl, 3-chloro- 4-ethoxy-phenyl, 3-fluoro-4-ethoxy-phenyl, 3-bromo-4-ethoxy-phenyl, 3-cyano-4-ethoxy-phenyl, or 2,2- difluoro-1 ,3-benzodioxole.

In some embodiments, the compound has the structure of Formula III or Ilia:

Formula III Formula Ilia

wherein p is 1 , 2, 3, 4, or 5;

each R ⁷ is, independently, halogen, nitrile, OR ⁸ , or optionally substituted C1 -C6 alkyl ; and each R ⁸ is, independently, hydrogen or optionally substituted C1 -C6 alkyl.

In some embodiments, the compound has the structure of Formula IV or IVa:

Formula IV Formula IVa

In some embodiments, each R ⁷ is OR ⁸ . In some em ibodiments, each R ⁸ is optionally substituted C1 -C6 alkyl (e.g., methyl or ethyl).

In some embodiments of any of the foregoing compounds, R ⁵ is optionally substituted C2-C9

In some embodiments of any of the foregoing compounds, R ¹ is optionally substituted C6-C10 aryl or optionally substituted C2-C9 heteroaryl. In some embodiments, R ¹ is optionally substituted C6-C10 aryl. For example, phenyl or a C6-C10 aryl substituted with 1 , 2, 3, 4, or 5 substituents independently selected from C1 -C6 alkyl (e.g., methyl or iso-propyl), C1 -C6 alkoxy (e.g., methoxy), or halogen (e.g., chloro). In some embodiments of any of the foregoing compounds R ¹ is 2-methoxy-phenyl, 3-methoxy-phenyl, 4- methoxy-phenyl, 3,4-dimethoxy-phenyl, phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3,4-methyl-phenyl, 4- iso-propyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, or 4-chloro-phenyl. In some embodiments of any of the foregoing compounds, R ¹ is a bicyclic C6-C10 aryl (e.g., naphthalene). In some embodiments of any of the foregoing compounds, R ¹ is C3-C7 cycloalkyl (e.g., cyclohexyl). In some embodiments of any of the foregoing compounds, R ¹ is optionally substituted C2-C9 heteroaryl or optionally substituted C2-C9

In some embodiments of any of the foregoing compounds, the compound has the structure of Formula V or Va:

Formula V Formula Va

wherein q is 1 , 2, 3, 4, or 5; and

R ⁹ is halogen or optionally substituted C1 -C6 alkyl.

In some embodiments of any of the foregoing compounds, the compound has the structure of Formula VI or Via

Formula VI Formula Via

In some embodiments of any of the foregoing compounds, n is 1 . In some embodiments of any of the foregoing compounds, n is 0.

In some embodiments of any of the foregoing compounds, L ¹ is optionally substituted C1 -C6 alkyl For example, L ¹ has the structure:

In some embodiments of any of the foregoing compounds, L ¹ is optionally substituted C1 -C6 alkenylene (e.g., ethenylene).

In some embodiments of any of the foregoing compounds, L ¹ is optionally substituted C2-C9 heterocyclene or optionally substituted C2-C9 heteroarylene. For example,

In some embodiments, L ¹ is .

In some embodiments of any of the foregoing compounds, L ¹ is optionally substituted C1 -C6 heteroalkylene. For example, in some embodiments, L ¹ is:

In some embodiments of any of the foregoing compounds, L ¹ is -NH-(CR ¹⁰ R ^{1 1} )r, wherein r is 1 , 2, 3, 4, 5, or 6, and each R ¹⁰ and R ^{1 1} is, independently, hydrogen or optionally substituted C1 -C6 alkyl. For example, in some embodiments, L ¹ is -NH-CH2-, -NH-CR ¹⁰ R ^{1 1} -, wherein each of R ¹⁰ and R ^{1 1} is methyl, or -NH-CHR ^{1 1} -, wherein R ^{1 1} is methyl.

In some embodiments of any of the foregoing compounds, m is 1 . In some embodiments of any of the foregoing compounds, m is 0.

In some embodiments of any of the foregoing compounds, the compound has the structure of Formula VII:

Formula VII

wherein

n is 0 or 1 ;

0 is 0, 1 , 2, or 3;

p is 1 or 2;

R ¹ is optionally substituted C1 -C6 alkyl, optionally substituted C3-C7 cycloalkyi, optionally substituted C2-C9 heterocycle, optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl ;

L ¹ is -0-;

L ² is O or O ;

each R ⁴ is, independently, halogen or optionally substituted C1 -C6 alkyl;

X ² is N or CH;

wherein

q is 0, 1 , 2, or 3; and

R ¹⁴ is halogen, hydroxyl, or optionally substituted C1 -C6 alkyl,

or a pharmaceutically acceptable salt thereof.

In some embodiments, X ² is CH. In some embodiments, X ² is N. In some embodiments, L ¹ is O . in some embodiments, L ¹ is

In some embodiments, n is 0. In some embodiments, n is 1 .

In some embodiments any of the foregoing compounds, the compound has the structure of Formula Vila, FormulaVllb, or Formula Vile:

Formula Vila Formula Vllb Formula Vile

In some embodiments any of the foregoing compounds, the compound has the structure of Formula Vllac:

Formula Vila

In some embodiments any of the foregoing compounds, the compound has the structure of FormulaVllb:

Formula Vllb

In some embodiments any of the foregoing compounds, the compound has the structure of Formula Vile:

Formula Vile

In some embodiments, o is 0, 1 , or 2.

In some embodiments, o is 0. In some embodiments, o is 1 . In some embodiments, o is 2. In some embodiments, p is 1 . In some embodiments, p is 2.

In some embodiments any of the foregoing compounds, the compound has the structure of Formula Vlld, Formula Vile, Formula Vllf, or Formula Vllg.

Formula Vlld Formula Vile

Formula Vllf Formula Vllg

In some embodiments any of the foregoing compounds, the compound has the structure of Formula VI Id:

Formula Vlld

In some embodiments any of the foregoing compounds, the compound has the structure of Formula Vile:

Formula Vile

In some embodiments any of the foregoing compounds, the compound has the structure of Formula Vllf:

Formula Vllf

In some embodiments any of the foregoing compounds, the compound has the structure of Formula Vllg :

Formula Vllg

In some embodiments, q is 0 or 1 .

In some embodiments, q is 0. In some embodiments, q is 1 .

In some embodiments, R ¹⁴ is halogen or hydroxyl.

In some embodiments, R ¹⁴ is halogen. In some embodiments, R ¹⁴ is hydroxyl.

In some embodiments, R ¹² is

In some embodiments, R ¹² is , , , or In some embodiments, R ¹² is In some embodiments, R ¹² is In some

embodiments, R ¹² is

In some embodiments, R ¹³ is or

In some embodiments, R ⁵ is is

In some embodiments, R ⁵ is

In some embodiments, R ⁵ is

In some embodiments, R ¹ is optionally substituted C1 -C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C9 heterocycle, or optionally substituted C2-C9 heteroaryl.

In some embodiments, R ¹ is optionally substituted C1 -C6 alkyl or optionally substituted C3-C10 C7 cycloalkyl.

In another aspect, the disclosure provides a compound, or pharmaceutically acceptable salt thereof, having the structure of any one of compounds 1 -1 195 in Table 1 , Table 2A, and Table 2B. In some embodiments, the compound is any one of compounds 1 -746 in Table 1 . In some embodiments, the compound is any one of compounds 1 -155 in Table 1 . In some embodiments, the compound is any one of compounds 156-746 in Table 1 . In some embodiments, the compound is any one of compounds 747-966. In some embodiments, the compound is any one of compounds 967-1 195. In some embodiments, the compound is any one of compounds 527, 615, 617, 676, 713, 735, In some embodiments, the compound is any one of compounds 1 -264, 266-271 , 274-276, 278-299, 302- 318, 320-329, 331 -340, 344-354, 358, 362-364, 367, 369, 371 -378, 385, 388-392, 396, 397, 399-401 , 403, 406-41 1 , 414, 41 8-420, 422, 425-432, 434-436, 438, 440-444, 446, 450-454, 456, 458, 460, 461 , 464, 466, 470, 472-474, 476, 477, or 481 -746 in Table 1 . In some embodiments, the compound is any one of compounds 1 -347, 349, 350, or 354-746 in Table 1 . In some embodiments, the compound is any one of compounds 1 -387, 389, 393-405, 407-430, 432-439, 441 -449, 452, 454-457, 459-472, 475, 477-480, 482-487, or 489-746 in Table 1 , In some embodiments, the compound is any one of compounds 1 -483 or 491 -746 in Table 1 . In some embodiments, the compound is any one of compounds 747-966. In some embodiments, the compound is any one of compounds 27, 40, 96, 128, 140, 168, 184, 204, 226, 244, 265, 268, 269, 284, 286 291 , 294, 302, 305, 306, 308, 317, 319, 343, 344, 345, 346, 349, 355-357, or 359-364. In some embodiments, the compound is any one of compounds 244, 265, 269, 319, 345, 349, 355-357, 361 , or 364. In some embodiments, the compound is any one of compounds 750, 767, 775- 778, 780, 784, 785, 789-792, 795, 799, 812, 813, 817, 828, 838, 839, 842-844, 846, 848, 850, 851, 853, 854, 861 , 862, 865, 874-881 , 884-888, 890-898, 902, 903, 907, 910, 916, 928, 932, 934, 953, 957, 960, 964, or 965. In some embodiments, the compound is any one of compounds 967-1195. In some embodiments, the compound is any one of compounds 970, 971 , 974, 975, 979-982, 986, 988, 990, 992, 997, 999, 1000, 1003-1006, 1010, 1012, 1013, 1015-1026, 1028, 1029, 1031 , 1034-1037, 1039-1050, 1052-1062, 1065-1073, 1075-1080, 1082-1087, 1090, 1092, 1093, 1096-1098, 1100, 1104, 1105, 1107, 1109-1114, 1125, 1131, 1134-1141, 1144, 1146, 1149, 1151-1154, 1156, 1161, 1162, 1164, 1170, 1171, 1175-1182, 1190, or 1192. In some embodiments, the compound is any one of compounds 970, 971 ,

974, 975, 979, 981, 982, 986, 988, 990, 992, 997, 999, 1005, 1012, 1016-1020, 1022, 1024, 1025, 1028, 1029, 1036, 1039, 1041-1043, 1046-1050, 1053-1062, 1065-1073, 1075, 1078, 1082-1084, 1086, 1087, 1092, 1093, 1096-1098, 1104, 1107, 1109-1112, 1114, 1134-1137, 1139, 1140, 1144, 1149, 1152, 1154, 1161 , 1162, 1171 , 1176, 1180, 1190, or 1192. In some embodiments, the compound is any one of compounds 970, 971 , 974, 975, 986, 988, 990, 997, 999, 1005, 1012, 1016-1019, 1022, 1024, 1025,

1028, 1029, 1036, 1039, 1041, 1043, 1046-1050, 1053-1059, 1061, 1062, 1065-1073, 1075, 1078, 1083, 1084, 1086, 1087, 1092, 1093, 1096, 1097, 1104, 1107, 1109, 1110, 1134, 1136, 1137, 1139, 1140, 1144, 1149, 1152, 1154, 1161 , 1162, 1171 , 1180, 1190, or 1192. In some embodiments, the compound is any one of compounds 970, 1053-1056, 1058, 1059, 1065-1069, 1071 -1073, 1093, or 1096.

Table 1. Compounds of the Invention









42





50

51

52

55





60

63

Table 2A. Compounds of the Invention

Table 2B. Compounds of the Invention

# Structure # Structure

1065 1180

1066 1181

1067 1182

1068 1183

1069 1184

1070 1185

1071 1186

1072 1187

In another aspect, the disclosure provides pharmaceutical composition comprising any of the foregoing compounds, or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.

In another aspect, the disclosure provides a method of treating a neurological disorder in a subject in need thereof, the method comprising administering an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions.

In another aspect, the disclosure provides a method of inhibiting toxicity in a cell (e.g., a mammalian neural cell) related to a protein (e.g., toxicity related to protein misfolding and/or aggregation such as protein aggregation related to misfolding of proteins such as a-synuclein or ApoE4), the method comprising administering, or contacting the cell with, an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof. In some embodiments, the toxicity is a- synuclein-related toxicity. In some embodiments, the toxicity is ApoE4-related toxicity.

Non-limiting exemplary neurological disorders include, but are not limited to Alexander disease,

Alper' s disease, AD, amyotrophic lateral sclerosis, ataxia telangiectasia, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Machado-Joseph disease, multiple sclerosis, PD, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Ref sum's disease, Sandhoff disease, Schilder' s disease, Steele-Richardson-Olszewski disease, tabes dorsalis, frontal temporal dementia, vascular dementia, Down's syndrome, and Guillain-Barre Syndrome.

In another aspect, the disclosure provides a method of treating a stearoyl-CoA desaturase (SCD)- associated disorder in a subject in need thereof, the method comprising administering, or contacting the cell with, an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof.

Non-limiting exemplary SCD-associated disorders include, but are not limited to metabolic disorders (e.g., diabetes (e.g., Type I diabetes and Type II diabetes), hyperglycemia, metabolic syndrome, obesity, lipid disorders, fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and hypertension), cancer, cardiovascular diseases, cerebrovascular diseases, kidney diseases, liver diseases, skin disorders (e.g., acne (e.g., acne vulgaris)), central nervous system (CNS) disorders, dementia, multiple sclerosis, schizophrenia, mild cognitive impairment, Alzheimer's Disease, cerebral amyloid angiopathy, and dementia associated with Down Syndrome.

In another aspect, the disclosure provides a method of treating cancer in a subject in need thereof, the method including administering, or contacting the cell with, an effective amount of the any of the foregoing compounds, or pharmaceutically acceptable salts thereof.

In some embodiments, the cancer is esophageal cancer, pancreatic cancer, endometrial cancer, kidney cancer, hepatoma, thyroid cancer, gallbladder cancer, prostate cancer, leukemia (e.g., lymphomas and myelomas), ENT-related cancer, brain cancer, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, uterine cancer, breast cancer, skin cancer, or prostate cancer.

Chemical Terms

It is to be understood that the terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting.

The term "acyl," as used herein, represents a hydrogen or an alkyl group, as defined herein, that is attached to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 1 1 , or from 1 to 21 carbons.

The term "alkyl," as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). An alkylene is a divalent alkyl group.

The term "alkenyl," as used herein, alone or in combination with other groups, refers to a straight- chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

The term "alkynyl," as used herein, alone or in combination with other groups, refers to a straight- chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

The term "amino," as used herein, represents -N(R ^{N 1} )2, wherein each R ^N1 is, independently, H,

OH, N0 ₂ , N(R ^N2 )2, S0 ₂ OR ^N2 , S0 ₂ R ^N2 , SOR ^N2 , an /V-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited R ^N1 groups can be optionally substituted; or two R ^N1 combine to form an alkylene or heteroalkylene, and wherein each R ^N2 is, independently, H, alkyl, or aryl. The amino groups of the invention can be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R ^N1 )2).

The term "aryl," as used herein, refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,2-dihydronaphthyl, indanyl, and 1 H-indenyl.

The term "arylalkyl," as used herein, represents an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1 -6 alkyl Ce-ιο aryl, C1-10 alkyl Ce-ιο aryl, or C1-20 alkyl Ce-ιο aryl), such as, benzyl and phenethyl. In some embodiments, the akyl and the aryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.

The term "azido," as used herein, represents a -N3 group.

The term "cyano," as used herein, represents a -CN group.

The terms "carbocyclyl," as used herein, refer to a non-aromatic C3-12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals.

The term "cycloalkyl," as used herein, refers to a saturated, non-aromatic, monovalent mono- or polycarbocyclic radical of three to ten, preferably three to six carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

The term "halogen," as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an "alkoxy" which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group.

The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkenyl groups. Examples of heteroalkenyl groups are an "alkenoxy" which, as used herein, refers alkenyl-O-. A heteroalkenylene is a divalent heteroalkenyl group.

The term "heteroalkynyl," as used herein, refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkynyl groups. Examples of heteroalkynyl groups are an "alkynoxy" which, as used herein, refers alkynyl-O-. A heteroalkynylene is a divalent heteroalkynyl group.

The term "heteroaryl," as used herein, refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, and S, with the remaining ring atoms being C. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.

The term "heteroarylalkyl," as used herein, represents an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-6 alkyl C2-9 heteroaryl, C1-10 alkyl C2-9 heteroaryl, or C1-20 alkyl C2-9 heteroaryl). In some embodiments, the akyl and the heteroaryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.

The term "heterocyclyl," as used herein, denotes a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing one, two, three, or four ring heteroatoms selected from N, O or S, wherein no ring is aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1 ,3-dioxanyl.

The term "heterocyclylalkyl," as used herein, represents an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-6 alkyl C2-9 heterocyclyl, C1-10 alkyl C2-9 heterocyclyl, or C1-20 alkyl C2-9 heterocyclyl). In some embodiments, the akyl and the heterocyclyl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.

The term "hydroxyl," as used herein, represents an -OH group. The term "/V-protecting group," as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used /V-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3 ^rd Edition (John Wiley & Sons, New York, 1999). /V-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4- nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p- toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,

p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l -methylethoxycarbonyl, α,α-dimethyl- 3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl,

diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups, such as trimethylsilyl. Preferred /V-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

The term "nitro," as used herein, represents an -NO2 group.

The term "thiol," as used herein, represents an -SH group.

The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified. Substituents include, for example: aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)).

Compounds of the invention can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. The appropriate technique and/or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art. "Racemate" or "racemic mixture" means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light. "Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S ^* ," "R ^* ," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9%) by weight relative to the other

stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure. Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer.

Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other

diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.

Definitions

In the practice of the methods of the present invention, an "effective amount" of any one of the compounds of the invention or a combination of any of the compounds of the invention or a

pharmaceutically acceptable salt thereof, is administered via any of the usual and acceptable methods known in the art, either singly or in combination.

The term "pharmaceutical composition," as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup) ; for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.

A "pharmaceutically acceptable excipient," as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

As used herein, the term "pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of the compound of formula (I). For example pharmaceutically acceptable salts of any of the compounds described herein include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid.

The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.

Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, 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, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

As used herein, the term "stearoyl-CoA desaturase (SCD)-associated disorder" refers to an undesired physiological condition, disorder, or disease that is associated with and/or mediated at least in part by an SCD protein. In some instances, SCD-associated disorders are associated with excess SCD levels and/or activity. SCDs introduce a double bond in the C9-C1 0 position of saturated fatty acids such as palmitoyl-CoA and stearoyl-CoA which are converted to palmitoleoyl-CoA and oleoyl-CoA, respectively. One SCD gene, SCD1 , has been characterized in humans for which there are two isoforms, SCD1 and SCD5. An SCD-associated disorder may be associated with and/or mediated at least in part by SCD1 and/or SCD5. Exemplary SCD-associated disorders include SCD-associated disorders include, but are not limited to metabolic disorders (e.g., diabetes (e.g., Type I diabetes and Type II diabetes), hyperglycemia, metabolic syndrome, obesity, lipid disorders, fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and hypertension), cancer, cardiovascular diseases, cerebrovascular diseases, kidney diseases, liver diseases, skin disorders (e.g., acne (e.g., acne vulgaris)), central nervous system (CNS) disorders, dementia, multiple sclerosis, schizophrenia, mild cognitive impairment, Alzheimer's Disease, cerebral amyloid angiopathy, and dementia associated with Down Syndrome. Additional SCD-associated disorders are described herein or known in the art.

As used herein, the term "subject" refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.

As used herein, the terms "treat," "treated," or "treating" mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

Brief Description of the Drawings

FIGS. 1 A and 1 B are graphs showing that growth inhibition by 1 ,2,4-oxadiazoles occurs through same mechanism as the rescue of toxicity in the apolipoprotein E4 (ApoE4) Alzheimer's disease yeast model. (Fig. 1 A) Compound 7, a representative 1 ,2,4-oxadiazole, was profiled in ApoE4 (top) and control (bottom) non-inducing conditions at 12-point dose (x-axis). The Y-axis shows raw Οϋβοο. Compound 7 exhibited a bell-shaped dose-response curve (DRC) in the ApoE4 model. Rescue decreased at concentrations just above the maximal efficacy (Emax). In the control condition (bottom panel), growth decreased at this same concentration. (Fig. 1 B) The relationship between Emax (rescue in ApoE4) and growth inhibition (in control condition) correlated across 34 tested 1 ,2,4-oxadiazoles. The maximal rescue dose (EC100) is shown on the y-axis for ApoE4 and minimal inhibitory dose (IC100) in the control condition is shown on the x-axis. This correlation indicates that growth inhibition is caused by the same on-target activity that rescues ApoE4 toxicity.

FIGS. 2A and 2B are graphs showing that exogenous oleic acid reverses growth inhibition and model rescue by Ole1 /SCD-targeting 1 ,2,4-oxadiazoles. Growth was measured by reading Οϋβοο in a microplate reader and normalized to solvent control DMSO samples. (Fig. 2A) Growth inhibition (24 h) of strain GM yapl flrl by Ole1 /SCD-targeting 1 ,2,4-oxadiazoles is reversed by exogenous 0.5 mM oleic/palmitoleic acid, which did not affect growth inhibition by other compounds (black dots indicate other scaffolds tested). Maximal growth inhibition across a dose range from 33 nM to 33 μΜ is plotted. (Fig. 2B) Rescue (40 h) of the yeast alpha-synuclein ("aSyn") model by 1 ,2,4-oxadiazoles was reversed by exogenous 0.5 mM oleic/palmitoleic acid, which did not affect rescue by other scaffolds. Maximal model rescue across a dose range from 33 nM to 33 μΜ is plotted. FIGS. 3A and 3B are graphs showing that point mutations in yeast OLE1 confer resistance to growth inhibition and alpha-synuclein model rescue by 1 ,2,4-oxadiazoles. Growth was measured by reading Οϋβοο in a microplate reader. (Fig. 3A) Yeast cells deleted for the chromosomal copy of OLE1 and expressing OLE1 (wild-type), ole1P123T, or ole1E188Q mutants from a pRS316-based plasmid were grown in complete synthetic medium (CSM)-glucose media at the indicated doses of 1 ,2,4-oxadiazole Compound 95 for 24 h. Growth was normalized to samples treated with the solvent control dimethyl sulfoxide (DMSO), set as "1 ". (Fig. 3B) Yeast cells deleted for the chromosomal copy of OLE1 and expressing OLE1 (Wild-type), ole1P123T, or ole1E188Q mutants from a pRS316-based plasmid were grown in CSM-galactose media (inducing expression of alpha-Synuclein) at the indicated doses of the 1 ,2,4-oxadiazole Compound 95 for 40 h. Growth was normalized to samples treated with the solvent control DMSO, where rescue is set as "1 ".

FIG. 4 is a graph showing that a o/e/Δ deletion mutant is resistant to the growth-inhibitory effects of 1 ,2,4-oxadiazoles, but not other compounds. Twenty-four hour growth (presented as raw Οϋβοο) of the o/e/Δ deletion strain in yeast extract-peptone-dextrose (YPD) media is shown, with drugs added at the indicated concentrations.

FIG. 5 is a graph showing that reducing OLE1 expression by deleting MGA2 rescues the growth of the ApoE4 yeast model. Yeast cells expressing ApoE4 were deleted for the MGA2 gene and their growth was assessed over time (compared to their isogenic, MGA2 wild-type counterpart). Growth was assessed by Οϋβοο. Where indicated, 0.08 or 0.32 mM of oleic and palmitoleic acids (each) as added to the growth media in 0.01 % tween (final).

FIG. 6 is a series of graphs showing that commercial Scd inhibitors target human SCD1 /SCD5 in yeast. Yeast surviving solely on yeast OLE1, or human SCD1 or SCD5, were treated with four commercial Scd inhibitors at indicated concentrations. Data are expressed as a percent of the DMSO- treated condition. All four compounds potently reduced growth of both SCD1 -expressing yeast and SCD5-expressing yeast, but not the strain expressing Ole1 . This growth inhibition was reversed by oleic/palmitoleic acid competition, similar to the results shown in Figs. 2A and 2B.

FIG. 7 is a series of graphs showing that 1 ,2,4-oxadiazoles target human SCD1 and SCD5. Three "SCD" strains expressing yeast OLE1 or human SCD1 or SCD5 were treated with five

representative 1 ,2,4-oxadiazoles and a cycloheximide toxicity control at concentrations indicated on the logio x-axis. The y-axis indicates the percent of the DMSO-treated condition. All of the 1 ,2,4-oxadiazole compounds potently inhibited Ole1 -expressing yeast and showed variable growth inhibition of the SCD1 or SCD5 yeast strains. These data confirm that 1 ,2,4-oxadiazoles target the human protein and link Scd inhibition to rescue of neurodegenerative disease models. Approximately one half of all (250) 1 ,2,4- oxadiazoles tested inhibited SCD1 or SCD5 in a manner that was reversed by oleic/palmitoleic acid treatment. Cyclohexamide, a translation inhibitor (top left panel), inhibited growth of all three strains with the same potency, indicating differences in growth inhibition was due to targeting the human protein.

FIGS. 8A-8D are graphs showing that treatment of yeast cells with the 1 ,2,4-oxadiazole

Compound 95 inhibits lipid desaturation. Exponentially-growing wild-type yeast cells were treated with the indicated doses of the 1 ,2,4-oxadiazole Compound 95 for the indicated times before cellular lysis, lipid extraction, and analysis by global LC-MS/MS profiling. The relative abundance (fraction of total cellular lipid signal) after 1 .5 h and 8 h of the most abundant saturated lipid, phosphatidylcholine 26:0, is depicted in Figs. 8A and 8B, respectively. The relative abundance after 1 .5 h and 8 h drug treatment of the most abundant lipid with 2 or more degrees of unsaturation, phosphatidylcholine 16:1 ; 18:1 , is depicted in Figs. 8C and 8D, respectively. The data indicate a >300-fold increase in the abundance of the saturated lipid phosphatidylcholine 26:0 after 8 h treatment with Compound 95, and a >12-fold decrease in the abundance of the unsaturated lipid phosphatidylcholine 16:1 , 18:1 , indicating that Compound 95 blocks cellular fatty acid desaturase activity (Ole1 is the only fatty acid desaturase in yeast).

FIG. 9 shows OLE1 mutations conferring resistance to growth inhibition to 1 ,2,4-oxadiazoles identified by genome sequencing of resistant mutants. Cells were plated on media containing 10 μΜ of the 1 ,2,4-oxadiazole Compound 155 and resistant colonies that emerged were isolated, and genomic DNA was prepared from mutants and the parental, drug-sensitive control strain. Genomic DNA sequence was aligned to the Saccharomyces cerevisiae reference and unique mutations in the 1 ,2,4-oxadiazole- resistant mutants were identified. The position of the mutations, the amino acid changes they encode, and the fold resistance (increase in minimal inhibitory concentration) of Compound 155 are shown.

Detailed Description of the Invention

The invention features compounds useful for the treatment of neurological disorders, e.g., by inhibiting a-synuclein toxicity in a cell such as a neural cell. Exemplary compounds described herein include compounds having a structure according to formula I or formula la:

Formula I Formula la or pharmaceutically acceptable salts thereof.

In some embodiments, the compound has the structure of any one of compounds 1 -746 in Table 1 . In some embodiments, the compound has the structure of any one of compounds 747-966 in Table 2A. In some emobdiments, the compound has the structure of any one of compounds 967-1 195 in Table

2B.

Other embodiments, as well as exemplary methods for the synthesis or production of these compounds, are described herein.

Pharmaceutical Uses

The compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to inhibit toxicity caused by protein aggregation, e.g., a-synuclein aggregation, in a cell.

Another aspect of the present invention relates to methods of treating and/or preventing a neurological disorder such as neurodegenerative diseases in a subject in need thereof. The pathology of neurodegenerative disease, may be characterized by the presence of inclusion bodies in brain tissue of affected patients.

In certain embodiments, neurological disorders that may be treated and/or prevented by the inventive methods include, but are not limited to, Alexander disease, Alper' s disease, AD, amyotrophic lateral sclerosis, ataxia telangiectasia, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Machado-Joseph disease, multiple sclerosis, PD, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Ref sum's disease, Sandhoff disease, Schilder' s disease, Steele- Richardson-Olszewski disease, tabes dorsalis, and Guillain-Barre Syndrome.

The compounds described herein are useful as inhibitors of stearoyl-CoA desaturase (SCD), including SCD1 and/or SCD5. SCD inhibitors are known in the art to be useful in methods of treating and/or preventing SCD-associated disorders. SCD-associated disorders are described, for example, in U.S. Patent No. 8,148,378, and in International Patent Application Publication Nos. WO 201 1 /047481 , WO 2010/1 12520, WO 2010/045374, WO 2010/028761 ; WO 2009150196, and WO

2009/106991 . Accordingly, another aspect of the present invention relates to methods of treating and/or preventing an SCD-associated disorder in a subject in need thereof.

SCD-associated disorders include metabolic disorders (e.g., insulin resistance, diabetes mellitus (e.g., Type I diabetes, Type II diabetes, non-insulin-dependent diabetes mellitus, gestational diabetes, and diabetic complications (e.g., diabetic peripheral neuropathy, diabetic nephropathy diseases, diabetic retinopathy, diabetic macroangiopathy, vascular complications of diabetes, and diabetic arteriosclerosis)), hyperglycemia, metabolic syndrome, hyperinsulinanemia, glucose intolerance, impaired glucose tolerance, body weight disorders (e.g., obesity (e.g., abdominal obesity), overweight, cachexia, body mass index, and anorexia), lipid disorders (e.g., abnormal lipid levels (e.g., elevated lipid levels, for example, in plasma), dyslipidemia (e.g., diabetic dyslipidemia), mixed dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, hyperbetalipoproteinemia, atherosclerosis,

hypercholesterolemia (e.g., familial hypercholesterolemia), low HDL, high LDL, diseases related to accumulation of lipids in liver, familial histiocytic reticulosis, lipoprotein lipase deficiency, polyunsaturated fatty acid (PUFA) disorder, fatty acid desaturation index (e.g. the ratio of 18:1 /1 8:0 fatty acids, or other fatty acids), and abnormal lipid metabolism disorders), disorders of abnormal plasma lipoprotein, disorders of pancreatic beta cell regeneration, fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), hypertension, and microalbuminemia, leptin related diseases, hyperleptinaemia, appetite disorder, essential fatty acid deficiency, and adverse weight gain associated with a drug therapy).

Additional SCD-associated disorders include cancer, including solid tumors or hematological malignancies (e.g., esophageal cancer, pancreatic cancer, endometrial cancer, kidney cancer, hepatoma, thyroid cancer, gallbladder cancer, prostate cancer, leukemia (e.g., lymphomas and myelomas), ENT- related cancer, brain cancer, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, uterine cancer, breast cancer, skin cancer, and prostate cancer), neoplasia, malignancy, metastases, tumors (benign or malignant), carcinogenesis, and hepatomas.

Further SCD-associated disorders include cardiovascular disease (e.g., heart disease, atherosclerosis, hypertension, lipidemia, dyslipidemia, elevated blood pressure, microalbuminemia, hyperuricaemia, hypercholesterolemia, hyperlipidemias, hypertriglyceridemias, arteriosclerosis, coronary artery disease, myocardial infarction, vascular complications of diabetes, and diabetic arteriosclerosis), inflammation, sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, hepatitis (e.g., sexual hepatitis), meibomitis, cystic fibrosis, pre-menstrual syndrome, osteoporosis, thrombosis, cardiovascular risks, weight loss, angina, high blood pressure, ischemia, cardiac ischemia, reperfusion injury, angioplastic restenosis, infertility, liver disease (e.g., fatty liver, cirrhosis, nonalcoholic steatohepatitis, liver fibrosis, and hepatitis C related steatosis), kidney disease (e.g., tubulointerstitial fibrosis, kidney lipid accumulation, glomerular sclerosis, and proteinuria), osteoarthritis (e.g., osteoarthritis of the knee), gastro-esophageal disease, sleep apnea, secondary hyperparathyroidism of renal osteodystrophy, peripheral vascular disease, cerebrovascular disease (e.g., stroke, ischemic stroke and transient ischemic attack (TIA), and ischemic retinopathy), hyperandrogenism, malignant syndrome, extrapyramidal symptoms, hyperuricemia, hypercoagulability, syndrome X, cataract, polycystic ovary syndrome, breathing abnormalities, sleep-disordered breathing, low back pain, gout, gallstone disease, myopathies, lipid myopathies (e.g., carnitine palmitoyltransferase deficiency (CPT I or CPT II)), autoimmune diseases (e.g., lupus, host versus graft rejection, and rejection of organ transplants), asthma, inflammatory bowel diseases, nephropathy, retinopathy, erythrohepatic protoporphyria, iron overload disorders, and hereditary hemochromatosis.

Still further SCD-associated disorders include central nervous system (CNS) disorders, dementia, schizophrenia, mild cognitive impairment, Alzheimer's Disease, cerebral amyloid angiopathy, dementia associated with Down Syndrome, other neurodegenerative diseases, psychiatric disorders, eye diseases, immune disorders, multiple sclerosis, neuropathy, and depression.

Additional SCD-associated disorders include skin disorders (e.g., acne (e.g., acne vulgaris), psoriasis, hirsutism, rosacea, seborrheic skin, oily skin (syn seborrhea), seborrheic dermatitis, hyperseborrhea, eczema, keloid scar, skin ageing, diseases related to production or secretions from mucous membranes, wrinkles, lack of adequate skin firmness, lack of adequate dermal hydration, insufficient sebum secretion, oily hair, shiny skin, greasy-looking skin, greasy-looking hair, and other skin conditions caused by lipid imbalance).

An SCD-associated disorder can also include a disease or condition which is, or is related to, viral diseases or infections.

In some embodiments, the SCD-associated disorder is acne (e.g., acne vulgaris). In some embodiments, the SCD-associated disorder is diabetes (e.g., type II diabetes, including diabetes with inadequate glycemic control). In some embodiments, the SCD-associated disorder is nonalcoholic fatty liver disease (NAFLD). In some embodiments, the SCD-associated disorder is nonalcoholic

steatohepatitis (NASH). In some embodiments, the SCD- associated disorder is cancer. In some embodiments, the SCD- associated disorder is obesity. In some embodiments, the SCD-associated disorder is metabolic syndrome (e.g., dyslipidemia, obesity, insulin resistance, hypertension,

microalbuminemia, hyperuricaemia, and hypercoagulability), syndrome X, diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, body weight disorders (e.g., obesity, overweight, cachexia, and anorexia), weight loss, body mass index, leptin related diseases, or a skin disorder (e.g., eczema, acne, psoriasis, and keloid scar). In some embodiments, the SCD-associated disorder is diabetes, metabolic syndrome, insulin resistance, obesity, a cardiovascular disorder, a CNS disorder, schizophrenia, or Alzheimer's disease.

Combination Formulations and Uses Thereof

The compounds of the invention can be combined with one or more therapeutic agents. In particular, the therapeutic agent can be one that treats or prophylactically treats any neurological disorder described herein.

Combination Therapies

A compound of the invention can be used alone or in combination with other agents that treat neurological disorders or symptoms associated therewith, or in combination with other types of treatment to treat, prevent, and/or reduce the risk of any neurological disorders. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, dosages of the compounds when combined should provide a therapeutic effect.

Pharmaceutical Compositions

The compounds of the invention are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.

Accordingly, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.

The compounds of the invention may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the scope of the invention. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

A compound of the invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound of the invention may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers.

A compound of the invention may also be administered parenterally. Solutions of a compound of the invention can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003, 20 ^th ed.) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer.

Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.

The compounds of the invention may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.

Dosages

The dosage of the compounds of the invention, and/or compositions comprising a compound of the invention, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds of the invention may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds of the invention are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form). Dose ranges include, for example, between 10-1000 mg (e.g., 50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered. Preferred dose ranges include, for example, between 0.05-15 mg/kg or between 0.5-1 5 mg/kg.

Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1 -50 mg/kg (e.g., 0.25-25 mg/kg). In exemplary, non-limiting embodiments, the dose may range from 0.5-5.0 mg/kg (e.g., 0.5, 1 .0, 1 .5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg/kg) or from 5.0-20 mg/kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg).

EXAMPLES

The synthesis of compounds of this invention can be synthesized according to one or more of the general schemes 1 -10 shown below. The variables recited in the general schemes below are as defined for Formulae I, II, III, and IV.

General sche

VI

An appropriately substituted carboxylic acid I can be coupled with an appropriately substituted piperidine II to provide ester III. This can be hydrolysed under variety of conditions to provide carboxylic acid intermediate IV. This can be condensed with a substituted N-hydroxyimidamide V to give the desired 1 ,2,4-oxadiazole compound VI.

XII

An appropriately substituted carboxylic acid VII can be coupled with an appropriately protected (where PG is an /V-protecting group) and substituted piperidine carboxylic acid VIII to provide intermediate IX. This can be deprotected using a variety of conditions to provide free amine intermediate X. This compound can be coupled using metal catalysis or under thermal conditions with a halogenated heterocycle such as XI to give the desired 1 ,2,4-oxadiazole (X ³ = O) or 1 ,2,4-thiadiazole (X ³ = S) compound XII.

General s

XIV

An appropriately substituted carboxylic acid I can be coupled with an appropriately substituted piperidine XIII to provide the desired heterocyclic compound XIV.

General scheme 4

XIV

An appropriately substituted acyl halide XV (where X is a halogen atom, e.g., chlorine) can be coupled with an appropriately substituted piperidine XIII to provide the desired heterocyclic compound XIV.

General scheme 5

An appropriately substituted alkyl intermediate XVI (where X is a good leaving group, e.g., a halogen atom or triflate) can undergo nucleophilic displacement with an appropriately substituted piperidine XIII to provide the desired heterocyclic compound XIV.

General

IXX

An appropriately substituted carboxylic acid IV can be coupled with an appropriately substituted ketone XVII (where X is a leaving group, e.g., bromine) to provide the intermediate compound XVII. This compound can be condensed with ammonium acetate to provide oxazole IXX.

Gene

XXIII

An appropriately protected and substituted thiomide XX can be coupled with an appropriately substituted ketone XVII (where X is a leaving group, most commonly bromine) to provide the protected (where PG is an amine protecting group, such as tert-butoxycarbonyl) thiazole compound XXI. This compound can be deprotected under appropriate conditions to give intermediate piperidine XXII. This can be coupled with and appropriately substituted carboxylic acid IV to provide thiazole XXIII. General

XXVI

An appropriately protected and substituted ester III can be treated with hydrazine to provide the hydrazide compound XXIV. This compound can coupled with an appropriately substituted acetimidate XXV to provide 1 ,3,4-oxadiazole XXVI.

General scheme 9

An appropriately substituted carboxylic acid IV can be couple with and appropriately substituted piperidine compound XXVII to give a compound XXVIM. This compound can be converted to the corresponding hydroxyimidamide compound XXIX. This is can be treated with an appropriately substituted acid halide (most commonly an acid chloride, where X=CI) XXX to provide 1 ,2,4-oxadiazole XXXI.

General scheme 10

XXXVI XXXVII

An appropriately substituted oxadiazolone XXXII can be converted to the appropriately substituted compound XXXIM. This compound can be coupled with the appropriate protected piperazine compound XXXIV (where PG is an /V-protecting group, for example, a tert-butyloxycarbonyl group) to give compound XXXV. This compound can be deprotected under the appropriate conditions to give piperazine compound XXXVI. This can be coupled with a carboxylic acid IV to provide 1 ,2,4-oxadiazole XXXVII. Experimental procedures

The compounds of the invention can be synthesized according to the following procedures. In the examples below, when purification by preparative HPLC was performed, a Gilson 281 semi-preparative HPLC system was used, using a variety of stationary and mobile phases which are described in the experimental section. For example, (column: Waters X bridge 150x2.5mm 5μιη ; mobile phase: [water (10 mM NH ₄ OAc)-acetonitrile]; B%: 36%-66%,12 min) indicates that the following purification conditions were used:

Mobile phase: A: 1 0mM NhUOAc in H2O; B: acetonitrile

Column: Waters Xbridge 150x2.5mm dimensions, 5 μιη particle size

Flow rate: 25ml_/min

Monitor wavelength: 220&254nm

Gradient:

Example 1. Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3^henyl-1,2,4-oxadiazol-5-yl)pi peridine-1^ carbonyl)pyrrolidin-2-one

Step 1: Preparation of 1-(3,4-dimethylphenyl)-5-oxopyrrolicline-3-carboxylic acid

A mixture of 2-methylenesuccinic acid (2.0 g, 1 .27 mL, 15.37 mmol) and 3,4-dimethylaniline (1 .86 g, 15.37 mmol) in water (20 mL) was stirred at 120 °C (reflux) for 16 h. The mixture was cooled to 25 °C and filtered. The filter cake was washed with cold water (5 mL) to give 1 -(3,4-dimethylphenyl)-5- oxopyrrolidine-3-carboxylic acid (3.0 g, 12.9 mmol, 84 %) as a yellow solid. This material was used directly in the next step without further purification. ¹ H NMR (400MHz, DMSO-d6) δ 7.40-7.35 (m, 2H), 7.13-7.1 1 (d, 1 H), 4.01 -3.93 (m, 2H), 3.34-3.30 (m, 1 H), 2.75-2.67 (m, 2H), 2.22 (s, 3H) 2.19 (s, 3H); LCMS (ESI) m/z: [M-H]- = 232.1 .

Step 2: Preparation of methyl 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperi dine-4- carboxylate

To a stirred solution of 1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carboxylic acid (1 .0 g, 4.29 mmol) and methyl piperidine-4-carboxylate (737 mg, 5.15 mmol) in N,N-dimethylformamide (10 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 .63 g, 4.29 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 .1 1 g, 8.58 mmol, 1 .50 mL). After stirring at 1 5 °C for 16 h, to the mixture was added water (20 mL) and the mixture extracted with ethyl acetate (20 mL x 4). The organic layer was washed with water (1 0 mL), saturated aqueous sodium chloride solution (10 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give crude product that was purified by chromatography on silica gel eluted with Petroleum ether/ethyl acetate from 1 /1 to 0/1 to give methyl 1 -(1 - (3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine- 4-carboxylate (1 .90 g, 5.30 mmol, quantitative) as a red oil. LCMS (ESI) m/z: [M+H]+ = 359.3. Step 3: Preparation of 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperi dine-4-carboxylic acid

To a stirred solution of methyl 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine -4- carboxylate (400 mg, 1 .12 mmol) in tetrahydrofuran (4 mL) was added aqueous sodium hydroxide (2 M, 1 .68 mL). The mixture was stirred at 40 °C for 2 h, then the mixture was acidified with concentrated hydrochloric acid until pH 1 . The mixture was extracted with dichloromethane (20 mL x 3), then the organic layer was washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3- carbonyl)piperidine-4-carboxylic acid (300 mg, 871 μιτιοΙ, 78 %) as a white solid that was used directly without further purification.

Step 4: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-phenyl- 1,2,4-oxadiazol-5-yl)piperidine- 1- carbonyl)pyrrolidin-2-one

To a stirred solution of 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine -4- carboxylic acid (253 mg, 734 μιτιοΙ) in N,N-dimethylformamide (1 mL) was added (2-(1 H-benzotriazol-1 - yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (279 mg, 734 μιτιοΙ) and N-ethyl-N-(propan-2- yl)propan-2-amine (285 mg, 2.20 mmol, 384 μί). The mixture was stirred at 25 °C for 5 min, then N- hydroxybenzimidamide (100 mg, 734 μιτιοΙ) was added. The mixture was warmed to 25 °C, stirred for 16 h, then the mixture was diluted with water (5 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined and washed with water (5 mL x 2) and saturated aqueous sodium chloride solution (5 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was dissolved in N,N-dimethylformamide (2 mL) and then heated at 120 °C for 3 h.

Without any additional work-up, the mixture was purified by prep-HPLC (Waters X bridge 1 50x25 5 μιη column; 36-66 % acetonitrile in a 1 0 mM ammonium acetate solution in water, 12 min gradient) to give 1 - (3,4-dimethylphenyl)-4-(4-(3-phenyl-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (73 mg, 164 μιτιοΙ, 22 %) as a white solid. Ή NMR (400MHz, CDC ) δ 8.1 0-8.09 (m, 2H), 7.55-7.49 (m, 3H), 7.39 (s, 1 H), 7.30 (s, 1 H), 7.15-7.13 (d, 1 H), 4.54-4.53 (m, 1 H), 4.31 -4.27 (m, 1 H), 3.98-3.90 (m., 2H), 3.60-3.56 (m, 1 H), 3.42-3.36 (m, 2H).3.15-2.95 (m, 2H), 2.86-2.79 (m, 1 H), 2.29-2.26(m, 8H), 2.03-1 .97 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 445.3. Example 2: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-y l)piperM carbonyl)pyrrolidin-2-one

To a stirred solution of 4-methylbenzonitrile (1 .0 g, 8.54 mmol, 1 .02 mL) in ethanol (10 mL) and water (1 mL) was added hydroxylamine hydrochloride (1 .19 g, 17.1 mmol) and triethylamine (1 .73 g, 1 7.1 mmol, 2.37 mL). The mixture was heated at 75 °C for 16 h, then the reaction mixture was concentrated under reduced pressure to give a residue that was diluted with water (5 mL), and then extracted with dichloromethane (8 mL x 10). The combined organic layers were washed with saturated aqueous sodium chloride solution (8 mL x 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a N-hydroxy-4-methylbenzimidamide (900 mg, 5.99 mmol, 70 %) as a light green solid. ¹ H NMR (400MHz, METHANOL-d4) d = 7.49 (d, J=8.2 Hz, 2H), 7.18 (d, J=7.9 Hz, 2H), 2.33 (s, 3H).

Step 2: Preparation of methyl 1-(3,4-dimethylphenyl)-4-(4-(3-(p-tolyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carbonyl)pyrrolidin-2-one

To a stirred solution of methyl 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine -4- carboxylate (229 mg, 666 μιηοΙ) in N,N-dimethylformamide (1 mL) was added (2-(1 H-benzotriazol-1 -yl)- 1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (253 mg, 666 μιηοΙ) and N-ethyl-N-(propan-2- yl)propan-2-amine (258 mg, 2.00 mmol, 349 μί). The mixture was stirred at 25 °C for 5 mins, then N- hydroxy-4-methylbenzimidamide (100 mg, 666 μιηοΙ) was added. After 16 h, the reaction mixture was extracted with ethyl acetate (5 mL x 3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Waters Xbridge 150x25 5μιτι; mobile phase: [water(10mM NH ₄ HC0 ₃ )-acetonitrile]; B%: 40%-70%,12min) to give 1 -(3,4-dimethylphenyl)-4-(4-(3-(p-tolyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (38 mg, 81 μιτιοΙ, 12%, 98.4% purity) as a white solid. H NMR (400MHz, CHLOROFORM-d) d = 7.89 (d, J=7.1

Hz, 2H), 7.29 (s, 1 H), 7.22 (t, J=7.9 Hz, 3H), 7.05 (d, J=8.2 Hz, 1 H), 4.50 - 4.38 (m, 1 H), 4.20 (t, J=8.4 Hz, 1 H), 3.95 - 3.79 (m, 2H), 3.49 (id, J=8.5, 1 6.9 Hz, 1 H), 3.36 - 3.20 (m, 2H), 3.12 - 2.97 (m, 1 H), 2.89 (td, J=8.7, 17.1 Hz, 1 H), 2.79 - 2.69 (m, 1 H), 2.35 (s, 3H), 2.18 (d, J=13.0 Hz, 7H), 2.00 - 1 .82 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 459.3.

Example 3: Preparation of 1-(3,4-dimethylphenyl)-4-[4-[3-(m-tolyl)-1,2,4-oxadiazol-5-y l]piper^ carbonyl]pyrrolidin-2-one

Step 1: Preparation of N-hydroxy-3-methylbenzimidamide.

To a stirred solution of 3-methylbenzonitrile (1 .0 g, 8.54 mmol, 1 .02 mL) in ethanol (10 mL) and water (1 mL) was added hydroxylamine hydrochloride (1 .19 g, 17.1 mmol) and triethylamine (1 .73 g, 17.1 mmol, 2.37 mL). The mixture was heated at 75 °C for 16 h and then concentrated under reduced pressure to give a residue that was then diluted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution (5mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give N-hydroxy-3-methyl-benzamidine (1 .05 g, solid) as a crude solid that was used directly in the next step without further purification. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.42 - 7.31 (m, 2H), 7.24 - 7.12 (m, 2H), 4.93 - 4.71 (s, 1 H), 3.67 - 3.58 (m, 1 H), 2.97 (q, J=7.3 Hz, 1 H), 2.30 (s, 3H), 1 .32 - 1 .23 (m, 1 H), 1 .18 - 1 .1 1 (m, 1 H).

Step 2: Preparation of 1-(3 -dimethylphenyl)-4-(4-(3-(m-tolyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1^ carbonyl)pyrrolidin-2-one

To a stirred solution of 1 -[1 -(3,4-dimethylphenyl)-5-oxo-pyrrolidine-3-carbonyl]piperidin e-4- carboxylic acid (229 mg, 666 μιηοΙ) in N,N-dimethylformamide (1 mL) was added (2-(1 H-benzotriazol-1 - yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (253 mg, 666 μιηοΙ) and N-ethyl-N-(propan-2- yl)propan-2-amine (258 mg, 2.00 mmol, 349 μί). The mixture was stirred at 25 °C for 5 mins then N- hydroxy-3-methyl-benzamidine (100 mg, 666 μιηοΙ) was added. After 16 h, the reaction mixture was diluted with water (1 mL) extracted with ethyl acetate (5 mL x 3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue that was purified by prep-HPLC (Waters X bridge 150x25 5μιη column, 41 %-71 % acetonitrile in an a 10 mM ammonium acetate solution in water, 12 min gradient) to give 1 -(3,4-dimethylphenyl)-4-[4-[3-(m-tolyl)-1 ,2,4-oxadiazol- 5-yl]piperidine-1 -carbonyl]pyrrolidin-2-one (1 18 mg, 266 μιηοΙ, 38 %) as a yellow solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.93 - 7.83 (m, 1 H), 7.40 - 7.30 (m, 3H), 7.16 - 7.07 (m, 1 H), 4.58 - 4.45 (m, 1 H), 4.29 - 4.25 (m 1 H), 4.00 -3.90 (m, 2H), 3.59 - 3.55 (m, 1 H), 3.43 - 3.24 (m, 2H), 3.19 - 3.01 (m, 1 H), 3.01 - 2.89 (m, 1 H), 2.87 - 2.74 (m, 1 H), 2.43 (s, 3H), 2.27 - 2.22 (m, 8H), 2.07 - 1 .90 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 459.3.

Example 4. 6-(5-( 1-( 1-(3,4-Dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidin -4-yl)- 1,2,4- oxadiazol-3-yl)-4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one Step 1: Preparation of 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile

To a stirred solution of 6-bromo-2H-benzo[b][1 ,4]oxazin-3(4H)-one (3.0g, 13.2 mmol) in N,N- dimethylformamide (35 mL) was added zinc cyanide (1 .24 g, 10.5 mmol, 668 μί) and

tetrakis(triphenylphosphine)palladium(0) (760 mg, 658 μιηοΙ) under nitrogen. The mixture was then stirred at 80 °C for 16 h, cooled to room temperature, and extracted with ethyl acetate (60 mL x 4). The combined organic layers were washed with saturated aqueous sodium chloride solution (15 mL) and dried over anhydrous sodium sulfate. The combined organic layers were concentrated to dryness to give the crude product. The crude product was further purified by trituration in ethyl acetate and used in the next step without further purification. 3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6-carbonitrile (3.40 g) was obtained as a white solid. LCMS (ESI) m/z: [M+H] ⁺ = 1 75.0.

Step 2: Preparation of 4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonit rile

To a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6-carbonitrile (3.30 g, 19.0 mmol) in N,N-dimethylformamide (35 mL) was added sodium hydride (758 mg, 19 mmol, 60% dispersion in mineral oil) and iodoethane (3.84 g, 25 mmol, 1 .97 mL) at 0 °C. The mixture was warmed to 20 °C.

After 3 h, the mixture was cooled to 0 °C, quenched by addition of water (50 mL), and extracted with ethyl acetate (60 ml_ x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50:1 to 5:1 ) to give 4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6-carbonitrile (1 .30 g, 6.43 mmol, 34 %) as a white solid. ¹ H NMR (400 MHz, CDCI3) δ 7.25 (dd, J = 1 .8, 8.3 Hz, 1 H), 7.17 (d, J = 1 .8 Hz, 1 H), 6.98 (d, J = 8.3 Hz, 1 H), 4.62 (s, 2H), 3.93 (q, J = 7.2 Hz, 2H), 1 .23 (t, J = 7.2 Hz, 3H); LCMS (ESI) m/z = 203.1

[M+H] ⁺ .

Step 3: Preparation of 4-ethyl-N-hydrox -3-oxo-3A-dihydro-2H-benzo[b][1A]oxazine-6-carboxi ida ide

To a stirred solution of 4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6-carbonitrile (1 .20 g, 5.93 mmol) In ethanol (20 mL) was added hydroxylamine hydrochloride (825 mg, 1 1 .9 mmol), triethylamine (1 .20 g, 1 1 .9 mmol, 1 .64 mL) and water (2 mL), then the mixture was heated at 75 °C. After 5 h, the mixture was cooled to 20 °C and water (20 mL) added. The mixture was extracted with ethyl acetate (30 mL x 3), then the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-ethyl- N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6-carboximidamide (1 .20 g, 5.10 mmol, 86 %) as a white solid that was used directly without further purification. Ή NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1 H), 7.44 (d, J = 1 .6 Hz, 1 H), 7.35 (dd, J = 1 .8, 8.4 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 5.87 (s, 2H), 4.66 (s, 2H), 3.96 (q, J = 7.0 Hz, 2H), 1 .18 (t, J = 7.0 Hz, 3H).

Step 4: Preparation of (E)- 1-(1-(3 -dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N-((4-ethyl-3- oxo-3,4- dihydro-2H-benzo[b][1 ]oxazin-6-yl)(hydroxyimino)methyl)piperidine-4-carboxamide

To a stirred solution of 4-ethyl-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-6- carboximidamide (150 mg, 638 μιηοΙ) in N,N-dimethylformamide (5 mL) was added 1 -(1 -(3,4- dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-car boxylic acid (220 mg, 638 μιηοΙ), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (242 mg, 638 μιηοΙ) and N-ethyl-N- (propan-2-yl)propan-2-amine (247 mg, 1 .91 mmol, 334 μί). After 16 h at 20 °C, the reaction mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (20 mL x 4), then the combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (E)-1 -(1 -(3,4-dimethylphenyl)-5- oxopyrrolidine-3-carbonyl)-N-((4-ethyl-3-oxo-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6- yl)(hydroxyimino)methyl)piperidine-4-carboxarriicle (450 mg) as a yellow oil. This material was used directly without further purification. LCMS (ESI) m/z = 562.3 [M+H] ⁺ .

Step 5: Preparation of 6-(5-(1-(1-(3 -dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidin

oxadiazol-3-yl)-4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one

(E)-1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N-((4-eth yl-3-oxo-3,4-dihydro-2H- benzo[b][1 ,4]oxazin-6-yl)(hydroxyimino)methyl)piperidine-4-carboxamide (450 mg, 801 μιηοΙ) was heated in N,N-dimethylformamide (3 mL) at 120 °C for 3 h. The mixture was cooled and purified directly by prep- HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-65%,12 min) to give 6-(5-(1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidin- 4-yl)- 1 ,2,4-oxadiazol-3-yl)-4-ethyl-2H-benzo[b][1 ,4]oxazin-3(4H)-one (142 mg, 255 μιτιοΙ, 32 %) as a white solid. Ή NMR (400 MHz, CDC ) δ 7.70-7.60 (m, 2H), 7.29 (s, 1 H), 7.22-7.1 9 (m, 1 H), 7.03 (dd, J = 8.3, 16.9 Hz, 2H), 4.60 (s, 2H), 4.56-4.40 (m, 1 H), 4.21 (d, J = 7.3 Hz, 1 H), 4.00 (d, J = 6.5 Hz, 2H), 3.96-3.78 (m, 2H), 3.49 (quin, J = 8.3 Hz, 1 H), 3.37-3.19 (m, 2H), 3.09-2.82 (m, 2H), 2.81 -2.69 (m, 1 H), 2.18 (d, J = 12.8 Hz, 8H), 1 .98-1 .82 (m, 2H), 1 .26 (t, J = 6.8 Hz, 3H); LCMS (ESI) [M+H] ⁺ = 544.2.

Example 5: Morpholino( 1-(3-phenyl- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)methanone.

Step 1: Preparation of tert-butyl 4-(morpholine-4-carbonyl)piperidine- 1-carboxylate

To a stirred solution of 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (300 mg, 1 .31 mmol) in N,N-dimethylformamide (10 mL) was added morpholine (136 mg, 1 .57 mmol, 138 μί), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (496 mg, 1 .31 mmol) and N-ethyl-N- (propan-2-yl)propan-2-amine (338 mg, 2.62 mmol, 457 μί). The mixture was stirred at 20 °C for 16 h, then quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 4-(morpholine-4-carbonyl)piperidine-1 - carboxylate (700 mg) as a yellow oil. This material was used directly without further purification. ¹ H NMR (400 MHz, CDC ) δ 3.72-3.51 (m, 5H), 3.45 (br. s., 1 H), 3.1 8-3.05 (m, 1 H), 2.93-2.86 (m, 3H), 2.81 (s, 3H), 2.75-2.71 (m, 2H), 2.59-2.48 (m, 1 H), 1 .39 (s, 9H).

Step 2: Preparation of morpholino(piperidin-

To a stirred solution of tert-butyl 4-(morpholine-4-carbonyl)piperidine-1 -carboxylate (700 mg, 2.35 mmol) in methanol (5 mL) was added 4N hydrochloric acid in methanol (15 mL). The mixture was stirred at 20 °C for 16 h then concentrated under reduced pressure to give morpholino(4-piperidyl)methanone (300 mg) as a colorless oil that was used directly without further purification. LCMS (ESI) [M+H] ⁺ = 199.1 .

Step 3: Preparation of 3-phenyl- 1 ,2,4-oxa

To a stirred solution of N-hydroxybenzamidine (2.0 g, 14.69 mmol) in dioxane (10 mL) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (2.46 g, 16 mmol, 2.44 mL) and 1 ,1 '-carbonyldiimidazole (3.57 g, 22 mmol). The mixture was stirred at 1 10 °C for 16 h, then cooled and quenched with water (10 mL). The mixture was extracted with dichloromethane (50 mL x 4), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product that was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :1 ) to give 3-phenyl-1 ,2,4-oxadiazol-5(4H)-one (1 .30 g, 8.02 mmol, 55 %) as a yellow solid. ¹ H NMR (400 MHz, Methanol-d4) δ 7.83-7.75 (m, 2H), 7.66-7.52 (m, 3H); LCMS (ESI) m/z = 163.2 [M+H] ⁺ . Step 4: Preparation of 5-chloro-3-phenyl- 1 ,2,4-oxadiazole

To a stirred solution of 3-phenyl-1 ,2,4-oxadiazol-5(4H)-one (500 mg, 3.08 mmol) equipped with calcium chloride tube was added N,N-dimethylformamide (1 mL). Phosphoryl chloride (10 mL) was added dropwise, and the resulting mixture was heated at 1 10 for 16 h. The reaction mixture was cooled to 20 °C and poured onto ice water (100 mL), and the resulting mixture was stirred for 30 min. The mixture was extracted with dichloromethane (20 mL x 5), then the combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50:1 ) to give 5-chloro-3-phenyl-1 ,2,4-oxadiazole (180 mg, 997 μιτιοΙ, 32 %) as a yellow oil. ¹ H NMR (400 MHz, CDCb) 6 8.10-7.98 (m, 2H), 7.57-7.46 (m, 3H).

Step 5: Preparation of morpholino(1 -(3-ph eridin-4-yl)methanone

To a stirred solution of morpholino(piperidin-4-yl)methanone (180 mg, 908 μιηοΙ) in N-methyl-2- pyrrolidone (5 mL) was added 5-chloro-3-phenyl-1 ,2,4-oxadiazole (163 mg, 908 μιηοΙ) and N-ethyl-N- (propan-2-yl)propan-2-amine (234 mg, 1 .82 mmol, 317 μί). The mixture was stirred at 120 °C for 16 h then cooled and purified directly by prep-HPLC (column: Waters Xbridge 150x25 5μιη; mobile phase: [water (1 0 mM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12 min) to give morpholino(1 -(3- phenyl-1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)methanone (130 mg, 380 μιηοΙ, 42 %) as a yellow solid. ¹ H NMR (400 MHz, Methanol-d4) 6 8.00-7.94 (m, 2H), 7.55-7.45 (m, 3H), 4.26 (d, J = 13.3 Hz, 2H), 3.74- 3.59 (m, 8H), 3.32-3.26 (m, 2H), 3.08-2.98 (m, 1 H), 1 .92-1 .75 ppm (m, 4H); LCMS (ESI) [M+H] ⁺ = 343.2.

Example 6: ( 1-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1- yl)

Step 1: Preparation of tert-butyl 4-(piperidine- 1 -carbonyl)piperidine- 1 -carboxylate.

To a mixture of 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (300 mg, 1 .31 mmol), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (496 mg, 1 .31 mmol) and N-ethyl-N- (propan-2-yl)propan-2-amine (338 mg, 2.62 mmol, 457 μΙ_) in N,N-dimethylformamide (1 mL) was added piperidine (133 mg, 1 .57 mmol, 155 μί) at 0°C. The mixture was stirred at 25 °C for 2 h. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl 4-(piperidine-1 - carbonyl)piperidine-1 -carboxylate (600 mg) as a yellow oil. This material was used directly without further purification. ¹ H NMR (400MHz, CDCb) δ 3.73 (dd, J = 6.4, 9.9 Hz, 1 H), 3.55 (br. s., 2H), 3.44 (br. s., 2H), 3.29-3.15 (m, 2H), 2.68-2.57 (m, 1 H), 1 .96-1 .83 (m, 1 H), 1 .77-1 .62 (m, 8H), 1 .56 (br. s., 4H), 1 .46 (s, 9H); LCMS (ESI) m/z = 297.3 [M+H] ⁺ .

Step 2: Preparation of piperidin- 1-yl(piperid

To a mixture of tert-butyl 4-(piperidine-1 -carbonyl)piperidine-1 -carboxylate (500 mg, 1 .69 mmol) in methanol (5 mL) was added 4M methanolic hydrochloric acid (10 mL) at 0°C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to give piperidin-1 -yl(piperidin-4-yl)methanone (300 mg) as a yellow oil which was used in the next step directly without further purification. LCMS (ESI) [M+H] ⁺ = 197.3.

Step 3: Preparation of 3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5(4H)-one.

A mixture of N-hydroxy-3,4-dimethoxybenzimidamide (1 .0 g, 5.10 mmol), 1 ,8- diazabicyclo[5.4.0]undec-7-ene (853 mg, 5.61 mmol, 845 μί) and 1 ,1 '-carbonyldiimidazole (1 .24 g, 7.65 mmol) in dioxane (10 mL) was prepared at 15°C. The mixture was warmed to 1 1 0°C for 12 h. The mixture was cooled to 15°C and then poured into water (5 mL). The aqueous phase was extracted with dichloromethane (10 mL x 5), then the combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5(4H)-one (800 mg) as a yellow solid. ¹ H NMR (400MHz, CDCb) δ 7.60-7.52 (m, 2H), 6.88 (d, J = 8.8 Hz, 1 H), 3.91 (d, J = 6.1 Hz, 6H); LCMS (ESI) m/z = 223.2 [M+H] ⁺ . Step 4: Preparation of 5-chloro-3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazole.

3-(3,4-Dimethoxyphenyl)-1 ,2,4-oxadiazol-5(4H)-one (500 mg, 2.25 mmol) was added to a mixture of phosphoryl chloride (13.2 g, 86.1 mmol, 8 mL) and N,N-dimethylformamide (1 mL). The mixture was equipped with a calcium chloride tube and heated at 100 °C for 16 h, at which time the mixture was cooled and concentrated in vacuo at 45 °C. The residue was poured into ice-water (w/w = 10/1 ) (1 1 mL) and stirred for 10 min. The mixture was extracted with dichloromethane (10 mL x 5), then the combined organic phases were washed with saturated aqueous sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by

chromatography (silica, petroleum ether: ethyl acetate = 5:1 to 1 :1 gradient) to afford 5-chloro-3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazole (200 mg, 0.83 mmol, 37 %) as a yellow solid. ¹ H NMR (400MHz, CDCb) δ 7.67 (dd, J = 2.0, 8.4 Hz, 1 H), 7.53 (d, J = 2.0 Hz, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 3.96 (d, J = 2.4 Hz, 6H); LCMS (ESI) m/z =241 .1 [M+H] ⁺ . Step 5: Preparation of (1 -(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin- 1- yl)methanone.

To a stirred solution of 5-chloro-3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazole (200 mg, 831 μιηοΙ) and triethylamine (252 mg, 2.49 mmol, 345 μί) in dichloromethane (2 mL) was added piperidin-1 - yl(piperidin-4-yl)methanone (163 mg, 831 μιηοΙ) at 0 °C. The mixture was warmed to 15 °C and stirred for 2h, then concentrated in vacuo to afford crude product. The residue was purified by prep-HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (10 mM ammonium carbonate)-acetonitrile]; B%: 20%- 55%, 12 min) to give (1 -(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1 - yl)methanone (36 mg, 89.7 μιτιοΙ, 1 1 %) as a yellow solid. Ή NMR (400MHz, CDCb) δ 7.61 (d, J = 8.4 Hz, 1 H), 7.51 (s, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 4.28 (d, J = 13.2 Hz, 2H), 3.95 (d, J = 8.8 Hz, 6H), 3.65- 3.41 (m, 4H), 3.30-3.15 (m, 2H), 2.85-2.69 (m, 1 H), 2.01 -1 .89 (m, 2H), 1 .88-1 .79 (m, 2H), 1 .68 (d, J = 4.9 Hz, 2H), 1 .61 (br. s., 1 H); LCMS (ESI) m/z = [M+H] ⁺ : 401 .2. Example 7: N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid.

To a stirred solution of methyl 1 -(2-benzamidoacetyl)piperidine-4-carboxylate (5.0 g, 1 6.4 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide (2 M, 16.4 mL). The mixture was stirred at 20 °C for 2 h and then acidified by the addition of concentrated hydrochloric acid until pH 1 . The mixture was extracted with dichloromethane (80 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (3.25 g, 1 1 .2 mmol, 68 %) as a yellow solid. Ή NMR (400 MHz, Methanol-d4) δ 7.87 (d, J=7.5 Hz, 2H), 7.59 - 7.42 (m, 3H), 4.39 - 4.20 (m, 3H), 3.92 (d, J=14.1 Hz, 1 H), 3.24 (t, J=1 1 .5 Hz, 1 H), 2.98 - 2.88 (m, 1 H), 2.62 (s, 1 H), 2.08 - 1 .89 (m, 2H), 1 .81 - 1 .53 (m, 2H).

Step 2: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (2.0 g, 6.89 mmol) in

N,N-dimethylformamide (30 mL) was added N-hydroxy-3,4-dimethoxybenzimidamide (1 .62 g, 8.27 mmol), N-ethyl-N-(propan-2-yl)propan-2-amine (2.67 g, 20.67 mmol, 3.61 mL) and 1 -

[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (2.62 g, 6.89 mmol). The mixture was stirred at 20 °C for 2 h and then warmed at 120 °C for 2 h. The reaction mixture was quenched by addition of water (40 mL), then the mixture was extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product that was purified by chromatography (silica, petroleum ether : ethyl acetate = 20 : 1 to 1 : 2) to give a yellow solid. The yellow solid was washed with ethyl acetate (30 mL), then the mixture was filtered, and the filter cake was dried in vacuo to give N-(2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (1 .29 g, 2.86 mmol, 42 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 7.92 - 7.84 (m, 2H), 7.80 (s, 1 H), 7.58 - 7.44 (m, 3H), 7.41 - 7.35 (m, 1 H), 7.28 - 7.26 (m, 2H), 6.92 (d, J=8.9 Hz, 1 H), 4.58 - 4.47 (m, 1 H), 4.32 (d, J=3.9 Hz, 2H), 3.99 - 3.88 (m, 7H), 3.37 - 3.06 (m, 3H), 2.28 - 2.13 (m, 2H), 2.07 - 1 .89 (m, 2H); LCMS (ESI) [M+H] ⁺ = 451 .3.

Example 8: (4-(3-(3-fluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)(4- isopropylphenyl)methanone.

Step 1: Preparation of methyl 1-(4-isopropylbenzoyl)piperidine-4-carboxylate.

To a stirred solution of 4-isopropylbenzoic acid (250 mg, 1 .52 mmol) in N,N-dimethylformamide

(10 mL) was added methyl piperidine-4-carboxylate (261 mg, 1 .82 mmol), (2-(1 H-benzotriazol-1 -yl)- 1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (576 mg, 1 .52 mmol) and N-ethyl-N-(propan-2- yl)propan-2-amine (392 mg, 3.04 mmol, 530 μί). The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with water (10 mL), then the mixture was extracted with ethyl acetate (20 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product methyl 1 -(4- isopropylbenzoyl)piperidine-4-carboxylate (900 mg) as a yellow oil. LCMS (ESI) m/z: 290.3 [M+H] ⁺ . Step 2: Preparation of 1-(4-isopropylbenzoyl)piperidine-4-carboxylic acid.

To a stirred solution of methyl 1 -(4-isopropylbenzoyl)piperidine-4-carboxylate (900 mg, 3.1 1 mmol) in tetrahydrofuran (10 mL) was added aqueous sodium hydroxide (2 M, 3.1 1 mL). The mixture was stirred at 20 for 16 h. The mixture was acidified to pH 1 by dropwise addition of concentrated hydrochloric acid. The mixture was extracted with dichloromethane (20 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 1 -(4-isopropylbenzoyl)piperidine-4- carboxylic acid (400 mg) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 276.2.

Step 3: Preparation of 3-fluoro-N-hydroxybenzimidamide.

To a stirred solution of 3-fluorobenzonitrile (1 .0 g, 8.26 mmol, 884 μί) in ethanol (10 mL) were added hydroxylamine hydrochloride (1 .15 g, 1 6.5 mmol), triethylamine (2.09 g, 20.7 mmol, 2.86 mL), and water (1 mL). Then the mixture was heated at 75 °C for 16 h. After cooling to 20 °C, water (10 mL) was added to the solution. The mixture was extracted with ethyl acetate (20 mL x 5). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-fluoro-N-hydroxybenzimidamide (2.0 g) as a green solid that was used directly in the next step without further purification. LCMS (ESI) m/z: 155.1

[M+H] ⁺ .

Step 4: Preparation of (E)^-((3 luorophenyl)(hydroxyimino)methyl)- 1-(4-isopropylbenzoyl)piperidine-4- carboxamide.

To a stirred solution of 1 -(4-isopropylbenzoyl)piperidine-4-carboxylic acid (400 mg, 1 .45 mmol) in

N,N-dimethylformamide (10 mL) were added 3-fluoro-N-hydroxybenzimidamide (223 mg, 1 .45 mmol), (2- (1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (550 mg, 1 .45 mmol) and N- ethyl-N-(propan-2-yl)propan-2-amine (563 mg, 4.36 mmol, 761 μί). The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (20 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (E)-N-((3- fluorophenyl)(hydroxyimino)methyl)-1 -(4-isopropylbenzoyl)piperidine-4-carboxam (350 mg) as a yellow oil. LCMS (ESI) m/z: 412.3 [M+H] ⁺ .

Step 5: Preparation of (4-(3-(3-fluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin

isopropylphenyl)methanone.

(E)-N-((3-Fluorophenyl)(hydroxyimino)methyl)-1 -(4-isopropylbenzoyl)piperidine-4-carboxamide (350 mg, 851 μιηοΙ) was added to N,N-dimethylformamide (3 mL), and the mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled and purified by direct injection and prep-HPLC (column:

Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 50%-80%,12 min) to give (4-(3-(3-fluorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)(4- isopropylphenyl)methanone (82 mg, 210 μιηοΙ, 25 %) as a yellow oil. ¹ H NMR (400 MHz, Methanol-d4) δ 7.92 (d, J = 7.8 Hz, 1 H), 7.79 (d, J = 9.7 Hz, 1 H), 7.57 (d, J = 5.6 Hz, 1 H), 7.42-7.28 (m, 5H), 4.69-4.50 (m, 1 H), 3.89 (br. s., 1 H), 3.53-3.42 (m, 1 H), 3.39-3.34 (m, 1 H), 3.32-3.28 (m, 1 H), 2.99 (td, J = 6.9, 13.8 Hz, 1 H), 2.43-2.09 (m, 2H), 2.07-1 .83 (m, 2H), 1 .30 (s, 3H), 1 .29 (s, 3H); LCMS (ESI) m/z [M+H] ⁺ = 394.2.

Example 9: N-(2-oxo-2-(4-(3-phenyl- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide.

Step 1: Preparation of methyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate.

To a stirred solution of 2-benzamidoacetic acid (3.0 g, 16.7 mmol) in N,N-dimethylformamide (30 mL) were added methyl piperidine-4-carboxylate (2.88 g, 20.09 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (6.35 g, 16.7 mmol), and N-ethyl-N-(propan-2-yl)propan-2- amine (6.49 g, 50.2 mmol, 8.77 mL). The mixture was stirred at 20 °C for 3 h and then quenched by addition of water (40 mL). The mixture was extracted with ethyl acetate (80 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product that was purified by chromatography (silica, petroleum ether : ethyl acetate = 5:1 to 1 :1 ) to give methyl 1 -(2- benzamidoacetyl)piperidine-4-carboxylate (7.0 g, 23.0 mmol, quantitative), as a yellow oil. LCMS (ESI) m/z = 305.1 [M+H] ⁺ . Step 2: Preparation of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid.

To a stirred solution of methyl 1 -(2-benzamidoacetyl)piperidine-4-carboxylate (7.0 g, 23.0 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide (2 M, 23 mL). The mixture was then stirred at 20 °C for 16 h. The mixture was then acidified to pH 1 using concentrated hydrochloric acid and then extracted with dichloromethane (80 mL x 4). The organic phases were combined, washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (4.20 g, 14.47 mmol, 63 %) as a yellow solid. This was used directly in the next step without further purification. ¹ H NMR (400 MHz, Methanol-d4) δ 7.93-7.85 (m, 2H), 7.59-7.54 (m, 1 H), 7.52-7.46 (m, 2H), 4.42-4.33 (m, 1 H), 4.29 (s, 2H), 4.01 -3.87 (m, 1 H), 3.30-3.20 (m, 1 H), 2.97-2.88 (m, 1 H), 2.63-2.52 (m, 1 H), 2.06-1 .92 (m, 2H), 1 .80-1 .55 (m, 2H).

Step 3: Preparation of N-(2-oxo-2-(4-(3-phenyl- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)ethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (200 mg, 689 μιηοΙ) in

N,N-dimethylformamide (4 mL) were added /V-hydroxybenzamidine (1 12 mg, 826 μιηοΙ), Ν,Ν,Ν',Ν'- tetramethyl-0-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate (261 mg, 689 μιηοΙ), and N,N- diisopropylethylamine (267 mg, 2.07 mmol, 360.96 μί). The reaction mixture was then stirred at 20 °C for 2 h, quenched by addition of water (5 mL), and extracted with ethyl acetate (20 mL x4). The organic extracts were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to provide a crude residue. To the residue was added N,N- dimethylformamide (4 mL), and the resulting mixture was stirred at 120 for 2 h, concentrated under vacuum, and purified by prep-HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-(2-oxo-2-(4-(3-phenyl-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)ethyl)benzamide (74 mg, 189 μιηοΙ, 27 %) as a white solid. ¹ H NMR (400

MHz, CDCb) δ 8.13-8.08 (m, 2H), 7.88 (d, J = 7.2 Hz, 2H), 7.55-7.46 (m, 6H), 7.36 (br. s., 1 H), 4.51 (d, J = 13.7 Hz, 1 H), 4.33 (d, J = 3.8 Hz, 2H), 3.94 (d, J = 13.3 Hz, 1 H), 3.42-3.32 (m, 2H), 3.20 (t, = 1 0.5 Hz, 1 H), 2.28 (br. s., 2H), 2.1 1 -1 .96 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 391 .1 . Example 10: N-(2-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) and

N-hydroxy-4-methoxybenzimidamide (82 mg, 496 μιηοΙ) in N,N-dimethylformamide (2 ml_) were added N,N-diisopropylamine (106 mg, 827 μιτιοΙ, 144 μΙ_) and (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ) at 15 °C, then the mixture was stirred for 15h. The mixture was heated to 1 1 0 °C and stirred for 5h. After cooling, the mixture was purified directly by prep-HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (1 OmM ammonium carbonate)- acetonitrile]; B%: 30%-65%,12 min) to give N-(2-(4-(3-(4-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)-2-oxoethyl)benzamide (87 mg, 205 μιτιοΙ, 50 %) as a yellow solid. ¹ H NMR (400 MHz, Methanol-d4) δ 7.98 (d, J=8.8 Hz, 2H), 7.88 (d, J=7.5 Hz, 2H), 7.60 - 7.51 (m, 1 H), 7.51 - 7.38 (m, 2H), 7.04 (d, J=8.4 Hz, 2H), 4.46 (d, J=13.2 Hz, 1 H), 4.38 - 4.21 (m, 2H), 4.04 (d, J=13.7 Hz, 1 H), 3.86 (s, 3H), 3.47 - 3.34 (m, 2H), 3.07 (t, J=1 1 .9 Hz, 1 H), 2.31 - 2.15 (m, 2H), 2.05 - 1 .80 (m, 2H); LCMS (ESI) m/z [M+H] ⁺ = 421 .1 .

Example 11

Step 1: Preparation of N-hydroxy-3-methoxybenzimidamide.

To a stirred solution of 3-methoxybenzonitrile (2.0 g, 1 5.0 mmol, 1 .83 mL) in ethanol (20 mL) was added hydroxylamine hydrochloride (2.09 g, 30.0 mmol), triethylamine (3.04 g, 30.0 mmol, 4.16 mL) and water (2 mL). Then the mixture was heated at 75 °C for 5 h. After cooling to 20 °C, water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (40 mL x 4). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. The combined organic phases were concentrated in vacuo to give N-hydroxy- 3-methoxybenzimidamide (2.60 g) as a white solid. This was used directly without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1 H), 7.37-7.24 (m, 3H), 7.10-6.88 (m, 1 H), 5.84 (br. s., 2H), 3.82 (s, 3H). Step 2: Preparation of N-(2-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin

oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) in N,N-dimethylformamide (3 mL) were added N-hydroxy-3-methoxybenzimidamide (82 mg, 496 μιηοΙ), (2- (1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ), and N- ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 μΙ_). The mixture was stirred at 20 °C for 2 h, then heated at 120 for 2 h. The reaction mixture was cooled and purified directly by prep-HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-60%,12 min) to give N-(2-(4-(3-(3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (83 mg, 198 μιηοΙ, 48 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 7.91 -7.85 (m, 2H), 7.72-7.68 (m, 1 H), 7.62 (dd, J = 1 .5, 2.5 Hz, 1 H), 7.57-7.52 (m, 1 H), 7.51 -7.45 (m, 2H), 7.42 (t, J = 8.0 Hz, 1 H), 7.38-7.32 (m, 1 H), 7.08 (ddd, J = 0.9, 2.6, 8.3 Hz, 1 H), 4.52 (d, J = 13.6 Hz, 1 H), 4.33 (d, J = 4.0 Hz, 2H), 3.95 (br. s., 1 H), 3.91 (s, 3H), 3.42-3.32 (m, 2H), 3.25-3.13 (m, 1 H), 2.33-2.22 (m, 2H), 2.1 1 -1 .94 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 421 .2.

Example 12: N-(2-(4-(3-(2-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoeth l benzamide

Step 1: Preparation of N-hydroxy-2-methoxybenzim

To a stirred solution of 2-methoxybenzonitrile (2.0 g, 1 5.0 mmol, 1 .83 mL) in ethanol (20 mL) were added hydroxylamine hydrochloride (2.09 g, 30.0 mmol), triethylamine (3.04 g, 30.0 mmol, 4.16 mL), and water (2 mL), then the mixture was heated to 70 °C for 15h. The mixture was cooled and quenched with water (20 mL), extracted with dichloromethane (30 mL x 3), and the combined organic phases were washed with water (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give N-hydroxy-2-methoxybenzimidamide (2.80 g) as a light green solid, which was used in next step directly. ¹ H NMR (400 MHz, Methanol-d4) δ 7.47 - 7.30 (m, 2H), 7.06 (d, J=8.4 Hz, 1 H), 6.95 (t, J=7.5 Hz, 1 H), 3.86 (s, 3H). Step 2: Preparation of N-(2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) and N-hydroxy-2-methoxybenzimidamide (68 mg, 413 μιηοΙ) in N,N-dimethylformamide (2 mL) were added N- ethyl-N-(propan-2-yl)propan-2-amine (106 mg, 826 μιτιοΙ, 144 μΙ_) and (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ), and the mixture was stirred for 15 h at 15 °C. The mixture was then heated to 1 1 0 °C and stirred for 5h. After cooling, the mixture was purified directly by prep-HPLC (column: Luna C8 100x30 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 25%-60%,12 min) to give N-(2-(4-(3-(2-methoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (90 mg, 212 μιτιοΙ, 51 %) as a yellow solid. ¹ H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J=7.5 Hz, 1 H), 7.88 (d, J=7.9 Hz, 2H), 7.61 - 7.41 (m, 4H), 7.18 (d, J=8.8 Hz, 1 H), 7.09 (t, J=7.5 Hz, 1 H), 4.47 (d, J=13.2 Hz, 1 H), 4.37 - 4.23 (m, 2H), 4.12 - 4.00 (m, 1 H), 3.93 (s, 3H), 3.50 - 3.35 (m, 2H), 3.08 (t, J=1 1 .5 Hz, 1 H), 2.33 - 2.1 5 (m, 2H), 2.12 - 1 .79 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 421 .1 .

Example 13: N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1^ipe ridyl]-2-ox

methyl-benzamide.

Step 1: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-oxoethyl)-4- methylbenzamide.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 μιτιοΙ) in N,N-dimethylformamide (2 mL) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 μί) and 2-[(4-methylbenzoyl)amino]acetic acid (105 mg, 544 μιτιοΙ). The mixture was stirred at 20 °C for 5 h. The crude product was purified by prep-HPLC (column: Luna C8 100x30mm 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%:30%-60%,12 min) to give N-(2-(4-(3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)-4-methylbenzamide.

1 H NMR (400MHz, METHANOL-d4) δ = 7.77 (d, J=7.5 Hz, 2H), 7.66 (d, J=8.2 Hz, 1 H), 7.59 (s, 1 H), 7.29 (d, J=7.7 Hz, 2H), 7.08 (d, J=8.4 Hz, 1 H), 4.47 (d, J=12.8 Hz, 1 H), 4.29 (m, J=6.0 Hz, 2H), 4.05 (d, J=14.1 Hz, 1 H), 3.89 (s, 6H), 3.50 - 3.34 (m, 3H), 3.06 (t, J=12.0 Hz, 1 H), 2.40 (s, 3H), 2.32 - 2.13 (t, 2H), 2.07 1 .79 (m, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 465.3.

Example 14: N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3- methylbenzamide.

Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2-oxoethyl)-3- methylbenzamide

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (200 mg, 691 μιτιοΙ) in N,N-dimethylformamide (2 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (268 mg, 2.07 mmol, 362 μΙ_), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (262 mg, 691 μιηοΙ) and 2-[(3-methylbenzoyl)amino]acetic acid (133 mg, 691 μιηοΙ). The mixture was stirred at 20 °C for 16 h. The crude product was purified by prep-HPLC (column: Luna C8 100x30 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-[2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]-3-methyl-benzamide (157 mg, 338 μιηοΙ, 49 %) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 8.48 (t, J=5.5 Hz, 1 H), 7.72 - 7.63 (m, 2H), 7.58 (dd, J=2.0, 8.4 Hz, 1 H), 7.46 (d, J=1 .8 Hz, 1 H), 7.34 (d, J=4.9 Hz, 2H), 7.1 1 (d, J=8.4 Hz, 1 H), 4.32 (br d, J=13.0 Hz, 1 H), 4.1 5 (dd, J=2.3, 5.4 Hz, 2H), 3.96 (d, J=13.7 Hz, 1 H), 3.87 - 3.77 (m, 6H), 3.51 - 3.39 (m, 1 H), 3.24 (s, 1 H), 2.90 (t, J=1 1 .6 Hz, 1 H), 2.35 (s, 3H), 2.20 - 2.04 (m, 2H), 1 .89 - 1 .75 (m, 1 H), 1 .72 - 1 .54 (m, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 465.3.

Example 15: N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4- dimethylbenzamide

Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2-oxoethyl)-3,4- dimethylbenzamide

To a stirred solution of 1 -[2-[(3,4-dimethylbenzoyl)amino]acetyl]piperidine-4-carboxyl ic acid (200 mg, 628 μιηοΙ) and N-hydroxy-3,4-dimethoxy-benzamidine (184 mg, 942 μιτιοΙ) in N,N-dimethylformamide (1 .50 mL) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (238 mg, 628 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (243 mg, 1 .88 mmol, 329 μί). The mixture was stirred at 20 for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. N,N-Dimethylformamide (2 mL) was added, then the mixture was heated to 120 °C and stirred for a further 4 h. The mixture was cooled to 25 °C, then water (5mL) was added, and the mixture extracted with ethyl acetate (1 0 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. This residue was purified by prep-HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-65%,12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]- 3,4-dimethyl-benzamide (209 mg, 436 μιτιοΙ, 69 %) as a yellow solid. ¹ H NMR (400MHz, DMSO-d6) δ = 8.40 (s, 1 H), 7.66 (s, 1 H), 7.59 (br d, J=7.9 Hz, 2H), 7.46 (s, 1 H), 7.21 (br d, J=7.7 Hz, 1 H), 7.1 1 (br d, J=8.4 Hz, 1 H), 4.32 (br d, J=12.6 Hz, 1 H), 4.14 (br s, 2H), 3.96 (br d, J=13.5 Hz, 1 H), 3.89 - 3.72 (m, 6H), 3.43 (br t, J=10.8 Hz, 1 H), 3.28 - 3.17 (m, 1 H), 2.90 (br t, J=1 1 .5 Hz, 1 H), 2.26 (s, 6H), 2.20-2.10 (m, 2H), 1 .80 (br d, J=10.4 Hz, 1 H), 1 .64 (br d, J=10.1 Hz, 1 H). (ESI) m/z: [M+H] ⁺ = 479.3. Example 16: N-(2-(4-(3-(4-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4- dimethylbenzamide

Step 1: Preparation of tert-butyl 2-(3,4-dimethylbenzamido)acetate.

To a stirred solution of 3,4-dimethylbenzoic acid (2.0 g, 13.3 mmol) and tert-butyl 2-aminoacetate (1 .92 g, 14.7 mmol) in N,N-dimethylformamide (20 mL) were added N-ethyl-N-(propan-2-yl)propan-2- amine (3.44 g, 26.6 mmol, 4.65 mL) and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (5.06 g, 13.3 mmol). After stirring at 1 5 °C for 3h, the mixture was treated with water (30 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phases were washed with water (20 mL), 1 N hydrochloric acid (30 mL), saturated aqueous sodium hydrogen carbonate (30 mL), saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 2-(3,4-dimethylbenzamido)acetate (4.0 g) as light brown oil, which was used in the next step directly without further purification. ¹ H NMR (400 MHz, CDC ) δ 7.52 (d, J=1 .6 Hz, 1 H), 7.46 (dd, J=1 .9, 7.9 Hz, 1 H), 7.1 1 (d, J=7.8 Hz, 1 H), 4.08 - 4.04 (m, 2H), 2.23 (s, 6H), 1 .44 (s, 9H).

Step 2: Preparation of 2-(3,4-dimethylbenzamido)acetic acid

A solution of tert-butyl 2-(3,4-dimethylbenzamido)acetate (4.0 g, 15.2 mmol) in TFA (20 mL) and dichloromethane (20 mL) was stirred for 20 h at 15 °C. The mixture was concentrated, and the residue was treated with water (1 0 mL) and extracted with dichloromethane/methanol (20/1 , 20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 2- (3,4-dimethylbenzamido)acetic acid (3.20 g) as a yellow oil, which was used in next step directly without further purification. Step 3: Preparation of methyl 1-(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylate.

To a stirred solution of 2-(3,4-dimethylbenzamido)acetic acid (3.20 g, 15.4 mmol) and methyl piperidine-4-carboxylate (2.65 g, 18.5 mmol) in N,N-dimethylformamide (20 mL) were added N-ethyl-N- (propan-2-yl)propan-2-amine (3.99 g, 30.9 mmol, 5.39 mL) and (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (5.86 g, 15.4 mmol) at 0 °C, then the mixture was warmed slowly to 15 °C and stirred for 15h. The mixture was treated with water (30 mL) at 0 °C, extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water (20 mL), 1 N hydrochloric acid (30 mL), saturated aqueous sodium hydrogen carbonate solution (30 mL), saturated aqueous sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Purification by chromatography (silica, petroleum ether/ethyl acetate from 10:1 to 1 :2) gave methyl 1 -(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylate (3.50 g, 10.5 mmol, 68 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 7.62 (s, 1 H), 7.57 (d, J=7.9 Hz, 1 H), 7.28 (m, 1 H), 7.19 (d, J=7.5 Hz, 1 H), 4.39 (d, J=13.2 Hz, 1 H), 4.24 (d, J=3.5 Hz, 2H), 3.78 (d, J=13.7 Hz, 1 H), 3.71 (s, 3H), 3.1 7 (t, J=1 1 .0 Hz, 1 H), 3.02 - 2.91 (m, 1 H), 2.67 - 2.54 (m, 1 H), 2.30 (s, 6H), 1 .98 (m, 2H), 1 .80 - 1 .64 (m, 2H).

Step 4: Preparation of 1-(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylic acid.

To a stirred solution of methyl 1 -(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylate (3.50 g, 10.5 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added aqueous sodium hydroxide (2 M, 7.90 mL), and the mixture was stirred at 15 °C for 5h. The mixture was concentrated to remove tetrahydrofuran and methanol, then then residue was acidified by 1 N hydrochloric acid to pH = 2-3 at 0 °C. The mixture was then extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (column: Phenomenex luna C18 250x50mm 10 phase: [water (0.1 %TFA)-acetonitrile]; B%: 10%-40%, 20min) to give 1 -(2-(3,4- dimethylbenzamido)acetyl)piperidine-4-carboxylic acid (1 .80 g, 5.65 mmol, 54 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) 58.39 (s, 1 H), 7.67 (s, 1 H), 7.61 (d, J=7.7 Hz, 1 H), 7.24 (d, J=7.7 Hz, 1 H), 4.21 (d, J=12.7 Hz, 1 H), 4.12 (d, J=4.9 Hz, 2H), 3.85 (d, J=13.8 Hz, 1 H), 3.14 (t, J=1 1 .7 Hz, 1 H), 2.79 (t, J=1 1 .5 Hz, 1 H), 2.28 (s, 6H), 1 .86 (m, 2H), 1 .63 - 1 .32 (m, 2H). Step 5: Preparation of N-(2-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-oxoethyl)-3 - dimethylbenzamide.

To a stirred solution of 1 -(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylic acid (150 mg, 471 μιτιοΙ) and N-hydroxy-4-methoxybenzimidamide (93 mg, 565 μιηοΙ) in N,N-dimethylformamide (2 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (121 mg, 942 μιτιοΙ, 164 μΙ_) and (2-(1 H-benzotriazol- 1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (178 mg, 471 μιτιοΙ) at 15 °C. After 15 h, the mixture was heated to 1 10 °C and stirred for 5 h. The mixture was cooled and directly purified by prep- HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)- acetonitrile]; B%: 40%-70%,12 min) to give N-(2-(4-(3-(4-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)-2-oxoethyl)-3,4-dimethylbenzamide (1 10 mg, 244 μιτιοΙ, 52 %) as a light yellow solid. ¹ H NMR (400 MHz, Methanol-d4) 57.98 (d, J=9.3 Hz, 2H), 7.66 (s, 1 H), 7.60 (d, J=7.5 Hz, 1 H), 7.23 (d, J=7.9 Hz, 1 H), 7.05 (d, J=9.3 Hz, 2H), 4.46 (d, J=13.2 Hz, 1 H), 4.34 - 4.23 (m, 2H), 4.04 (d, J=13.7 Hz, 1 H), 3.86 (s, 3H), 3.47 - 3.36 (m, 2H), 3.07 (t, J=1 1 .0 Hz, 1 H), 2.42 - 2.26 (s, 6H), 2.21 (d, J=17.6 Hz, 2H), 2.04 - 1 .82 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 449.2.

Example 17: N-(2-(4-(3-(3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4- dimethylbenzamide.

To a stirred solution of 1 -(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylic acid (150 mg, 471 μιτιοΙ) in N,N-dimethylformamide (3 mL) were added N-hydroxy-3-methoxybenzimidamide (93 mg, 565 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 78 mg, 471 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (182 mg, 1 .41 mmol, 246 μί). The mixture was stirred at 20 °C for 2 h and then heated at 120 °C for 2 h. The reaction mixture was cooled and then purified directly by prep-HPLC (column: Luna C8 100x30 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give N-(2-(4-(3-(3-methoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)-3,4-dimethylbenzamide (1 19 mg, 263 μιηοΙ, 56 %) as a white solid. ¹ H NMR (400MHz, CDC ) δ 7.63-7.47 (m, 4H), 7.32 (t, J = 7.9 Hz, 1 H), 7.23-7.20 (m, 1 H), 7.15-7.10 (m, 1 H), 6.98 (dd, J = 1 .8, 8.3 Hz, 1 H), 4.48-4.37 (m, 1 H), 4.22 (d, J = 3.9 Hz, 2H), 3.88-3.82 (m, 1 H), 3.81 (s, 3H), 3.31 -3.22 (m, 2H), 3.13-3.04 (m, 1 H), 2.24 (s, 6H), 2.22-2.12 (m, 2H), 2.00-1 .87 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 449.3. Example 18: 4-(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)pipericline- 1 -carbonyl)- 1 - phenylpyrrolidin-2-one

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 μιτιοΙ) in N,N-dimethylformamide (1 .5 mL) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (196 mg, 518 μιηοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 μΙ_) and 5-oxo-1 -phenyl-pyrrolidine-3-carboxylic acid (1 1 1 mg, 544 μιτιοΙ). The mixture was stirred at 20 °C for 16 h. The mixture was filtered, and the filtrate was purified directly by prep-HPLC (column: Luna C8 100x30 5μιη ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 30%-60%,12 min) to give 4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperidine- 1 -carbonyl]-1 -phenyl-pyrrolidin-2-one (86 mg, 181 μmol, 35 %) as a white solid. ¹ H NMR (400MHz, METHANOL-d4) δ = 7.69 - 7.56 (m, 4H), 7.38 (br t, J=7.2 Hz, 2H), 7.22 - 7.16 (m, 1 H), 7.08 (br d, J=8.4 Hz, 1 H), 4.56 - 4.42 (m, 1 H), 4.19 - 4.04 (m, 3H), 3.89 (s, 6H), 3.86 - 3.81 (m, 1 H), 3.50 - 3.37 (m, 2H), 3.14 - 3.00 (m, 1 H), 2.94 - 2.78 (m, 2H), 2.31 - 2.16 (m, 2H), 2.01 - 1 .81 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 477.3.

Example 19: 4-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin e-1 '-carbonyl)-1-(3,4- dimethylphenyl)pyrrolidin-2-on

To a stirred solution of 1 -[1 -(3,4-dimethylphenyl)-5-oxo-pyrrolidine-3-carbonyl]piperidin e-4- carboxylic acid (200 mg, 581 μιηοΙ) in N,N-dimethylformamide (1 .5 mL) were added (2-(1 H-benzotriazol-

1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (220 mg, 581 μιηοΙ), N-ethyl-N-(propan-2- yl)propan-2-amine (225 mg, 1 .74 mmol, 304 μί), and N-hydroxy-3,4-dimethoxy-benzamidine (125 mg,

639 μιηοΙ). The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (5mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved in N,N- dimethylformamide (2 mL) then heated at 120 °C for 5 h. The mixture was cooled to 25 °C then diluted with water (5ml_) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by prep- HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)- acetonitrile]; B%: 35%-65%,12 min), to give 4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperidine- 1 -carbonyl]-1 -(3,4-dimethylphenyl)pyrrolidin-2-one (7 mg, 15 μιηοΙ, 3 %) as a pink solid. ¹ H NMR

(400MHz, METHANOL-d4) δ = 7.66 (br d, J=8.2 Hz, 1 H), 7.58 (s, 1 H), 7.36 (s, 1 H), 7.27 (br d, J=8.2 Hz, 1 H), 7.1 6 - 7.04 (m, 2H), 4.49 (br d, J=8.4 Hz, 1 H), 4.18 - 3.98 (m, 3H), 3.93 - 3.77 (m, 7H), 3.48 - 3.36 (m, 2H), 3.12 - 2.97 (m, 1 H), 2.92 - 2.78 (m, 2H), 2.32 - 2.14 (m, 8H), 2.01 - 1 .79 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 505.4.

Example 20: 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1- carbonyl)pyrrolidin-2-one.

Step 1: Preparation of N-hydroxy-4-methoxybenzimidamide.

HO— NH /=\ /

HN ^ ^J

To a stirred solution of 4-methoxybenzonitrile (2.0 g, 1 5.02 mmol) in ethanol (20 mL) was added hydroxylamine hydrochloride (2.09 g, 30.0mmol) and triethylamine (3.04 g, 30.0mmol, 4.16 mL) and water (2 mL), then the mixture was heated to 70 °C for 15h. The mixture was treated with water (20 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with water (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude N-hydroxy-4-methoxybenzimidamide (2.50 g) as a white solid, which was used in the next step directly. ¹ H NMR (400 MHz, Methanol-d4) δ 7.61 - 7.48 (m, 2H), 6.98 - 6.85 (m, 2H), 3.81 (s, 3H).

Step 2: Preparation of 1-(3 -dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)pipe^ 1 -carbonyl)pyrrolidin-2-one.

To a stirred solution of 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine -4- carboxylic acid (250 mg, 726 μιηοΙ) and N-hydroxy-4-methoxybenzimidamide (120 mg, 726 μιηοΙ) in N,N- dimethylformamide (3 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (187 mg, 1 .45 mmol, 253 μί) and (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (275 mg, 726 μιηοΙ), After 15h at 1 5 °C, the mixture was heated to 1 10 °C and stirred for 5 h. The reaction mixture was cooled and purified directly by prep-HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 36%-66%,12 min) to give 1 -(3,4-dimethylphenyl)-4-(4-(3-(4- methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (101 mg, 213 μιηοΙ, 29 %) as a light yellow solid. ¹ H NMR (400 MHz, Methanol-d4) δ 7.98 (d, J=7.5 Hz, 2H), 7.36 (s, 1 H), 7.27 (d, J=7.9 Hz, 1 H), 7.13 (d, J=8.4 Hz, 1 H), 7.04 (d, J=8.4 Hz, 2H), 4.47 (m., 1 H), 4.19 - 3.96 (m, 3H), 3.86 (s, 3H), 3.84 - 3.78 (m, 1 H), 3.42 (m, 2H), 3.16 - 2.98 (m, 1 H), 2.93 - 2.74 (m, 2H), 2.37 - 2.10 (m, 8H), 2.02 - 1 .78 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 475.3.

Example 21: 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1,2,4-oxadi azol-5-yl)piperidin^ carbonyl)pyrrolidin-2-one.

To a stirred solution of 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine -4- carboxylic acid (200 mg, 581 μιηοΙ) in N,N-dimethylformamide (3 mL) was added N-hydroxy-3- methoxybenzimidamide (96 mg, 581 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (220 mg, 581 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (225 mg, 1 .74 mmol, 304 μΙ_). The mixture was stirred at 20 °C for 2 h, then heated at 120 °C for 2 h. The reaction mixture was purified directly by prep-HPLC (column: Luna C8 1 00x30 5μιη; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 40%-60%,12 min) to give 1 -(3,4-dimethylphenyl)-4-(4-(3-(3- methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (80 mg, 168 μιηοΙ, 29 %) as a yellow solid. ¹ H NMR (400MHz, CDCI3) δ 7.72-7.67 (m, 1 H), 7.62 (s, 1 H), 7.45-7,37 (m, 2H), 7.30 (d, J = 2.3 Hz, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 7.1 1 -7.06 (m, 1 H), 4.61 -4.47 (m, 1 H), 4.30 (dd, J = 7.3, 9.5 Hz, 1 H), 3.91 (s, 5H), 3.64-3.54 (m, 1 H), 3.46-3.30 (m, 2H), 3.21 -3.05 (m, 1 H), 3.03-2.92 (m, 1 H), 2.89-2.79 (m, 1 H), 2.28 (d, J = 13.1 Hz, 8H), 2.1 0-1 .90 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 475.3. Example 22: N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-N- methylbenzamide.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 μιτιοΙ) in N,N-dimethylformamide (2 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 μί) and 2-[benzoyl(methyl)amino]acetic acid (105 mg, 544 μιτιοΙ). The mixture was stirred at 20 °C for 5 h, then cooled and purified directly by prep-HPLC (column: Luna C8 100x30 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-[2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]-N-methyl-benzamide (133 mg, 282 μιτιοΙ, 54 %) as a white solid. ¹ H NMR (400MHz, DMSO-de) δ = 7.59 (dd, J=1 .8, 8.4 Hz, 1 H), 7.49 - 7.32 (m, 5H), 7.27 (br d, J=6.8 Hz, 1 H), 7.16 - 7.08 (m, 1 H), 4.44 - 4.24 (m, 2H), 4.21 - 4.03 (m, 1 H), 4.02 - 3.88 (m, 1 H), 3.88 - 3.74 (m, 6H), 3.56 (br d, J=13.7 Hz, 1 H), 3.48 - 3.33 (m, 1 H), 3.1 1 - 2.77 (m, 5H), 2.20 - 1 .99 (m, 2H), 1 .86 (br t, J=12.6 Hz, 1 H), 1 .74 - 1 .48 (m, 2H), 1 .43 - 1 .26 (m, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 465.3.

Example 23: N-(2-(4-(3-(3,4-dichlorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of 3,4-dichloro-N-hydroxybenzimidamide.

To a stirred solution of 3,4-dichlorobenzonitrile (1 .0 g, 5.81 mmol) in ethanol (20 mL) was added hydroxylamine hydrochloride (807 mg, 1 1 .6 mmol), triethylamine (1 .18 g, 1 1 .6 mmol, 1 .61 mL) and water (2 mL). The mixture was heated at 75 °C for 5 h, then cooled to 20 °C. Water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (40 mL x 4). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give 3,4-dichloro-N-hydroxybenzimidamide (1 .20 g) as a white solid. This was used directly without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1 H), 7.87 (d, J = 1 .8 Hz, 1 H), 7.69-7.58 (m, 2H), 5.95 (s, 2H).

Step 2: Preparation of N-(2-(4-(3-(3,4-dichlorophenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (200 mg, 688.92 μιτιοΙ) in N,N-dimethylformamide (4 mL) was added 3,4-dichloro-N-hydroxybenzimidamide (169 mg, 826 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (261 mg, 688.92 μιτιοΙ) and N- ethyl-N-(propan-2-yl)propan-2-amine (267 mg, 2.07 mmol, 360 μί). The mixture was stirred at 20 °C for 2 h, then heated at 120 °C for 2 h. The reaction mixture cooled then purified directly by prep-HPLC

(column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 40%-70%,12 min) to give N-(2-(4-(3-(3,4-dichlorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2-oxoethyl)benzamide (92 mg, 201 μιτιοΙ, 29 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 8.14- 8.09 (m, 1 H), 7.85 (dd, J = 2.0, 8.2 Hz, 1 H), 7.78 (d, J = 7.1 Hz, 2H), 7.39 (s, 4H), 7.25 (br. s., 1 H), 4.43 (d, J = 13.7 Hz, 1 H), 4.24 (d, J = 3.5 Hz, 2H), 3.84 (d, J = 14.1 Hz, 1 H), 3.33-3.22 (m, 2H), 3.14-3.03 (m, 1 H), 2.23-2.13 (m, 2H), 1 .99-1 .86 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 459.1 .

Example 24: N-(2-(4-(3-(3,4-difluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of 3,4-difluoro-N-hydroxybenzimidamide.

To a stirred solution of 3,4-difluorobenzonitrile (1 .0 g, 7.19 mmol) in ethanol (20 mL) were added hydroxylamine hydrochloride (999 mg, 14.4 mmol), triethylamine (1 .46 g, 14.4 mmol, 1 .99 mL), and water (2 mL). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (30 mL x 4). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, then filtered, and concentrated in vacuo to give 3,4-difluoro-N-hydroxybenzimidamide (1 .24 g) as a white solid. This was used directly without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1 H), 7.68 (ddd, J = 2.0, 8.0, 12.2 Hz, 1 H), 7.55 (br. s., 1 H), 7.50-7.39 (m, 1 H), 5.92 (br. s., 2H).

Step 2: Preparation of N-(2-(4-(3-(3,4-difluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin

oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) in N,N-dimethylformamide (4 mL) were added 3,4-difluoro-N-hydroxybenzimidamide (85 mg, 496 μιηοΙ), (2- (1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ), and N- ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 μί). The mixture was stirred at 20 °C for 2 h, then heated at 120 for 2 h. The reaction mixture was cooled then purified directly by prep-HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-60%,12 min) to give N-(2-(4-(3-(3,4-difluorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (50 mg, 1 18 μιτιοΙ, 28 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 7.78 (d, J = 7.1 Hz, 4H), 7.44 (d, J = 7.1 Hz, 1 H), 7.42-7.35 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 4.43 (d, J = 13.7 Hz, 1 H), 4.23 (d, J = 4.0 Hz, 2H), 3.84 (d, J = 13.7 Hz, 1 H), 3.32-3.21 (m, 2H), 3.13-3.03 (m, 1 H), 2.23-2.12 (m, 2H), 1 .99-1 .84 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 427.2.

Example 25: 2-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)carbamate.

BocHN

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (2.0 g, 6.91 mmol) in N,N-dimethylformamide (20 mL) was added 2-(tert-butoxycarbonylamino)acetic acid (1 .21 g, 6.91 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (2.62 g, 6.91 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (2.68 g, 20.7 mmol, 3.62 mL). The mixture was stirred at 1 5 °C for 2 h. The reaction mixture was quenched by addition of water (20 mL), then the mixture was extracted with ethyl acetate (60 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude residue. Purification by chromatography (silica, petroleum ether : ethyl acetate = 5:1 to 1 :1 ) gave tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)carbamate (2.60 g, 5.82 mmol, 84 %) as a brown solid that was used directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ = 447.2.

Step 2: Preparation of 2-amino- 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1- yl)ethanone.

To a stirred solution of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)-2-oxoethyl)carbamate (2.50 g, 5.60 mmol) in methanol (1 0 mL) was added methanolic hydrogen chloride solution (4M, 30 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give crude product. A part of crude product (0.1 g) was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12 min) to give 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (32 mg) for analysis. The remaining crude 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)ethanone (1 .90 g, 5.49 mmol, 98 %), obtained as a brown solid, was used directly. Ή NMR (400 MHz, CDC ) δ 7.73-7.67 (m, 1 H), 7.58 (d, J = 1 .5 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 4.54 (d, J = 12.2 Hz, 1 H), 3.98 (d, J = 7.2 Hz, 6H), 3.84 (d, J = 12.0 Hz, 1 H), 3.54 (s, 2H), 3.34-3.21 (m, 2H), 3.08 (d, J = 12.3 Hz, 1 H), 2.21 (d, J = 13.1 Hz, 2H), 1 .98 (d, J = 9.4 Hz, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 347.1 .

Step 3: Preparation of 2-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (185 mg, 537 μιτιοΙ) in N,N-dimethylformamide (3 mL) was added 2-chlorobenzoic acid (70 mg, 447 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (169 mg, 447 μιηοΙ), and N-ethyl-N-(propan-2-yl)propan-2-amine (231 mg, 1 .79 mmol, 312 μΙ_). The mixture was stirred at 20 °C for 2 h, then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 26%-56%,12 min) to give 2-chloro-N-(2-(4- (3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (124 mg, 256 μιηοΙ, 57 %) as a pink solid. Ή NMR (400 MHz, CDC ) δ 7.72 (ddd, J = 1 .9, 6.3, 7.9 Hz, 2H), 7.59 (d, J = 1 .9 Hz, 1 H), 7.49-7.33 (m, 4H), 6.98 (d, J = 8.4 Hz, 1 H), 4.52 (d, J = 13.6 Hz, 1 H), 4.36 (d, J = 4.0 Hz, 2H), 3.99 (d, J = 7.8 Hz, 6H), 3.92 (d, J = 13.8 Hz, 1 H), 3.41 -3.30 (m, 2H), 3.1 6 (t, J = 10.9 Hz, 1 H), 2.33-2.21 (m, 2H), 2.1 1 -1 .94 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 485.2.

Example 26: 3-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (185 mg, 537 μιτιοΙ) in N,N-dimethylformamide (3 mL) were added 3-chlorobenzoic acid (70 mg, 447 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (169 mg, 447 μιηοΙ), and N-ethyl-N-(propan-2-yl)propan-2-amine (231 mg, 1.79 mmol, 312 μΙ_). The mixture was stirred at 20 °C for 2 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μΓη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 26%-56%,12 min) to give 3-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (126 mg, 261 μιτιοΙ, 58 %) as a white solid. ^> H NMR (400MHz, CDC ) δ 7.89-7.86 (m, 1H), 7.72 (d, J= 2.0 Hz, 2H), 7.59 (d, J= 1.9 Hz, 1H), 7.54-7.50 (m, 1H), 7.45-7.39 (m, 1H), 7.34 (br. s., 1H), 6.98 (d, J= 8.5 Hz, 1H), 4.53 (d, J = 14.3 Hz, 1H), 4.31 (d, J = 3.9 Hz, 2H), 3.98 (d, J= 7.4 Hz, 6H), 3.96-3.87 (m, 1 H), 3.41 -3.30 (m, 2H), 3.18 (t, J = 10.9 Hz, 1 H), 2.33-2.22 (m, 2H), 2.10-1.94 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 485.3.

Example 27: 4-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of 4-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (185 mg, 536.5 μιηοΙ) in N,N-dimethylformamide (3 mL) were added 4-chlorobenzoic acid (70 mg, 447 μιτιοΙ), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (169 mg, 447 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (231 mg, 1.79 mmol, 312 μΙ_). The mixture was stirred at 20 °C for 2 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm δμίτι; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give 4-chloro-N-(2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (144 mg, 294 μιτιοΙ, 66 %) as a white solid. Ή NMR (400MHz, CDCb) δ 7.82 (d, J = 8.5 Hz, 2H), 7.71 (dd, J= 1.9, 8.3 Hz, 1H), 7.59 (d, J= 1.8 Hz, 1H), 7,45 (d, J= 8.5 Hz, 2H), 7.33 (br. s., 1H), 6.98 (d, J= 8.4 Hz, 1H), 4.52 (d, J= 14.2 Hz, 1H), 4.31 (d, J = 3,9 Hz, 2H), 3.98 (d, J= 7.3 Hz, 6H), 3.92 (d, J= 13,7 Hz, 1H), 3.41-3.30 (m, 2H), 3,17 (t, J= 10,7 Hz, 1H), 2.34-2.21 (m, 2H), 2,10-1.94 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 485,2. Example 28: N-( 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-1-oxopropan-2- yl)benzamide.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 μιτιοΙ) in N,N-dimethylformamide (2 mL) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μιηοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 μί), and 2-benzamidopropanoic acid (105 mg, 544 μιτιοΙ). The mixture was stirred at 20 °C for 7 h, then the crude product was purified directly by prep-HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile; B%: 35%-60%,12 min] to give N-[2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-1 -methyl-2-oxo-ethyl]benzamide (52 mg, 1 12 μιτιοΙ, 22 %) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 8.63 (br dd, J=7.3, 16.1 Hz, 1 H), 7.88 (br d, J=7.3 Hz, 2H), 7.66 - 7.34 (m, 5H), 7.1 1 (br d, J=7.9 Hz, 1 H), 4.97 (br d, J=6.0 Hz, 1 H), 4.45 - 4.22 (m, 1 H), 4.08 - 3.94 (m, 1 H), 3.82 (s, 6H), 3.42 (br t, J=10.7 Hz, 1 H), 3.29 - 3.21 (m, 1 H), 3.00 - 2.80 (m, 1 H), 2.09 (br d, J=1 1 .9 Hz, 2H), 1 .87 - 1 .56 (m, 1 H), 1 .29 (s, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 465.3.

Example 29: N-( 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-methyl-1- oxopropan-2-yl)benzamide.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 μιτιοΙ) in N,N-dimethylformamide (2 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μιηοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 μί) and 2-benzamido-2-methyl-propanoic acid (1 12 mg, 544 μιτιοΙ). The mixture was stirred at 20 °C for 5 h. The crude product was purified directly by prep-HPLC (column: Waters Xbridge 1 50x25 5μιη; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 27%-57%,12 min) to give N-[2-[4- [3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-1 ,1 -dimethyl-2-oxo-ethyl]benzamide (47 mg, 99 μιτιοΙ, 19 %) as a pale yellow solid. ¹ H NMR (400MHz, METHANOL-d4) δ = 7.88 - 7.81 (m, 2H), 7.62 (dd, J=2.0, 8.4 Hz, 1 H), 7.57 - 7.51 (m, 2H), 7.49 - 7.42 (m, 2H), 7.06 (d, J=8.4 Hz, 1 H), 4.61 - 4.45 (m, 2H), 3.88 (d, J=5.1 Hz, 6H), 3.13 (s, 3H), 2.08 (br s, 2H), 1 .90 - 1 .74 (m, 2H), 1 .60 (s, 6H); LCMS (ESI) m/z: [M+H] ⁺ = 477.1 . Example 30: 2-(benzylamino)-1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1- yl)ethanone.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 μιτιοΙ) in N,N-dimethylformamide (1 .50 mL) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (196 mg, 518 μιηοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 μΙ_), and 2-(benzylamino)acetic acid (89 mg, 544 μιτιοΙ). The mixture was stirred at 20 °C for 16 h and filtered, and the crude filtrate was purified directly by prep-HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%- 60%, 12 min) to give 2-(benzylamino)-1 -[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]ethanone (48 mg, 1 10 μιτιοΙ, 21 %) as a yellow solid. ¹ H NMR (400MHz, METHANOL-d4) δ = 7.65 (dd, J=1 .8, 8.2 Hz, 1 H), 7.57 (d, J=1 .8 Hz, 1 H), 7.40 - 7.30 (m, 4H), 7.28 - 7.22 (m, 1 H), 7.06 (d, J=8.4 Hz, 1 H), 4.45 (br d, J=13.7 Hz, 1 H), 3.94 - 3.83 (m, 7H), 3.78 (s, 2H), 3.57 - 3.44 (m, 2H), 3.40 - 3.33 (m, 1 H), 3.27 - 3.20 (m, 1 H), 3.01 (t, J=1 1 .2 Hz, 1 H), 2.1 7 (dd, J=2.8, 13.3 Hz, 2H), 1 .93 - 1 .73 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 437.3.

Example 31 : 2-(benzyloxy)-1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1- yl)ethanone.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 μιτιοΙ) in N,N-dimethylformamide (2 mL) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 , 3, 3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μιηοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 μί), and 2-benzyloxyacetic acid (90 mg, 544 μιτιοΙ, 77 μί). The mixture was stirred at 20 °C for 5 h. The crude product was purified directly by prep-HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 32%-62%,12 min) to give 2-benzyloxy-1 - [4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]ethanone (68 mg, 157 μιτιοΙ, 30 %) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 7.60 (dd, J=1 .9, 8.3 Hz, 1 H), 7.48 (d, J=1 .9 Hz, 1 H), 7.40 - 7.35 (m, 4H), 7.34 - 7.26 (m, 1 H), 7.14 (d, J=8.4 Hz, 1 H), 4.54 (s, 2H), 4.33 (br d, J=13.2 Hz, 1 H), 4.25 (br d, J=7.8 Hz, 2H), 3.93 - 3.78 (m, 7H), 3.43 (tt, J=3.9, 1 1 .0 Hz, 1 H), 3.22 (br t, J=1 1 .7 Hz, 1 H), 2.90 (br t, J=1 1 .7 Hz, 1 H), 2.1 7 - 2.04 (m, 2H), 1 .88 - 1 .59 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 438.3. Example 32: N-[2-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]ethyl]benzamide

Step 1: Preparation of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1- yl)ethyl)carbamate

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (750 mg, 2.59 mmol) in N,N-dimethylformamide (1 mL) were added cesium carbonate (844 mg, 2.59 mmol) and tert- butyl N-(2-bromoethyl)carbamate (871 mg, 3.89 mmol). The mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled then extracted with ethyl acetate (5 mL x 2). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl N-[2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]ethyl]carbamate (1 .30 g) which was used directly without further purification. LCMS (ESI) m/z = 433.3 [M+H] ⁺ .

Step 2: Preparation of 2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)ethanamine

A solution of tert-butyl N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]ethyl]carbamate (1 .0 g, 2.31 mmol) in hydrochloric acid/ethyl acetate (4M, 25 mL) was stirred at 25 °C for 30 mins. The reaction mixture was concentrated under reduced pressure to give 2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]ethanamine (750 mg) which was used directly without further purification. LCMS (ESI) m/z = 333.1 [M+H] ⁺ . Step 3: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1- yl) ethyl)benzamide

To a mixture of 2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]ethanamine (200 mg, 602 μιτιοΙ) and benzoyl chloride (109 mg, 782 μιτιοΙ, 90 μΙ_) in dichloromethane (1 mL) was added triethylamine (182 mg, 1 .81 mmol, 250 μί) at 0 °C. The mixture was stirred at 20 °C for 5 h, then purified directly by prep-HPLC (column: Luna C8 100x30 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 35%-50%,12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol- 5-yl]-1 -piperidyl]ethyl]benzamide (25 mg, 56 μιτιοΙ, 9 %) as a white solid. ¹ H NMR (400MHz,

METHANOL-d4) δ = 7.86 - 7.79 (m, 2H), 7.66 (dd, J=1 .8, 8.4 Hz, 1 H), 7.58 (d, J=1 .8 Hz, 1 H), 7.55 - 7.43 (m, 3H), 7.07 (d, J=8.6 Hz, 1 H), 3.89 (s, 6H), 3.58 (t, J=6.8 Hz, 2H), 3.1 6 - 3.09 (m, 2H), 2.67 (t, J=6.8 Hz, 2H), 2.37 - 2.29 (m, 2H), 2.18 (br d, J=1 1 .2 Hz, 2H), 2.07 - 1 .91 (m, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 437.3. Example 33: (E)-1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-4-phenylbut-2- ene-1 ,4-dione

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (250 mg, 864 μιηοΙ) in N,N-dimethylformamide (4 mL) were added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (327 mg, 864 μιτιοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (335 mg, 2.59 mmol, 452 μί) and (E)-4-oxo-4-phenyl-but-2-enoic acid (152 mg, 864 μιτιοΙ). The mixture was stirred at 20 °C for 5 h, then the crude mixture was purified directly by prep-HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give (E)-1 -[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-4-phenyl-but-2-ene-1 ,4-dione (1 18 mg, 251 μιηοΙ,

29 %) as a yellow solid. ¹ H NMR (400MHz, DMSO-d6) δ = 8.03 (br d, J=7.3 Hz, 2H), 7.75 (d, J=15.4 Hz, 1 H), 7.71 - 7.65 (m, 1 H), 7.61 - 7.53 (m, 3H), 7.51 - 7.43 (m, 2H), 7.1 1 (d, J=8.4 Hz, 1 H), 4.41 (br d, J=13.2 Hz, 1 H), 4.1 1 - 3.99 (m, 1 H), 3.88 - 3.77 (m, 6H), 3.54 - 3.34 (m, 2H), 3.02 (br t, J=1 1 .2 Hz, 1 H), 2.15 (br d, J=13.0 Hz, 2H), 1 .88 - 1 .67 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 448.2. Example 34: 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-((2,2,2-trifluoro-1- phenylethyl)amino)ethanone.

Step 1: Preparation of 2,2,2-trifluoro- 1-phenyl trifluoromethanesulfonate.

To a stirred solution of 2,2,2-trifluoro-1 -phenylethanol (100 mg, 568 μιηοΙ, 76 μΙ_) in

dichloromethane (2 mL) were added 2,6-dimethylpyridine (121 mg, 1 .14 mmol, 132 μί) and

trifluoromethanesulfonic anhydride (288 mg, 1 .02 mmol, 168 μί) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and then diluted with dichloromethane (5 mL) and water (5 mL), and the phases separated. The aqueous phase was extracted with dichloromethane (1 5 mL x 2), then the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 2,2,2-trifluoro-1 -phenylethyl trifluoromethanesulfonate (380 mg) as a brown oil. This material was used directly without further purification.

Step 2: Preparation of 1-(4-(3-(3^-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-^

1 -phenyiethyi) amino) ethanon

To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (120 mg, 346 μιηοΙ) in dichloromethane (2.5 mL) was added 2, 2, 2-trifluoro-1 -phenyiethyi trifluoromethanesulfonate (213 mg, 692.88 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (179 mg, 1 .39 mmol, 242 μί). The mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 1 50x2.5mm 5μιη; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give 1 -(4-(3- (3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-((2,2,2-trifluoro-1 - phenylethyl)amino)ethanone (52 mg, 101 μιτιοΙ, 29 %) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.63-7.56 (m, 1 H), 7.51 -7.37 (m, 6H), 7.14 (d, J = 8.4 Hz, 1 H), 4.53-4.43 (m, 1 H), 4.30 (br. s., 1 H), 3.84 (s, 6H), 3.71 (d, J = 10.2 Hz, 1 H), 3.44-3.36 (m, 2H), 3.18-3.07 (m, 1 H), 2.99 (d, J = 5.5 Hz, 1 H), 2.87 (br. s., 1 H), 2.08 (d, J = 12.5 Hz, 2H), 1 .75-1 .56 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 505.3. Example 35: N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-thiadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide

Step 1: Preparation of tert-butyl 4-(3-bromo- 1 ,2,4-thiadiazol-5-yl)-5,6-dihydropyridine- 1 (2H)-carboxylate

A mixture of 3-bromo-5-chloro-1 ,2,4-thiadiazole (500 mg, 2.51 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (931 mg, 3.01 mmol), cesium fluoride (762 mg, 5.02 mmol, 1 85 μΙ_) in dioxane (3.5 mL) was degassed and purged with nitrogen 3 times, then 4-ditert-butylphosphanyl-N,N-dimethyl-aniline;dichloropallad ium (88 mg, 125.50 μιηοΙ, 88 μί, 0.05 eq) was added. The mixture was stirred at 80 °C for 2 h under an atmosphere of nitrogen. The mixture was cooled to 25 °C and concentrated in vacuo at 40 °C. The residue was poured into water (15 mL), the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford crude product. The crude product was purified by chromatography (silica, petroleum ether/ ethyl acetate (from 20/1 to 2/1 ) to give tert-butyl 4-(3-bromo- 1 ,2,4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (260 mg, 750.92 μιτιοΙ, 30 %) as a yellow oil. LCMS (ESI) m/z: 368.3 [M+Na] ⁺ . Step 2: Preparation of tert-butyl 4-(3-(3,4-dimethoxyphenyl)- 1,2,4-thiadiazol-5-yl)-5,6-dihydropyridine- 1 (2H) -carboxylate

A mixture of tert-butyl 4-(3-bromo-1 ,2, 4-thiadiazol-5-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (260 mg, 751 μιηοΙ), (3,4-dimethoxyphenyl)boronic acid (163 mg, 901 μιηοΙ), and sodium carbonate (103 mg, 976 μιηοΙ) in water (400 μί) and dimethoxyethane(1 .2 mL) was degassed and purged with nitrogen 3 times, and then tetrakis(triphenylphosphine)palladium(0) (17 mg, 15 μιηοΙ) was added. The mixture was stirred at 100 °C for 6 h under a nitrogen atmosphere. The mixture was cooled to 25 °C and concentrated in vacuo at 40 °C. The residue was poured into water (5 mL), and the aqueous phase was extracted with dichloromethane (1 0 ml_ x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (1 0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford crude product. The crude residue was purified by prep-TLC (silica, petroleum ether/ ethyl acetate=3 :1 ) to give tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-thiadiazol-5-yl]-3,6-dihydro-2H-pyridine-1 - carboxylate (122 mg, 303 μιτιοΙ, 40 %) as a yellow oil. LCMS (ESI) m/z: 404.1 [M+H] ⁺ .

Step 3: Preparation of tert-butyl 4-(3-(3,4-dimethoxyphenyl)- 1,2,4-thiadiazol-5-yl)piperidine- 1 -carboxylate

To a stirred solution of tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-thiadiazol-5-yl]-3,6-dihydro-2H- pyridine-1 -carboxylate (1 00 mg, 248 μιηοΙ) in methanol (1 0 mL) was added palladium(O) on carbon (1 0%, 1 50 mg) under nitrogen . The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (1 5 psi) at 20 °C for 48 h. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1 ,2,4- thiadiazol-5-yl]piperidine-1 -carboxylate (79 mg) that was used into the next step without further purification. LCMS (ESI) m/z: 406.2 [M+H] ⁺ .

Step 4: Preparation of 3-(3,4-dimethoxyphen 1,2,4-thiadiazole

A solution of tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1 , 2, 4-thiadiazol-5-yl]piperidine-1 -carboxylate (79 mg, 1 95 μιηοΙ) in hydrochloric acid/ethyl acetate (4M, 1 5 mL) was stirred at 20 °C for 3 h. The reaction mixture was concentrated in vacuo to give 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4- thiadiazole (65 mg) that was used into the next step without further purification.

Step 5: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-thiadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-thiadiazole (65 mg, 214 μιηοΙ) and 2-benzamidoacetic acid (46 mg, 257 μιτιοΙ) in N,N-dimethylformamide (1 mL) were added (2-

(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate) (81 mg, 214 μιτιοΙ) and N-ethyl- N-(propan-2-yl)propan-2-amine (69 mg, 536 μιηοΙ, 93 xL). After 2 h, the reaction mixture purified directly by prep-H PLC (column : Waters Xbridge 1 50x25 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile] ; B%: 26%-56%, 12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-thiadiazol-

5-yl]-1 -piperidyl]-2-oxo-ethyl]benzamide (1 0 mg, 22 μιτιοΙ, 1 0 %) as a yellow solid. ¹ H NMR (400MHz,

METHANOL-d4) δ = 7.92 - 7.82 (m, 4H), 7.59 - 7.52 (m , 1 H), 7.51 - 7.44 (m, 2H), 7.06 (d, J=8.4 Hz, 1 H), 4.61 (d, J=12.9 Hz, 1 H), 4.41 - 4.24 (m, 2H), 4.1 1 (br d, J=14.9 Hz, 1 H), 3.98 - 3.84 (m, 6H), 3.63 - 3.52 (m, 1 H), 3.39 (br t, J=1 1 .7 Hz, 1 H), 2.99 (br t, J=1 1 .6 Hz, 1 H), 2.35 - 2.20 (m, 2H), 2.03 - 1 .74 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 467.2.

Example 36: N-(2-(4-(5-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-3-yl)piperidin-1-yl)-2- oxoethyl)benzamide

Step 1: Preparation of (Z)-tert-butyl 4-(N'- iperidine- 1 -carboxylate

A mixture of tert-butyl 4-cyanopiperidine-1 -carboxylate (2.0 g, 9.51 mmol), hydroxylamine hydrochloride (1 .32 g, 19.0 mmol), and triethylamine (1 .92 g, 19.0 mmol, 2.64 mL) in ethanol (20 mL) and water (2 mL) was heated at 75 °C for 16 h. The reaction mixture was cooled, diluted with water (1 0 mL), and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]piperidine-1 - carboxylate (1 .90 g) which was used directly without further purification. ¹ H NMR (400MHz, METHANOL- d4) δ = 4.15 (br d, J=13.3 Hz, 2H), 2.78 (br s, 2H), 2.27 (tt, J=3.6, 12.1 Hz, 1 H), 1 .84 - 1 .70 (m, 2H), 1 .62 (dq, J=4.3, 12.6 Hz, 2H), 1 .53 - 1 .39 (m, 9H).

Step 2: Preparation of tert-butyl 4-(5-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-3-yl)piperidine- 1 -carboxylate

To a stirred solution of tert-butyl 4-[(Z)-N'-hydroxycarbamimidoyl]piperidine-1 -carboxylate (750 mg, 3.08 mmol) in N,N-dimethylformamide (5 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (1 .17 g, 3.08 mmol), N-ethyl-N-(propan-2-yl)propan-2-amine (1 .19 g, 9.24 mmol, 1 .61 mL) and 3,4-dimethoxybenzoic acid (561 mg, 3.08 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (1 0 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Tetrahydrofuran (500 μΙ_) and tetrabutylammonium fluoride / tetrahydrofuran (1 M, 4.62 mL) were added to the residue, and the resulting mixture was heated at 50 °C for 16 h. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=5:1 ) to give tert-butyl 4-[5-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-3-yl]piperidine-1 -carboxylate (970 mg, 2.49 mmol, 81 %) as a white solid. LCMS (ESI) m/z: 412.3 [M+Na] ⁺ = 334.2.

Step 3: Preparation of 5-(3,4-dimethoxyphe 1 ,2,4-oxadiazole

A solution of tert-butyl 4-[5-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-3-yl]piperidine-1 -carboxylate

(750 mg, 1 .93 mmol) in hydrochloric acid / ethyl acetate (4M, 30 mL) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 5-(3,4-dimethoxyphenyl)-3-(4-piperidyl)- 1 ,2,4-oxadiazole (683 mg) that was used directly without further purification. Step 4: Preparation of N-(2-(4-(5-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-3-yl)piperidin- 1-yl)-2- oxoethyl)benzamide

To a stirred solution of 5-(3,4-dimethoxyphenyl)-3-(4-piperidyl)-1 ,2,4-oxadiazole (180 mg, 622 μιτιοΙ) in N,N-dimethylformamide (2 mL) were added 2-benzamidoacetic acid (1 1 1 mg, 622 μιτιοΙ), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (235 mg, 622 μιτιοΙ), and N-ethyl-N- (propan-2-yl)propan-2-amine (241 mg, 1 .87 mmol, 325 μί). The mixture was stirred at 20 °C for 16 h. The crude product was purified by prep-HPLC (column : Waters Xbridge 150x25 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-[2-[4-[5-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-3-yl]-1 -piperidyl]-2-oxo-ethyl]benzamide (169 mg, 376 μιηοΙ, 60 %) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 8.55 (br t, J=5.4 Hz, 1 H), 7.87 (br d, J=7.5 Hz, 2H), 7.70 (br d, J=8.4 Hz, 1 H), 7.57 - 7.41 (m, 4H), 7.17 (br d, J=8.4 Hz, 1 H), 4.34 (br d, J=12.3 Hz, 1 H), 4.16 (br d, J=4.2 Hz, 2H), 3.97 (br d, J=13.0 Hz, 1 H), 3.90 - 3.74 (m, 6H), 3.27 - 3.09 (m, 2H), 2.88 (br t, J=1 1 .6 Hz, 1 H), 2.03 (br t, J=1 1 .8 Hz, 2H), 1 .75 (br d, J=1 0.4 Hz, 1 H), 1 .59 (br d, J=9.9 Hz, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 451 .2. Example 37: N-(2-(4-(4-(3,4-dimethoxyphenyl)oxazol-2-yl)piperidin-1-yl)- 2-oxoe

Step 1: Preparation of 2-bromo- 1-(3,4-dimethoxyphenyl)ethanone.

To a stirred solution of 1 -(3,4-dimethoxyphenyl)ethanone (1 .0 g, 5.55 mmol) in dichloromethane (6 mL) and methanol (3 mL) was added benzyltrimethylammonium tribromide (2.1 6 g, 5.55 mmol). After 16 h, the mixture was diluted with dichloromethane (80 mL) and water (40 mL), the organic layer was separated, and the water phase was extracted with dichloromethane (80 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-bromo-1 -(3,4- dimethoxyphenyl)ethanone (1 .20 g, 4.63 mmol, 83 %) as a brown solid. ¹ H NMR (400 MHz, CDC ) δ 7.63 (s, 1 H), 7.57 (d, J=2.1 Hz, 1 H), 6.94 (d, J=8.4 Hz, 1 H), 4.43 (s, 2H), 3.98 (d, J=8.4 Hz, 6H).

Step 2: Preparation of 2-(3,4-dimethoxyphenyl)-2-oxoethyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (200 mg, 689 μιηοΙ) in acetonitrile (6 mL) was added 2-bromo-1 -(3,4-dimethoxyphenyl)ethanone (214 mg, 826 μιηοΙ) and triethylamine (209 mg, 2.07 mmol, 286 μί) under nitrogen. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated in vacuo to give 2-(3,4-dimethoxyphenyl)-2-oxoethyl 1 -(2- benzamidoacetyl)piperidine-4-carboxylate (233 mg, 497 μιτιοΙ, 72 %) as a yellow solid. This was used directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ = 469.3. Step 3: Preparation of N-(2-(4-(4-( -dimethoxyphenyl)oxazol-2-yl)piperidin- 1-yl)-2-oxoethyl)benzamide.

To a stirred solution of 2-(3,4-dimethoxyphenyl)-2-oxoethyl 1 -(2-benzamidoacetyl)piperidine-4- carboxylate (180 mg, 384 μιτιοΙ) in acetic acid (8 mL) was added ammonium acetate (148 mg, 1 .92 mmol) under nitrogen, then the mixture was heated at 100 °C for 16 h. The reaction mixture was concentrated in vacuo to give crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-55%,12 min) to give N- (2-(4-(4-(3,4-dimethoxyphenyl)oxazol-2-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (55 mg, 120 μιηοΙ, 31 %) as a pink solid. ¹ H NMR (400 MHz, CDC ) δ 7.92 - 7.84 (m, 2H), 7.80 (s, 1 H), 7.58 - 7.44 (m, 3H), 7.41 - 7.35 (m, 1 H), 7.28 - 7.26 (m, 2H), 6.92 (d, J=8.9 Hz, 1 H), 4.58 - 4.47 (m, 1 H), 4.32 (d, J=3.9 Hz, 2H), 3.99 - 3.88 (m, 7H), 3.37 - 3.06 (m, 3H), 2.28 - 2.13 (m, 2H), 2.07 - 1 .89 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 450.3.

Example 38: N-(2-(4-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidin-1-yl) -2-oxo

Step 1: Preparation of tert- butyl 4-carbamothioylpiperidine- 1 -carboxylate.

To a stirred solution of tert-butyl 4-carbamoylpiperidine-1 -carboxylate (1 .0 g, 4.38 mmol) in a mixture of dimethoxyethane (16 mL) and dichloromethane (8 mL) was added 2,4-bis(4-methoxyphenyl)- 1 ,3,2,4-dithiadiphosphetane-2,4-disulfide (885 mg, 2.19 mmol). The mixture was stirred at 20 °C for 16 h, then concentrated in vacuo. The residue dissolved in ethyl acetate and washed with saturated aqueous potassium carbonate (10 mL x 2). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give tert-butyl 4-carbamothioylpiperidine-1 -carboxylate (1 .0 g) as a yellow solid. This was used directly without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 9.45 (br. s., 1 H), 9.17 (br. s., 1 H), 4.14-3.98 (m, 2H), 3.91 -3.79 (m, 1 H), 2.80-2.66 (m, 2H), 1 .74-1 .55 (m, 4H), 1 .46 (s, 9H). Step 2: Preparation of tert-butyl 4-(4-( -dimethoxyphenyl)thiazol-2-yl)piperidine- 1-carboxylate.

To a stirred solution of tert-butyl 4-carbamothioylpiperidine-1 -carboxylate (200 mg, 818.5 μιηοΙ) in N,N-dimethylformamide (5 mL) was added 2-bromo-1 -(3,4-dimethoxyphenyl)ethanone (212 mg, 818.50 μιηοΙ) and potassium carbonate (124 mg, 900 μιηοΙ). The mixture was stirred at 1 10 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 4-(4-(3,4- dimethoxyphenyl)thiazol-2-yl)piperidine-1 -carboxylate (300 mg, 742 μιτιοΙ, 91 %) as a yellow solid. This was used directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ = 405.3.

Step 3: Preparation of 4-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)thiazole.

To a stirred solution of tert-butyl 4-(4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidine-1 -carboxylate (300 mg, 742 μιτιοΙ) in methanol (3 mL) was added methanolic hydrogen chloride solution (4M, 10 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to provide 4-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)thiazole (260 mg) as a yellow solid. LCMS (ESI) m/z: [M+H] ⁺ = 305.1 . Step 4: Preparation of N-(2-(4-(4-(3A-dimethoxyphenyl)thiazol-2-yl)piperidin- 1-yl)-2-oxoethyl)ben

To a stirred solution of 4-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)thiazole (203 mg, 670 μιηοΙ) in N,N-dimethylformamide (4 mL) were added 2-benzamidoacetic acid (100 mg, 558 μιηοΙ), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (21 1 mg, 558 μιηοΙ) and N-ethyl-N- (propan-2-yl)propan-2-amine (288 mg, 2.23 mmol, 389 μΐ). T he mixture was stirred at 20 °C for 16 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%-60%, 12 min) to give N-(2-(4- (4-(3,4-dimethoxyphenyl)thiazol-2-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (1 1 1 mg, 239 μιηοΙ, 43 %) as a yellow solid. Ή NMR (400 MHz, CDC ) δ 7.91 -7.85 (m, 2H), 7.57-7.42 (m, 5H), 7.39 (br. s., 1 H), 6.94 (d, J = 8.2 Hz, 1 H), 4.70 (d, J = 13.6 Hz, 1 H), 4.40-4.26 (m, 2H), 3.97 (d, J = 19.7 Hz, 7H), 3.43-3.26 (m, 2H), 3.05-2.95 (m, 1 H), 2.37-2.23 (m, 2H), 1 .98-1 .83 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 466.3. Example 39: N-(2-(4-(5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl)piperi din-1-yl)-2- oxoethyl)benzamide.

Step 1: Ethyl 3,4-dimethoxybenzimidate.

To a stirred solution of 3,4-dimethoxybenzonitrile (2.0 g, 12.3 mmol) in dry ethanol (50 mL) was added dropwise acetyl chloride (7.70 g, 98.1 mmol, 7.0 mL) at 0 °C , after complete addition, the mixture was warmed to 15 °C and stirred for 30 h. The reaction was concentrated in vacuo, and then saturated hydrochloric acid in ethanol (50 mL) was added. After 5h, the mixture was concentrated in vacuo to give crude ethyl 3,4-dimethoxybenzenecarboximidate (2.50 g) as a light yellow solid, which was used in next step directly.

Step 2: Methyl 1-(2-benzamidoacetyl)piperidine-4-carboxylate.

To a stirred solution of 2-benzamidoacetic acid (3.0 g, 16.7 mmol) and methyl piperidine-4- carboxylate (3.60 g, 25.1 mmol) in dry N,N-dimethylformamide (50 mL) was added N-ethyl-N-(propan-2- yl)propan-2-amine (4.33 g, 33.5 mmol, 5.9 mL) and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (7.0 g, 18.4 mmol) at 0 °C, then the mixture was warmed to 15 °C and stirred for 15h. The mixture was poured into ice water (100 mL) then extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with 1 N hydrochloric acid (30 mL x 2), saturated aqueous sodium carbonate (30 mL), and saturated aqueous sodium chloride solution (30 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude methyl 1 -(2- benzamidoacetyl)piperidine-4-carboxylate (5.30 g) as a brown oil, which was used in next step directly. ¹ H NMR (400 MHz, Methanol-d4) δ 7.87 (d, J=7.1 Hz, 2H), 7.58 - 7.51 (m, 1 H), 7.49 - 7.40 (m, 2H), 4.39 - 4.29 (m, 1 H), 4.28 - 4.17 (m, 2H), 3.96 - 3.84 (m, 1 H), 3.68 (s, 3H), 3.28 - 3.17 (m, 1 H), 2.96 - 2.86 (m, 1 H), 2.69 - 2.62 (m, 1 H), 2.00 - 1 .88 (m, 2H), 1 .78 - 1 .51 (m, 2H). Step 3: N-(2-(4-(hydrazinecarbonyl)piperidin- 1-yl)-2-oxoethyl)benzamide.

A solution of methyl 1 -(2-benzamidoacetyl)piperidine-4-carboxylate (500 mg, 1 .64 mmol) and hydrazine hydrate (328 mg, 6.56 mmol, 318 μΙ_) in methanol (3 mL) was heated to 80 °C for 15 h. The mixture was concentrated in vacuo to give a crude residue that was washed with tert-butyl methyl ether (10 mL) to obtain N-[2-[4-(hydrazinecarbonyl)-1 -piperidyl]-2-oxo-ethyl]benzamide (500 mg) as a light yellow solid that was used directly without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1 H), 8.54 (t, J=5.6 Hz, 1 H), 7.94 - 7.82 (m, 2H), 7.60 - 7.43 (m, 3H), 4.41 - 4.29 (m, 1 H), 4.13 (d, J=5.6 Hz, 2H), 3.93 (d, J=12.9 Hz, 1 H), 3.05 (t, J=1 1 .9 Hz, 1 H), 2.68 - 2.57 (m, 1 H), 2.34 (tdd, J=3.9, 7.5, 1 1 .2 Hz, 1 H), 1 .73 - 1 .34 (m, 4H).

Step 4: N-(2-(4-(5-(3,4-dimethoxyphenyl) 1-yl)-2-oxoethyl)benzamide.

A solution of N-[2-[4-(hydrazinecarbonyl)-1 -piperidyl]-2-oxo-ethyl]benzamide (200 mg, 657 μιτιοΙ) and ethyl 3,4-dimethoxybenzenecarboximidate (151 mg, 723 μιηοΙ) in ethanol (4 mL) was heated to 80 °C for 15h. The mixture was concentrated to give a crude product, which was purified by prep-HPLC

(column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-35%,12 min) to give N-[2-[4-[5-(3,4-dimethoxyphenyl)-1 ,3,4-oxadiazol-2-yl]-1 -piperidyl]-2-oxo- ethyl]benzamide (23 mg, 48 μιτιοΙ, 7 %) as a white solid. ¹ H NMR (400 MHz, Methanol-d4) δ 7.92 - 7.82 (m, 2H), 7.62 (dd, J=1 .8, 8.4 Hz, 1 H), 7.59 - 7.52 (m, 2H), 7.51 - 7.44 (m, 2H), 7.12 (d, J=8.4 Hz, 1 H), 4.49 (d, J=13.2 Hz, 1 H), 4.38 - 4.24 (m, 2H), 4.06 (d, J=13.7 Hz, 1 H), 3.97 - 3.80 (m, 6H), 3.48 - 3.34 (m, 2H), 3.06 (t, J=1 1 .2 Hz, 1 H), 2.33 - 2.15 (m, 2H), 2.06 - 1 .94 (m, 1 H), 1 .92 - 1 .75 (m, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 451 .2. Example 40: N-(2-(4-(3-(1 ,3-dimethyl-1H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of 1 ,3-dimethyl- 1 H-indazole-6-carbonitrile.

To a stirred solution of 6-bromo-1 ,3-dimethyl-1 H-indazole (400 mg, 1 .78 mmol) in N,N- dimethylformamide (5 mL) was added zinc cyanide (209 mg, 1 .78 mmol, 1 12 μί) and

tetrakis(triphenylphosphine)palladium(0) (205 mg, 178 μιηοΙ, 0.10 eq) under nitrogen. The mixture was heated at 100 for 16 h, then cooled to 20 °C, water (10 mL) added, and the resulting mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 mL) and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated in vacuo to give crude product. Petroleum ether (40 mL) was added to the crude product, then the mixture was filtered, and the filter cake dried in vacuo to give 1 ,3-dimethyl-1 H- indazole-6-carbonitrile (250 mg, 1 .46 mmol, 82 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 7.78 - 7.71 (m, 2H), 7.34 (dd, J=1 .3, 8.3 Hz, 1 H), 4.07 (s, 3H), 2.61 (s, 3H).

Step 2: Preparation of (Z)-N'-hydroxy- l ,3-dimeth - 1 H-indazole-6-carboximidamide.

To a stirred solution of 1 ,3-dimethyl-1 H-indazole-6-carbonitrile (100 mg, 584 μιτιοΙ) in ethanol (2 mL) was added hydroxylamine hydrochloride (81 mg, 1 .17 mmol), triethylamine (1 18 mg, 1 .17 mmol, 161 μί) and water (200 μί). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, water (5 mL) was added to the solution. The mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give (Z)-N'-hydroxy-l ,3-dimethyl-1 H- indazole-6-carboximidamide (140 mg) as a white solid. LCMS (ESI) m/z: [M+H] ⁺ = 205.1 .

Step 3: Preparation of N-(2-(4-(3-(1 ,3-dimethyl- 1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) in N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-6-carboximidamide (101 mg, 496 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 μΙ_). The mixture was stirred at 20 °C for 2 h, then heated at 120 for 2 h. The reaction mixture cooled then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-65%,12 min) to give N-(2-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (46 mg, 101 μιηοΙ, 25 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 8.02 (s, 1 H), 7.81 - 7.73 (m, 3H), 7.66 (dd, J=0.6, 8.4 Hz, 1 H), 7.48 - 7.42 (m, 1 H), 7.42 - 7.35 (m, 2H), 7.26 (br. s., 1 H), 4.46 (d, J=14.1 Hz, 1 H), 4.24 (d, J=3.9 Hz, 2H), 4.01 (s, 3H), 3.86 (d, J=13.7 Hz, 1 H), 3.29 (ddd, J=3.6, 10.5, 14.2 Hz, 2H), 3.13 - 3.04 (m, 1 H), 2.53 (s, 3H), 2.26 - 2.15 (m, 2H), 2.04 - 1 .89 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 459.3. Example 41 : N-(2-(4-(3-(4-fluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

DIPEA,HBTU,DMF

Step 1: Preparation of 4-fluoro-N-hydroxybenzimidamide.

To a stirred solution of 4-fluorobenzonitrile (1 .0 g, 8.26 mmol) in ethanol (1 0 mL) was added hydroxylamine hydrochloride (1 .15 g, 16.5 mmol), triethylamine (1 .67 g, 16.52 mmol, 2.29 mL) and water (1 mL). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (40 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give 4-fluoro-N-hydroxybenzimidamide (1 .0 g, 6.49 mmol, 79 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1 H), 7.85-7.64 (m, 2H), 7.21 (t, J = 8.9 Hz, 2H), 5.84 (br. s., 2H).

Step 2: Preparation of N-(2-(4-(3-(4-fluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) in

N,N-dimethylformamide (3 mL) was added 4-fluoro-N-hydroxybenzimidamide (76 mg, 496 μιηοΙ), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ) and N-ethyl-N- (propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 μί). The mixture was stirred at 20 °C for 2 h, then heated at 120 °C for 2 h. The reaction mixture cooled then purified directly by prep-HPLC (column: Luna C18 1 50x2.5mm 5μιτι ; mobile phase: [water (0.225%FA)-acetonitrile]; B%: 35%-65%,12 min) to give N- (2-(4-(3-(4-fluorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (56 mg, 135 μιηοΙ, 33 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 8.13-8.07 (m, 2H), 7.90-7.86 (m, 2H), 7.58-7.52 (m, 1 H), 7.51 -7.45 (m, 2H), 7.35 (br. s., 1 H), 7.23-7.1 6 (m, 2H), 4.56-4.47 (m, 1 H), 4.33 (d, J = 3.9 Hz, 2H), 3.93 (d, J = 13.9 Hz, 1 H), 3.41 -3.31 (m, 2H), 3.23-3.13 (m, 1 H), 2.33-2.21 (m, 2H), 2.02 (ddq, = 4.1 , 10.5, 14.2 Hz, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 409.2.

Example 42: N-(2-(4-(3-(3-fluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

Step 1: Preparation of N-(2-(4-(3-(3-fluorophenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin

oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) in N,N-dimethylformamide (4 mL) was added 3-fluoro-N-hydroxybenzimidamide (76 mg, 496 μιηοΙ), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ) and N-ethyl-N- (propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 μΙ_). The mixture was stirred at 20 °C for 2 h, then heated at 120 °C for 2 h. The reaction mixture was cooled then purified directly by prep-HPLC (column: Luna C8 100 ^* 30 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-60%,12 min) to give N-(2-(4-(3-(3-fluorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (59 mg, 145 μιτιοΙ, 35 %) as a yellow solid. Ή NMR (400MHz, CDCIs) δ 7.85-7.76 (m, 3H), 7.71 (d, J=9,3 Hz, 1 H), 7.49-7.35 (m, 4H), 7.26 (br. s., 1 H), 7.15 (s, 1 H), 4.43 (d, J=13.7 Hz, 1 H), 4.24 (d, J=3.5 Hz, 2H), 3.84 (d, J=14.1 Hz, 1 H), 3.33-3.22 (m, 2H), 3.14-3.04 (m, 1 H), 2.26-2.13 (m, 2H), 2.00-1 .85 ppm (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 409.2.

Example 43: N-(2-(4-(3-(2-fluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide.

Step 1: Preparation of 2-fluoro-N-hydroxybenzimidamide.

To a stirred solution of 2-fluorobenzonitrile (1 .0 g, 8.26 mmol, 877 μί) in ethanol (10 mL) was added hydroxylamine hydrochloride (1 .15 g, 1 6.5 mmol), triethylamine (1 .67 g, 16.5 mmol, 2.29 mL) and water (1 mL). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, water (20 mL) was added. The mixture was extracted with dichloromethane (40 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give 2-fluoro-N-hydroxybenzimidamide (1 .20 g, 7.79 mmol, 94 %) as a white solid. LCMS (ESI) m/z: [M+H] ⁺ = 1 55.1 . Step 2: Preparation of N-(2-(4-(3-(2-fluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (150 mg, 51 6.7 μιτιοΙ) in N,N-dimethylformamide (4 ml_) was added 2-fluoro-N-hydroxybenzimidamide (95 mg, 620 μιηοΙ), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (195 mg, 51 6.7 μιτιοΙ) and N-ethyl-N- (propan-2-yl)propan-2-amine (200 mg, 1 .55 mmol, 270 μΙ_). The mixture was stirred at 20 °C for 2 h, then heated at 120 °C for 2 h. The reaction mixture was cooled then purified directly by prep-HPLC (column: Luna C8 100 ^* 30 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-(2-(4-(3-(2-fluorophenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (85 mg, 208.6 μιτιοΙ, 40 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 7.98 (s, 1 H), 7.81 -7.75 (m, 2H), 7.48- 7.34 (m, 4H), 7.28-7.20 (m, 2H), 7.16 (d, J = 8.5 Hz, 1 H), 4.42 (d, J = 14.1 Hz, 1 H), 4.23 (d, J = 3.9 Hz, 2H), 3.84 (d, J = 13.9 Hz, 1 H), 3.29 (dt, J = 4.1 , 10.4 Hz, 2H), 3.14-3.04 (m, 1 H), 2.25-2.13 (m, 2H), 2.02- 1 .86 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 409.2.

Example 44: 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-phenylethanone.

Step 1: Preparation of 1 -(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin

phenylethanone.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 μιτιοΙ) in N,N-dimethylformamide (1 .50 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (196 mg, 518 μιηοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 μί) and 2-phenylacetic acid (74 mg, 544 μιτιοΙ, 68 μί). The mixture was stirred at 20 °C for 16 h. The crude product was purified directly by prep-HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,12 min) to give 1 -[4-[3- (3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-phenyl-ethanone (24 mg, 59 μιηοΙ, 1 1 %) as a white solid. ¹ H NMR (400MHz, METHANOL-d4) δ = 7.63 (dd, J=2.0, 8.4 Hz, 1 H), 7.55 (d, J=1 .8 Hz, 1 H), 7.39 - 7.20 (m, 5H), 7.05 (d, J=8.4 Hz, 1 H), 4.49 (br d, J=13.5 Hz, 1 H), 4.04 (br d, J=13.2 Hz, 1 H), 3.88 (s, 6H), 3.82 (s, 2H), 3.34 (br d, J=2.6 Hz, 1 H), 3.29 - 3.23 (m, 1 H), 3.05 - 2.95 (m, 1 H), 2.19 - 2.1 1 (m, 1 H), 2.06 - 1 .98 (m, 1 H), 1 .83 - 1 .71 (m, 1 H), 1 .67 - 1 .54 (m, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 408.3.

Example 45: 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-(6-methylpyrazin- 2-yl)ethanone.

Step 1: Preparation of diethyl 2-(6-methylpyrazin-2-yl)malonate.

To a stirred solution of 2-chloro-6-methylpyrazine (1 .0 g, 7.78 mmol) in N,N-dimethylformamide (20 mL) was added diethyl malonate (3.12 g, 19.5 mmol, 2.94 mL) and potassium carbonate (2.69 g, 19.5 mmol), then the mixture was stirred at 1 10 °C for 16 h. The reaction mixture was cooled to 20 °C, quenched with water (20 mL), and then extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica, petroleum ether : ethyl acetate = 50 : 1 to 10 : 1 ) gave diethyl 2-(6-methylpyrazin-2-yl)malonate (180 mg, 713.5 μιτιοΙ, 9 %) as a green oil. ¹ H NMR (400 MHz, CDC ) δ 8.58 (s, 1 H), 8.44 (s, 1 H), 4.91 (s, 1 H), 4.20-4.15 (q, J = 7.2 Hz, 4H), 2.58 (s, 3H), 1 .25-1 .22 (t, J = 7.2 Hz, 6H); LCMS (ESI) m/z: 253.1 [M+H] ⁺ . Step 2: Preparation of 2-(6-methylpyrazin-2-yl)a

To a stirred solution of diethyl 2-(6-methylpyrazin-2-yl)malonate (180 mg, 713.5 μιηοΙ) in ethanol (10 mL) was added sodium hydroxide (2 M, 1 .96 mL) and the mixture warmed at 60 °C for 2 h. The reaction was cooled to 20 °C, and acidified with 1 M hydrochloric acid (5 mL). The mixture was concentrated in vacuo to give 2-(6-methylpyrazin-2-yl) acetic acid (1 .42 g) as a light yellow solid that was used directly without further purification. Step 3: Preparation of 1 -(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin

methylpyrazin-2-yl) ethanone.

To a stirred solution of 2-(6-methylpyrazin-2-yl)acetic acid (1 .05 g, 41 5 μιηοΙ, purity 6 %) in N,N- dimethylformamide (4 ml_) was added 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (120 mg, 41 5 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate) (1 57 mg, 41 5 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (21 4 mg, 1 .66 mmol, 289 μΙ_). The mixture was stirred at 20 °C for 4 h. The reaction mixture was purified directly by prep-H PLC (column : Waters Xbridge 1 50x2.5mm 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 25%-50%, 12 min) to give 1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-(6-methylpyrazin-2- yl)ethanone (26 mg, 62 μιτιοΙ, 1 5 %) as a yellow solid. ¹ H NMR (400 MHz, Methanol-d4) δ 8.41 (s, 2H), 7.68 (dd, J=1 .9, 8.3 Hz, 1 H), 7.61 (d, J=1 .8 Hz, 1 H), 7.1 0 (d, J=8.4 Hz, 1 H), 4.51 (d, J=13.4 Hz, 1 H), 4.22 (d, J=13.9 Hz, 1 H), 4.12 - 3.93 (m , 2H), 3.92 (s, 6H), 3.52 - 3.38 (m, 2H), 3.12 - 3.02 (m, 1 H), 2.57 (s, 3H), 2.28 - 2.1 7 (m , 2H), 2.04 - 1 .80 (m , 2H) ; LCMS (ESI) m/z: [M+H] ⁺ = 424.2.

Example 46: N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)pipe din-1-yl)-2- oxoethyl)acetamide.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (250 mg, 864 μιηοΙ) in N,N-dimethylformamide (1 .5 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (327 mg, 864 μιτιοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (335 mg, 2.59 mmol, 452 μΙ_) and 2-acetamidoacetic acid (1 06 mg, 907 μιτιοΙ). The mixture was stirred at 20 °C for 1 6 h. The crude product was purified by prep-HPLC (column : Luna C8 1 00x30 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile] ; B%: 20%-50%,1 2 min) to give N-[2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]acetamide (36 mg, 94 μιτιοΙ, 1 1 %) as a white solid. ¹ H NMR (400MHz, METHANOL-d4) δ = 7.69 (dd, J=1 .9, 8.3 Hz, 1 H), 7.61 (d, J=1 .9 Hz, 1 H), 7.1 0 (d, J=8.4 Hz, 1 H), 4.47 (br d, J=14.2 Hz, 1 H), 4.21 - 4.06 (m, 2H), 3.98 (br d, J=13.1 Hz, 1 H), 3.92 (s, 6H), 3.47 - 3.38 (m , 2H), 3.13 - 3.00 (m , 1 H), 2.31 - 2.1 6 (m, 2H), 2.05 (s, 3H), 2.00 - 1 .79 (m, 2H) ; LCMS (ESI) m/z: [M+H] ⁺ = 389.2.

Example 47: N-(2-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperi din-1-yl)-2- oxoethyiyisobutyramide.

To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (150 mg, 433 μιηοΙ) in dichloromethane (3 mL) was added isobutyryl chloride (55 mg, 520 μιτιοΙ, 54 μΙ_) and triethylamine (131 mg, 1 .30 mmol, 180 μΙ_) at 0 °C. The mixture was warmed and stirred at 20 for 1 h. The reaction mixture was concentrated in vacuo to give crude product that was purified by HPLC prep-HPLC (column: Waters Xbridge 150x2.5mm 5μΓη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 23%-53%,12 min) to give N-(2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol- 5-yl)piperidin-1 -yl)-2-oxoethyl)isobutyramide (85 mg, 204 μιτιοΙ, 47 %) as a white solid. ^J ' NMR (400MHz, CDC ) δ 7.74-7.68 (m, 1 H), 7,58 (d, J = 1 .9 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.63 (br. s., 1 H), 4.49 (d, J = 13.3 Hz, 1 H), 4.12 (d, J = 4.0 Hz, 2H), 3.98 (d, J = 7.3 Hz, 6H), 3.87 (d, J = 14.1 Hz, 1 H), 3.36-3.26 (m, 2H), 3.13 (t, J = 1 0.9 Hz, 1 H), 2.50 (td, J = 6.9, 13.8 Hz, 1 H), 2.23 (br. s., 2H), 2.06-1 .92 (m, 2H), 1 .22 (d, J = 6.9 Hz, 6H); LCMS (ESi) m/z: [M+H] ⁺ = 41 7.3.

Example 48: N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)cyclohexanecarboxamide.

To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (150 mg, 433 μιηοΙ) in dichloromethane (3 mL) was added cyclohexanecarbonyl chloride (76 mg, 520 μιηοΙ, 69 μί) and triethylamine (131 mg, 1 .30 mmol, 180 μί) at 0 °C. The mixture was warmed and stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μίη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 23%-53%,12 min) to give N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)cyclohexanecarboxamide (78 mg, 171 μιτιοΙ, 39 %) as a white solid. Ή NMR (400MHz, CDCb) δ 7.73-7.68 (m, 1 H), 7.60-7.57 (m, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.64-6.59 (m, 1 H), 4.53-4.45 (m, 1 H), 4.1 1 (d, J = 4.0 Hz, 2H), 3.98 (d, J = 7.2 Hz, 6H), 3.86 (d, J = 13.3 Hz, 1 H), 3.36-3.26 (m, 2H), 3.12 (t, J = 10.7 Hz, 1 H), 2.28-2.18 (m, 3H), 2.05-1 .89 (m, 4H), 1 .82 (d, J = 12.3 Hz, 2H), 1 .71 (d, = 10.9 Hz, 1 H), 1 .54-1 .42 (m, 2H), 1 .37-1 .22 (m, 3H); LCMS (ESi) m/z: [M+H] ⁺ = 457.3. Example 49: 1-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-N-(2^henyle thyl)piperffl carboxamide.

Step 1: Preparation of tert-butyl 4-(phenethylcarbamoyl)piperidine- 1-carboxylate.

To a stirred solution of 1 -tert-butoxycarbonylpiperidine-4-carboxylic acid (1 .0 g, 4.36 mmol) in dichloromethane (15 mL) was added 2-phenylethanamine (528 mg, 4.36 mmol, 544 μΙ_), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (835 mg, 4.36 mmol) and triethylamine (44 mg, 436 μιηοΙ, 60 μΙ_). The mixture was stirred at 20 °C for 5 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by chromatography (silica, petroleum ether / ethyl acetate from 10/1 to 1 /1 ) to give tert-butyl 4-(2-phenylethylcarbamoyl)piperidine-1 -carboxylate (800 mg, 2.41 mmol, 55 %) as a white solid. LCMS (ESI) m/z: 355.2 [M+Na] ⁺ .

Step 2: Preparation of N-phenethylpiperidine-4-carboxamide.

A solution of tert-butyl 4-(2-phenylethylcarbamoyl)piperidine-1 -carboxylate (800 mg, 2.41 mmol) in 4N hydrochloric acid / ethyl acetate (1 0 mL) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give N-(2-phenylethyl)piperidine-4-carboxamide (720 mg) as a hydrochloric acid salt and as a white solid.

Step 3: Preparation of 5-chloro-3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazole.

c _l Q O-M ^o e ^Me

3-(3,4-dimethoxyphenyl)-4H-1 ,2,4-oxadiazol-5-one (900 mg, 4.05 mmol) was added to a mixture of N,N-dimethylformamide (2 mL) and phosphoryl chloride (24.8 g, 161 .4 mmol, 15 mL). The mixture was equipped with calcium chloride tube and the mixture was heated at 100 °C for 16 h. The mixture was cooled to 0°C and concentrated under reduced pressure. The residue was poured into ice-water (20 mL) and stirred for 10 min, then the aqueous phase was extracted with dichloromethane (10 mL x 5). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=5/1 , 1 /1 ) to give 5-chloro-3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazole (104 mg, 432 μιτιοΙ, 1 1 %) as a white solid. Step 4: Preparation of 1 -(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)-N-phenethylpiperidine-4- carboxamide.

To a stirred solution of 5-chloro-3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazole (95 mg, 395 μιηοΙ) in N-methyl-2-pyrrolidone (2 mL) was added N-(2-phenylethyl)piperidine-4-carboxamide (1 10 mg, 474 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (102 mg, 790 μιηοΙ, 137 μί) at 20 °C. Then the mixture was heated to 120 and stirred for 5 h. The crude product was purified by prep-HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-65%,12 min), Compound 1 -[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-N-(2-phenylethyl)piperidine-4-carboxami de (1 17 mg, 266 μιτιοΙ, 67 %) as a white solid. ¹ H NMR (400MHz, METHANOL-d4) δ = 7.57 (dd, J=2.0, 8.4 Hz, 1 H), 7.51 (d, J=1 .9 Hz, 1 H), 7.33 - 7.27 (m, 2H), 7.25 - 7.18 (m, 3H), 7.06 (d, J=8.4 Hz, 1 H), 4.22 (br d, J=13.3 Hz, 2H), 3.90 (s, 6H), 3.44 (t, J=7.3 Hz, 2H), 3.27 - 3.17 (m, 2H), 2.82 (t, J=7.2 Hz, 2H), 2.51 - 2.40 (m, 1 H), 1 .92 - 1 .67 (m, 4H); LCMS (ESI) m/z: [M+H] ⁺ = 437.3.

Example 50: 1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)- 1,2,4-oxadiazol-3-yl)piperidine-1- carbonyl)pyrrolidin-2-one.

To a stirred solution of 1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carboxylic acid (1 .0 g, 4.29 mmol) in N,N-dimethylformamide (10 mL) was added piperidine-4-carbonitrile (567 mg, 5.15 mmol), (2- (1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 .63 g, 4.29 mmol) and N-ethyl- N-(propan-2-yl)propan-2-amine (1 .66 g, 12.87 mmol, 2.25 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with water (10 mL), then the mixture was extracted with ethyl acetate (20 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a yellow oil (1 .6 g). A portion of the crude product (0.3 g) was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12 min) to give 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine -4-carbonitrile for analysis (144 mg). The remainder of the crude product was used directly without purification. ¹ H NMR (400 MHz, Methanol-d4) δ 7.37 (d, J = 2.5 Hz, 1 H), 7.31 -7.25 (m, 1 H), 7.15 (d, J = 8.2 Hz, 1 H), 4.08 (d, J = 7.0 Hz, 5H), 3.59-3.37 (m, 2H), 3.1 6-3.03 (m, 1 H), 2.91 -2.79 (m, 2H), 2.28 (d, J = 10.2 Hz, 6H), 2.10-1 .72 (m, 4H); LCMS (ESI) m/z: [M+H] ⁺ = 326.2.

Step 2: Preparation of (Z)- 1-(1-(3A-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'-hyd roxy carboximidamide.

To a stirred solution of 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine -4- carbonitrile (1 .30 g, 4.00 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (555 mg, 8.00 mmol), triethylamine (809 mg, 8.00 mmol, 1 .1 1 mL) and water (1 mL). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (40 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid (1 .4 g). A portion of crude product (0.3 g) was purified by prep-HPLC

(column: Luna C18 150x2.5mm 5μιτι; mobile phase: [water (0.225% TFA)-acetonitrile]; B%: 15%-40%,12 min) to give (Z)-1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'-hydrox ypiperidine-4- carboximidamide. The remainder was used directly in the next step. ¹ H NMR (400 MHz, DMSO-d6) δ 8.86-8.77 (m, 1 H), 8.15 (s, 1 H), 7.45-7.33 (m, 2H), 7.12 (dd, J = 8.2, 2.4 Hz, 1 H), 5.36 (br. s., 2H), 4.47- 4.32 (m, 1 H), 4.06-3.86 (m, 3H), 3.75-3.60 (m, 1 H), 3.07 (br. s., 1 H), 2.80-2.57 (m, 3H), 2.36-2.24 (m, 1 H), 2.21 (d, J = 1 1 .8 Hz, 6H), 1 .83-1 .67 (m, 2H), 1 .56 ppm (br. s., 2H); LCMS (ESI) m/z: [M+H] ⁺ = 359.3.

Step 3: Preparation of 1-(3 -dimethylphenyl)-4-(4-(5-(p-tolyl)- 1,2,4-oxadiazol-3-yl)piperidine- 1- carbonyl)pyrrolidin-2-one.

To a stirred solution of (Z)-1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'- hydroxypiperidine-4-carboximidamide (300 mg, 837 μιτιοΙ) in tetrahydrofuran (8 mL) was added 4- methylbenzoyl chloride (155 mg, 1 .00 mmol, 132 μί) and triethylamine (254 mg, 2.51 mmol, 348 μί) at 0 °C, then the mixture was warmed at 20 °C. After 3 h, to the reaction mixture was added ethyl acetate and water and the organic phase was separated. The organic phase was washed with water and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. To the residue were added tetrahydrofuran (8 mL) and a tetrabutylammonium fluoride in tetrahydrofuran (1 M, 2.51 mL) solution, and the mixture warmed at 50 °C for 16 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Luna C18 100 ^* 30 5μιτι; mobile phase: [water (0.225%TFA)-acetonitrile]; B%: 45%-75%,12 min) to give the racemic of 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1 ,2,4-oxadiazol-3- yl)piperidine-1 -carbonyl)pyrrolidin-2-one (106 mg, 0.23 mmol, 28 %) as a white solid. ¹ H NMR (400 MHz, CDCb) δ 8.06-7.99 (m, 2H), 7.41 -7.33 (m, 3H), 7.31 (d, J = 2.0 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 4.60 (t, J = 13.2 Hz, 1 H), 4.30 (dd, J = 7.4, 9.5 Hz, 1 H), 4.04-3.88 (m, 2H), 3.60 (quin, J = 8.5 Hz, 1 H), 3.42-3.31 (m, 1 H), 3.25-3.14 (m, 1 H), 3.1 1 -2.94 (m, 2H), 2.88-2.78 (m, 1 H), 2.47 (s, 3H), 2.32-2.12 (m, 8H), 2.03- 1 .86 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 459.3.

Example 51: 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1,2,4-oxadiazol-3-y l)piperidine-1- carbonyl)pyrrolidin-2-one.

To a stirred solution of (Z)-1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)-N'- hydroxypiperidine-4-carboximidamide (280 mg, 781 μιηοΙ) in tetrahydrofuran (8 mL) was added 3- methylbenzoyl chloride (144 mg, 937 μιτιοΙ, 123 iL) and triethylamine (237 mg, 2.34 mmol, 324 iL) at 0 °C, the mixture was stirred at 20 °C for 3 h. To the reaction mixture was added ethyl acetate and water and the organic phase was separated. The organic phase was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. To the residue were addded tetrahydrofuran (8 mL) and a tetrabutylammonium fluoride in tetrahydrofuran solution (1 M, 2.34 mL). The mixture was warmed to 50 °C and stirred for 16 h. The reaction mixture was cooled and concentrated in vacuo to give a crude product that was purified by prep- HPLC (column: Luna C8 100x30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-75%,12 min) to give the racemic of 1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3- yl)piperidine-1 -carbonyl)pyrrolidin-2-one (156 mg, 0.34 mmol, 44 %) as a white solid. ¹ H NMR (400 MHz, CDCb) δ 7.99-7.91 (m, 2H), 7.43 (d, J = 1 .0 Hz, 3H), 7.32-7.29 (m, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 4.60 (t, J = 14.1 Hz, 1 H), 4.30 (dd, J = 7.3, 9.6 Hz, 1 H), 4.04-3.88 (m, 2H), 3.65-3.54 (m, 1 H), 3.37 (d, J = 7.0 Hz, 1 H), 3.21 (d, J = 3.5 Hz, 1 H), 3.1 1 -2.94 (m, 2H), 2.88-2.78 (m, 1 H), 2.48 (s, 3H), 2.32-2.13 (m, 8H), 1 .93 (d, J = 12.2 Hz, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 459.3.

Example 52: (4-(5-(3-fluorophenyl)- 1,2,4-oxadiazol-3-yl)piperidin-1-yl)(4- isopropylphenyl)methanone.

To a stirred solution of 4-isopropylbenzoic acid (1 .0 g, 6.09 mmol) in N,N-dimethylformamide (10 mL) was added piperidine-4-carbonitrile (805 mg, 7.31 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (2.31 g, 6.09 mmol) and N-ethyl-N-(propan-2-yl)propan-2- amine (2.36 g, 1 8.27 mmol, 3.19 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with water (10 mL), then the mixture was extracted with ethyl acetate (40 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give yellow oil (1 .8 g). A portion of crude product (0.2 g) was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 25%-55%,12 min) to give 1 -(4- isopropylbenzoyl)piperidine-4-carbonitrile (1 15 mg) as a sample for analysis. The remainder was used directly. ¹ H NMR (400 MHz, Methanol-d4) δ 7.37 (s, 4H), 4.16-3.40 (m, 4H), 3.15-3.07 (m, 1 H), 3.02-2.93 (m, 1 H), 2.10-1 .76 (m, 4H), 1 .31 -1 .26 (m, 6H); LCMS (ESI) m/z: [M+H] ⁺ = 257.2.

Step 2: Preparation of N-hydroxy- 1-(4-isopropylbenzoyl)piperidine-4-carboximidamide.

To a stirred solution of 1 -(4-isopropylbenzoyl)piperidine-4-carbonitrile (1 .60 g, 6.24 mmol) in ethanol (15 mL) was added hydroxylamine hydrochloride (867 mg, 12.5 mmol), triethylamine (1 .26 g, 12.48 mmol, 1 .73 mL) and water (1 .50 mL). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (40 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo to give N-hydroxy- 1 -(4-isopropylbenzoyl)piperidine-4-carboximidamide (1 .60 g, 5.53 mmol, 89 %) as a white solid that was used directly without further purification. ¹ H NMR (400 MHz, Methanol-d4) δ 7.40-7.33 (m, 4H), 4.78-4.58 (m, 1 H), 3.94-3.73 (m, 1 H), 3.22 (d, J = 7.3 Hz, 2H), 3.02-2.95 (m, 1 H), 2.50-2.35 (m, 1 H), 1 .96-1 .67 (m, 4H), 1 .31 -1 .27 (m, 6H).

Step 3: Preparation of (4-(5-(3-fluorophenyl)- 1,2,4-oxadiazol-3-yl)piperidin- 1-yl)(4- isopropylphenyl)methanone.

To a stirred solution of N-hydroxy-1 -(4-isopropylbenzoyl)piperidine-4-carboximidamide (200 mg, 691 μιηοΙ) in tetrahydrofuran (5 mL) was added 3-fluorobenzoyl chloride (131 mg, 829 μιτιοΙ, 99 μΙ_) and triethylamine (209 mg, 2.07 mmol, 287 μΙ_) at 0 °C. The mixture was warmed and then stirred at 20 °C for 16 h. To the reaction mixture was added ethyl acetate and water and the organic phase was separated. The organic phase was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. To the obtained residue were added tetrahydrofuran (5 mL) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 2.07 mL), then the mixture was warmed at 50 °C for 16 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 1 50x2.5mm 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 50%-80%,12 min) to give (4-(5-(3-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)piperidin-1 -yl)(4-isopropylphenyl)methanone (76 mg, 193.5 μιηοΙ, 28 %) as a yellow oil. ¹ H NMR (400 MHz, CDC ) δ 7.85 (d, J = 7.7 Hz, 1 H), 7.78-7.72 (m, 1 H), 7.45 (dt, J = 5.6, 8.0 Hz, 1 H), 7.32-7.27 (m, 2H), 7.26-7.20 (m, 2H), 7.18 (s, 1 H), 4.76-3.64 (m, 2H), 3.20-2.97 (m, 3H), 2.86 (td, J = 6.9, 13.8 Hz, 1 H), 2.18-1 .74 (m, 4H), 1 .19 (d, J = 6.9 Hz, 6H); LCMS (ESI) m/z: [M+H] ⁺ = 394.2.

Example 53: (4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1-

Step 1: Preparation of 4-ethoxy-3-methoxybenzonitrile.

To a stirred solution of 4-hydroxy-3-methoxybenzonitrile (5.0 g, 33.5 mmol) in N,N- dimethylformamide (50 mL) was added iodoethane (6.27 g, 40.2 mmol, 3.22 mL) and potassium carbonate (9.27 g, 67.0 mmol) at 0 °C, then the reaction was warmed and stirred at 40 °C for 16 h. The reaction mixture was quenched by addition of water (50 mL) then the mixture was extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 4-ethoxy-3- methoxybenzonitrile (5.80 g, 32.7 mmol, 98 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 7.20-7.16 (m, 1 H), 7.00 (d, J = 1 .9 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 4.07 (q, J = 6.9 Hz, 2H), 3.82 (s, 3H), 1 .45-1 .39 (m, 3H).

Step 2: Preparation of (Z)-4-ethoxy-N'-hydro -3-methoxybenzimidamide.

To a stirred solution of 4-ethoxy-3-methoxybenzonitrile (5.80 g, 32.7 mmol) in ethanol (50 mL) was added hydroxylamine hydrochloride (4.55 g, 65.5 mmol), triethylamine (6.62 g, 65.46 mmol, 9.07 mL) and water (5 mL). The mixture was heated at 75 °C for 2 h. After cooling to 20 °C, the solvents were evaporated under vacuum, and water (20 mL) was added to the solution. The mixture was extracted with dichloromethane (60 mL x 3). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and then filtered and

concentrated in vacuo to give (Z)-4-ethoxy-N'-hydroxy-3-methoxybenzimidamide (5.96 g, 28.4 mmol, 87 %) as a white solid. Ή NMR (400 MHz, DMSO-d6) δ 9.44 (br. s., 1 H), 7.28-7.14 (m, 2H), 6.90 (d, J = 8.4 Hz, 1 H), 5.73 (s, 2H), 4.00 (q, J = 6.9 Hz, 2H), 3.75 (s, 3H), 1 .31 (t, J = 7.1 Hz, 3H).

Step 3: Preparation of tert-butyl 4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carboxylate.

To a stirred solution of (Z)-4-ethoxy-N'-hydroxy-3-methoxybenzimidamide (1 .0 g, 4.76 mmol) in N,N-dimethylformamide (15 mL) was added 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1 .09 g, 4.76 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 .81 g, 4.76 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 .85 g, 14.28 mmol, 2.49 mL). The mixture was stirred at 20 °C for 16 h then heated at 120 for 2 h. The reaction mixture was cooled then quenched by addition of water (40 mL), then the mixture was extracted with ethyl acetate (80 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 4-(3-(4-ethoxy-3- methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carboxylate (2.56 g) as a yellow oil. LCMS (ESI) m/z: [M+H] ⁺ = 404.3.

Step 4: Preparation of 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)- 1,2,4-oxadiazole. To a stirred solution of tert-butyl 4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine- 1 -carboxylate (1 .0 g, 2.48 mmol) in methanol (5 mL) was added 4 M methanolic hydrochloric acid (20 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to provide the crude 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (900 mg) as a yellow solid that was used directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ = 304.1

Step 5: Preparation of (4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)(piperti yl)methanone

To a stirred solution of 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (200 mg, 659 μιηοΙ) in dichloromethane (3 mL) was added piperidine-1 -carbonyl chloride (1 16 mg, 791 μιτιοΙ, 98iL) and triethylamine (200 mg, 1 .98 mmol, 274 iL) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 40%-70%,12 min) to give (4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)(piperidin-1 -yl)methanone (65 mg, 158 μιηοΙ, 24 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 7.71 -7.66 (m, 1 H), 7.59 (d, J = 1 .9 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 4.1 9 (q, J = 6.9 Hz, 2H), 3.98 (s, 3H), 3.75 (d, J = 13.6 Hz, 2H), 3.29-3.13 (m, 5H), 3.04-2.94 (m, 2H), 2.17 (dd, J = 3.1 , 13.3 Hz, 2H), 2.05-1 .93 (m, 2H), 1 .60 (d, J = 8.4 Hz, 6H), 1 .53 (t, J = 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 415.3.

Example 54: (4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1- yl)methanone.

Step 1: Preparation of (4-(3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)(piperidin- 1- yl)methanone.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (100 mg, 346 μιτιοΙ) in dichloromethane (3 mL) was added piperidine-1 -carbonyl chloride (61 mg, 41 5 μιηοΙ, 51 μί) and triethylamine (104 mg, 1 .04 mmol, 143 μί) at 0 °C. The mixture was stirred at 20 for 1 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,12 min) to give (4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)(piperidin-1 - yl)methanone (81 mg, 202 μιτιοΙ, 58 %) as a white solid. ¹ H NMR (400MHz, CDC ) δ 7.74-7.68 (m, 1 H), 7.59 (d, J = 1 .9 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 3.98 (d, J = 8.4 Hz, 6H), 3.76 (d, J = 13.4 Hz, 2H), 3.29- 3.14 (m, 5H), 3.04-2.95 (m, 2H), 2.17 (dd, J = 13.3, 3.4 Hz, 2H), 2.05-1 .94 (m, 2H), 1 .60 ppm (d, J = 8.5 Hz, 6H); LCMS (ESI) m/z: [M+H] ⁺ = 401 .3.

Example 55: 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-(isoquinolin-1-

Step 1: Preparation of 1-(4-(3-(3 -dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-(isoqu ylamino)ethanone.

To a stirred solution of 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)ethanone (150 mg, 433 μιηοΙ) in toluene (2 mL) was added 1 -chloroisoquinoline (70 mg, 433 μιηοΙ), cesium carbonate (423 mg, 1 .30 mmol), (±)-2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthalene (26 mg, 43 μιηοΙ, 0.1 0 eq), and palladium(ll) acetate (9 mg, 43 μιηοΙ, 0.10 eq) under nitrogen. The mixture was stirred at 100 °C for 1 6 h. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Luna C8 100 ^* 30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give 1 -(4- (3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-(isoquinolin-1 -ylamino)ethanone (57 mg, 1 19 μιτιοΙ, 27 %) as a white solid. NMR (400MHz, CDC ) δ 8.04-7.96 (m, 2H), 7.75-7.50 (m, 5H), 7.03- 6,95 (m, 2H), 6.66 (br. s., 1 H), 4,60 (d, J - 13.7 Hz, 1 H), 4,45 (br, s., 2H), 4.08 (d, J - 12.5 Hz, 1 H), 3.98 (d, J = 7,9 Hz, 6H), 3.46-3.30 (m, 2H), 3.24-3.13 (m, 1 H), 2,28 (br, s., 2H), 2.13-1 ,97 (m, 2H); LCMS (ES!) m/z: [M+H] ⁺ = 474,3. Example 56: N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperazin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of 5-chloro-3-(3,4-dimethoxyphenyl)- 1 ,2,4-oxadiazole.

To a mixture of N,N-dimethylformamide (1 mL) and phosphoryl chloride (8.25 g, 53.8 mmol, 5 mL) was added 3-(3,4-dimethoxyphenyl)-4H-1 ,2,4-oxadiazol-5-one (300 mg, 1 .35 mmol) at 25 °C under calcium chloride tube. The mixture was heated to 100 °C and stirred for 16 h. The mixture was cooled to 25 °C and concentrated in vacuo carefully. The residue was poured into ice-water (20 mL) and stirred for 10 min. The aqueous phase was extracted with dichloromethane (10 mL x 5). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography

(petroleum ether / ethyl acetate=5/1 to 1 /1 ) to afford 5-chloro-3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazole (99 mg, 414 μιτιοΙ, 31 %) as a white solid. LCMS (ESI) m/z: 241 .1 [M+H] ⁺ .

Step 2: Preparation of tert-butyl 4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperazine- 1 -carboxylate.

To a stirred solution of 5-chloro-3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazole (90 mg, 374 μιτιοΙ) and tert-butyl piperazine-1 -carboxylate (83 mg, 448.80 μιηοΙ) in N-methyl-2-pyrrolidone (1 .50 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (96 mg, 748 μιηοΙ, 130 μί). The mixture was stirred at 120 °C for 2 h. The mixture was cooled to 25 °C and concentrated in vacuo at 40 °C. The residue was poured into water (10 mL) then the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperazine-1 -carboxylate (900 mg) that was used directly without further purification.

Step 3: Preparation of 3-(3,4-dimethoxypheny 1 ,2,4-oxadiazole. A solution of tert-butyl 4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperazine-1 -carboxylate (146 mg, 374 μιτιοΙ) in hydrochloric acid / ethyl acetate (4M, 1 0 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated in vacuo to give 3-(3,4-dimethoxyphenyl)-5-piperazin-1 -yl-1 ,2,4- oxadiazole hydrochloride (900 mg) which was used directly without further purification.

Step 4: Preparation of N-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperazin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-piperazin-1 -yl-1 ,2,4-oxadiazole hydrochloride (667 mg, 306 μιηοΙ,) and 2-benzamidoacetic acid (137 mg, 765 μιηοΙ) in N,N-dimethylformamide (2 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 74 mg, 459 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 1 8 mg, 918.51 μιηοΙ, 1 60 μΙ_) at 20 °C. The mixture was stirred at 20 °C for 5 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x25 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-60%,12 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperazin-1 -yl]-2-oxo-ethyl]benzamide (55 mg, 121 μιτιοΙ, 39 %) as a yellow solid. ¹ H NMR (400MHz, DMSO-d6) δ = 8.59 (br t, J=5.6 Hz, 1 H), 7.93 - 7.83 (m, 2H), 7.60 - 7.44 (m, 4H), 7.39 (d, J=1 .9 Hz, 1 H), 7.08 (d, J=8.5 Hz, 1 H), 4.20 (d, J=5.6 Hz, 2H), 3.81 (d, J=1 .1 Hz, 6H), 3.73 - 3.58 (m, 8H); LCMS (ESI) m/z: [M+H] ⁺ = 452.2. Example 57: ( 1-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1- yl)methanone.

Step 1: Preparation of tert-butyl 4-(piperidine- 1 -carbonyl)piperidine- 1 -carboxylate.

To a stirred solution of 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1 .0 g, 4.36 mmol) in N,N- dimethylformamide (15 mL) was added piperidine (445 mg, 5.23 mmol, 518 μί), 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1 .99 g, 5.23 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 .69 g, 13.1 mmol, 2.29 mL). The mixture was stirred at 20 °C for 3 h. The reaction mixture was quenched by addition of water (20 mL) then the mixture was extracted with ethyl acetate (40 mL x 4), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 4-(piperidine-1 -carbonyl)piperidine-1 -carboxylate (1 .90 g) as a yellow oil. This was used directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ = 297.2

Step 2: Preparation of piperidin- 1-yl(piperi

To a stirred solution of tert-butyl 4-(piperidine-1 -carbonyl)piperidine-1 -carboxylate (500 mg, 1 .69 mmol) in methanol (5 mL) was added 4N methanolic hydrogen chloride solution (15 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to provide piperidin-1 -yl(piperidin-4-yl)methanone (400 mg) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d6) δ 3.51 - 3.36 (m, 4H), 3.28-3.18 (m, 2H), 2.90 (s, 4H), 1 .82-1 .68 (m, 4H), 1 .64-1 .37 (m, 6H).

Step 3: Preparation of 3-(4-ethoxy-3-meth ,2,4-oxadiazol-5(4H)-one.

To a stirred solution of 4-ethoxy-N-hydroxy-3-methoxybenzimidamide (800 mg, 3.81 mmol) in dioxane (8 mL) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (638 mg, 4.19 mmol, 631 μί) and 1 ,1 '- carbonyldiimidazole (926 mg, 5.72 mmol). The mixture was stirred at 1 1 0 °C for 16 h. The reaction mixture was quenched with water (10 mL), then the mixture was extracted with dichloromethane (50 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by chromatography (silica, dichloromethane : methanol = 50 :1 ) gave 3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5(4H)- one (1 .20 g, quant.) as a yellow oil. LCMS (ESI) m/z: [M+H] ⁺ = 237.1 .

Step 4: Preparation of 5-chloro-3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazole.

To a stirred mixture of 3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5(4H)-one (500 mg, 2.12 mmol) and N,N-dimethylformamide (1 mL) was equipped with calcium chloride tube and phosphoryl chloride (10 mL) was added dropwise. The mixture was heated at 1 10 °C for 1 6 h. The reaction mixture was cooled to 20 °C, then poured onto ice water (1 00 mL), and stirred for 30 min. The mixture was extracted with dichloromethane (20 mL x 5), then the combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 5-chloro-3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazole (360 mg, 1 .41 mmol, 67 %) as a brown solid. LCMS (ESI) m/z: [M+H] ⁺ = 255.1

Step 5: Preparation of (1-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidi

yl)methanone.

To a stirred solution of piperidin-1 -yl(piperidin-4-yl)methanone (100 mg, 509 μιηοΙ) in N-methyl-2- pyrrolidone (4 mL) was added 5-chloro-3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazole (194 mg, 764 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (131 mg, 1 .02 mmol, 177 μί). The mixture was stirred at 120 °C for 16 h. The reaction mixture was purified directly by prep-HPLC (column: Luna C8 100 ^* 30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,12 min) to give (1 - (3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)(piperidin-1 -yl)methanone (61 mg, 147.6 μιτιοΙ, 29 %) as a yellow solid. Ή NMR (400 MHz, CDC ) δ 7.53-7.47 (m, 1 H), 7.42 (d, J = 1 .9 Hz, 1 H), 6.84 (d, J = 8.5 Hz, 1 H), 4.24-4.16 (m, 2H), 4.08 (q, J = 6.9 Hz, 2H), 3.87 (s, 3H), 3.50 (br. s., 2H), 3.40 (br. s., 2H), 3.19-3.09 (m, 2H), 2.69 (tt, J = 3.8, 10.7 Hz, 1 H), 1 .94-1 .71 (m, 4H), 1 .63-1 .48 (m, 6H), 1 .42 (t, J = 7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 41 5.3. Example 58: N-(2-(4-(3-(2-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)-3,4- dimethylbenzamide.

Step 1: N-(2-(4-(3-(2-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2-oxoethyl)-3,4- dimethylbenzamide.

To a stirred solution of 1 -(2-(3,4-dimethylbenzamido)acetyl)piperidine-4-carboxylic acid (150 mg, 471 μιτιοΙ) and N-hydroxy-2-methoxybenzimidamide (78 mg, 471 μιτιοΙ) in N,N-dimethylformamide (2 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (121 mg, 942 μιτιοΙ, 164 μί) and (2-(1 H-benzotriazol- 1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (178 mg, 471 μιτιοΙ) at 15 °C. The mixture was stirred for 15 h, then the mixture was heated to 1 1 0 °C and stirred for 5 h. The mixture was cooled and then purified by prep-HPLC (column: Waters Xbridge 150x25 5μιη; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 37%-67%,12 min) to obtain N-(2-(4-(3-(2-methoxyphenyl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)-3,4-dimethylbenzamide (1 10 mg, 244 μιτιοΙ, 52 %) as yellow solid. ¹ H NMR (400 MHz, Methanol-d4) 57.96 (dd, J=1 .5, 7.7 Hz, 1 H), 7.66 (s, 1 H), 7.60 (d, J=7.9 Hz, 1 H), 7.56 - 7.49 (m, 1 H), 7.23 (d, J=7.5 Hz, 1 H), 7.1 8 (d, J=8.4 Hz, 1 H), 7.09 (t, J=7.5 Hz, 1 H), 4.47 (d, J=12.8 Hz, 1 H), 4.35 - 4.23 (m, 2H), 4.04 (d, J=13.7 Hz, 1 H), 3.92 (s, 3H), 3.49 - 3.35 (m, 2H), 3.07 (t, J=1 1 .0 Hz, 1 H), 2.32 (s, 6H), 2.27 - 2.1 0 (m, 2H), 2.06 - 1 .83 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 449.3. Example 59: N-[2-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-1-methyl-2-oxo- ethyljbenzamide, Enantiomer 1 and Example 60: N-[2-[4-[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol- -yl]-1-piperidyl]-1-methyl-2-oxo-ethyl]benzamide, Enantiomer 2

Step 1: Preparation of N-[(R)-2-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]- 1-piperidyl]- 1-methyl-2- oxo-ethyl]benzamide and N-[(S)- 2-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]- 1-piperidyl]- 1- methyl-2-oxo-ethyl]benzamide.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (150 mg, 518 μιηοΙ) and 2-benzamidopropanoic acid (105 mg, 544 μιτιοΙ) in N,N-dimethylformamide (2 mL) was added

(2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (196 mg, 518 μιηοΙ) and N- ethyl-N-(propan-2-yl)propan-2-amine (201 mg, 1 .56 mmol, 271 μί). The mixture was stirred at 20 °C for 5 h. The crude product was purified by prep-HPLC (column: Luna C18 150x25 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-65%, 12 min) to give rac-N-(1 -(4-(3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-1 -oxopropan-2-yl)benzamide then the product purified by SFC separation (column: AD(250x30mm, 5μιη); mobile phase: [Neu-IPA]; B%: 42%-42%,min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-1 -methyl-2-oxo- ethyl]benzamide, Enantiomer 1 (63 mg, 134.93 μιτιοΙ, 26 %) as a white solid and N-[2-[4-[3-(3,4- dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-1 -methyl-2-oxo-ethyl]benzamide, Enantiomer 2 (56 mg, 120 μιηοΙ, 23% as a white solid.

N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-1 -methyl-2-oxo- ethyl]benzamide, Enantiomer 1 :

¹ H NMR (400MHz, DMSO-de) δ = 8.63 (br dd, J=7.3, 1 6.1 Hz, 1 H), 7.88 (br d, J=7.5 Hz, 2H), 7.62 - 7.41 (m, 5H), 7.1 1 (br d, J=8.2 Hz, 1 H), 4.97 (br d, J=6.4 Hz, 1 H), 4.43 - 4.24 (m, 1 H), 4.10 - 3.95 (m, 1 H), 3.82 (s, 6H), 3.42 (br t, J=10.8 Hz, 1 H), 3.30 - 3.21 (m, 1 H), 2.99 - 2.83 (m, 1 H), 2.09 (br d, J=1 1 .9 Hz, 2H), 1 .83 - 1 .60 (m, 2H), 1 .30 (br s, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 465.3. ee = 100%.

N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-1 -methyl-2-oxo- ethyl]benzamide, Enantiomer 2:

¹ H NMR (400MHz, DMSO-de) δ = 8.65 (br dd, J=7.6, 1 6.1 Hz, 1 H), 7.98 - 7.86 (m, 2H), 7.70 - 7.41 (m, 5H), 7.13 (br d, J=8.2 Hz, 1 H), 5.00 (br d, J=5.5 Hz, 1 H), 4.49 - 4.24 (m, 1 H), 4.12 - 3.96 (m, 1 H), 3.85 (s, 6H), 3.45 (br t, J=10.7 Hz, 1 H), 3.27 (br s, 1 H), 3.05 - 2.83 (m, 1 H), 2.12 (br d, J=12.5 Hz, 2H), 1 .89 - 1 .61 (m, 2H), 1 .32 (br s, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 465.3. ee = 99.6

Example 61: (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)- 1,2,4-oxadiazol-5-yl)piperidine-1- carbonyl)pyrrolidin-1-yl)phenyl)methylium, Enantiomer 1 and Example 62: (2-methyl-4-(2-oxo-4-(4- (3-(p-tolyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrr olidin-1-yl)phenyl)me

Enantiomer 2

Step 1: Preparation of (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carbonyl)pyrrolidin- 1-yl)phenyl)methylium, Enantiomer 1 and (2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)- 1,2,4- oxadiazol-5-yl)piperidine- 1-carbonyl)pyrrolidin- 1-yl)phenyl)methylium, Enantiomer 2

To a stirred solution of N-hydroxy-4-methylbenzimidamide (300 mg, 2.0 mmol), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (834 mg, 2.20 mmol) and 1 -(1 -(3,4- dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine-4-car boxylic acid (688 mg, 2.00 mmol) in N,N- dimethylformamide (10 mL) were added N-ethyl-N-(propan-2-yl)propan-2-amine (516 mg, 4.00 mmol, 698 μί) at 0 °C. Then the reaction was warmed to 25 °C. After 17 h, the reaction was warmed to 90 °C. After 3 h, the mixture was cooled, diluted with water (10 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by prep-HPLC (column: Phenomenex luna(2) C18 250x50 10μιτι ; mobile phase: [water (0.1 %TFA)- acetonitrile]; B%: 40%-70%,20min) to give the racemic of 1 -(3,4-dimethylphenyl)-4-(4-(3-(p-tolyl)-1 ,2,4- oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one (600 mg, 1 .31 mmol, 65 %). This was purified by SFC (column: AS(250x30mm, 5μιτι); mobile phase: [C0 ₂ base-methanol]; B%: 40%-40%) to give (2- methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-1 - yl)phenyl)methylium, Enantiomer 1 (193 mg, 421 μιτιοΙ, 21 %) as a white solid, and (2-methyl-4-(2-oxo-4- (4-(3-(p-tolyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-1 -yl)phenyl)methylium, Enantiomer 2 (199 mg, 433 μιτιοΙ, 22 %) as a white solid.

(2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-1 - yl)phenyl)methylium, Enantiomer 1 :

1 H NMR (400MHz, DMSO-d6) δ = 7.91 (br d, J=6.9 Hz, 2H), 7.43 (br s, 1 H), 7.38 (br d, J=8.0 Hz, 3H), 7.12 (br d, J=6.3 Hz, 1 H), 4.35 (br s, 1 H), 4.09 - 3.98 (m, 2H), 3.92 (td, J=5.0, 10.0 Hz, 1 H), 3.80 - 3.63 (m, 1 H), 3.45 (br t, J=10.8 Hz, 1 H), 3.36 (br s, 1 H), 3.00 - 2.90 (m, 1 H), 2.82 - 2.65 (m, 2H), 2.39 (s, 3H), 2.27 - 2.10 (m, 8H), 1 .91 - 1 .61 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 459.3; ee = 98.6

(2-methyl-4-(2-oxo-4-(4-(3-(p-tolyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-1 - yl)phenyl)methylium, Enantiomer 2:

¹ H NMR (400MHz, DMSO-d6) δ = 7.91 (br d, J=6.9 Hz, 2H), 7.43 (br s, 1 H), 7.38 (br d, J=8.0 Hz, 3H), 7.12 (br d, J=6.4 Hz, 1 H), 4.35 (br s, 1 H), 4.1 1 - 3.97 (m, 2H), 3.92 (td, J=5.0, 9.9 Hz, 1 H), 3.81 - 3.68 (m, 1 H), 3.53 - 3.37 (m, 1 H), 3.36 (br s, 1 H), 3.02 - 2.90 (m, 1 H), 2.82 - 2.65 (m, 2H), 2.39 (s, 3H), 2.25 - 2.09 (m, 8H), 1 .89 - 1 .62 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 459.3; ee = 99%. Example 63: 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1- carbonyl)pyrrolidin-2-one, Enantiomer 1 and Example 64: 1-(3,4-dimethylphenyl)-4-(4-(3-(4- methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, Enantiomer 2

Step 1: Preparation of 1-(3 -dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1 -carbonyl)pyrrolidin-2-one, Enantiomer 1 and 1-(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)- 1,2,4- oxadiazol-5-yl)piperidine- 1-carbonyl)pyrrolidin-2-one, Enantiomer 2 To a stirred solution of 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine -4- carboxylic acid (350 mg, 1 .02 mmol) and N-hydroxy-4-methoxybenzimidamide (168 mg, 1 .02 mmol) in N,N-dimethylformamide (3 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (262 mg, 2.03 mmol, 354 μΙ_) and (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (385 mg, 1 .02 mmol), then the mixture was stirred for 15 h at 15 °C. The the mixture was then heated to 1 10 °C and stirred for 5 h. The mixture was cooled and purified by prep-HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 37%-67%, 12 min) to give racemic 1 -(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2- one (0.2 g) as a white solid. This was purified by SFC separation: (column: OJ(250x30mm,1 Ομιη); mobile phase: [CO2 base-ethanol]; B%: 45%-45%) to give ((1 -(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one, Enantiomer 1 (84 mg, 177 μιτιοΙ, 1 7 %) as a white solid and 1 -(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 - carbonyl)pyrrolidin-2-one, Enantiomer 2 (96 mg, 198 μιηοΙ, 19 %) as a yellow solid

1 -(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 - carbonyl)pyrrolidin-2-one, Enantiomer 1 :

Ή NMR (400 MHz, Methanol-d4) δ 7.98 (dd, J=2.2, 8.8 Hz, 2H), 7.36 (s, 1 H), 7.27 (d, J=7.9 Hz, 1 H), 7.13 (d, J=8.4 Hz, 1 H), 7.04 (d, J=7.1 Hz, 2H), 4.53 - 4.43 (m, 1 H), 4.18 - 3.99 (m, 3H), 3.95 - 3.73 (m, 4H), 3.49 - 3.36 (m, 2H), 3.14 - 3.01 (m, 1 H), 2.93 - 2.77 (m, 2H), 2.47 - 2.04 (m, 8H), 2.01 - 1 .80 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 475.3; ee = 100 %.

1 -(3,4-dimethylphenyl)-4-(4-(3-(4-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 - carbonyl)pyrrolidin-2-one, Enantiomer 2: ¹ H NMR (400 MHz, Methanol-d4) δ 7.98 (dd, J=2.4, 9.0 Hz, 2H), 7.36 (s, 1 H), 7.27 (d, J=8.4 Hz, 1 H), 7.13 (d, J=8.4 Hz, 1 H), 7.04 (d, J=7.1 Hz, 2H), 4.48 (d, J=7.5 Hz, 1 H), 4.1 6 - 4.00 (m, 3H), 3.92 - 3.74 (m, 4H), 3.49 - 3.37 (m, 2H), 3.13 - 3.03 (m, 1 H), 2.91 - 2.80 (m, 2H), 2.34 - 2.1 1 (m, 8H), 1 .98 - 1 .83 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 475.3; ee = 100 %.

Example 65: (4S)-4-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1- phenyl-pyrrolidin-2-one

Step 1: (4R)-4-benzyl-3-[(3S)-5-oxo- 1-phenyl-pyrrolidine-3-carbonyl]oxazolidin-2-one

o 0

To a stirred solution of 5-oxo-1 -phenyl-pyrrolidine-3-carboxylic acid (20.0 g, 97.5 mmol) in chloroform (100 ml_) was added (4R)-4-benzyloxazolidin-2-one (20.72 g, 1 17 mmol), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (20.74 g, 108.2 mmol) and DMAP (6.43 g, 52.6 mmol) at 0 °C. After addition, the mixture was stirred for 15 min, then warmed and stirred at 20 °C for 18 h. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=1 /1 to 1 :9) to give (4R)-4-benzyl-3- [(3S)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]oxazolidin-2-one (10.0 g, 27.4 mmol, 28 %) and (4R)-4- benzyl-3-[(3R)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]oxazolidin-2-one (1 0.0 g, 27 mmol, 28 %) each as a white solid. LCMS (ESI) m/z: 365.1 [M+H] ⁺ .

Step 2: (3S)-5-oxo- 1-phenyl-pyrrolidine-3-carboxylic acid

To a stirred solution of lithium hydroxide monohydrate (2.63 g, 62.8 mmol) in water (30 mL) was added dropwise hydrogen peroxide (15.5 g, 456.6 mmol, 13.2 mL) at 0°C. The mixture was stirred for 30 min. To the mixture was then added tetrahydrofuran (80 mL), water (30 mL) followed by a solution of 3- [(3S)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]-4-phenyl-oxazolidin-2-one (1 0.0 g, 28.5 mmol) in

tetrahydrofuran (80 mL) dropwise. The mixture was stirred at 0 °C for 1 h, quenched by addition of a sodium sulfate solution in water (10 mL) at 0 °C, and made basic (pH 1 1 ) by addition of an aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (100 mL), acidified to pH 2 using 1 M HCI, and extracted again with ethyl acetate (100 mL). The organic layers were washed with a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered and

concentrated under reduced pressure to give (3S)-5-oxo-1 -phenyl-pyrrolidine-3-carboxylic acid (4.80 g, 23.39 mmol, 82 %) as a white solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ 7.57 (dd, J=0.9, 8.6 Hz, 2H), 7.40 - 7.34 (m, 2H), 7.20 - 7.15 (m, 1 H), 4.18 - 4.13 (m, 1 H), 4.10 - 4.04 (m, 1 H), 3.45 - 3.35 (m, 1 H), 3.03 - 2.86 (m, 2H). Step 3: methyl 1-[(3S)-5-oxo- 1-phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylate

A mixture of (3S)-5-oxo-1 -phenyl-pyrrolidine-3-carboxylic acid (4.50 g, 21 .93 mmol), methyl piperidine-4-carboxylate (3.77 g, 26.32 mmol), 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide in ethyl acetate (27.91 g, 43.86 mmol, 26.08 mL, 50% purity), triethylamine (44.38 g, 438.60 mmol, 60 mL) in dichloromethane (60 mL) was degassed, purged with nitrogen 3 times, and then the mixture was stirred at 20 °C for 16 h under a nitrogen atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (50 mL). The organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over Na2S04, filtered, concentrated under reduced pressure and purified by chromatography (silica, petroleum ether / ethyl acetate=1 :1 ) to give methyl 1 -[(3S)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylate (4.70 g, 14.2 mmol, 65 %) as a white solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ 7.56 (d, J=7.7 Hz, 2H), 7.35 (t, J=7.5 Hz, 2H), 7.16 - 7.1 1 (m, 1 H), 4.47 - 4.34 (m, 1 H), 4.24 (dd, J=7.3, 9.5 Hz, 1 H), 3.91 - 3.81 (m, 2H), 3.69 (s, 3H), 3.52 (quin, J=8.5 Hz, 1 H), 3.24 - 3.12 (m, 1 H), 2.98 - 2.87 (m, 2H), 2.80 - 2.73 (m, 1 H), 2.64 - 2.52 (m, 1 H), 1 .97 (br dd, J=4.3, 8.3 Hz, 2H), 1 .73 - 1 .63 (m, 2H).

Step 4: 1-[(3S)-5-oxo- 1-phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid.

To a stirred solution of methyl 1 -[(3S)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]piperidine-4- carboxylate (3.00 g, 9.08 mmol) in tetrahydrofuran (60 mL) was added a solution of lithium hydroxide monohydrate (0.5 M, 21 .79 mL) in water. The mixture was then stirred at 0 °C for 2 h. The mixture was acidified to pH 4-5 using 1 M HCI, and then extracted with dichloromethane (60 mL; 30 mL x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution 40 mL; 20 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1 -[(3S)-5-oxo-1 - phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (2.70 g, 8.53 mmol, 94 %) as a white solid.

Step 5: (4S)-4-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]piperidine- 1-carbonyl]- 1-phenyl-pyrrolidin- 2-one

A mixture of N'-hydroxy-3,4-dimethoxy-benzamidine (1 .04 g, 5.32 mmol), 1 -[(3S)-5-oxo-1 -phenyl- pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (1 .40 g, 4.43 mmol), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (2.1 8 g, 5.76 mmol) and N-ethyl-N-(propan-2-yl)propan-2- amine (1 .72 g, 1 3.29 mmol, 2.32 mL) in N,N-dimethylformamide (8.00 mL), was stirred at 20 °C for 1 5h and at 1 1 0 °C for 1 h. The mixture was cooled to room temperature, concentrated under reduced pressure to give a residue purified by prep-HPLC [column : Phenomenex luna C1 8 250x50mmx1 0 μιη ; mobile phase: water / ammonium carbonate (1 OmM) / acetonitrile] ; B%: 30%-60%,30 min. The desired compound (4S)-4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]-1 -phenyl- pyrrolidin-2-one was isolated as a light yellow solid (608 mg, 1 .28 mmol, 29 %). ¹ H NMR (400MHz, CHLOROFORM-d) δ 7.68 (br d, J=8.2 Hz, 1 H), 7.61 - 7.53 (m, 3H), 7.40 - 7.33 (m , 2H), 7.1 8 - 7.12 (m, 1 H), 6.95 (d, J=8.4 Hz, 1 H), 4.61 - 4.46 (m , 1 H), 4.30 (dd, J=7.2, 9.6 Hz, 1 H), 4.01 - 3.92 (m, 8H), 3.57 (quin, J=8.4 Hz, 1 H), 3.43 - 3.26 (m , 2H), 3.14 - 2.91 (m , 2H), 2.86 - 2.80 (m, 1 H), 2.23 (br t, J=13.1 Hz, 2H), 2.02 - 1 .93 (m , 2H) ; LCMS (ESI) m/z: [M+H] ⁺ = 477.3.

Example 66 [(4R)-4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]-1 - phenyl-pyrrolidin-2-one]

To a stirred solution of 1 -[(3R)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid

(1 1 5 mg, 363.52 μιτιοΙ) and N'-hydroxy-3,4-dimethoxy-benzamidine (71 mg, 363.52 μιτιοΙ) in N,N- dimethylformamide (500 μί) was added (2-(1 H-benzotriazol-1 -yl)-1 , 1 , 3, 3-tetramethyluronium

hexafluorophosphate) (137 mg, 363.52 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (93 mg, 727 μιτιοΙ, 126 iL) at 25 °C. The mixture was then stirred at 25 °C for 2 h, and at 1 1 0 °C for 2h. The mixture was concentrated under reduced pressure and the resulting crude product was purified by

chromatography (column : Waters Xbridge 150x2.5mm 5μπι ; mobile phase: water / ammonium carbonate (10mM) / acetonitrile]; B%: 25%-60%,12 min to give (4R)-4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol- 5-yl]piperidine-1 -carbonyl]-1 -phenyl-pyrrolidin-2-one (32 mg, 67.45 μιηοΙ, 19 %) as a yellow solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.68 (br d, J=8.2 Hz, 1 H), 7.61 - 7.55 (t, 3H), 7.37 (t, J=7.8 Hz, 2H), 7.19 - 7.14 (t, 1 H), 6.95 (d, J=8.4 Hz, 1 H), 4.60 - 4.46 (m, 1 H), 4.31 (dd, J=7.2, 9.6 Hz, 1 H), 3.98 - 3.94 (m, 7H), 3.98 - 3.92 (m, 1 H), 3.58 (quin, J=8.5 Hz, 1 H), 3.43 - 3.26 (m, 2H), 3.16 - 2.91 (m, 2H), 2.88 - 2.79 (m, 1 H), 2.24 (br t, J=13.3 Hz, 2H), 2.06 - 1 .88 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 477.3.

Examples 67: 4-(4-(3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl)piperidin e-1 -carbonyl)-1-(3,4- dimethylphenyl)pyrrolidin-2-one, Enantiomer 1 and Example 68: 4-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-(3,4-dimethylp henyl)pyrrolidin-2-one, Enantiomer 2.

Step 1: Preparation of 4-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1-carbonyl)- 1-(3,4- dimethylphenyl)pyrrolidin-2-one

To a stirred solution of 1 -[1 -(3,4-dimethylphenyl)-5-oxo-pyrrolidine-3-carbonyl]piperidin e-4- carboxylic acid (351 mg, 1 .02 mmol) in N,N-dimethylformamide (1 .50 mL) was added (2-(1 H-benzotriazol- 1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (386 mg, 1 .02 mmol), N-ethyl-N-(propan-2- yl)propan-2-amine (395 mg, 3.06 mmol, 534 μί) and N-hydroxy-3,4-dimethoxy-benzamidine (200 mg, 1 .02 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was then diluted with water (5mL) and extracted with ethyl acetate (1 0 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. N,N-dimethylformamide (2 mL) was added to the residue and the resulting mixture was heated at 120 °C for 5 h. The mixture was cooled to 25 °C, diluted by addition of water (5mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Waters Xbridge 150x25 μιη; mobile phase: water / ammonium carbonate (1 OmM) / acetonitrile]; B%: 33%-63%,12 min) to give racemic 4-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidine-1 -carbonyl)-1 -(3,4-dimethylphenyl)pyrrolidin-2-one. This was separated by chiral-SFC (column: AS(250x30mm, 10μιτι); mobile phase: [CO2 base-methanol]; B%: 40%-40%,min) to give firstly 4- [4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]-1 -(3,4-dimethylphenyl)pyrrolidin-2- one, Enantiomer 1 (51 mg, 102 μιτιοΙ, 10 %) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 7.61 (br d, J=8.4 Hz, 1 H), 7.48 (s, 1 H), 7.43 (br s, 1 H), 7.38 (br d, J=7.5 Hz, 1 H), 7.16 - 7.10 (m, 2H), 4.37 (br s, 1 H), 4.08 - 3.99 (m, 2H), 3.96 - 3.88 (m, 1 H), 3.85 (s, 6H), 3.79 - 3.67 (m, 1 H), 3.45 (br t, J=10.8 Hz, 1 H), 3.32 - 3.28 (m, 1 H), 3.02 - 2.87 (m, 1 H), 2.82 - 2.70 (m, 2H), 2.24 - 2.18 (m, 6H), 2.18 - 2.10 (m, 2H), 1 .91 - 1 .61 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 505.4 and secondly 4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4- oxadiazol-5-yl]piperidine-1 -carbonyl]-1 -(3,4-dimethylphenyl)pyrrolidin-2-one, Enantiomer 2 (48 mg, 95 μιτιοΙ, 9 %) also as a white solid. Ή NMR (400MHz, DMSO-d6) δ = 7.61 (br d, J=8.4 Hz, 1 H), 7.48 (s, 1 H), 7.43 (br s, 1 H), 7.41 - 7.35 (m, 1 H), 7.17 - 7.10 (m, 2H), 4.37 (br s, 1 H), 4.09 - 3.99 (m, 2H), 3.98 - 3.89 (m, 1 H), 3.85 (s, 6H), 3.78 - 3.68 (m, 1 H), 3.50 - 3.39 (m, 1 H), 3.35 (br s, 1 H), 3.00 - 2.88 (m, 1 H), 2.81 - 2.70 (m, 2H), 2.26 - 2.19 (m, 6H), 2.17 - 2.09 (m, 2H), 1 .88 - 1 .63 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 505.4

Example 69 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1- carbonyl)pyrrolidin-2-one, Enantiomer 1 and Example 70 1-(3,4-dimethylphenyl)-4-(4-(3-(3- methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)pyrrolidin-2-one, Enantiomer 2

Step 1: Preparation of 1-(1-(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperi dine-4-carboxylic acid

To a stirred solution of methyl 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine -4- carboxylate (470 mg, 1 .31 mmol) in tetrahydrofuran (5 mL) was added sodium hydroxide (2 M, 1 .31 mL). The mixture was stirred at 20 °C for 16 h. The mixture was acidified with concentrated hydrochloric acid until pH = 1 . The mixture was extracted with dichloromethane (20 mL x 4). The organic layers were combined and washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3- carbonyl)piperidine-4-carboxylic acid (300 mg) as a brown solid. LCMS (ESI) m/z: [M+H] ⁺ = 345.2.

Step 2: Preparation of 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1 -carbonyl)pyrrolidin-2-one, Enantiomer 1 and 1-(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)- 1,2,4- oxadiazol-5-yl)piperidine- 1-carbonyl)pyrrolidin-2-one, Enantiomer 2

To a stirred solution of 1 -(1 -(3,4-dimethylphenyl)-5-oxopyrrolidine-3-carbonyl)piperidine -4- carboxylic acid (300 mg, 871 μιτιοΙ) in N,N-dimethylformamide (4 mL) was added N-hydroxy-3-methoxy- benzamidine (173 mg, 1 .05 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (330 mg, 871 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (337 mg, 2.61 mmol, 456 μΙ_). The mixture was stirred at 20°C for 2 h and then at 120 °C for 2 h. The reaction mixture was cooled, concentrated under reduced pressure and purified directly by preparative HPLC (column: Luna C8 100 ^* 30 5μπι; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 45%-65%,12 min) to give (rac)- 1 -(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 - carbonyl) pyrrolidin-2-one that was was purified by chiral-SFC (column: AD(250mm ^* 30mm,5mm); mobile phase: [Base-isopropanol]; B%: 42%-42%,min) to give firstly 1 -(3,4-dimethylphenyl)-4-(4-(3-(3- methoxyphenyl)-1 ,2, 4-oxadiazol-5-yl)piperidine-1 -carbonyl) yrrolidin-2-one, Enantiomer 1 (75 mg, 158.7 μιτιοΙ, 18 %, ee 100 %) as a white solid, then 1 -(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1 ,2,4- oxadiazol-5-yl)piperidine-1 -carbonyl)pyrrolidin-2-one, Enantiomer 2 (75 mg, 160 μιηοΙ, 18 %, ee 99.7 %) as a yellow solid.

1 -(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1 , 2, 4-oxadiazol-5-yl)piperidine-1 -carbonyl) pyrrolidin-2-one, Enantiomer 1 .

¹ H NMR (400 MHz, CDCb) δ 7.63-7.57 (m, 1 H), 7.55-7.50 (m, 1 H), 7.31 (d, J = 12.3 Hz, 2H), 7.22-7.19 (m, 1 H), 7.05 (d, J = 8.2 Hz, 1 H), 7.00 (d, J = 1 .8 Hz, 1 H), 4.53-4.37 (m, 1 H), 4.21 (dd, J = 7.3, 9.6 Hz,

1 H), 3.95-3.77 (m, 5H), 3.49 (td, J = 8.6, 1 6.9 Hz, 1 H), 3.36-3.20 (m, 2H), 3.12-2.96 (m, 1 H), 2.89 (td, J = 8.3, 16.9 Hz, 1 H), 2.79-2.70 (m, 1 H), 2.18 (d, J = 13.1 Hz, 8H), 1 .99-1 .83 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 475.1 .

1 -(3,4-dimethylphenyl)-4-(4-(3-(3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 - carbonyl)pyrrolidin-2-one, Enantiomer 2.

¹ H NMR (400 MHz, CDCb) δ 7.63-7.57 (m, 1 H), 7.53 (s, 1 H), 7.36-7.27 (m, 2H), 7.21 (d, J = 2.0 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 2.0 Hz, 1 H), 4.53-4.37 (m, 1 H), 4.21 (dd, J = 7.3, 9.5 Hz, 1 H), 3.96- 3.77 (m, 5H), 3.55-3.44 (m, 1 H), 3.37-3.19 (m, 2H), 3.12-2.82 (m, 2H), 2.76 (d, J = 9.4 Hz, 1 H), 2.18 (d, J = 13.1 Hz, 8H), 1 .92 (br. s., 2H); LCMS (ESI) m/z: [M+H] ⁺ = 475.1 .

Example 71 ( 1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)- 1,2,4-oxadiazol-3-yl)piperidine-1- carbonyl)pyrrolidin-2-one), Enantiomer 1 and Example 72 (1-(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)- 1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one) , Enantiomer 2

Racemic 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 - carbonyl)pyrrolidin-2-one (80 mg) was purified by SFC separation (column: AD (250x30mm, 5μιη); mobile phase: [CO2 base-isopropanol]; B%: 50%-50%,min) to give firstly 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)- 1 ,2,4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2-one, Enantiomer 1 (26 mg, 59 μιηοΙ, 7 %) as a white solid and secondly 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 - carbonyl)pyrrolidin-2-one, Enantiomer 2 as a white solid (23 mg, 52 μιτιοΙ, 6 %).

1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2- one, Enantiomer 1 .

¹ H NMR (400 MHz, CDCb) δ 8.06-8.00 (m, 2H), 7.41 -7.33 (m, 3H), 7.32-7.29 (m, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 4.66-4.54 (m, 1 H), 4.30 (dd, J = 7.4, 9.5 Hz, 1 H), 4.05-3.88 (m, 2H), 3.65-3.55 (m, 1 H), 3.43-3.30 (m, 1 H), 3.20 (d, J = 3.4 Hz, 1 H), 3.12-2.94 (m, 2H), 2.85 (d, J = 9.7 Hz, 1 H), 2.47 (s, 3H), 2.32-2.14 (m, 8H), 1 .94 (br. s., 2H); LCMS (ESI) m/z: [M+H] ⁺ = 459.3. 1 -(3,4-dimethylphenyl)-4-(4-(5-(p-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2- one, Enantiomer 2.

¹ H NMR (400 MHz, CDCb) δ 7.96-7.90 (m, 2H), 7.32-7.24 (m, 3H), 7.22-7.19 (m, 1 H), 7.05 (d, J=8.2 Hz, 1 H), 4.58-4.43 (m, 1 H), 4.20 (s, 1 H), 3.94-3.79 (m, 2H), 3.50 (quin, J = 8.5 Hz, 1 H), 3.28 (br. s., 1 H), 3.10 (d, J = 3.9 Hz, 1 H), 3.02-2.84 (m, 2H), 2.78-2.68 (m, 1 H), 2.38 (s, 3H), 2.23-2.03 (m, 8H), 1 .83 (d, J = 10.8 Hz, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 459.3

Examples 73 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)- 1,2,4-oxadiazol-3-yl)piperidine-1- carbonyl)pyrrolidin-2-one, Enantiomer 1 and Example 74 1-(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)- 1,2,4-oxadiazol-3-yl)piperidine-1-carbonyl)pyrrolidin-2-one, Enantiomer 2

Racemic 1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 - carbonyl)pyrrolidin-2-one (120 mg) was purified by SFC separation (column: OJ(250mmX30mm,5mm); mobile phase: [CO2 base-ethanol]; B%: 30%-30%,min) to give firstly 1 -(3,4-dimethylphenyl)-4-(4-(5-(m- tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2-one, Enantiomer 1 (39 mg, 86.7 μιτιοΙ, 1 1 %) as a pink solid and secondly 1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 - carbonyl)pyrrolidin-2-one, Enantiomer 2 (36 mg, 77.9 μιτιοΙ, 10 %) as a pink solid.

1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2- one, Enantiomer 1 :

¹ H NMR (400 MHz, CDCb) δ 7.94 (br. s., 2H), 7.39 (d, J = 15.0 Hz, 3H), 7.29 (br. s., 1 H), 7.12 (d, J = 8.4 Hz, 1 H), 4.58 (t, J = 13.9 Hz, 1 H), 4.28 (f, J = 8.6 Hz, 1 H), 4.01 -3.87 (m, 2H), 3.62-3.53 (m, 1 H), 3.35 (br. s., 1 H), 3.19 (br. s., 1 H), 3.08-2.93 (m, 2H), 2.86-2.76 (m, 1 H), 2.45 (s, 3H), 2.32-2.1 1 (m, 8H), 1 .90 (d, J = 13.7 Hz, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 459.3.

1 -(3,4-dimethylphenyl)-4-(4-(5-(m-tolyl)-1 ,2,4-oxadiazol-3-yl)piperidine-1 -carbonyl)pyrrolidin-2- one, Enantiomer 2:

1 H NMR (400 MHz, Methanol-d4) 58.00-7.90 (m, 2H), 7.53-7.45 (m, 2H), 7.41 -7.37 (m, 1 H), 7.32-7.27 (m, 1 H), 7.1 9-7.13 (m, 1 H), 4.53 (dd, J=3.5, 13.2 Hz, 1 H), 4.19-4.03 (m, 3H), 3.90-3.80 (m, 1 H), 3.49-3.39 (m, 1 H), 3.30-3.20 (m, 1 H), 3.12-3.00 (m, 1 H), 2.94-2.82 (m, 2H), 2.47 (s, 3H), 2.35-2.1 1 (m, 8H), 1 .99-1 .77 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 459.3. Example 75: (2-amino-1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethanone).

Step 1: Preparation of tert-butyl (2-(4-(3-(3^-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)carbamate.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (2.0 g, 6.91 mmol) in N,N-dimethylformamide (20 mL) was added 2-(tert-butoxycarbonylamino)acetic acid (1 .21 g, 6.91 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (2.62 g, 6.91 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (2.68 g, 20.7 mmol, 3.62 mL). The mixture was stirred at 15 °C for 2 h. The reaction mixture was quenched by addition of water (20 mL) then the mixture was extracted with ethyl acetate (60 mL x 4). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and

concentrated to give a crude material that was purified by chromatography (silica, petroleum ether : ethyl acetate = 5:1 to 1 :1 ) to give tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)- 2-oxoethyl)carbamate (2.60 g, 5.82 mmol, 84 %) as a brown solid. LCMS (ESI) m/z: [M+H] ⁺ = 447.2.

Step 2: Preparation of 2-amino- 1-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1- yl)ethanone

To a stirred solution of tert-butyl (2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)-2-oxoethyl)carbamate (2.50 g, 5.60 mmol) in methanol (1 0 mL) was added methanolic hydrogen chloride solution (30 mL). The mixture was stirred at 20 °C for 1 h and then concentrated to give 2-amino- 1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)ethanone (1 .90 g, 5.49 mmol, 97.95 %), isolated as a brown solid and used for the next step without further purification. A small amount (0.1 g) of the crude product was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12 min) to give a pure sample for analysis: 2-amino-1 -(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)ethanone (32 mg). ¹ H NMR (400 MHz, CDCb) δ 7.73-7.67 (m, 1 H), 7.58 (d, J = 1 .5 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 4.54 (d, J = 1 2.2 Hz, 1 H), 3.98 (d, J = 7.2 Hz, 6H), 3.84 (d, J = 12.0 Hz, 1 H), 3.54 (s, 2H), 3.34-3.21 (m, 2H), 3.08 (d, J = 12.3 Hz, 1 H), 2.21 (d, J = 13.1 Hz, 2H), 1 .98 (d, J = 9.4 Hz, 2H); LCMS (ES!) m/z: [M+H] ⁺ = 347.1 .

Example 76: (5-hydroxy-2,2-dimethyl-7-(2-oxo-2-(4-(3-phenyl-1,2,4-oxadia zol-5-yl)piperid^ yl)ethoxy)choman-4-one).

Step 1: Preparation of tert-butyl 4-(3-phenyl- 1,2,4-oxadiazol-5-yl)piperidine- 1 -carboxylate

To a stirred solution of (Z)-N'-hydroxybenzimidamide (214 mg, 1 .57 mmol) in N,N- dimethylformamide (5 mL) was added 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (300 mg, 1 .31 mmol), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (496 mg, 1 .31 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (507 mg, 3.93 mmol, 686 μΙ_). The mixture was stirred at 20 °C for 2 h, and then heated at 120 °C for 2 h. The reaction mixture was quenched with water (10 mL), then the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was extracted with petroleum ether (30 mL x 2). The combined organic extracts were concentrated under reduced pressure to give tert-butyl 4-(3-phenyl-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carboxylate (310 mg, 941 μιτιοΙ, 72 %) as a yellow oil. This product was used in the next step without further purification.

Step 2: Preparation of 3-phenyl-5-(piperidin- -yl)- 1 ,2,4-oxadiazole

To a stirred solution of tert-butyl 4-(3-phenyl-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carboxylate (310 mg, 941 μιτιοΙ) in ethyl acetate (2 mL) was added an anhydrous solution of hydrochloric acid in ethyl acetate (20 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to provide the crude 3-phenyl-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (233 mg) as a yellow solid that was used for the next step without further purification. LC S (ESI) m/z: [M+H] ⁺ = 230.2.

Step 3: Preparation of 5-hydroxy-2,2-dimethyl-7-(2-oxo-2-(4-(3-phenyl- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 - yl)ethoxy)choman-4-one

To a stirred solution of 2-((5-hydroxy-2,2-dimethyl-4-oxochoman-7-yl)oxy)acetic acid (150 mg, 563 μιηοΙ) in N,N-dimethylformamide (2 mL) was added 3-phenyl-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (142 mg, 620 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (213 mg, 563 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (291 mg, 2.25 mmol, 393 μΙ_). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 45%-75%,12 min) to give 5-hydroxy-2,2-dimethyl-7-(2-oxo-2-(4- (3-phenyl-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)ethoxy)choman-4-one (120 mg, 250.6 μιηοΙ, 44 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 12.00 (s, 1 H), 8.12 - 8.07 (m, 2H), 7.56 - 7.48 (m, 3H), 6.07 (d, J=2.4 Hz, 1 H), 6.04 (d, J=2.3 Hz, 1 H), 4.74 (s, 2H), 4.46 (d, J=13.8 Hz, 1 H), 3.98 (d, J=13.1 Hz, 1 H), 3.42 - 3.28 (m, 2H), 3.13 (t, J=1 1 .1 Hz, 1 H), 2.71 (s, 2H), 2.23 (br. s., 2H), 2.07 - 1 .92 (m, 2H), 1 .49 - 1 .46 (m, 6H); LCMS (ESI) m/z: [M+H] ⁺ = 478.2. Example 77 (7-(2-(4-(3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethoxy)-5- hydroxy-2,2-dimethylchoman-4-one).

To a stirred solution of 2-((5-hydroxy-2,2-dimethyl-4-oxochoman-7-yl)oxy)acetic acid (150 mg,

563 μιηοΙ) in N,N-dimethylformamide (2 mL) was added 3-(3,4-dimethoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4- oxadiazole (195 mg, 676 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium

hexafluorophosphate) (213 mg, 563 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (291 mg, 2.25 mmol, 393 μί). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μπι ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give 7- (2-(4-(3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethoxy)-5-hydroxy-2,2- dimethylchoman-4-one (133 mg, 245.66 μιτιοΙ, 44 %) as a white solid. Ή NMR (400MHz, CDCI3) δ 12.00 (s, 1 H), 7.71 (dd, J=1 .9, 8.3 Hz, 1 H), 7.58 (d, J=1 .9 Hz, 1 H), 6.98 (d, J=8.4 Hz, 1 H), 6.06 (d, J=2.4 Hz, 1 H), 6,03 (d, J=2.4 Hz, 1 H), 4,74 (s, 2H), 4,47 (d, J=14.2 Hz, 1 H), 4,01 - 3.94 (m, 7H), 3.41 - 3.26 (m, 2H), 3.1 1 (t, J=1 1 .0 Hz, 1 H), 2.71 (s, 2H), 2.22 (br. s., 2H), 2.06 - 1 .93 (m, 2H), 1 .47 (s, 6H); LCMS (ESI) m/z: [M+H] ⁺ = 538.3.

Example 78: (N-(2-oxo-2-(4-(3-(pyridin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide.

Step 1: Preparation of (Z)-N'-hydroxypicolin

To a stirred solution of picolinonitrile (3.0 g, 28.8 mmol, 2.78 mL) in ethanol (30 mL) was added hydroxylamine hydrochloride (4.01 g, 57.6 mmol), triethylamine (5.83 g, 57.6 mmol, 8.0 mL) and water (5 mL). The mixture was heated at 75 °C for 5 h. The mixture was then concentrated to give a residue. The solid residue was triturated with water (30 mL), filtered, and dried under reduced pressure to give (Z)-N'- hydroxypicolinimidamide (2.0 g, 14.6 mmol, 51 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1 H), 8.57 (d, J=4.5 Hz, 1 H), 7.92 - 7.75 (m, 2H), 7.47 - 7.35 (m, 1 H), 5.85 (br. s., 2H).

Step 2: Preparation of N-(2-oxo-2-(4-(3-(pyridin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)ethyl)benzamide

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) in N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxypicolinimidamide (56 mg, 413 μιηοΙ), N-ethyl-N- (propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 μΐ) and (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ). The mixture was stirred at 20 °C for 2 h, then heated at 120 for 2 h. The reaction mixture was cooled, concentrated under reduced pressure and the resulting residue was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-55%,12 min) to give N-(2-oxo-2-(4-(3- (pyridin-2-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)ethyl)benzamide (75 mg, 192 μιτιοΙ, 47 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 8.84 (td, J=0.8, 4.0 Hz, 1 H), 8.18 - 8.12 (m, 1 H), 7.93 - 7.84 (m, 3H), 7.58 - 7.43 (m, 4H), 7.35 (br. s., 1 H), 4.53 (d, J=13.6 Hz, 1 H), 4.32 (t, J=3.5 Hz, 2H), 3.93 (d, J=14.1 Hz, 1 H), 3.45 - 3.31 (m, 2H), 3.21 - 3.10 (m, 1 H), 2.37 - 2.24 (m, 2H), 2.15 - 1 .98 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 392.2.

Example 79: N-(2-oxo-2-(4-(3-(quinolin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethyl)benzamide

Step 1: Preparation of (Z)-N '-hydrox 'quinoline-2-carboximidamide.

To a stirred solution of quinoline-2-carbonitrile (900 mg, 5.84 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (81 1 mg, 1 1 .7 mmol), triethylamine (1 .18 g, 1 1 .7 mmol, 1 .6 mL) and water (1 mL). The mixture was heated at 75 °C for 5 h. The reaction mixture was cooled and filtered, and the filter cake dried in vacuo to give (Z)-N'-hydroxyquinoline-2-carboximidamide (1 .0 g, 5.34 mmol, 91 %) as a light yellow solid. This was used directly without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1 H), 8.34 (d, J=8.7 Hz, 1 H), 8.10 - 7.93 (m, 3H), 7.80 (s, 1 H), 7.67 - 7.59 (m, 1 H), 6.02 (br. s., 2H). Step 2: Preparation of N-(2-oxo-2-(4-(3-(quinolin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)ethyl)benzamide

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) in N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxyquinoline-2-carboximidamide (77 mg, 413 μιτιοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (1 60 mg, 1 .24 mmol, 216 μί) and (2-(1 H-benzotriazol-1 - yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ). The mixture was stirred at 20 °C for 2 h firstly, then heated at 120 °C for 2 h. The reaction mixture was cooled and purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%:30%-60%,12 min) to give N-(2-oxo-2-(4-(3-(quinolin-2-yl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)ethyl)benzamide (66 mg, 150 μιτιοΙ, 36 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 8.26 (dd, J=2.1 , 8.5 Hz, 2H), 8.14 (d, J=8.5 Hz, 1 H), 7.86 - 7.77 (m, 3H), 7.72 (dt, J=1 .3, 7.7 Hz, 1 H), 7.61 - 7.53 (m, 1 H), 7.49 - 7.34 (m, 3H), 7.27 (br. s., 1 H), 4.50 (d, J=13.8 Hz, 1 H), 4.24 (d, J=3.6 Hz, 2H), 3.87 (d, J=13.8 Hz, 1 H), 3.42 - 3.22 (m, 2H), 3.09 - 2.98 (m, 1 H), 2.31 - 2.16 (m, 2H), 2.10 - 1 .91 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 442.2. Example 80: 4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)-N-(2- phenylcyclopropyl)piperidine-1-carboxamide

Step 1: (2-isocyanatocyclopropyl)benzene.

To a stirred solution of 2-phenylcyclopropanecarboxylic acid (1 .0 g, 6.17 mmol) in toluene (10 mL) was added diphenylphosphoryl azide (2.04 g, 7.40 mmol, 1 .60 mL) and triethylamine (935 mg, 9.25 mmol, 1 .28 mL) under nitrogen. The mixture was stirred at 120 °C for 2 h. The reaction mixture was cooled then concentrated in vacuo to give (2-isocyanatocyclopropyl)benzene (2.0 g) as a yellow oil that was used directly without purification.

Step 2: Preparation of methyl 1-((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylate.

To a stirred solution of methyl piperidine-4-carboxylate (800 mg, 5.59 mmol) in toluene (10 mL) was added (2-isocyanatocyclopropyl)benzene (2.0 g, 12.58 mmol, 2.25 eq) and N-ethyl-N-(propan-2- yl)propan-2-amine (722 mg, 5.59 mmol, 975 μί). After 16 h, the reaction mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (50 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to a residue which was purified by chromatography (silica, petroleum ether : ethyl acetate = 50 : 1 to 2 :1 ) to give methyl 1 -((2- phenylcyclopropyl)carbamoyl)piperidine-4-carboxylate (820 mg, 2.71 mmol, 48 %) as a yellow oil. ¹ H NMR (400 MHz, CDC ) δ 7.22 - 7.19 (m, 1 H), 7.17 (s, 1 H), 7.1 0 (d, J=7.4 Hz, 3H), 4.75 (br. s., 1 H), 3.79 (d, J=13.3 Hz, 2H), 3.63 (s, 3H), 2.89 - 2.73 (m, 3H), 2.47 - 2.33 (m, 1 H), 2.02 - 1 .78 (m, 3H), 1 .61 (dd, J=2.1 , 13.1 Hz, 2H), 1 .1 6 - 1 .1 1 (m, 1 H), 1 .08 - 1 .03 (m, 1 H).

Step 3: Preparation of 1-((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylic acid.

To a stirred solution of methyl 1 -((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylate (770 mg, 2.55 mmol) in tetrahydrofuran (10 mL) was added lithium hydroxide (1 M, 5.10 mL). After 2 h, the reaction was acidified with 1 M hydrochloric acid (8 mL). The mixture was extracted with dichloromethane (40 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride solution (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give 1 -((2- phenylcyclopropyl)carbamoyl)piperidine-4-carboxylic acid (660 mg, 2.29 mmol, 90 %) as a yellow solid that was used directly without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1 H), 7.33 - 7.01 (m, 5H), 6.78 (d, J=2.5 Hz, 1 H), 3.85 (d, J=13.3 Hz, 2H), 2.81 - 2.66 (m, 3H), 2.40 (br. s., 1 H), 1 .95 - 1 .69 (m, 3H), 1 .39 (d, J=12.0 Hz, 2H), 1 .21 - 1 .13 (m, 1 H), 1 .10 - 1 .04 (m, 1 H). Step 4: Preparation of 4-(3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)-N-(2- phenylcyclopropyl)piperidine-

To a stirred solution of 1 -((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylic acid (100 mg, 347 μιτιοΙ) in N,N-dimethylformamide (2 ml_) was added (Z)-4-ethoxy-N'-hydroxy-3- methoxybenzimidamide (72 mg, 347 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (131 mg, 347 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (134 mg, 1 .04 mmol, 181 μΙ_). The mixture was stirred at 20 °C for 2 h, then heated at 120 for 2 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 40 %-75 %,12 min) to give 4-(3-(4-ethoxy-3- methoxyphenyl)-1 ,2, 4-oxadiazol-5-yl)-N-(2-phenylcyclopropyl)piperidine-1 -carboxamide (81 mg, 173 μιτιοΙ, 50 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 7.70 - 7.66 (m, 1 H), 7.58 (d, J=1 .9 Hz, 1 H), 7.31 (s, 1 H), 7.27 (s, 1 H), 7.23 - 7.17 (m, 3H), 6.97 (d, J=8.5 Hz, 1 H), 4.91 (s, 1 H), 4.19 (q, J=7.0 Hz, 2H), 3.98 (s, 5H), 3.25 - 3.16 (m, 1 H), 3.13 - 3.03 (m, 2H), 2.91 - 2.85 (m, 1 H), 2.1 8 (dd, J=3.5, 13.4 Hz, 2H), 2.07 (ddd, J=3.3, 6.2, 9.5 Hz, 1 H), 2.03 - 1 .91 (m, 2H), 1 .53 (t, J=7.0 Hz, 3H), 1 .28 - 1 .22 (m, 1 H), 1 .1 7 (td, J=5.0, 9.7 Hz, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 463.2.

Example 81 ': N-(2-phenylcyclopropyl)-4-(3-(pyridin-2-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1- carboxamide.

Step 1: Preparation of N-(2-phenylcyclopropyl)-4-(3-(pyridin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carboxamide.

To a stirred solution of 1 -((2-phenylcyclopropyl)carbamoyl)piperidine-4-carboxylic acid (130 mg, 451 μιηοΙ) in N,N-dimethylformamide (1 mL) was added (Z)-N'-hydroxypicolinimidamide (74 mg, 541 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (170 mg, 451 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (174 mg, 1 .35 mmol, 236 μΙ_). The mixture was stirred at 20

°C for 2 h, then heated at 1 10 °C for 2 h. The reaction mixture was cooled then purified by prep-HPLC

(column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 30%-60%,12 min) to give N-(2-phenylcyclopropyl)-4-(3-(pyridin-2-yl)-1 ,2,4-oxadiazol-5- yl)piperidine-1 -carboxamide (47 mg, 121 .6 μιτιοΙ, 27 %) as a yellow solid. ¹ H NMR (400MHz, DMSO-d6) δ 8.76 (d, J=4.0 Hz, 1 H), 8.12 - 7.97 (m, 2H), 7.65 - 7.55 (m, 1 H), 7.30 - 7.19 (m, 2H), 7.18 - 7.05 (m, 3H), 6.87 (br. s., 1 H), 3.96 (d, J=13.2 Hz, 2H), 2.93 (t, J=1 1 .7 Hz, 2H), 2.71 (d, J=3.1 Hz, 1 H), 2.06 (d, J=1 1 .5 Hz, 2H), 1 .89 (br. s., 1 H), 1 .68 (d, J=1 1 .9 Hz, 3H), 1 .20 - 1 .04 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 390.1 . Example 82: N-(2-phenylcyclopropyl)-4-(3-(quinolin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidine-1-

carboxamide.

To a stirred solution of 1 -[(2-phenylcyclopropyl)carbamoyl]piperidine-4-carboxylic acid (130 mg, 451 μιηοΙ) in N,N-dimethylformamide (2 ml_) was added (Z)-N'-hydroxyquinoline-2-carboximidamide (101 mg, 541 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (170 mg, 451 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (174 mg, 1 .35 mmol, 236 μΙ_). The mixture was stirred at 20 for 2 h, and then heated at 120 for 2 h. The reaction mixture was cooled then purified by prep- HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 40%-70%,12 min) to give N-(2-phenylcyclopropyl)-4-(3-(quinolin-2-yl)-1 ,2,4-oxadiazol-5- yl)piperidine-1 -carboxamide (34 mg, 77 μιτιοΙ, 17 %) as a yellow solid. ¹ H NMR (400MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.22 - 8.07 (m, 3H), 7.88 (br. s., 1 H), 7.74 (d, J=7.5 Hz, 1 H), 7.30 - 7.20 (m, 2H), 7.18 - 7.06 (m, 3H), 6.89 (br. s., 1 H), 3.99 (d, J=13.7 Hz, 2H), 3.45 - 3.37 (m, 1 H), 2.94 (t, J=1 1 .7 Hz, 2H), 2.72 (d, J=3.5 Hz, 1 H), 2.10 (d, J=1 1 .0 Hz, 2H), 1 .89 (br. s., 1 H), 1 .72 (d, J=1 1 .5 Hz, 2H), 1 .18 (td, J=4.6, 9.3 Hz, 1 H), 1 .1 1 - 1 .05 (m, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 440.1 .

Example 83: 4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)-N-phenethylpiperidine-1-

Step 1: Preparation of 4-(3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)-N-phenethylpiperidine- 1 - carboxamide.

To a stirred solution of (2-isocyanatoethyl)benzene (72 mg, 494 μιτιοΙ, 68 μΙ_) in toluene (2 ml_) was added 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (150 mg, 494 μιτιοΙ) and N- ethyl-N-(propan-2-yl)propan-2-amine (63 mg, 494 μιτιοΙ, 86 μΙ_). Then mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep- HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 35%-60%,12 min) to give 4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)-N- phenethylpiperidine-1 -carboxamide (58 mg, 130 μιτιοΙ, 26 %) as a white solid. ¹ H NMR (400MHz, CDC ) δ 7.59 (dd, J=2.0, 8.4 Hz, 1 H), 7.49 (d, J=1 .9 Hz, 1 H), 7.28 - 7.22 (m, 2H), 7.18 - 7.12 (m, 3H), 6.87 (d, J=8.4 Hz, 1 H), 4.40 (br. s., 1 H), 4.10 (q, J=7.0 Hz, 2H), 3.88 (s, 3H), 3.86 - 3.80 (m, 2H), 3.48 - 3.41 (m, 2H), 3.14 - 3.05 (m, 1 H), 2.97 - 2.88 (m, 2H), 2.78 (t, J=6.8 Hz, 2H), 2.04 (dd, J=3.2, 13.1 Hz, 2H), 1 .89 - 1 .77 (m, 2H), 1 .43 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 451 .3.

Example 84: 4-(4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1- phenylpyrrolidin-2-one, Example 85: (R)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazol-5- yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, and Example 86: (S)-4-(4-(3-(4-ethoxy-3- methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolid in-2-one.

Step 1: Preparation of 4-(4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1 -carbonyl)- 1 phenylpyrrolidin-2-one, (S)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carbonyl)- 1-phenylpyrrolidin-2-one, and (R)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazol-5-

To a stirred solution of 5-oxo-1 -phenyl-pyrrolidine-3-carboxylic acid (200 mg, 975 μιηοΙ) in N,N- dimethylformamide (4 ml_) was added 3-(4-ethoxy-3-methoxy-phenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (295 mg, 975 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (369 mg, 975 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (377 mg, 2.92 mmol, 510 μΙ_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12 min) to give racemic 4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one (151 mg, 31 %). A portion of this racemic mixture (140 mg) underwent SFC separation (column: OJ(250x30mm, 5μιη);ιτιο^ΐ6 phase: [CO2 base-isopropanol]; B%: 45%-45%, min]) to give (R)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one (64 mg, 132 μιτιοΙ, 14 %, 99.7% purity) as a white solid then (S)-4-(4-(3-(4-ethoxy- 3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 -phenylpyrrolidin-2-one (65 mg, 133.9 μιτιοΙ, 14 %, 99.58% purity) also as a white solid.

4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one:

¹ H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J=8.0 Hz, 2H), 7.62 - 7.56 (m, 1 H), 7.48 (s, 1 H), 7.39 (t, J=6.7 Hz, 2H), 7.19 - 7.09 (m, 2H), 4.38 (d, J=13.8 Hz, 1 H), 4.14 - 3.93 (m, 5H), 3.85 (s, 3H), 3.80 - 3.71 (m, 1 H), 3.51 - 3.40 (m, 1 H), 3.30 (br. s., 1 H), 3.00 - 2.89 (m, 1 H), 2.83 - 2.73 (m, 2H), 2.22 - 2.09 (m, 2H), 1 .90 - 1 .64 (m, 2H), 1 .37 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 491 .2.

(R)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one:

Ή NMR (400 MHz, DMSO-d6) δ 7.68 (d, J=7.9 Hz, 2H), 7.62 - 7.56 (m, 1 H), 7.51 - 7.46 (m, 1 H), 7.39 (t, J=6.7 Hz, 2H), 7.19 - 7.09 (m, 2H), 4.38 (d, J=13.4 Hz, 1 H), 4.13 - 3.95 (m, 5H), 3.85 (s, 3H), 3.80 - 3.71 (m, 1 H), 3.44 (d, J=10.0 Hz, 2H), 2.94 (br. s., 1 H), 2.81 - 2.74 (m, 2H), 2.1 6 (t, J=13.6 Hz, 2H), 1 .91 - 1 .64 (m, 2H), 1 .37 (t, J=6.9 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 491 .1 .

(S)-4-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one.

¹ H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J=6.6 Hz, 2H), 7.57 (d, J=8.4 Hz, 1 H), 7.46 (s, 1 H), 7.41 - 7.33 (m, 2H), 7.17 - 7.07 (m, 2H), 4.37 (d, J=12.8 Hz, 1 H), 4.12 - 3.92 (m, 5H), 3.83 (s, 3H), 3.78 - 3.69 (m, 1 H), 3.43 (t, J=10.6 Hz, 1 H), 3.28 (br. s., 1 H), 2.92 (t, J=13.0 Hz, 1 H), 2.81 - 2.70 (m, 2H), 2.14 (t, J=13.5 Hz, 2H), 1 .88 - 1 .78 (m, 1 H), 1 .74 - 1 .64 (m, 1 H), 1 .35 (t, J=7.1 Hz, 3H); LCMS (ESI) m/z: C27H30N4O5 [M+H] ⁺ = 491 .1

Alternatively, Example 85: (4R)-4-[4-[3-(4-ethoxy-3-methoxy-phenyl)- 1 ,2,4-oxadiazol-5-yl]pipericline- 1 - carbonyl]- 1-phenyl-pyrrolidin-2-one can be prepared in an enantioselective fashion as follows:

Step 1: Preparation of (4R)-4-[4-l3-(4-ethoxy-3- ethoxy^henyl)- 1,2,4-oxadiazol-5-yl]piperidine- 1- carbonyl]- 1 -phenyl-pyrrolidin-2-on

To a stirred solution of 1 -[(3R)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (100 mg, 316 μιηοΙ) and 4-ethoxy-N'-hydroxy-3-methoxy-benzamidine (66 mg, 316 μιηοΙ) in DMF (1 .50 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 1 9 mg, 316 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (81 mg, 632 μιτιοΙ, 1 10 μΐ) at 25 ^q C. After 12h, the mixture was heated and stirred at 1 10 °C for 1 h. The mixture was cooled then purified by prep_HPLC (Waters Xbridge 150x25 5μιη; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 25%-65%,12 min) to give (4R)-4-[4-[3-(4-ethoxy-3-methoxy-phenyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 - carbonyl]-1 -phenyl-pyrrolidin-2-one (59 mg,122 μmol, 39 %) as a pink solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.66 (br d, J=8.2 Hz, 1 H), 7.61 - 7.54 (m, 3H), 7.37 (m, J=7.9 Hz, 2H), 7.19 - 7.14 (m, 1 H), 6.94 (d, J=8.4 Hz, 1 H), 4.59 - 4.46 (m, 1 H), 4.31 (dd, J=7.3, 9.7 Hz, 1 H), 4.17 (q, J=7.0 Hz, 2H), 3.99 - 3.90 (m, 5H), 3.58 (quin, J=8.4 Hz, 1 H), 3.43 - 3.26 (m, 2H), 3.16 - 2.92 (m, 2H), 2.88 - 2.79 (m, 1 H), 2.24 (br t, J=12.9 Hz, 2H), 2.05 - 1 .89 (m, 2H), 1 .50 (t, J=6.9 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 491 .3.

Example 87: N-(2-(4-(3-(3-chloro-4-ethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of 3-chloro-4-ethoxybenz

To a stirred solution of 3-chloro-4-hydroxybenzonitrile (2.0 g, 13.0 mmol) in N,N- dimethylformamide (20 mL) was added iodoethane (2.44 g, 15.6 mmol, 1 .25 mL) and potassium carbonate (3.60 g, 26.1 mmol) at 0 °C. The reaction was warmed to 40 °C. After 16 h, the reaction mixture was quenched by addition of water (30 mL) then the mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude 3-chloro- 4-ethoxybenzonitrile (2.50 g) as a yellow solid. ¹ H NMR (400 MHz, CDCb) δ 7.57 (d, J=1 .9 Hz, 1 H), 7.45 (dd, J=2.0, 8.7 Hz, 1 H), 6.88 (d, J=8.5 Hz, 1 H), 4.10 (q, J=7.0 Hz, 2H), 1 .43 (t, J=7.0 Hz, 3H). Step 2: Preparation of (Z)-3-chloro-4-ethoxy-N'-hydroxybenzimidamide.

To a stirred solution of 3-chloro-4-ethoxybenzonitrile (2.40 g, 13.2 mmol) in ethanol (30 mL) was added hydroxylamine hydrochloride (1 .84 g, 26.4 mmol), triethylamine (2.67 g, 26.4 mmol, 3.66 mL) and water (3 mL). The mixture was heated at 80 °C for 2 h. The reaction mixture was filtered and the filter cake dried in vacuo to give (Z)-3-chloro-4-ethoxy-N'-hydroxybenzimidamide (700 mg, 3.62 mmol, 69 %) as a brown oil. ¹ H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1 H), 7.72 (d, J=2.0 Hz, 2H), 7.14 (d, J=8.8 Hz, 1 H), 5.83 (s, 2H), 4.14 (q, J=6.9 Hz, 2H), 1 .45 - 1 .30 (m, 3H).

Step 3: Preparation of N-(2-(4-(3-(3-chloro-4-ethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) in N,N-dimethylformamide (2 mL) was added (Z)-3-chloro-4-ethoxy-N'-hydroxybenzimidamide (97 mg, 455 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 μί). The mixture was stirred at

20 °C for 2 h, then heated at 120 °C for 2 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 45%-80%,12 min) to give N-(2-(4-(3-(3-chloro-4-ethoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (104 mg, 223 μιηοΙ, 54 %) as a yellow solid. ¹ H NMR (400 MHz, CDCb) δ 8.12 (d, J=2.0 Hz, 1 H), 7.95 (dd, J=2.1 , 8.6 Hz, 1 H), 7.91 - 7.86 (m, 2H), 7.58 - 7.44 (m, 3H), 7.35 (br. s., 1 H), 7.02 (d, J=8.7 Hz, 1 H), 4.51 (d, J=13.7 Hz, 1 H), 4.33 (d, J=3.9 Hz, 2H), 4.21 (q, J=7.0 Hz, 2H), 3.93 (d, J=13.9 Hz, 1 H), 3.41 - 3.29 (m, 2H), 3.18 (t, J=10.8 Hz, 1 H), 2.33 - 2.20 (m, 2H), 2.09 - 1 .93 (m, 2H), 1 .53 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 469.3. Example 88: N-(2-(4-(3-( ¹ H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-oxoethyl)benzamide

Step 1: Preparation of ¹ H-indazole-6-carbonitri

To a stirred solution of 6-bromo-1 H-indazole (1 .0 g, 5.08 mmol) in N,N-dimethylformamide (12 mL) was added zinc cyanide (595 mg, 5.08 mmol, 322 μΙ_) and tetrakis(triphenylphosphine)palladium(0) (586 mg, 508 μιηοΙ), and the mixture was degassed with nitrogen three times. The mixture heated at 100 °C for 4 h under nitrogen. The reaction cooled to 20 °C, water (15 mL) was added, and the reaction mixture was extracted with ethyl acetate (40 mL x 3). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product. This was triturated with petroleum ether (30 mL) and dichloromethane (5 mL), and the mixture filtered. The filter cake was dried in vacuo to give 1 H-indazole- 6-carbonitrile (880 mg) as a yellow solid that was used directly without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 13.65 (br. s., 1 H), 8.33 - 8.12 (m, 2H), 7.99 (d, J=8.4 Hz, 1 H), 7.88 - 7.80 (m, 1 H).

Step 2: Preparation of (Z)-N'-hydroxy- 1H-indazol -6-carboximidamide.

To a stirred solution of 1 H-indazole-6-carbonitrile (800 mg, 5.59 mmol) in ethanol (1 mL) was added hydroxylamine hydrochloride (776 mg, 1 1 .18 mmol), triethylamine (1 .13 g, 1 1 .1 8 mmol, 1 .55 mL) and water (100 μί). The mixture was heated at 80 °C for 2 h. The reaction mixture was cooled, concentrated under reduced pressure, and then diluted with water (5 mL). The solid that formed was filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-l H-indazole-6- carboximidamide (500 mg, 2.84 mmol, 51 %) as a yellow solid that was used directly without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 13.22 - 13.10 (m, 1 H), 9.68 (br. s., 1 H), 8.04 (s, 1 H), 7.78 (s, 1 H), 7.70 - 7.66 (m, 1 H), 7.47 - 7.42 (m, 1 H), 5.87 (br. s., 2H). Step 3: Preparation of N-(2-(4-(3-( ¹ H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) in N,N-dimethylformamide (2 ml_) was added (Z)-N'-hydroxy-l H-indazole-6-carboximidamide (94 mg, 537 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 μΙ_). The mixture was stirred at 20 °C for 1 h, then heated at 1 1 0 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Luna C18 100 ^* 30 5μιτι ; mobile phase: [water (0.225%TFA)-acetonitrile]; B%: 30%-55%,12 min) to give N-(2-(4-(3-( ¹ H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (21 mg, 44 μιτιοΙ, 1 1 %) as a brown solid. Ή NMR (400 MHz, DMSO-d6) δ 13.34 (br s, 1 H), 8.55 (t, J=5.6 Hz, 1 H), 8.18 - 8.16 (m, 1 H), 7.94 - 7.89 (m, 1 H), 7.88 - 7.83 (m, 2H), 7.72 (dd, J=1 .1 , 8.4 Hz, 1 H), 7.54 - 7.41 (m, 3H), 4.36 - 4.27 (m, 1 H), 4.16 (d, J=5.7 Hz, 2H), 3.97 (br d, J=14.1 Hz, 1 H), 3.59 (br s, 1 H), 3.47 (s, 1 H), 3.34 - 3.24 (m, 1 H), 2.98 - 2.88 (m, 1 H), 2.20 - 2.08 (m, 2H), 1 .89 - 1 .77 (m, 1 H), 1 .66 (br d, J=1 1 .5 Hz, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 431 .1 .

Example 89: 4-(4-(3-( 1,3-dimethyl-1H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1- phenylpyrrolidin-2-one, example 90: 4-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5- yl)piperidine-1-carbonyl)-1-phenylpyrrolidin-2-one, Enantiomer 1 and Example 91 : (R)-4-(4-(3-(1,3- dimethyl-1H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-1-phenylpyrrolid in-2-one,

Step 1: Preparation of 1 ,3-dimethyl- 1H-indazol

To a stirred solution of 6-bromo-1 ,3-dimethyl-1 H-indazole (480 mg, 2.13 mmol) in N,N- dimethylformamide (5 mL) was added zinc cyanide (250 mg, 2.13 mmol) and

tetrakis(triphenylphosphine)palladium(0) (246 mg, 213 μιηοΙ) under nitrogen, then the mixture was heated to 100 °C. After 16 h, the reaction was cooled to 20 °C, water (10 mL) was added, and the reaction mixture extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give crude product. The residue was triturated with petroleum ether (30 mL), then filtered and the filter cake dried in vacuo to give 1 ,3-dimethyl-1 H-indazole-6-carbonitrile (300 mg, 1 .75 mmol, 82 %) as a yellow solid. Ή NMR (400 MHz, CDC ) δ 7.78 - 7.71 (m, 2H), 7.38 - 7.31 (m, 1 H), 4.08 (s, 3H), 2.61 (s, 3H).

Step 2: Preparation of (Z)-N'-hydroxy- l ,3-dimethyl- -indazole-6-carboximidamide.

To a stirred solution of 1 ,3-dimethyl-1 H-indazole-6-carbonitrile (300 mg, 1 .75 mmol) in ethanol (5 mL) was added hydroxylamine hydrochloride (243 mg, 3.50 mmol), triethylamine (354 mg, 3.50 mmol, 485 μί) and water (500 μί). The mixture was heated at 80 °C for 5 h, then cooled and filtered, and the filter cake was dried in vacuo to give (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-6-carboximidamide (290 mg, 1 .42 mmol, 81 %) as a white solid that was used directly without further purification. ¹ H NMR (400

MHz, DMSO-d6) δ 9.71 (s, 1 H), 7.86 (s, 1 H), 7.65 (d, J=8.5 Hz, 1 H), 7.49 (d, J=8.5 Hz, 1 H), 5.90 (s, 2H), 3.97 (s, 3H), 2.47 (s, 3H).

Step 3: Preparation of methyl 1-(5-oxo- 1-phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylate.

To a stirred solution of 5-oxo-1 -phenylpyrrolidine-3-carboxylic acid (500 mg, 2.44 mmol) in N,N- dimethylformamide (10 mL) was added methyl piperidine-4-carboxylate (349 mg, 2.44 mmol), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (925 mg, 2.44 mmol) and N-ethyl-N- (propan-2-yl)propan-2-amine (946 mg, 7.32 mmol, 1 .28 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition of water (20 mL) then extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by

chromatography (silica, petroleum ether : ethyl acetate = 20 : 1 to 1 : 1 ) gave methyl 1 -(5-oxo-1 - phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylate (940 mg) as a yellow oil.

Step 4: Preparation of 1-(5-oxo- 1-phe e-4-carboxylic acid

To a stirred solution of methyl 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylate (900 mg, 2.72 mmol) in tetrahydrofuran (10 mL) was added lithium hydroxide (2 M, 2.72 mL). Afterr 2 h, the reaction mixture was acidified to pH 1 with 1 M hydrochloric acid (6 mL). The mixture was extracted with ethyl acetate (40 mL x 3). The organic extracts were combined and washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1 -(5-OXO-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (600 mg, 1 .90 mmol, 70 %) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.37 - 12.17 (m, 1 H), 7.66 (dd, J=5.8, 7.2 Hz, 2H), 7.38 (t, J=7.9 Hz, 2H), 7.19 - 7.09 (m, 1 H), 4.28 - 4.19 (m, 1 H), 4.04 (s, 1 H), 3.93 (br. s., 2H), 3.76 - 3.66 (m, 1 H), 3.18 (br. s., 1 H), 2.86 - 2.67 (m, 4H), 1 .87 (t, J=13.2 Hz, 2H), 1 .61 - 1 .35 (m, 2H).

Step 5: Preparation of 4-(4-(3-( 1 ,3-dimethyl- 1H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidine- 1 -carbonyl)- 1- phenylpyrrolidin-2-one, 4-(4-(3-( 1 ,3-dimethyl- 1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidine- 1-carbonyl)- 1-phenylpyrrolidin-2-one, Enantiomer 1 and 4-(4-(3-(1 ,3-dimethyl- 1H-indazol-6-yl)- 1 ,2,4-oxadiazol-5- yl)piperidine- 1 -carbonyl)- 1 -phenylpyrrolidin-2-one, Enantiomer 2.

To a stirred solution of 1 -(5-oxo-1 -phenyl-pyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (150 mg, 474 μιτιοΙ) in N,N-dimethylformamide (2 mL) was added N'-hydroxy-1 ,3-dimethyl-indazole-6- carboxamidine (96 mg, 474 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium

hexafluorophosphate) (179 mg, 474 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (183 mg, 1 .42 mmol, 248 iL). The mixture was stirred at 20 °C for 2 h, then heated at 120 for 1 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 30%-55%,12 min) to give the racemic of 4-(4-(3- (1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 -phenylpyrrolidin-2-one (85 mg) as a white solid. A portion (25 mg, 53 μιηοΙ, 1 1 %, 99.83% purity) was retained for analysis. The remainder (60 mg) was purified by SFC (column: OJ (250x30mm, 5μιη); mobile phase: [CO2 base- methanol]; B%: 45%-45%,min) to give 4-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5- yl)piperidine-1 -carbonyl)-1 -phenylpyrrolidin-2-one, Enatiomer 1 (27 mg, 56 μιηοΙ, 12 %) as a brown solid then 4-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 -phenylpyrrolidin- 2-one, Enantiomer 2 (26 mg, 55 μιηοΙ, 12 %) as a white solid.

4-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one:

¹ H NMR (400 MHz, CDC ) δ 8.13 - 8.07 (m, 1 H), 7.83 (s, 1 H), 7.78 - 7.72 (m, 1 H), 7.61 (d, J=8.0 Hz, 2H), 7.39 (t, J=7.9 Hz, 2H), 7.18 (s, 1 H), 4.65 - 4.50 (m, 1 H), 4.34 (t, J=7.3 Hz, 1 H), 4.09 (d, J=3.3 Hz, 3H),

4.05 - 3.92 (m, 2H), 3.60 (quin, J=8.4 Hz, 1 H), 3.46 - 3.32 (m, 2H), 2.98 (d, J=6.7 Hz, 2H), 2.91 - 2.81 (m, 1 H), 2.61 (s, 3H), 2.35 - 2.22 (m, 2H), 2.02 (d, J=6.1 Hz, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 485.2.

4-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one, Enantiomer 1 :

Ή NMR (400 MHz, CDCb) δ 8.12 (d, J=4.1 Hz, 1 H), 7.86 (br d, J=8.5 Hz, 1 H), 7.80 - 7.74 (m, 1 H), 7.63 (d, J=7.9 Hz, 2H), 7.41 (t, J=8.0 Hz, 2H), 7.23 - 7.18 (m, 1 H), 4.67 - 4.52 (m, 1 H), 4.36 (br t, J=7.0 Hz, 1 H), 4.1 1 (d, J=3.4 Hz, 3H), 4.07 - 3.94 (m, 2H), 3.62 (quin, J=8.5 Hz, 1 H), 3.49 - 3.35 (m, 2H), 3.22 - 2.96 (m, 2H), 2.93 - 2.81 (m, 1 H), 2.63 (s, 3H), 2.37 - 2.25 (m, 2H), 2.1 1 - 1 .97 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 485.3. 4-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 - phenylpyrrolidin-2-one, Enantiomer 2:

¹ H NMR (400 MHz, CDC ) 5 8.12 (d, J=3.9 Hz, 1 H), 7.86 (d, J=8.4 Hz, 1 H), 7.80 - 7.74 (m, 1 H), 7.63 (d, J=8.3 Hz, 2H), 7.41 (t, J=8.0 Hz, 2H), 7.24 - 7.18 (m, 1 H), 4.66 - 4.53 (m, 1 H), 4.36 (br t, J=7.3 Hz, 1 H), 4.1 1 (d, J=3.5 Hz, 3H), 4.07 - 3.94 (m, 2H), 3.62 (quin, J=8.5 Hz, 1 H), 3.48 - 3.36 (m, 2H), 3.21 - 2.96 (m, 2H), 2.93 - 2.81 (m, 1 H), 2.63 (s, 3H), 2.36 - 2.26 (m, 2H), 2.06 (br d, J=13.4 Hz, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 485.3.

Examples 90 and 91 can be synthesized in an enantiospecific fashion using appropriate enantiopure starting materials, following the representative procedure below:

Preparation of (4R)-4-[4-[3-( 1 ,3-dimethylindazol-6-yl)- 1 ,2,4-oxadiazol-5-yl]piperidine- 1 -carbonyl]- 1 -phenyl- pyrrolidin-2-one.

To a stirred solution of 1 -[(3R)-5-oxo-1 -phenyl-pyrrolidine-3-carbonyl]piperidine-4-carboxylic acid (1 15 mg, 363.52 μιτιοΙ) and N'-hydroxy-1 ,3-dimethyl-indazole-6-carboxamidine (74 mg, 364 μιτιοΙ) in DMF (1 .50 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (137 mg, 364 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (93 mg, 727 μιτιοΙ, 126 μΙ_) at 25 °C. After 3 h, the mixture was warmed to 1 10 °C. After 1 h, the mixture was purified by chromatography (Waters

Xbridge 150x25 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-60%,12 min) to give (4R)-4-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]-1 -phenyl- pyrrolidin-2-one (64 mg,133 μιτιοΙ, 37 %) as a pink solid. Ή NMR (400MHz, CHLOROFORM-d) δ = 8.09 (d, J=4.0 Hz, 1 H), 7.84 - 7.80 (d, 1 H), 7.75 - 7.71 (d, 1 H), 7.59 (d, J=7.9 Hz, 2H), 7.38 (t, J=7.9 Hz, 2H), 7.20 - 7.14 (t, 1 H), 4.62 - 4.49 (m, 1 H), 4.36 - 4.29 (m, 1 H), 4.07 (d, J=3.3 Hz, 3H), 4.04 - 3.89 (m, 2H), 3.58 (quin, J=8.4 Hz, 1 H), 3.45 - 3.30 (m, 2H), 3.1 8 - 2.92 (m, 2H), 2.90 - 2.80 (m, 1 H), 2.59 (s, 3H), 2.27 (br t, J=13.2 Hz, 2H), 2.09 - 1 .91 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 485.3. Example 92: (4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)(3- phenylisoxazol-5-yl)methanone.

Step 1: Preparation of 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)- 1,2,4-oxadiazole.

To a stirred solution of tert-butyl 4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine- 1 -carboxylate (800 mg, 1 .98 mmol) in ethyl acetate (5 mL) was added 4M hydrochloric acid / ethyl acetate (20 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was filtered and the filter cake was dried in vacuo to give 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (450 mg,

1 .48 mmol, 75 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 7.67 (dd, J=1 .6, 8.3 Hz, 1 H), 7.60 - 7.54 (m, 1 H), 6.97 (d, J=8.4 Hz, 1 H), 4.24 - 4.13 (m, 2H), 3.98 (s, 3H), 3.56 (br s, 2H), 3.39 (br s, 1 H), 3.33 - 3.15 (m, 2H), 2.51 (br s, 2H), 2.48 - 2.33 (m, 2H), 2.19 - 1 .83 (m, 1 H), 1 .53 (t, J=7.0 Hz, 3H). Step 2: Preparation of (4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)(3- phenylisoxazol-5-yl)methanone.

To a stirred solution of 3-phenylisoxazole-5-carboxylic acid (75 mg, 396 μιηοΙ) in N,N- dimethylformamide (2 mL) was added 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (120 mg, 396 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (150 mg, 396 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (153 mg, 1 .19 mmol, 207 μί). The mixture was stirred at 20 °C for 2 h. The reaction mixture was then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%:40%-70%,12 min) to give (4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)(3-phenylisoxazol-5- yl)methanone (41 mg, 87 μιτιοΙ, 22 %) as a white solid. Ή NMR (400 MHz, CDC ) δ 7.87 (br s, 2H), 7.70 (br d, J=7.8 Hz, 1 H), 7.60 (br s, 1 H), 7.53 (br s, 3H), 7.14 (s, 1 H), 6.99 (br d, J=7.5 Hz, 1 H), 4.59 (br s, 1 H), 4.36 (br d, J=12.5 Hz, 1 H), 4.21 (br d, J=6.4 Hz, 2H), 4.00 (s, 3H), 3.55 (br s, 1 H), 3.46 - 3.25 (m, 2H), 2.32 (br s, 2H), 2.15 (br s, 2H), 1 .54 (br t, J=6.8 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 475.2. Example 93: N-(2-(4-(3-(3-methyl-1H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 6-bromo-3-methyl-1 H-indazole (440 mg, 2.08 mmol) in N,N- dimethylformamide (5 mL) was added zinc cyanide (244 mg, 2.08 mmol) and

tetrakis(triphenylphosphine)palladium(0) (240 mg, 208 μιηοΙ), then the mixture was degassed with nitrogen three times. The mixture stirred at 100 °C for 4 h under nitrogen, then cooled to 20 °C, water (10 mL) added, and the reaction mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product. Petroleum ether (20 mL) was added to the crude product, then the mixture was filtered and the filter cake dried in vacuo to give 3- methyl-1 H-indazole-6-carbonitrile (220 mg, 1 .40 mmol, 67 %) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 13.29 - 13.09 (m, 1 H), 8.09 - 8.05 (m, 1 H), 7.96 - 7.90 (m, 1 H), 7.41 (d, J=8.3 Hz, 1 H), 2.54 (s, 3H). Step 2: Preparation of (Z)-N'-hydroxy-3-methyl- 1H-indazole-6-carboximidamide.

To a stirred solution of 3-methyl-1 H-indazole-6-carbonitrile (200 mg, 1 .27 mmol) in ethanol (1 mL) was added hydroxylamine hydrochloride (176 mg, 2.55 mmol), triethylamine (257 mg, 2.55 mmol, 352 μί) and water (100 μί). The mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled and then concentrated under reduced pressure to remove ethanol. The residue was diluted with water (5 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-3-methyl-1 H-indazole- 6-carboximidamide (150 mg, 789 μιτιοΙ, 62 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1 H), 9.67 (s, 1 H), 7.73 (s, 1 H), 7.65 (d, J=8.5 Hz, 1 H), 7.45 (d, J=8.5 Hz, 1 H), 5.86 (s, 2H), 2.49 (s, 3H). Step 3: Preparation of N-(2-(4-(3-(3-methyl- 1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) in

N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxy-3-methyl-1 H-indazole-6-carboximidamide (78 mg, 413 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 μΙ_). The mixture was stirred at 20°C for 2 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-55%,12 min) to give N-(2-(4-(3-(3-methyl-1 H-indazol-6-yl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (93 mg, 209 μιηοΙ, 51 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1 H), 8.59 - 8.53 (m, 1 H), 8.08 (s, 1 H), 7.86 (d, J=8.4 Hz, 3H), 7.71 - 7.65 (m, 1 H), 7.55 - 7.42 (m, 3H), 4.30 (d, J=13.2 Hz, 1 H), 4.16 (d, J=5.7 Hz, 2H), 3.97 (d, J=14.6 Hz, 1 H), 3.49 - 3.43 (m, 1 H), 3.29 - 3.24 (m, 1 H), 2.92 (t, J=1 1 .2 Hz, 1 H), 2.50 (s, 3H), 2.14 (t, J=13.0 Hz, 2H), 1 .88 - 1 .78 (m, 1 H), 1 .66 (d, J=9.7 Hz, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 445.3.

Example 94: N-(2-(4-(3-(1-methyl-1H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of 1 -methyl- 1 H-indazole-

To a stirred solution of 6-bromo-1 -methyl-1 H-indazole (500 mg, 2.37 mmol) in N,N- dimethylformamide (8 mL) was added zinc cyanide (278 mg, 2.37 mmol) and

tetrakis(triphenylphosphine)palladium(0) (273 mg, 236.90 μιηοΙ), the mixture was degassed with nitrogen three times. The mixture was stirred at 100 for 4 h under nitrogen, then cooled to 20 °C, water (10 mL) added, and the reaction mixture extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product. The mixture was triturated with petroleum ether (20 mL) and dichloromethane (3 mL), then filtered and dried in vacuo to give 1 -methyl- 1 H-indazole-6-carbonitrile (300 mg, 1 .91 mmol, 81 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 8.10 (s, 1 H), 7.88 - 7.83 (m, 1 H), 7.82 (s, 1 H), 7.39 (dd, J=1 .1 , 8.3 Hz, 1 H), 4.1 6 (s, 3H).

Step 2: Preparation of (Z)-N'-hydroxy- l -methyl- 1 H-indazole-6-carboximidamide.

To a stirred solution of 1 -methyl-1 H-indazole-6-carbonitrile (250 mg, 1 .59 mmol) in ethanol (1 mL) was added hydroxylamine hydrochloride (221 mg, 3.1 8 mmol), triethylamine (321 mg, 3.18 mmol, 440 μί) and water (100 μί). The mixture was heated at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue then triturated with water (4 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-l -methyl-1 H-indazole-6-carboximidamide (500 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.65 (br. s., 2H), 9.65-9.84 (m, 1 H), 7.98 (d, J=18.1 Hz, 2H), 7.67 (d, J=8.8 Hz, 1 H), 7.46-7.52 (m, 1 H), 4.03 ppm (s, 3H).

Step 3: Preparation of N-(2-(4-(3-(1 -methyl- 1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) in

N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxy-l -methyl-1 H-indazole-6-carboximidamide (125 mg, 661 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 μί). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 for 1 h. The reaction mixture was cooled then purified by prep- HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 33%-63%,12 min) to give N-(2-(4-(3-(1 -methyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (29 mg, 64 μιτιοΙ, 15 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 8.19 (s, 1 H), 8.06 (s, 1 H), 7.92 - 7.82 (m, 4H), 7.58 - 7.45 (m, 3H), 7.36 (br. s., 1 H), 4.56 (d, J=14.2 Hz, 1 H), 4.34 (d, J=3.9 Hz, 2H), 4.19 (s, 3H), 4.00 - 3.92 (m, 1 H), 3.44 - 3.34 (m, 2H), 3.19 (t, J=10.9 Hz, 1 H), 2.36 - 2.26 (m, 2H), 2.14 - 1 .98 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 445.2. Example 95: N-(2-(4-(3-(1,3-dimethyl-1H-indazol-5-yl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of 1 ,3-dimethyl- 1H-in .

To a stirred solution of 5-bromo-1 ,3-dimethyl-1 H-indazole (600 mg, 2.67 mmol) in N,N- dimethylformamide (10 mL) was added zinc cyanide (313 mg, 2.67 mmol, 169 μί) and

tetrakis(triphenylphosphine)palladium(0) (308 mg, 267 μιτιοΙ) under nitrogen. The mixture was stirred at 100 °C for 16 h, then cooled to 20 °C, and diluted with water (15 mL). The reaction mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product. This was triturated with petroleum ether (30 mL) and dichloromethane (5 mL), filtered and the filter cake dried in vacuo to give 1 ,3-dimethyl-1 H-indazole-5-carbonitrile (340 mg, 1 .99 mmol, 74 %) as a brown solid. ¹ H NMR (400 MHz, CDC ) δ 8.02 (s, 1 H), 7.54 (d, J=8.8 Hz, 1 H), 7.37 (d, J=8.8 Hz, 1 H), 4.02 (s, 3H), 2.57 (s, 3H).

Step 2: Preparation of (Z)-N'-hydroxy- l ,3-dimethyl- 1 H-indazole-5-carboximidamide.

To a stirred solution of 1 ,3-dimethyl-1 H-indazole-5-carbonitrile (340 mg, 1 .99 mmol) in ethanol (6 mL) was added hydroxylamine hydrochloride (276 mg, 3.97 mmol), triethylamine (401 mg, 3.97 mmol, 550 μί) and water (600 μί). The mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was triturated with water (4 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-5- carboximidamide (250 mg, 1 .22 mmol, 62 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1 H), 7.99 (s, 1 H), 7.72 (dd, J=1 .5, 9.0 Hz, 1 H), 7.48 (d, J=8.8 Hz, 1 H), 5.82 (s, 2H), 3.92 (s, 3H), 2.46 (s, 3H). Step 3: Preparation of N-(2-(4-(3-(1 ,3-dimethyl- 1 H-indazol-5-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (120 mg, 413 μιηοΙ) in N,N-dimethylformamide (2 mL) was added N'-hydroxy-1 ,3-dimethyl-indazole-5-carboxamidine (84 mg, 413 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 56 mg, 413 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (160 mg, 1 .24 mmol, 216 μΙ_). The mixture was stirred at 20 °C for 2 h, and then heated at 1 10 °C for 2 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-64%,12 min) to give N-(2-(4-(3-(1 ,3-dimethyl-1 H-indazol-5-yl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (54 mg, 1 18 μιηοΙ, 29 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.55 (t, J=5.5 Hz, 1 H), 8.34 (s, 1 H), 7.96 (dd, J=1 .3, 8.8 Hz, 1 H), 7.86 (d, J=7.1 Hz, 2H), 7.70 (d, J=8.8 Hz, 1 H), 7.55 - 7.42 (m, 3H), 4.31 (d, J=13.2 Hz, 1 H), 4.16 (dd, J=2.2, 5.3 Hz, 2H), 4.03 - 3.92 (m, 4H), 3.49 - 3.40 (m, 1 H), 3.34 - 3.30 (m, 1 H), 2.92 (t, J=1 1 .5 Hz, 1 H), 2.52 (s, 3H), 2.14 (t, J=13.0 Hz, 2H), 1 .83 (d, J=10.1 Hz, 1 H), 1 .71 - 1 .62 (m, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 459.3.

Example 96: 4-(4-(3-( 1,3-dimethyl-1H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperazine-1-carbonyl)-1- phenylpyrrolidin-2-one.

Step 1: Preparation of 3-(1 ,3-dimethyl- 1 H-indazol-6-yl)- 1 ,2,4-oxadiazol-5(4H)-one.

To a stirred solution of (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-6-carboximidamide (180 mg, 881 μιτιοΙ) in dioxane (3 mL) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (147 mg, 970 μιηοΙ, 146 μί) and 1 ,1 '-carbonyldiimidazole (214 mg, 1 .32 mmol). The mixture was stirred at 1 10 °C for 16 h. The reaction mixture was concentrated in vacuo then purified by chromatography (silica, dichloromethane : methanol = 50 :1 ) to give 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5(4H)-one (220 mg) as a yellow solid. ¹ H NMR (400 MHz, Methanol-d4) δ 7.97 - 7.93 (m, 1 H), 7.82 - 7.77 (m, 1 H), 7.62 (d, J=1 .1 Hz, 1 H), 4.05 (s, 3H), 2.57 (s, 3H). Step 2: Preparation of 5-chloro-3-(1 ,3-dimeth 1 ,2,4-oxadiazole

A flask 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5(4H)-one (220 mg, 956 μιηοΙ) was charged with N,N-dimethylformamide (1 mL) then phosphoryl chloride (10 mL) was added dropwise. The mixture was heated at 1 10 °C for 16 h, then cooled and concentrated under reduced pressure, poured onto ice water (10 mL), and stirred for 10 min. The mixture was extracted with dichloromethane (20 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 5-chloro-3-(1 ,3-dimethyl-1 H- indazol-6-yl)-1 ,2,4-oxadiazole (1 00 mg) as a brown solid.

Step 3: Preparation of tert-butyl 4-(3-( 1 ,3-dimethyl- 1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperazine- 1- carboxylate

To a stirred solution of 5-chloro-3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazole (100 mg, 402.1 μμιηοΙ) in N-methyl-2-pyrrolidone (3 mL) was added tert-butyl piperazine-1 -carboxylate (74 mg, 402 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (103 mg, 804 μιτιοΙ, 140 μί). The mixture was stirred at 120 for 16 h. The reaction mixture was cooled, quenched by addition of water (5 mL) then the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and

concentrated. Purification by prep-TLC (silica, petroleum ether : ethyl acetate = 1 :1 ) gave tert-butyl 4-(3- (1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazine-1 -carboxylate (65 mg, 163 μιηοΙ, 41 %) as a brown solid.

Step 4: Preparation of 3-( 1 ,3-dimethyl- 1H-indazol-6-yl)-5-(piperazin- 1-yl)- 1 ,2,4-oxadiazole

To a stirred solution of tert-butyl 4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]piperazine-1 - carboxylate (65 mg, 163 μιηοΙ) in ethyl acetate (1 mL) was added hydrochloric acid / ethyl acetate (4M, 5 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-5-(piperazin-1 -yl)-1 ,2,4-oxadiazole (40 mg, 134 μιτιοΙ, 82 %) as a white solid. LCMS (ESI) m/z: [M+H] ⁺ = 299.1 .

Step 5: Preparation of 4-(4-(3-( 1 ,3-dimethyl- 1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperazine- 1-carbonyl)- 1 -phenylpyrrolidin-2-one

To a stirred solution of 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-5-(piperazin-1 -yl)-1 ,2,4-oxadiazole (35 mg, 1 17 μιτιοΙ) in N,N-dimethylformamide (1 mL) was added 5-oxo-1 -phenylpyrrolidine-3-carboxylic acid (24 mg, 1 17 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (44 mg, 1 17 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (45 mg, 352 μmol, 61 μΙ_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give 4-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazine-1 -carbonyl)-1 - phenylpyrrolidin-2-one (26 mg, 54.58 μιτιοΙ, 47 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 8.05 (s, 1 H), 7.83 - 7.69 (m, 2H), 7.63 (br d, J=7.5 Hz, 2H), 7.42 (br t, J=7.5 Hz, 2H), 7.22 (br d, J=7.9 Hz, 1 H), 4.37 (br t, J=8.0 Hz, 1 H), 4.09 (s, 3H), 4.03 - 3.96 (m, 1 H), 3.93 - 3.72 (m, 8H), 3.63 (br d, J=9.7 Hz, 1 H), 3.04 - 2.85 (m, 2H), 2.62 (s, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 486.3.

Example 97: N-(2-(4-(3-(4-ethoxy-3-fluorophenyl)-1,2,4-oxadiazol-5-yl)pi perffl

oxoeth l)benzamide

Step 1: Preparation of 4-ethoxy-3-fluorobenz

To a stirred solution of 3-fluoro-4-hydroxybenzonitrile (800 mg, 5.83 mmol) in N,N- dimethylformamide (10 mL) was added iodoethane (1 .09 g, 7.00 mmol, 559 μί) and potassium carbonate (1 .61 g, 1 1 .7 mmol) at 0 °C. The reaction was warmed at 40 °C for 16 h. The reaction mixture was quenched with water (10 mL), then the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude 4-ethoxy-3-fluorobenzonitrile (750 mg, 4.54 mmol, 78 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 7.43 - 7.30 (m, 2H), 6.98 (t, J=8.3 Hz, 1 H), 4.15 (q, J=7.0 Hz, 2H), 1 .47 (tt, J=1 .2, 7.0 Hz, 3H). Step 2: Preparation of (Z)-4-ethoxy-3-fluoro-N'-hydroxybenzimidamide

To a stirred solution of 4-ethoxy-3-fluorobenzonitrile (400 mg, 2.42 mmol) in ethanol (6 mL) was added hydroxylamine hydrochloride (336 mg, 4.84 mmol), triethylamine (490 mg, 4.84 mmol, 671 μΙ_) and water (600 μΙ_). The mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled then concentrated under reduced pressure. The residue was triturated with water (5 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-4-ethoxy-3-fluoro-N'-hydroxybenzimidamide (300 mg, 1 .51 mmol, 63 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1 H), 7.47 - 7.39 (m, 2H), 7.12 (t, J=8.9 Hz, 1 H), 5.80 (s, 2H), 4.13 - 4.06 (m, 2H), 1 .34 - 1 .29 (m, 3H).

Step 3: Preparation of N-(2-(4-(3-(4-ethoxy-3-fluorophenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide

To a stirred solution of 1 -(2-benzamidoacetyi)piperidine-4-carboxyiic acid (100 mg, 344 μιτιοΙ) in Ν,Ν-dimethylformamide (2 mL) was added (Z)-4-ethoxy-3-fluoro-N'-hydroxybenzimidamide (68 mg, 344 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafiuorophosphate) (130 mg, 344 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (133 mg, 1 .03 mmol, 180 μί). The mixture was stirred at 20 °C for 1 h, then heated at 1 1 0 °C for 1 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2, 5mm δμιτι; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 40%-7Q%,12 min) to give N-(2-(4-(3-(4-ethoxy-3-fluorophenyl)-1 ,2,4-oxadiazoi-5- yi)piperidin-1 -yi)-2-oxoethyi)benzamide (43 mg, 96 μιηοΙ, 28 %) as a pink solid. Ή NMR (400 MHz, CDC ) δ 7.88 (d, J=7.0 Hz, 2H), 7.85 - 7.79 (m, 2H), 7.58 - 7.44 (m, 3H), 7,35 (br s, 1 H), 7.05 (t, J=8.5 Hz, 1 H), 4.51 (br d, J=13.6 Hz, 1 H), 4.33 (d, J=3.8 Hz, 2H), 4.20 (q, J=7.0 Hz, 2H), 3.93 (br d, J=13.7 Hz, 1 H), 3.41 - 3.29 (m, 2H), 3.23 - 3.13 (m, 1 H), 2.32 - 2.20 (m, 2H), 2.08 - 1 .93 (m, 2H), 1 .51 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 453.1 .

Example 98: [4-[3-(4-ethoxy-3-methoxy-phenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-(2-phenyl-1H- imidazol-5-yl)methanone

Step 1: Preparation of 2-phenyl-4H-oxazol- -one

A mixture of 2-benzamidoacetic acid (1 .0 g, 5.58 mmol) and 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (953 mg, 6.14 mmol, 1 .08 mL) in dichloromethane (25 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 20 °C for 6h under a nitrogen atmosphere. The mixture was concentrated in vacuum to get a crude product. The crude product, 2-phenyl-4H-oxazol-5-one (1 .20 g) was used directly without further purification.

Step 2: Ethyl 2-phenyl- 1H-imidazole-5-carboxylate

A mixture of 2-phenyl-4H-oxazol-5-one (1 .0 g, 6.21 mmol), ethyl cyanoformate (676 mg, 6.83 mmol, 669 μί) and tributylphosphine (753 mg, 3.72 mmol, 918 μί) in dichloromethane (3 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 20 °C for 6h under a nitrogen atmosphere. The reaction mixture was quenched by addition of water (3 mL), then extracted with dichloromethane (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (silica, petroleum ether / ethyl acetate = 2:1 ) to give ethyl 2-phenyl-1 H-imidazole-5-carboxylate (480 mg, 2.22 mmol, 36 %) as a white solid.

Step 3: 2-phenyl- 1H-imidazole-5-carboxylic acid

A mixture of ethyl 2-phenyl-1 H-imidazole-5-carboxylate (300 mg, 1 .39 mmol) and sodium hydroxide (166 mg, 4.1 7 mmol) in tetrahydrofuran (3 mL) and water (1 .50 mL) was stirred at 20 °C for 2 h.

The reaction mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-phenyl-1 H-imidazole-5-carboxylic acid (200 mg) that was used directly without further purification.

Step 4: [4-[3-(4-ethoxy-3-methoxy-phenyl)- 1,2,4-oxadiazol-5-yl]- 1-piperidyl]-(2-phenyl- 1H-imidazol-5- yl)methanone

A mixture of 2-phenyl-1 H-imidazole-5-carboxylic acid (62 mg, 330 μιηοΙ), 3-(4-ethoxy-3-methoxy- phenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (100 mg, 330 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (125 mg, 330 μιηοΙ) and diisopropylethylamine (85 mg, 659 μιτιοΙ, 1 15 μΙ_) in N,N-dimethylformamide (3 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 20 °C for 2 h under a nitrogen atmosphere. The mixture was purified by prep-HPLC (column: Waters Xbridge 150x25 5μιη; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 40%-65%,12 min) to give [4-[3-(4-ethoxy-3-methoxy-phenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]-(2-phenyl-1 H-imidazol-5-yl)methanone (25 mg, 105 μιηοΙ, 16 %) as a white solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.95 (br d, J=7.7 Hz, 2H), 7.65 (dd, J=1 .8, 8.4 Hz, 1 H), 7.54 (s, 2H), 7.47 - 7.32 (m, 3H), 6.92 (d, J=8.4 Hz, 1 H), 5.56 - 5.27 (m, 1 H), 4.77 - 4.46 (m, 1 H), 4.14 (q, J=6.8 Hz, 2H), 3.99 - 3.88 (m, 3H), 3.66 - 3.09 (m, 3H), 2.24 (br d, J=9.7 Hz, 2H), 2.07 (br s, 1 H), 1 .84 (br s, 1 H), 1 .47 (t, J=6.8 Hz, 3H); LCMS(ESI) m/z: [M+H] ⁺ = 474.3.

Example 99: N-(2-(4-(3-(3-bromo-4-ethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide

Step 1: Preparation of N-(2-(4-(3-(3-bromo-4-ethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (100 mg, 344 μιτιοΙ) in N,N-dimethylformamide (2 mL) was added (Z)-3-bromo-4-ethoxy-N'-hydroxybenzimidamide (89 mg, 344 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (130 mg, 344 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (133 mg, 1 .03 mmol, 180 μΙ_). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 45%-75%,12 min) to give N-(2-(4-(3-(3-bromo-4-ethoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (43 mg, 83 μιηοΙ, 24 %) as a yellow solid. ¹ H NMR (400MHz, CDC ) δ 8.30 (d, J=2.1 Hz, 1 H), 8.00 (dd, J=2.1 , 8.6 Hz, 1 H), 7.91 - 7.85 (m, 2H), 7.58 - 7.44 (m, 3H), 7.35 (br s, 1 H), 6.98 (d, J=8.7 Hz, 1 H), 4.50 (br d, J=14.1 Hz, 1 H), 4.33 (d, J=3.9 Hz, 2H), 4.20 (q, J=6.9 Hz, 2H), 3.93 (br d, J=13.8 Hz, 1 H), 3.41 - 3.29 (m, 2H), 3.18 (br t, J=10.6 Hz, 1 H), 2.32 - 2.20 (m, 2H), 2.09 - 1 .93 (m, 2H), 1 .53 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 513.2.

Example 100: (1-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperi din-4-yl)(3- phenylpiperidin-1 -yl)methanone.

Step 1: Preparation of 3-(4-ethoxy-3-meth diazol-5(4H)-one

To a stirred solution of 4-ethoxy-N-hydroxy-3-methoxybenzimidamide (1 .0 g, 4.76 mmol) in dioxane (10 mL) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (796 mg, 5.24 mmol, 788 μί) and 1 ,1 '- carbonyldiimidazole (1 .16 g, 7.14 mmol). The mixture was heated at 1 10 °C for 1 6 h. The reaction mixture was cooled, quenched with water (10 mL), and then extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with 1 M aqueous hydrochloric acid (5 mL x 2), then with saturated aqueous sodium chloride solution (10 mL), filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated to give 3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5(4H)-one (1 .02 g, 4.32 mmol, 91 %) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.78 (br s, 1 H), 7.38 - 7.28 (m, 2H), 7.08 (d, J=8.4 Hz, 1 H), 4.05 (q, J=7.1 Hz, 2H), 3.77 (s, 3H), 1 .30 (t, J=6.9 Hz, 3H).

Step 2: Preparation of 5-chloro-3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazole.

A flask 3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5(4H)-one (1 .02 g, 4.32 mmol) was equipped with calcium chloride tube, then phosphoryl chloride (12 mL) and pyridine (170 mg, 2.16 mmol, 174 μί) were added dropwise and the mixture was heated at 1 10 °C for 16 h. The reaction mixture was cooled then concentrated under reduced pressure to remove phosphoryl chloride, and the residue added to ice water (20 mL) and stirred for 10 min. The mixture was extracted with dichloromethane (40 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude 5-chloro-3-(4-ethoxy-3- methoxyphenyl)-1 ,2,4-oxadiazole (910 mg) as a yellow solid.

Step 3: Preparation of methyl 1-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-4- carboxylate.

To a stirred solution of 5-chloro-3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazole (600 mg, 2.36 mmol) in N-methyl-2-pyrrolidone (8 mL) was added methyl piperidine-4-carboxylate (337 mg, 2.36 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (610 mg, 4.72 mmol, 824 μί). The mixture was stirred at 120 for 16 h. The reaction mixture was quenched with water (10 mL), then the mixture was extracted with ethyl acetate (40 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50 : 1 to 10:1 ) to give methyl 1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-4-carboxylate (510 mg, 1 .41 mmol, 60 %) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.47 (dd, J=1 .9, 8.3 Hz, 1 H), 7.38 (d, J=2.0 Hz, 1 H), 7.06 (d, J=8.4 Hz, 1 H), 4.08 (q, J=7.0 Hz, 2H), 4.00 (td, J=3.5, 13.2 Hz, 2H), 3.82 (s, 3H), 3.64 (s, 3H), 3.31 - 3.24 (m, 2H), 2.68 (tt, J=3.9, 10.9 Hz, 1 H), 1 .98 (br dd, J=3.2, 13.5 Hz, 2H), 1 .70 - 1 .58 (m, 2H), 1 .36 (t, J=7.0 Hz, 3H).

Step 4: Preparation of 1-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidine-4-carboxylic acid.

To a stirred solution of methyl 1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-4- carboxylate (490 mg, 1 .36 mmol) in tetrahydrofuran (1 0 mL) was added lithium hydroxide (2 M, 2.04 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, then the mixture was acidified with concentrated hydrochloric acid until pH 1 . The mixture was extracted with dichloromethane (40 mL x 3). The organic layer was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude 1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-4- carboxylic acid (400 mg, 1 .15 mmol, 85 %) as a white solid. ¹ H NMR (400 MHz, Methanol-d4) δ 7.52 - 7.45 (m, 2H), 6.99 (d, J=8.4 Hz, 1 H), 4.15 - 4.05 (m, 4H), 3.86 (s, 3H), 3.32 (br d, J=3.1 Hz, 1 H), 3.28 - 3.25 (m, 1 H), 2.61 (tt, J=3.8, 10.8 Hz, 1 H), 2.07 - 1 .98 (m, 2H), 1 .80 - 1 .68 (m, 2H), 1 .41 (t, J=6.9 Hz, 3H). Step 5: Preparation of (1 -(3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin

phenylpiperidin- 1 -yljmethanone.

To a stirred solution of 1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-4- carboxylic acid (100 mg, 288 μιηοΙ) in N,N-dimethylformamide (500 μΙ_) was added 3-phenylpiperidine (46 mg, 288 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (109 mg, 288 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 1 1 mg, 863.66 μιηοΙ, 1 50 μΙ_). The mixture was stirred at 20 °C for 2 h. The reaction mixture was then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-60%,12 min) to give (1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)(3-phenylpiperidin-1 - yl)methanone (80 mg, 162 μιτιοΙ, 56 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.40 (m, 1 H), 7.36 - 7.16 (m, 6H), 7.02 (d, J=8.4 Hz, 1 H), 4.49 - 4.36 (m, 1 H), 4.09 - 3.92 (m, 5H), 3.78 (s, 3H), 3.28 - 2.92 (m, 4H), 2.70 - 2.50 (m, 2H), 1 .89 (br d, J=1 1 .7 Hz, 1 H), 1 .82 - 1 .44 (m, 7H), 1 .31 (t, J=6.9 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 491 .3.

Example 101: N-(2-(4-(3-(3-cyano-4-ethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of 3-bromo-4-ethoxybenz

To a stirred solution of 3-bromo-4-hydroxybenzonitrile (1 .0 g, 5.05 mmol) in N,N- dimethylformamide (10 mL) was added iodoethane (945 mg, 6.06 mmol, 484 μΙ_) and potassium carbonate (1 .40 g, 10.1 mmol) at 0 °C. The reaction was warmed at 40 °C for 16 h. The reaction mixture was quenched by addition of water (15 mL), then the mixture was extracted with ethyl acetate (40 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-bromo-4- ethoxybenzonitrile (1 .20 g) as a yellow solid. Ή NMR (400 MHz, CDC ) δ 7.80 (d, J=2.0 Hz, 1 H), 7.55 (dd, J=2.0, 8.6 Hz, 1 H), 6.89 (d, J=8.6 Hz, 1 H), 4.14 (q, J=7.0 Hz, 2H), 1 .49 (t, J=6.9 Hz, 3H).

Step 2: Preparation of (Z)-3-bromo-4-ethoxy-N'-hydroxybenzimidamide.

To a stirred solution of 3-bromo-4-ethoxybenzonitrile (1 .15 g, 5.09 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (706 mg, 10.2 mmol), triethylamine (1 .03 g, 10.2 mmol, 1 .41 mL) and water (1 mL). The mixture was heated at 80 °C for 1 h, then cooled and concentrated under reduced pressure to remove ethanol. The residue was triturated with water (5 mL) and filtered, and the filter cake was dried under reduced pressure to give (Z)-3-bromo-4-ethoxy-N'-hydroxybenzimidamide (1 .31 g, 5.06 mmol, 99 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.55 (br s, 1 H), 7.82 (d, J=2.2 Hz, 1 H), 7.60 (dd, J=2.2, 8.6 Hz, 1 H), 7.05 (d, J=8.8 Hz, 1 H), 5.79 (s, 2H), 4.12 - 4.05 (m, 2H), 1 .31 (t, J=7.1 Hz, 3H).

Step 3: Preparation of (Z)-3-cyano-4-ethoxy- '-hydroxybenzimidamide.

To a stirred solution of zinc cyanide (226 mg, 1 .93 mmol, 122 μί) in N,N-dimethylformamide (10 mL) was added (Z)-3-bromo-4-ethoxy-N'-hydroxybenzimidamide (500 mg, 1 .93 mmol) and

tetrakis(triphenylphosphine)palladium(0) (222 mg, 193 μιηοΙ), then the mixture was degassed with nitrogen three times. The mixture was heated at 1 10 °C for 16 h under nitrogen then cooled to 20 °C, water (10 mL) was added, and the reaction mixture extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 13%-43%,12 min) to give (Z)-3-cyano-4-ethoxy-N'-hydroxybenzimidamide (60 mg, 292 μιτιοΙ, 15 %) as a white solid.

Step 4: Preparation of N-(2-(4-(3-(3-cyano-4-ethoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (70 mg, 241 μιτιοΙ) in N,N-dimethylformamide (1 mL) was added (Z)-3-cyano-4-ethoxy-N'-hydroxybenzimidamide (49 mg, 241 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (91 mg, 241 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (93 mg, 723 μιηοΙ, 126 μί). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 40%-65%,12 min) to give N-(2-(4-(3-(3-cyano-4-ethoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2- oxoethyl)benzamide (20 mg, 43 μιτιοΙ, 18 %) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.55 (t, J=5.5 Hz, 1 H), 8.26 - 8.1 7 (m, 2H), 7.84 (dd, J=1 .2, 8.3 Hz, 2H), 7.57 - 7.34 (m, 4H), 4.26 (q, J=6.9 Hz, 3H), 4.14 (br d, J=5.5 Hz, 2H), 3.94 (br d, J=14.6 Hz, 1 H), 3.48 - 3.40 (m, 1 H), 3.29 - 3.22 (m, 1 H), 2.90 (br t, J=1 1 .4 Hz, 1 H), 2.10 (br t, J=12.8 Hz, 2H), 1 .87 - 1 .72 (m, 1 H), 1 .68 - 1 .55 (m, 1 H), 1 .37 (t, J=6.9 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 460.2.

Example 102: N-(2-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazin-1-yl)-2- oxoethyl)benzamide

Step 1: Preparation of 1 ,3-dimethyl- 1H-indazole-6-carbonitrile.

To a stirred solution of 6-bromo-1 ,3-dimethyl-1 H-indazole (1 .0 g, 4.44 mmol) in N,N- dimethylformamide (10 mL) was added zinc cyanide (521 mg, 4.44 mmol, 281 μΙ_) and

tetrakis(triphenylphosphine)palladium(0) (513 mg, 444 μιτιοΙ), then the mixture was degassed with nitrogen three times. The mixture was stirred at 100 for 16 h under nitrogen, then cooled to 20 °C, water (10 mL) added, and the reaction mixture extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50 : 1 to 10:1 ) to give 1 ,3-dimethyl-1 H-indazole- 6-carbonitrile (660 mg, 3.86 mmol, 87 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 7.74 - 7.66 (m, 2H), 7.30 (d, J=8.4 Hz, 1 H), 4.03 (s, 3H), 2.57 (s, 3H).

Step 2: Preparation of (Z)-N'-hydroxy- l ,3-dimethyl- 1H-indazole-6-carboximidamide.

To a stirred solution of 1 ,3-dimethyl-1 H-indazole-6-carbonitrile (660 mg, 3.86 mmol) in ethanol (8 mL) was added hydroxylamine hydrochloride (536 mg, 7.72 mmol), triethylamine (781 mg, 7.72 mmol, 1 .07 mL) and water (800 μί). The mixture was heated at 80 °C for 2 h, then cooled and concentrated under reduced pressure. The residue was triturated with water (5 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-6-carboximidamide (650 mg, 3.18 mmol, 82 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.72 (br. s., 1 H), 7.86 (s, 1 H), 7.65 (d, J=8.5 Hz, 1 H), 7.49 (dd, J=1 .1 , 8.5 Hz, 1 H), 5.91 (s, 2H), 3.97 (s, 3H), 2.47 (s, 3H).

Step 3: Preparation of 3-(1 ,3-dimethyl- 1 H-indazol-6-yl)- 1 ,2,4-oxadiazol-5(4H)-one.

To a stirred solution of (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-6-carboximidamide (510 mg, 2.50 mmol) in dioxane (8 mL) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (418 mg, 2.75 mmol, 414 μί) and 1 ,1 '-carbonyldiimidazole (608 mg, 3.75 mmol). The mixture was stirred at 1 10 °C for 16 h. The reaction mixture was cooled, quenched with water (1 0 mL), and then extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with 1 M hydrochloric acid (5 mL x 2), then washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5(4H)-one (430 mg, 1 .87 mmol, 75 %) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 13.29 - 12.78 (m, 1 H), 8.03 (s, 1 H), 7.87 (d, J=8.4 Hz, 1 H), 7.48 (dd, J=1 .1 , 8.4 Hz, 1 H), 3.98 (s, 3H), 2.48 (br s, 3H).

Step 4: Preparation of 5-chloro-3-(1 ,3-dimethyl- 1H-indazol-6-yl)- 1 ,2,4-oxadiazole.

A flask 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5(4H)-one (180 mg, 781 .86 μιτιοΙ) was equipped with calcium chloride tube then pyridine (123 mg, 1 .56 mmol, 126 μί) and phosphoryl chloride (5 mL) were added dropwise. The mixture was heated at 1 1 0 °C for 16 h, then cooled and concentrated under reduced pressure to remove phosphoryl chloride, and then added to ice water (20 mL). The mixture was extracted with dichloromethane (40 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 5-chloro-3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazole (250 mg) as a brown solid.

Step 5: Preparation of tert-butyl 4-(3-( 1 ,3-dimethyl- 1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperazine- 1- carboxylate.

To a stirred solution of 5-chloro-3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazole (230 mg, 925 μιτιοΙ) in N-methyl-2-pyrrolidone (3 mL) was added tert-butyl piperazine-1 -carboxylate (172 mg, 925 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (239 mg, 1 .85 mmol, 323 μΙ_). The mixture was heated at 120 °C for 2 h. The reaction mixture was cooled, quenched by addition of water (5 mL), then the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and

concentrated in vacuo. Purification by prep-TLC (silica, petroleum ether : ethyl acetate = 1 :1 ) gave tert- butyl 4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazine-1 -carboxylate (150 mg, 376 μιτιοΙ, 41 %) as a pink solid.

Step 6: Preparation of 3-( 1 ,3-dimethyl- 1H-indazol-6-yl)-5-(piperazin- 1-yl)- 1 ,2,4-oxadiazole.

To a stirred solution of tert-butyl 4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5- yl)piperazine-1 -carboxylate (150 mg, 376 μιηοΙ) in ethyl acetate (1 mL) was added hydrochloric acid / ethyl acetate (4M, 5 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was

concentrated under reduced pressure to give 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-5-(piperazin-1 -yl)-1 ,2,4- oxadiazole (1 10 mg, 369 μιτιοΙ, 98 %) as a pink solid. LCMS (ESI) m/z: [M+H] ⁺ = 299.2.

Step 7: Preparation of N-(2-(4-(3-(1 ,3-dimethyl- 1 H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperazin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-5-(piperazin-1 -yl)-1 ,2,4-oxadiazole (50 mg, 168 μιηοΙ) in N,N-dimethylformamide (1 mL) was added 2-benzamidoacetic acid (30 mg, 168 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (63 mg, 168 μιηοΙ) and N- ethyl-N-(propan-2-yl)propan-2-amine (64 mg, 503 μιηοΙ, 87 μί). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give N-(2-(4- (3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazin-1 -yl)-2-oxoethyl)benzamide (29 mg, 64 μιτιοΙ, 38 %) as a white solid. Ή NMR (400 MHz, CDC ) δ 8.00 (s, 1 H), 7.84 (d, J=7.7 Hz, 2H), 7.76 - 7.66 (m, 2H), 7.55 - 7.41 (m, 3H), 7.27 - 7.25 (m, 1 H), 4.33 (d, J=3.7 Hz, 2H), 4.05 (s, 3H), 3.89 - 3.75 (m, 6H), 3.66 (br d, J=5.1 Hz, 2H), 2.57 (s, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 460.3.

Example 103: (4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazin-1-yl)(3- phenylisoxazol-5-yl)methanone.

To a stirred solution of 3-(1 ,3-dimethyl-1 H-indazol-6-yl)-5-(piperazin-1 -yl)-1 ,2,4-oxadiazole (50 mg, 168 μιηοΙ) in N,N-dimethylformamide (1 mL) was added 3-phenylisoxazole-5-carboxylic acid (31 mg, 168 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (63 mg, 168 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (64 mg, 502.8 μιηοΙ, 87 μΙ_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μπΊ ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-75%,12 min) to give (4- (3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperazin-1 -yl)(3-phenylisoxazol-5-yl)methanone (26 mg, 56.9 μιτιοΙ, 34 %) as a white solid. Ή NMR (400MHz, CDC ) δ 8.01 (s, 1 H), 7.83 (td, J=2.8, 4.1 Hz, 2H), 7.76 - 7.73 (m, 1 H), 7.71 - 7.67 (m, 1 H), 7.51 - 7.47 (m, 3H), 7.18 (s, 1 H), 4.05 (s, 3H), 4.03 - 3.93 (m, 4H), 3.89 - 3,84 (m, 4H), 2,57 (s, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 470.3.

Example 104: N-(2-(4-(3-(benzo[c][1 ,2,5]thiadiazol-5-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of benzo[c][1 ,2,5]thiadiazole-5-carbonitrile. To a stirred solution of 5-bromobenzo[c][1 ,2,5]thiadiazole (200 mg, 930 μιηοΙ) in N,N- dimethylformamide (2 mL) was added zinc cyanide (109 mg, 930 μιηοΙ, 59 μΙ_) and

tetrakis(triphenylphosphine)palladium(0) (107 mg, 93 μmol), the mixture was degassed with nitrogen three times. The mixture was heated at 1 10 °C for 1 6 h under nitrogen. After cooling to 20 °C, water (5 mL) was added to the reaction, and the mixture extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product. The mixture was triturated with petroleum ether (20 mL) and dichloromethane (2 mL), then the mixture was filtered, and the filter cake dried in vacuo to give benzo[c][1 ,2,5]thiadiazole-5-carbonitrile (100 mg, 620 μιηοΙ, 67 %) as a red solid. LCMS (ESI) m/z: [M+H] ⁺ = 162.0.

Step 2: Preparation of (Z)-N'-hydroxybenzo[c][1,2,5]thiadiazole-5-carboxi idarnide.

To a stirred solution of benzo[c][1 ,2,5]thiadiazole-5-carbonitrile (100 mg, 620 μιηοΙ) in ethanol (2 mL) was added hydroxylamine hydrochloride (86 mg, 1 .24 mmol), triethylamine (125 mg, 1 .24 mmol, 172A.) and water (200 μί). The mixture was heated at 80 °C for 1 h. The reaction mixture was cooled and then concentrated under reduced pressure to remove ethanol. The residue was triturated with water (5 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-N'- hydroxybenzo[c][1 ,2,5]thiadiazole-5-carboximidamide (70 mg, 360 μιηοΙ, 58 %) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1 H), 8.35 (d, J=0.9 Hz, 1 H), 8.10 (dd, J=1 .5, 9.3 Hz, 1 H), 8.01 - 7.96 (m, 1 H), 6.08 (s, 2H).

Step 3: Preparation of N-(2-(4-(3-(benzo[c][ 1 ,2,5]thiadiazol-5-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (80 mg, 276 μιηοΙ) in

N,N-dimethylformamide (2 mL) was added (Z)-N'-hydroxybenzo[c][1 ,2,5]thiadiazole-5-carboximidamide

(53 mg, 276 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (104 mg,

276 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (106 mg, 827 μιτιοΙ, 144 μί). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 for 1 h. The reaction mixture was purified directly by prep-

HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 45%-65%,12 min) to give N-(2-(4-(3-(benzo[c][1 ,2,5]thiadiazol-5-yl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (30 mg, 67 μιτιοΙ, 24 %) as a brown solid. ¹ H NMR (400 MHz,

DMSO-d6) δ 8.66 (t, J=1 .2 Hz, 1 H), 8.55 (t, J=5.7 Hz, 1 H), 8.28 - 8.22 (m, 2H), 7.87 - 7.83 (m, 2H), 7.54 - 7.42 (m, 3H), 4.31 (br d, J=13.0 Hz, 1 H), 4.16 (dd, J=1 .5, 5.7 Hz, 2H), 3.98 (br d, J=13.5 Hz, 1 H), 3.54 - 3.51 (m, 1 H), 3.29 (br t, J=1 1 .5 Hz, 1 H), 2.93 (br t, J=1 1 .2 Hz, 1 H), 2.16 (br t, J=13.2 Hz, 2H), 1 .90 - 1 .78 (m, 1 H), 1 .73 - 1 .62 (m, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 449.2.

Example 105: N-(2-(4-(3-(1,4-dimethylphthalazin-6-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 2-benzamidoacetic acid (5.0 g, 27.9 mmol) in N,N-dimethylformamide (50 mL) was added methyl piperidine-4-carboxylate (4.40 g, 30.7 mmol), 1 -[bis(dimethylamino)methylene]- 1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1 0.6 g, 27.9 mmol) and N-ethyl-N- (propan-2-yl)propan-2-amine (10.8 g, 83.7 mmol, 14.6 mL). The mixture was stirred at 20 °C for 2 h, then quenched by addition of water (50 mL). The mixture was extracted with ethyl acetate (100 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 5:1 to 1 :1 ) to give methyl 1 -(2- benzamidoacetyl)piperidine-4-carboxylate (9.17 g) as a yellow solid. ¹ H NMR (400 MHz, Methanol-d4) δ 7.88 - 7.83 (m, 2H), 7.55 - 7.49 (m, 1 H), 7.48 - 7.41 (m, 2H), 4.35 - 4.28 (m, 1 H), 4.24 (d, J=5.3 Hz, 2H), 3.88 (d, J=14.1 Hz, 1 H), 3.66 (s, 3H), 3.20 (d, J=2.2 Hz, 1 H), 2.92 - 2.84 (m, 1 H), 2.65 (tt, J=4.0, 10.8 Hz, 1 H), 1 .99 - 1 .87 (m, 2H), 1 .74 - 1 .64 (m, 1 H), 1 .62 - 1 .51 (m, 1 H).

Step 2: Preparation of 1-(2-benzamidoacetyl)piperidine-4-carboxylic acid.

To a stirred solution of methyl 1 -(2-benzamidoacetyl)piperidine-4-carboxylate (9.1 7 g, 30.1 mmol) tetrahydrofuran (90 mL) was added sodium hydroxide (2 M, 30.1 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure then acidified with concentrated hydrochloric acid until pH 1 . The mixture was extracted with dichloromethane (80 mL x 4). The organic phases were combined and then washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue (8.85 g). A portion of crude product (2.5 g) was purified by prep-HPLC (column: Daiso 250 ^* 50mm, ^" Ι Ομιη; mobile phase: [water (0.1 %TFA)-acetonitrile]; B%: 1 %-30%, 20 min) to provide 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (0.95 g). The remaining crude product was used directly without purification. ¹ H NMR (400 MHz, Methanol-d4) δ 7.87 - 7.83 (m, 2H), 7.55 - 7.50 (m, 1 H), 7.48 - 7.42 (m, 2H), 4.36 (td, J=3.2, 13.2 Hz, 1 H), 4.25 (d, J=3.3 Hz, 2H), 3.94 - 3.86 (m, 1 H), 3.22 - 3.14 (m, 1 H), 2.89 - 2.80 (m, 1 H), 2.46 (tt, J=3.9, 1 1 .0 Hz, 1 H), 2.00 - 1 .87 (m, 2H), 1 .74 - 1 .52 (m, 2H).

Step 3: Preparation of 2-acetyl-4-chlorophenyl trifluoromethanesulfonate.

Triflic anhydride (9.92 g, 35.2 mmol, 5.80 mL) was added dropwise at 0° C to a stirred solution of 1 -(5-chloro-2-hydroxy-phenyl)ethanone (5.0 g, 29.3 mmol) in pyridine (50 mL) The reaction was warmed slowly to 15 °C and stirred for 15 h. The reaction solution was diluted with dichloromethane (100 mL), then poured into 1 N aqueous hydrochloric acid (100 mL) at 0 °C and the phases separated. The organic phase was washed with 1 N hydrochloric acid (50 mL x 2), saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification by chromatography (silica, petroleum ether : ethyl acetate from 100/1 to 30/1 ) gave 2-acetyl- 4-chlorophenyl trifluoromethanesulfonate (7.50 g, 24.8 mmol, 85 %) as a yellow liquid.

Step 4: Preparation of 1, 1 '-(4-chloro- 1,2-phenylene)diethanone.

To a stirred solution of 2-acetyl-4-chlorophenyl trifluoromethanesulfonate (3.0 g, 9.91 mmol) in

N,N-dimethylformamide (30 mL) was added 1 -vinyloxybutane (4.96 g, 49.6 mmol, 6.36 mL), palladium(ll) acetate(1 1 1 mg, 495.5 μιηοΙ), 3-diphenylphosphanylpropyl(diphenyl)phosphane (245 mg, 594.6 μιηοΙ) and TEA (1 .20 g, 1 1 .9 mmol, 1 .65 mL), then the mixture was degassed with nitrogen three times. The mixture was heated at 80 °C for 16 h under nitrogen. After cooling to 20 °C, 2M hydrochloric acid (20 mL) was added and the solution stirred at 20 °C for 2 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and

concentrated in vacuo to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50 : 1 to 10:1 ) to give 1 ,1 '-(4-chloro-1 ,2-phenylene)diethanone (800 mg, 4.07 mmol, 41 %) as a red oil. ¹ H NMR (400 MHz, CDC ) δ 7.58 - 7.54 (m, 1 H), 7.51 - 7.47 (m, 1 H), 7.43 (t, J=1 .9 Hz, 1 H), 2.52 (d, J=2.0 Hz, 3H), 2.50 (d, J=2.0 Hz, 3H). Step 5: Preparation of 6-chloro- 1,4-dimethy

1 ,1 '-(4-chloro-1 ,2-phenylene)diethanone (800 mg, 4.07 mmol) in ethanol (15 mL) was added to hydrazine hydrate (224 mg, 4.48 mmol, 217 μί) in ethanol (15 mL) at 0 °C over a period of 5 min under argon. The mixture was stirred at 20 °C for 18 h. The reaction mixture was concentrated under reduced pressure to -15 mL, then extracted with dichloromethane (50 mL x 3). The combined organic phases were washed water (20 mL x 2), then the separated organic layer was washed saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 6-chloro- 1 ,4-dimethylphthalazine (662 mg, 3.44 mmol, 84 %) as a red solid. ¹ H NMR (400 MHz, CDCb) δ 7.98 - 7.93 (m, 2H), 7.75 (dd, J=2.1 , 8.8 Hz, 1 H), 2.88 (d, J=5.1 Hz, 6H).

Step 6: Preparation of 1,4-dimethylphthalazine-6-carbonitrile.

To a stirred solution of 6-chloro-1 ,4-dimethylphthalazine (640 mg, 3.32 mmol) in N,N- dimethylformamide (10 mL) was added zinc cyanide (390 mg, 3.32 mmol, 210 μί) and

tetrakis(triphenylphosphine)palladium(0) (383 mg, 332 μιτιοΙ) under nitrogen. The mixture was heated at 1 10 °C for 16 h, then cooled to 20 °C. Water (15 mL) was added then the reaction mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product. Trituration with petroleum ether (30 mL) and dichloromethane (5 mL) followed by filtration and drying the filter cake in vacuo gave 1 ,4-dimethylphthalazine-6-carbonitrile (400 mg, 2.18 mmol, 66 %) as a brown solid. Ή NMR (400 MHz, CDCb) δ 8.47 (s, 1 H), 8.21 (d, J=8.5 Hz, 1 H), 8.09 (dd, J=1 .4, 8.5 Hz, 1 H), 3.04 (s, 6H).

Step 7: Preparation of (Z)-N'-hydroxy- l ,4-dimethylphthalazine-6-carboximidamide.

To a stirred solution of 1 ,4-dimethylphthalazine-6-carbonitrile (380 mg, 2.07 mmol) in ethanol (1 mL) was added hydroxylamine hydrochloride (288 mg, 4.15 mmol), triethylamine (419 mg, 4.15 mmol, 575 μί) and water (100 μί). The mixture was heated at 80 °C for 1 h. The reaction mixture was cooled then concentrated under reduced pressure. The residue was triturated with water (5 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-l ,4-dimethylphthalazine-6- carboximidamide (330 mg, 1 .53 mmol, 74 %) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 1 0.06 (s, 1 H), 8.38 (d, J=1 .3 Hz, 1 H), 8.28 (dd, J=1 .7, 8.7 Hz, 1 H), 8.12 (d, J=8.8 Hz, 1 H), 6.19 (s, 2H), 2.85 (d, J=17.0 Hz, 6H).

Step 8: Preparation of N-(2-(4-(3-( 1 ,4-dimethylphthalazin-6-yl)- 1 ,2,4-oxadiazol-5-yl)piperidin

oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (100 mg, 344 μιτιοΙ) in N,N-dimethylformamide (2 mL) was added N'-hydroxy-1 ,4-dimethyl-phthalazine-6-carboxamidine (74 mg, 344 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (130 mg, 344 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (133 mg, 1 .03 mmol, 180 μί). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 for 1 h. The reaction mixture was cooled, then purified by prep- HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 25%-55%,12 min) to give N-(2-(4-(3-(1 ,4-dimethylphthalazin-6-yl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (37 mg, 77 μιτιοΙ, 22 %) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=1 .5 Hz, 1 H), 8.59 (t, J=5.6 Hz, 1 H), 8.54 (dd, J=1 .5, 8.6 Hz, 1 H), 8.39 (d, J=8.6 Hz, 1 H), 7.90 - 7.86 (m, 2H), 7.57 - 7.45 (m, 3H), 4.37 (br d, J=13.2 Hz, 1 H), 4.25 - 4.13 (m, 2H), 4.02 (br d, J=13.5 Hz, 1 H), 3.55 (tt, J=3.8, 1 1 .1 Hz, 1 H), 3.32 - 3.27 (m, 1 H), 2.96 (s, 3H), 2.98 - 2.91 (m, 1 H), 2.93 (s, 3H), 2.20 (br t, J=13.7 Hz, 2H), 1 .95 - 1 .82 (m, 1 H), 1 .77 - 1 .65 (m, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 471 .3.

Example 106: 2-(2-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)p iperidin-1-yl)-2^ oxoethyl)isoindolin-1 -one.

Step 1: Preparation of 2-(2-(4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)isoindolin- 1 -one.

To a stirred solution of 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (50 mg, 165 μιηοΙ) in N,N-dimethylformamide (1 mL) was added 2-(1 -oxoisoindolin-2-yl)acetic acid (31 mg, 165 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (62 mg, 165 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (63 mg, 494 μιτιοΙ, 86 μί). The mixture was stirred at 20 °C for 1 h, then the reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12 min) to give 2- (2-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)isoindolin-1 -one (41 mg, 86 μιτιοΙ, 52 %) as a gray solid. ¹ H NMR (400MHz, CDC ) δ 7.88 (d, J=8.2 Hz, 1 H), 7.66 (dd, J=1 .9, 8.3 Hz, 1 H), 7.59 - 7.54 (m, 2H), 7.48 (t, J=6.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 1 H), 4.59 (d, J=3.4 Hz, 2H), 4.53 - 4.40 (m, 3H), 4.18 (q, J=7.0 Hz, 2H), 4.08 (br d, J=13.7 Hz, 1 H), 3.96 (s, 3H), 3.43 - 3.24 (m, 2H), 3.1 1 - 3.02 (m, 1 H), 2.28 - 2.15 (m, 2H), 2.05 - 1 .90 (m, 2H), 1 .51 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 477.3.

Example 107: N-[2-[4-[3-(5-ethoxy-6-methoxy-2^yridyl)-1,2,4-oxadiazol-5-y l]-1^iperM^

ethyljbenzamide.

A mixture of 2-bromopyridin-3-ol (5.0 g, 28.7 mmol), iodine (8.02 g, 31 .6 mmol, 6.37 mL), and potassium carbonate (7.94 g, 57.5 mmol) in water (66 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 20 °C for 1 6 h under a nitrogen atmosphere. Excess iodine was quenched by addition of solid sodium bisulfite. The pH of the solution was adjusted to 5-6 using glacial acetic acid, and the solid formed was collected by filtration and dried in vacuum to give 2-bromo-6-iodo- pyridin-3-ol (10.0 g) that was used directly without further purification. Step 2: 2-bromo-3-ethoxy-6-iodo-pyridine.

To a stirred solution of 2-bromo-6-iodo-pyridin-3-ol (10.0 g, 33.4 mmol) in tetrahydrofuran (200 mL) was added potassium carbonate (6.91 g, 50.0 mmol) and the mixture was stirred for 10 min at 0 in an ice bath, lodoethane (6.24 g, 40.0 mmol, 3.20 mL) was added dropwise, then the reaction mixture was warmed to 40 °C. After 16 h, the reaction mixture was quenched by addition of water (10 mL), and then extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-bromo-3-ethoxy-6-iodo-pyridine (7.50 g, 22.9 mmol, 69 %) that was used directly without further purification.

Step 3: 3-ethoxy-6-iodo-2-methoxy-pyridine.

A mixture of 2-bromo-3-ethoxy-6-iodo-pyridine (7.0 g, 21 .4 mmol) and sodium methoxide (1 .73 g, 32.0 mmol) in N,N-dimethylformamide (3 mL) was degassed and purged with nitrogen 3 times, and then the mixture was heated at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was quenched by addition of water (20 mL), then extracted with ethyl acetate (20 mL x 3). The organic layer phases were combined and then washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-ethoxy-6- iodo-2-methoxy-pyridine (5.0 g, 17.9 mmol). This was used directly without further purification.

Step 4: 5-ethoxy-6-methoxy-pyridine-2-ca

A mixture of 3-ethoxy-6-iodo-2-methoxy-pyridine (2.50 g, 8.96 mmol) and coper(l) cyanide (962 mg, 10.75 mmol, 2.35 mL) in N,N-dimethylformamide (10 mL) was degassed and purged with nitrogen 3 times, and then the mixture was heated at 100 for 1 6 h under a nitrogen atmosphere. The reaction mixture was quenched by addition of water (20 mL), then extracted with ethyl acetate (20 mL x 3). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-ethoxy-6- methoxy-pyridine-2-carbonitrile (1 .40 g). This was used directly without further purification.

Step 5: 5-ethoxy-6-methoxy-pyridine-2-

A mixture of 5-ethoxy-6-methoxy-pyridine-2-carbonitrile (1 .0 g, 5.61 mmol), hydroxylamine hydrochloride (857 mg, 12.34 mmol) and triethylamine (1 .25 g, 12.34 mmol, 1 .71 mL) in ethanol (10 mL) was heated at 75 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled, diluted with water (10 mL), and filtered. The filter cake was dried in vacuo to give 5-ethoxy-N'-hydroxy-6-methoxy- pyridine-2-carboxamidine (950 mg, 4.50 mmol, 80 %) as a yellow solid. ¹ H NMR (400MHz,

CHLOROFORM-d) δ = 7.40 (d, J=8.2 Hz, 1 H), 6.99 (d, J=8.2 Hz, 1 H), 5.45 (br s, 2H), 4.05 (q, J=6.9 Hz, 2H), 3.98 (s, 3H), 1 .41 (t, J=7.0 Hz, 3H). Step 6: N-[2-[4-[3-(5-ethoxy-6-methoxy-2-pyridyl)- 1,2,4-oxadiazol-5-yl]- 1-piperidyl]-2- ethyl enzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (100 mg, 344 μιτιοΙ) in N,N-dimethylformamide (2 mL) was added 5-ethoxy-N'-hydroxy-6-methoxy-pyridine-2-carboxamidine (72 mg, 344 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (156 mg, 413 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (133 mg, 1 .03 mmol, 180 μί). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 for 1 h. The crude product was purified by prep-HPLC (column: Waters Xbridge 150x25 5μιη; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%- 60%, 12 min) to give N-[2-[4-[3-(5-ethoxy-6-methoxy-2-pyridyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo- ethyl]benzamide (37 mg, 79.9 μιτιοΙ, 23 %) as a yellow solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.91 - 7.85 (m, 2H), 7.70 (d, J=8.0 Hz, 1 H), 7.57 - 7.52 (m, 1 H), 7.51 - 7.44 (m, 2H), 7.36 (br s, 1 H), 7.13 (d, J=8.2 Hz, 1 H), 4.57 - 4.48 (m, 1 H), 4.32 (d, J=3.9 Hz, 2H), 4.23 - 4.12 (m, 5H), 4.06 - 3.90 (m, 1 H), 3.42 - 3.32 (m, 2H), 3.20 - 3.1 1 (m, 1 H), 2.32 - 2.20 (m, 2H), 2.08 - 1 .95 (m, 2H), 1 .54 (t, J=7.0 Hz, 3H); LCMS(ESI) m/z: [M+H] ⁺ = 466.3.

Example 108: 4-[4-[3-(5-ethoxy-6-methoxy-2^yridyl)-1,2,4-oxadiazol-5-yl]p iperirt

phenyl-pyrrolidin-2-one.

Step 1: 4-[4-[3-(5-ethoxy-6-methoxy-2-pyridyl)- 1,2,4-oxadiazol-5-yl]piperidine- 1-carbonyl]- 1-phenyl- pyrrolidin-2-one.

To a stirred solution of 5-ethoxy-N'-hydroxy-6-methoxy-pyridine-2-carboxamidine (66 mg, 316 μιτιοΙ) in N,N-dimethylformamide (2 mL) was added 1 -(5-oxo-1 -phenyl-pyrrolidine-3-carbonyl)piperidine-4- carboxylic acid (100 mg, 316 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium

hexafluorophosphate) (143 mg, 379 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (122 mg, 948 μιηοΙ, 165 μί). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The mixture was cooled and the crude product was purified by prep-HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-70%,12 min) to give 4-[4-[3-(5- ethoxy-6-methoxy-2-pyridyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]-1 -phenyl-pyrrolidin-2-one (47 mg, 96 μιτιοΙ, 3 %) as a yellow solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.71 (dd, J=4.6, 8.0 Hz, 1 H), 7.62 (dd, J=1 .1 , 8.7 Hz, 2H), 7.43 - 7.38 (m, 2H), 7.22 - 7.17 (m, 1 H), 7.13 (d, J=7.8 Hz, 1 H), 4.63 - 4.48 (m, 1 H), 4.34 (t, J=7.9 Hz, 1 H), 4.22 - 4.15 (m, 5H), 4.03 - 3.93 (m, 2H), 3.60 (m, 1 H), 3.46 - 3.33 (m, 2H), 3.15 - 2.95 (m, 2H), 2.91 - 2.82 (m, 1 H), 2.27 (m, 2H), 2.08 - 1 .94 (m, 2H), 1 .54 (t, J=7.0 Hz, 3H);

LCMS(ESI) m/z: [M+H] ⁺ = 492.3.

Example 109: N-[2-[4-[3-(2,2-difluoro-1,3-benzodioxol-5-yl)-1,2,4-oxadiaz o

ethyljbenzamide

Step 1: 2,2-difluoro- 1,3-benzodioxole-5-

A mixture of 5-bromo-2,2-difluoro-1 ,3-benzodioxole (500 mg, 2.1 1 mmol), zinc cyanide (247 mg, 2.1 1 mmol, 133 μΙ_) and tetrakis(triphenylphosphine)palladium(0) (243 mg, 21 1 μιτιοΙ) in N,N- dimethylformamide (4 mL) was degassed and purged with nitrogen 3 times, and then the mixture was heated at 100 for 16 h under a nitrogen atmosphere. The reaction mixture was cooled, diluted with water (5 mL), and extracted with ethyl acetate (10 mL x 2 ). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2,2-difluoro-1 ,3-benzodioxole-5-carbonitrile (300 mg,

1 .64 mmol, 78 %) as a solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.38 (dd, J=1 .5, 8.3 Hz, 1 H), 7.27 (d, J=1 .5 Hz, 1 H), 7.08 (d, J=8.3 Hz, 1 H).

Step 2: 2,2-difluoro-N'-hydroxy- 1,3-b .

A mixture of 2,2-difluoro-1 ,3-benzodioxole-5-carbonitrile (300 mg, 1 .64 mmol), triethylamine (331 mg, 3.28 mmol, 454 μΙ_) and hydroxylamine hydrochloride (227 mg, 3.28 mmol) in water (500 μΙ_) and ethanol (5 mL) was heated at 70 for 1 6 h. The reaction mixture was cooled, diluted with water (1 0 mL) and filtered. The collected solid was dried in vacuo to give 2,2-difluoro-N'-hydroxy-1 ,3-benzodioxole-5- carboxamidine (21 0 mg) as a solid.

Step 3: N-[2-[4-[3-(2,2-difluoro- 1 ,3-benzodioxol-5-yl)- 1,2,4-oxadazo\-5-y\]-1-pperdy\]-2-oxo- ethyl enzamide,

A mixture of 2,2-difiuoro-N'-hydroxy-1 ,3-benzodioxole-5-carboxamidine (74 mg, 344 μιτιοΙ), 1 -(2- benzamidoacetyl)piperidine-4-carboxylic acid (1 00 mg, 344 μιηοΙ), N-ethyl-N-(propan-2-yl)propan-2- amine (133 mg, 1 .03 mmol, 1 80 μί) and (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3 ₁ 3-tetramethyluronium

hexafluorophosphate) (1 56 mg, 413 μιηοΙ) In Ν,Ν-dimethylformamide (2 mL) was stirred at 20 °C for 1 h under a nitrogen atmosphere. The mixture was heated at 1 20 °C for 1 h, then cooled and purified by prep- HPLC (column : Waters Xbridge 150x25 5μιη ; mobile phase: [water (1 0m ammonium carbonate)- acetonitrilej; B%: 4Q%-70%,12 min) to give N-[2-[4-[3-(2,2-difluoro-1 ,3-benzodioxol-5-yl)-1 ,2,4-oxadiazol- 5-y!]-1 -piperidyi]-2-oxo-ethyi]benzam!de (58 mg, 124 μηιοΙ, 36 %) as a white solid. Ή NMR (400MHz, CHLOROFORM-d) δ = 7.85 - 7.76 (m , 3H), 7.72 (d, J=1 .5 Hz, 1 H), 7.48 - 7.42 (m , 1 H), 7.41 - 7.35 (m, 2H), 7.26 (br s, 1 H), 7.1 0 (d, J=8.4 Hz, 1 H), 4.53 - 4.37 (m, 1 H), 4.23 (d, J=4.0 Hz, 2H), 3.84 (br d, J=1 3.9 Hz, 1 H), 3.35 - 3.21 (m , 2H), 3.12 - 3.02 (m , 1 H), 2.26 - 2.1 0 (m, 2H), 1 .98 - 1 .85 (m , 2H) ; LC S (ES!) m/z: [M+H] ⁺ :471 .2.

Example 110: N-(2-(4-(3-(4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl^

yl)piperidin-1-yl)-2-oxoethyl)benzamide.

Step 1: Preparation of 7-bromo-4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a stirred solution of 7-bromo-4-ethyl-2H-benzo[b][1 ,4]oxazin-3(4H)-one (900 mg, 3.51 mmol) in tetrahydrofuran (1 0 mL) was added a solution of borane in tetrahydrofuran (1 M, 12.28 mL), and the mixture was stirred 20 °C for 1 h, then heated at 80 °C for 2 h. The reaction mixture was cooled then quenched by addition of methanol (15 mL). The mixture was concentrated under reduced pressure, then diluted with water (20 mL), extracted with ethyl acetate (60 mL x 2), and the combined organic phases washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 7-bromo-4-ethyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazine (750 mg, 3.10 mmol, 88 %) as a yellow oil. Ή NMR (400 MHz, CDC ) δ 6.86 - 6.80 (m, 2H), 6.45 (d, J=8.3 Hz, 1 H), 4.19 - 4.13 (m, 2H), 3.28 - 3.18 (m, 4H), 1 .06 (t, J=7.1 Hz, 3H).

Step 2: Preparation of 4-ethyl-3,4-dihydro ,4]oxazine-7-carbonitrile.

To a stirred solution of 7-bromo-4-ethyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazine (80 mg, 330 μιηοΙ) in N,N-dimethylformamide (1 mL) was added zinc cyanide (38 mg, 330 μιηοΙ) and

tetrakis(triphenylphosphine)palladium(0) (38 mg, 33 μιηοΙ), then the mixture was degassed with nitrogen three times. The mixture was heated at 1 10 °C for 1 6 h under nitrogen, then cooled to 20 °C, and water (3 mL) added. The reaction mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give a crude residue that was purified by prep- TLC (petroleum ether : ethyl acetate=2:1 ) to give 4-ethyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-7- carbonitrile (60 mg, 319 μιτιοΙ, 96 %) as a brown solid. ¹ H NMR (400 MHz, CDCb) δ 7.1 0 (td, J=1 .4, 8.5 Hz, 1 H), 7.00 - 6.92 (m, 1 H), 6.59 (d, J=8.4 Hz, 1 H), 4.20 (dt, J=0.9, 4.5 Hz, 2H), 3.42 - 3.33 (m, 4H), 1 .16 (dt, J=0.9, 7.2 Hz, 3H).

Step 3: Preparation of (Z)-4-ethyl^'-hydroxy-3 -dihydro-2H-benzo[b][1,4]oxazine-7-carboximidamide.

To a stirred solution of 4-ethyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-7-carbonitrile (60 mg, 319 μιτιοΙ) in ethanol (1 mL) was added hydroxylamine hydrochloride (44 mg, 638 μιηοΙ), triethylamine (64 mg, 638 μιηοΙ, 88 μί) and water (100 μί). The mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled, concentrated under reduced pressure, and then diluted with water (5 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude (Z)-4-ethyl-N'-hydroxy-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-7- carboximidamide (60 mg, 271 μιτιοΙ, 85 %) as a white solid.

Step 4: Preparation of N-(2-(4-(3-(4-ethyl-3,4-dihydro-2H-benzo[b][ 1 ,4]oxazin-7-yl)- 1 ,2,4-oxadiazol-5- yl)piperidin- 1-yl)-2-oxoethyl)be

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (60 mg, 207 μιτιοΙ) in N,N-dimethylformamide (1 mL) was added (Z)-4-ethyl-N'-hydroxy-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-7- carboximidamide (45 mg, 207 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium

hexafluorophosphate) (78 mg, 207 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (80 mg, 620 μιηοΙ, 108 μί). The mixture was stirred at 20 °C for 1 h, then heated at 1 1 0 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Luna C1 8 1 50x2.5mm 5μιη; mobile phase: [water (0.225% TFA)- acetonitrile]; B%: 40%-65%,16 min) to give N-(2-(4-(3-(4-ethyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-7-yl)- 1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (17 mg, 35.8 μιηοΙ, 17 %) as a brown solid. ¹ H NMR (400 MHz, CDC ) δ 7.89 - 7.84 (m, 2H), 7.58 - 7.43 (m, 5H), 7.35 (br s, 1 H), 6.72 (d, J=8.5 Hz, 1 H), 4.45 (br d, J=13.8 Hz, 1 H), 4.33 - 4.24 (m, 4H), 3.89 (br d, J=14.1 Hz, 1 H), 3.45 - 3.25 (m, 6H), 3.18 (br t, J=10.4 Hz, 1 H), 2.28 - 2.18 (m, 2H), 2.07 - 1 .92 (m, 2H), 1 .20 (t, J=7.2 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 476.3. Example 111: N-(2-(4-(3-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin -7-yl)-^

yl)piperidin-1-yl)-2-oxoethyl)benzamide.

Step 1: Preparation of 7-bromo-4-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one.

To a stirred solution of 7-bromo-4H-1 ,4-benzoxazin-3-one (2.0 g, 8.77 mmol) in N,N- dimethylformamide (20 mL) was added iodoethane (1 .64 g, 10.52 mmol, 841 μί) and potassium carbonate (3.64 g, 26.3 mmol) at 0 °C. The reaction was warmed at 40 °C for 2 h. The reaction mixture was cooled then quenched by addition of water (30 mL), and then the mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 7-bromo-4-ethyl- 2H-benzo[b][1 ,4]oxazin-3(4H)-one (2.06 g, 8.04 mmol, 92 %) as a yellow solid. ¹ H NMR (400 MHz, CDCb) 5 7.1 1 - 7.05 (m, 2H), 6.78 (d, J=8.9 Hz, 1 H), 4.52 (s, 2H), 3.89 (q, J=7.2 Hz, 2H), 1 .20 (t, J=7.2 Hz, 3H).

Step 2: Preparation of 4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonit rile.

To a stirred solution of 7-bromo-4-ethyl-2H-benzo[b][1 ,4]oxazin-3(4H)-one (800 mg, 3.12 mmol) in N,N-dimethylformamide (10 mL) was added copper(l) cyanide (559 mg, 6.25 mmol, 1 .36 mL) and tetrakis(triphenylphosphine)palladium(0) (360 mg, 312 μιτιοΙ). The mixture was degassed with nitrogen, then heated at 1 10 °C for 1 6 h under nitrogen. The reaction mixture was cooled to 20 °C, then water (1 5 mL) was added and the reaction mixture extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filetered and concentrated in vacuo to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :0 to 5:1 ) to give 4-ethyl-3-oxo-3,4-dihydro-2H- benzo[b][1 ,4]oxazine-7-carbonitrile (70 mg, 346 μιτιοΙ, 1 1 %) as a white solid. ¹ H NMR (400 MHz, CDCb) δ 7.38 (dd, J=1 .9, 8.4 Hz, 1 H), 7.30 - 7.29 (m, 1 H), 7.08 (d, J=8.3 Hz, 1 H), 4.68 (s, 2H), 4.04 (q, J=7.2 Hz, 2H), 1 .32 (t, J=7.2 Hz, 3H). Step 3: Preparation of (Z)-4-ethyl-N'-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxa zine-7- carboximidamide.

To a stirred solution of 4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazine-7-carbonitrile (70 mg, 346 μιηοΙ) in ethanol (1 mL) was added hydroxylamine hydrochloride (48 mg, 692 μιτιοΙ), triethylamine (70 mg, 692 μιτιοΙ, 95 μί) and water (100 μί). The mixture was heated at 80 °C for 5 h. The reaction mixture was cooled then concentrated under reduced pressure. The residue was diluted with water (5 mL), then the reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (Z)-4-ethyl-N'-hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1 ,4]oxazine-7-carboximidamide (60 mg, 255 μιηοΙ, 74 %) as a white solid.

Step 4: Preparation of N-(2-(4-(3-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][ 1 ,4]oxazin-7-yl)- 1 ,2,4-oxadiazol- 5-yl)piperidin- 1 -yl) -2-oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (60 mg, 206.7 μιτιοΙ) in N,N-dimethylformamide (1 mL) was added (Z)-4-ethyl-N'-hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1 ,4]oxazine-7-carboximidamide (48 mg, 206.7 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (78 mg, 206.7 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2- amine (80 mg, 620 μιτιοΙ, 108 μΐ). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled then purified by prep-HPLC (column: Luna C1 8 1 00x30 5μιη; mobile phase: [water (0.1 %TFA)-methanol]; B%: 38%-68%,12 min) to give N-(2-(4-(3-(4-ethyl-3-oxo-3,4-dihydro- 2H-benzo[b][1 ,4]oxazin-7-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (6 mg, 13 μιηοΙ, 6 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 7.86 (d, J=7.2 Hz, 2H), 7.77 (dd, J=1 .8, 8.5 Hz, 1 H), 7.71 (d, J=1 .8 Hz, 1 H), 7.56 - 7.43 (m, 3H), 7.34 (br s, 1 H), 7.10 (d, J=8.4 Hz, 1 H), 4.66 (s, 2H), 4.50 (br d, J=13.7 Hz, 1 H), 4.31 (d, J=3.8 Hz, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.92 (br d, J=14.7 Hz, 1 H), 3.40 - 3.29 (m, 2H), 3.17 (br t, J=10.7 Hz, 1 H), 2.31 - 2.19 (m, 2H), 2.00 (br t, J=13.4 Hz, 2H), 1 .32 (t, J=7.2 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 490.2.

Example 112: (1-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)piperi din-4-yl)(2- phenylmorpholino)methanone.

To a stirred solution of 1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-4- carboxylic acid (80 mg, 230 μιηοΙ) in N,N-dimethylformamide (1 mL) was added 2-phenylmorpholine (37 mg, 230 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (87 mg, 230 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (89 mg, 690.93 μιηοΙ, 120 μί). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μπι ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-70%,12 min) to give (1 - (3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)(2-phenylmorpholino)metha none (94 mg, 191 .6 μιτιοΙ, 83 %) as a yellow oil. ¹ H NMR (400MHz, Methanoi-d4) δ 7.55 - 7.41 (m, 3H), 7.40 - 7.26 (m, 4H), 6.99 (d, J=8.4 Hz, 1 H), 4.51 - 4.36 (m, 2H), 4.26 - 4.13 (m, 2H), 4.12 - 3.98 (m, 4H), 3.86 (s, 3H), 3.75 - 3.58 (m, 1 H), 3.46 - 3.30 (m, 1 H), 3.28 - 3.17 (m, 2H), 3.04 (br s, 1 H), 2.95 - 2.64 (m, 1 H), 1 .93 - 1 .68 (m, 4H), 1 .40 (t, J=6.9 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 493.3.

Example 113: ( 1-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-4-yl)(4-methyl-3- phenylpiperazin-1-yl)methanone. HBTU, DIPEA, DMF

Step 1: Preparation of (1-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidi

phenylpiperazin- 1 -yl)me

To a stirred solution of 1 -(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-4- carboxylic acid (70 mg, 201 .5 μιηοΙ) in N,N-dimethylformamide (1 mL) was added 1 -methyl-2- phenylpiperazine dihydrochloride (50 mg, 201 .5 μιηοΙ,), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (76 mg, 201 .5 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2- amine (78 mg, 604.6 μιηοΙ, 105 μΙ_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 38%-68%,12 min) to give (1 -(3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)piperidin-4-yl)(4-methyl-3-phenylpiperaz in-1 -yl)methanone (60 mg, 1 17 μιτιοΙ, 58 %) as a yellow solid. Ή N R (400MHz, CDC ) δ 7,57 (br d, J=7.9 Hz, 1 H), 7,50 (br s, 1 H), 7.45 - 7,29 (m, 5H), 6.91 (d, J=8.3 Hz, 1 H), 4.68 - 4.48 (m, 1 H), 4.35 - 4.1 1 (m, 4H), 3.94 (s, 3H), 3.92 - 3.69 (m, 1 H), 3.52 - 3.10 (m, 3H), 3.09 - 2.60 (m, 4H), 2.33 - 2.17 (m, 1 H), 2.07 (br d, J=4.9 Hz, 3H), 2.04 - 1 .73 (m, 4H), 1 .49 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 506.4.

Example 114: N-(2-(4-(3-(1,3-dimethyl-1H^yrazolo[4,3-c]pyridin-6-yl)-1,2, 4-oxa&

1-yl)-2-oxoethyl)benzamide.

Step 1: Preparation of 4,6-dichloro-N-methoxy-N-methylnicotinamide.

To a stirred solution of 4,6-dichloronicotinic acid (1 .0 g, 5.21 mmol) in N,N-dimethylformamide (15 mL) was added Ν,Ο-dimethylhydroxylamine (1 .02 g, 10.42 mmol), hydroxybenzotriazole (1 .41 g, 10.4 mmol), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.0 g, 10.4 mmol) and N-ethyl-N-(propan-2- yl)propan-2-amine (2.02 g, 15.6 mmol, 2.73 mL). The mixture was stirred at 20 °C for 48 h. The reaction mixture was quenched by addition of water (20 mL) then the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50 : 1 to 5:1 to give 4,6-dichloro-N- methoxy-N-methylnicotinamide (660 mg, 2.81 mmol, 54 %) as a yellow oil. ¹ H NMR (400 MHz, CDC ) δ 8.37 (s, 1 H), 7.45 (s, 1 H), 3.51 (br s, 3H), 3.40 (br s, 3H).

Step 2: Preparation of 1-(4,6-dichloropyridi -3-yl)ethanone.

To a stirred solution of 4,6-dichloro-N-methoxy-N-methylnicotinamide (600 mg, 2.55 mmol) in tetrahydrofuran (1 0 mL) was added methylmagnesium bromide (3 M, 2.16 mL) at 0 °C, then the mixture was stirred at 0 °C for 2 h. After addition of saturated aqueous ammonium chloride (20 mL), the mixture was concentrated to -20 mL and the residue that remained was extracted with dichloromethane (40 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1 -(4,6- dichloropyridin-3-yl)ethanone (430 mg, 2.26 mmol, 89 %) as a yellow oil. ¹ H NMR (400 MHz, CDCb) δ 8.64 (s, 1 H), 7.48 (s, 1 H), 2.70 (s, 3H).

Step 3: Preparation of 6-chloro-3-methyl- 1H-pyrazolo[4,3-c]pyridine.

1 -(4,6-dichloropyridin-3-yl)ethanone (430 mg, 2.26 mmol) in hydrazine hydrate (10 mL) was stirred at 20 °C for 4 h. The reaction mixture was diluted with water (10 mL), then the mixture was extracted with dichloromethane (40 mL x 3). The combined organic phases were washed with water (10 mL x 2), then saturated aqueous sodium chloride solution (20 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give crude 6-chloro-3-methyl-1 H-pyrazolo[4,3-c]pyridine (370 mg, 2.21 mmol, 98 %) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 13.23 (br s, 1 H), 8.95 (br s, 1 H), 7.59 (s, 1 H), 2.61 (br s, 3H).

Step 4: Preparation of 6-chloro- 1 ,3-dimethy - 1H-pyrazolo[4,3-c]pyridine.

To a stirred solution of 6-chloro-3-methyl-1 H-pyrazolo[4,3-c]pyridine (330 mg, 1 .97 mmol) in N,N- dimethylformamide (5 mL) was added iodomethane (558 mg, 3.94 mmol, 245 μί) and potassium carbonate (81 6 mg, 5.91 mmol) at 0 °C. The reaction was heated at 60 °C for 2 h. The reaction mixture was cooled then quenched with water (10 mL), and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (1 0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by prep-TLC (Petroleum ether : ethyl acetate=1 :1 ) to give 6-chloro-1 ,3-dimethyl-1 H-pyrazolo[4,3- c]pyridine (120 mg, 661 μιτιοΙ, 34 %) as a yellow solid. Ή NMR (400 MHz, CDC ) δ 8.77 (s, 1 H), 7.29 - 7.27 (m, 1 H), 3.98 (s, 3H), 2.63 (s, 3H).

Step 5: Preparation of 1 ,3-dimethyl- 1 H-pyrazolo[4,3-c]pyridine-6-carbonitrile.

To a stirred solution of 6-chloro-1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine (100 mg, 551 μιηοΙ) in N,N-dimethylformamide (2 mL) was added zinc cyanide (64 mg, 551 μιηοΙ) and

tetrakis(triphenylphosphine)palladium(0) (63 mg, 55 μιηοΙ), then the mixture was degassed with nitrogen three times. The mixture was stirred at 1 10 for 16 h under nitrogen. The reaction was cooled to 20 °C, then water (3 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue that was purified by prep-TLC (silica, petroleum ether : ethyl acetate = 1 :1 ). 1 ,3-dimethyl-1 H-pyrazolo[4,3- c]pyridine-6-carbonitrile (50 mg, 290 μιτιοΙ, 53 %) as a white solid. LCMS (ESI) m/z: [M+H] ⁺ = 173.1 .

Step 6: Preparation of (Z)Ή'-hydroxy- 1,3-dimethyl- 1H yrazolo[4,3-c]pyridine-6-carboximidamide.

To a stirred solution of 1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine-6-carbonitrile (50 mg, 290 μιηοΙ) in ethanol (1 mL) was added hydroxylamine hydrochloride (40 mg, 580.76 μιηοΙ), triethylamine (58 mg, 580.76 μιηοΙ, 80 μί) and water (100 μί). The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure then diluted with water (5 mL). The reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and

concentrated in vacuo to give crude (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine-6- carboximidamide (60 mg) as a white solid. LCMS (ESI) m/z: [M+H] ⁺ = 206.2. Step 7: Preparation of N-(2-(4-(3-(1 ,3-dimethyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)- 1 ,2,4-oxadiazol-5- yl)piperidin- 1-yl)-2-oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (35 mg, 120.6 μιηοΙ) in N,N-dimethylformamide (1 mL) was added (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine-6- carboximidamide (24 mg, 120.6 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium

hexafluorophosphate) (45 mg, 120.6 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (46 mg, 361 .7 μιηοΙ, 63 μΙ_). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 for 1 h. The reaction mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12 min) to give N-(2-(4-(3-(1 ,3-dimethyl- 1 H-pyrazolo[4,3-c]pyridin-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (5 mg, 1 1 μιτιοΙ, 9 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 9.13 (d, J=1 .1 Hz, 1 H), 8.12 (d, J=1 .0 Hz, 1 H), 7.89 - 7.84 (m, 2H), 7.56 - 7.43 (m, 3H), 7.34 (br s, 1 H), 4.55 (br d, J=13.7 Hz, 1 H), 4.32 (d, J=3.9 Hz, 2H), 4.09 (s, 3H), 3.94 (br d, J=13.8 Hz, 1 H), 3.44 - 3.32 (m, 2H), 3.14 (br t, J=10.9 Hz, 1 H), 2.68 (s, 3H), 2.37 - 2.24 (m, 2H), 2.16 - 1 .96 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 460.1 .

Example 115: N-[2-[4-[3-(1,3-dimethylpyrazolo[3,4-b]pyridin-6-yl)-1,2,4-o xad^

2-oxo-ethyl]benzamide.

Step 1 : 2, 6-difluoro-N-methoxy-N-methyl-pyridine-3-carboxamide.

A mixture of 2,6-difluoropyridine-3-carboxylic acid (3.0 g, 18.9 mmol), N-methoxymethanamine hydrochloride (12.9 g, 132.0 mmol) hydroxybenzotriazole (10.2 g, 75.4 mmol), diisopropylethylamine (3.70 g, 28.7 mmol, 5.01 mL) and 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (7.20 g, 37.5 mmol) in N,N-dimethylformamide (50 mL) was stirred at 20 °C for 16 h under a nitrogen atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2,6-difluoro-N- methoxy-N-methyl-pyridine-3-carboxamide (2.80 g, 13.9 mmol, 73 %) as a solid.

Step 2: 1-(2,6-difluoro-3-pyridyl)ethanone.

To a stirred solution of 2,6-difluoro-N-methoxy-N-methyl-pyridine-3-carboxamide (3.0 g, 14.8 mmol) in tetrahydrofuran (60 mL) was added dropwise methylmagnesium bromide (1 .77 g, 14.84 mmol) at 0°C. The resulting mixture was stirred at 0°C for 2 h, and then quenched by water at 0 °C. The mixture was diluted with ethyl acetate (60 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (25 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.

Purification by chromatography (silica, petroleum ether / ethyl acetate=2:1 ) gave 1 -(2,6-difluoro-3- pyridyl)ethanone (2.20 g, 14.0 mmol, 94 %) as a white solid. Step 3: 3-ethoxy-6-iodo-2-methoxy-pyridine.

A solution of 1 -(2,6-difluoro-3-pyridyl)ethanone (1 .50 g, 9.55 mmol) in dichloromethane (55 mL) was treated with titanium(IV) isopropoxide (1 0.37 g, 36.48 mmol, 10.80 mL) at room temperature. The resulting mixture was stirred for 15 min, then hydrazine hydrate (2.06 g, 41 .16 mmol, 2 mL) was added. Stirring continued for an additional 1 .5 h, then water (5 mL) was added, and the resulting thick mixture was stirred vigorously for 20 min. The reaction mixture was filtered, and the solids were washed with dichloromethane (10 mL). The filtrate was concentrated in vacuo to provide the crude hydrazone intermediate as an oil. The crude hydrazine was dissolved in ethanol (1 5 mL), and the solution was heated at 80 °C for 24 h. The reaction mixture was quenched by addition of water (10 mL) at 20°C, and then extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-fluoro-3-methyl-1 H-pyrazolo[3,4-b]pyridine (1 .20 g) which was used directly without further purification. Step 4: 6-fluoro- 1 ,3-dimethyl-pyrazolo[3, 4-b]pyridine.

A mixture of 6-fluoro-3-methyl-1 H-pyrazolo[3,4-b]pyridine (1 .20 g, 7.94 mmol), dimethylsulfate (1 .20 g, 9.53 mmol, 903 μί), sodium hydroxide (952 mg, 23.82 mmol) in water (30 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 70 °C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled, extracted with ethyl acetate (50 mL x 2), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=2:1 ) to give 6-fluoro- 1 ,3-dimethyl-pyrazolo[3,4-b]pyridine (400 mg, 2.42 mmol, 3 %) as a yellow solid.

Step 5: 1,3-dimethylpyrazolo[3,4-b]pyridine

A mixture of 6-fluoro-1 ,3-dimethyl-pyrazolo[3,4-b]pyridine (350 mg, 2.12 mmol), tetra-n- butylammonium bromide (1 .37 g, 4.24 mmol) and sodium cyanide (727 mg, 14.84 mmol) in

dimethylsulfoxide (10 mL) was degassed and purged with nitrogen 3 times, and then the mixture was heated at 150 for 2 h under a nitrogen atmosphere. The reaction mixture was cooled then extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=2:1 ) to give 1 ,3-dimethylpyrazolo[3,4-b]pyridine-6-carbonitrile (1 50 mg, 871 μιτιοΙ, 41 %) as a yellow solid.

Step 6: N'-hydroxy- 1,3-dimethyl-pyrazolo[3,4-b]pyridine-6-carboxamidine

A mixture of 1 ,3-dimethylpyrazolo[3,4-b]pyridine-6-carbonitrile (150 mg, 871 μιτιοΙ),

hydroxylamine hydrochloride (121 mg, 1 .74 mmol) and triethylamine (176 mg, 1 .74 mmol, 241 μί) in ethanol (3 mL) and water (300 μί) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 70 °C for 5 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give N'-hydroxy-1 ,3-dimethyl-pyrazolo[3,4-b]pyridine-6- carboxamidine (120 mg, 584.7 μιτιοΙ, 67 %) as a yellow solid.

Step 7: N-[2-[4-[3-(1,3-dimethylpyrazolo[3,4-b]pyridin-6-yl)- 1,2,4-oxadiazol-5-yl]- 1-piperidyl]-2-oxo- ethyljbenzamide

A mixture of N'-hydroxy-1 ,3-dimethyl-pyrazolo[3,4-b]pyridine-6-carboxamidine (50 mg, 243.6 μιηοΙ), 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (84 mg, 292 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)- 1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 10 mg, 292 μιτιοΙ) and N-ethyl-N-(propan-2- yl)propan-2-amine (94 mg, 730.92 μιτιοΙ, 127 μί) in N,N-dimethylformamide (1 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 20°C for 1 h under a nitrogen atmosphere. The mixture was stirred at 120 for 1 h. The mixture was cooled then purified via Prep- HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (1 0mM ammonium carbonate)- acetonitrile]; B%: 20%-50%,12 min) to give N-[2-[4-[3-(1 ,3-dimethylpyrazolo[3,4-b]pyridin-6-yl)-1 ,2,4- oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]benzamide (14 mg, 31 .71 μιτιοΙ, 13 %) as a brown solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.17 - 8.15 (d, J=8.3 Hz, 1 H), 7.96 - 7.94 (d, J=8.2 Hz, 1 H), 7.90 - 7.86 (m, 2H), 7.57 - 7.52 (m, 1 H), 7.51 - 7.46 (m, 2H), 7.36 (br s, 1 H), 4.60 - 4.56 (br d, J=13.9 Hz, 1 H), 4.34 - 4.33 (d, J=4.0 Hz, 2H), 4.20 (s, 3H), 3.98- 3.95 (br d, J=13.3 Hz, 1 H), 3.49 - 3.33 (m, 2H), 3.22 - 3.10 (m, 1 H), 2.64 (s, 3H), 2.38 - 2.26 (m, 2H), 2.15 - 1 .99 (m, 2H); LCMS(ESI) m/z: [M+H] ⁺ = 460.3. Example 116: 4-[4-[3-(1,3-dimethylpyrazolo[3,4-b]pyridin-6-yl)-1,2,4-oxad iazol-5-yl]pfa

carbonyl]-1-phenyl-pyrrolidin-2-one.

Prepared using a similar experimental procedure as for example 1 15.

4-[4-[3-(1 ,3-dimethylpyrazolo[3,4-b]pyridin-6-yl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]-1 -phenyl- pyrrolidin-2-one (4.06 mg, 8.36 μιτιοΙ, 3.43% yield) was obtained as a white solid. ¹ H NMR (400MHz,

CHLOROFORM-d) δ 8.1 5-8.17 (d, J=8.4 Hz, 1 H), 7.96-7.93 (dd, J=3.2, 8.2 Hz, 1 H), 7.61 -7.63 (d, J=7.7 Hz, 2H), 7.42-7.40 (t, J=8.0 Hz, 2H), 7.23 - 7.17 (m, 1 H), 4.65-4.62 (br t, J=14.0 Hz, 1 H), 4.36-4.32 (dd, J=7.3, 9.6 Hz, 1 H), 4.21 (s, 3H), 4.07 - 3.94 (m, 2H), 3.69 - 3.58 (m, 1 H), 3.50 - 3.37 (m, 2H), 3.16 - 2.96 (m, 2H), 2.91 - 2.84 (m, 1 H), 2.64 (s, 3H), 2.33 (br t, J=13.9 Hz, 2H), 2.13 - 1 .97 (m, 2H); LCMS(ESI) m/z: [M+H] ⁺ = 486.3.

Example 117: (4-(3-( 1,3-dimethyl-1H-indazol-5-yl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)(piperidin-1- yl)methanone.

To a stirred solution of 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (150 mg, 654 μιτιοΙ) in N,N-dimethylformamide (2 ml_) was added (Z)-N'-hydroxy-l ,3-dimethyl-1 H-indazole-5-carboximidamide (133 mg, 654 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (248 mg, 654 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (253 mg, 1 .96 mmol, 342 μΙ_). The mixture was stirred at 20 °C for 1 h, then heated at 120 for 1 h. The reaction mixture was quenched by addition of water (5 mL) then the mixture was extracted with ethyl acetate (20 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by prep-TLC (silica, petroleum ether : ethyl acetate = 1 :1 ) to furnish tert-butyl 4-(3-(1 ,3-dimethyl-1 H-indazol-5-yl)-1 ,2,4- oxadiazol-5-yl)piperidine-1 -carboxylate (1 90 mg, 478 μιηοΙ, 73 %) as a white solid.

Step 2: Preparation of 3-( 1 ,3-dimethyl- 1H-indazol-5-yl)-5-(piperidin-4-yl)- 1 ,2,4-oxadiazole.

To a stirred solution of tert-butyl 4-(3-(1 ,3-dimethyl-1 H-indazol-5-yl)-1 ,2,4-oxadiazol-5- yl)piperidine-1 -carboxylate (190 mg, 478 μιηοΙ) in methanol (3 mL) was added methanolic hydrogen chloride solution (4M, 10 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to provide 3-(1 ,3-dimethyl-1 H-indazol-5-yl)-5-(piperidin-4-yl)-1 ,2,4- oxadiazole (140 mg, 471 μιτιοΙ, 98 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.04 (br s, 1 H), 8.33 (d, J=0.7 Hz, 1 H), 7.96 (dd, J=1 .3, 8.8 Hz, 1 H), 7.71 (d, J=8.8 Hz, 1 H), 3.98 (s, 3H), 3.53 - 3.43 (m, 1 H), 3.34 (br d, J=12.6 Hz, 2H), 3.1 1 - 3.00 (m, 2H), 2.52 (s, 3H), 2.26 (br d, J=10.8 Hz, 2H), 2.08 - 1 .95 (m, 2H).

Step 3: Preparation of (4-(3-(1,3-dimethyl- 1H-indazol-5-yl)- 1,2,4-oxadiazol-5-yl)piperid ^

yl)methanone.

To a stirred solution of 3-(1 ,3-dimethyl-1 H-indazol-5-yl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole (130 mg, 437 μιτιοΙ) in dichloromethane (500 μΙ_) was added piperidine-1 -carbonyl chloride (77 mg, 524.6 μιηοΙ, 65 μΙ_) and triethylamine (132 mg, 1 .31 mmol, 181 μΙ_) at 0 °C. The mixture was warmed and then stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to give a crude product that was purified by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-70%,12 min) to give (4-(3-(1 ,3-dimethyl-1 H-indazol-5-yl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)(piperidin-1 -yl)methanone (68 mg, 166.6 μιηοΙ, 38 %) as a pale yellow solid. ¹ H NMR (400 MHz, CDC ) δ 8.42 (s, 1 H), 8.08 (dd, J=1 .4, 8.8 Hz, 1 H), 7.40 (d, J=8.8 Hz, 1 H), 4.03 (s, 3H), 3.80 - 3.70 (m, 2H), 3.28 - 3.14 (m, 5H), 3.05 - 2.93 (m, 2H), 2.62 (s, 3H), 2.18 (br dd, J=3.3, 13.6 Hz, 2H), 2.07 - 1 .93 (m, 2H), 1 .60 (br s, 6H); LCMS (ESI) m/z: [M+H] ⁺ = 409.1 .

Example 118: 4-(4-(3-(5-ethoxy-4-methoxypyridin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)- 1-phenylpyrrolidin-2-one.

Step 1: Preparation of 2-c ioro-5-et oxy pyridine.

^Cl~ l _° -

To a stirred solution of 6-chloropyridin-3-ol (3.0 g, 23.2 mmol) in N,N-dimethylformamide (30 mL) was added iodoethane (4.33 g, 27.8 mmol, 2.22 mL), and potassium carbonate (9.60 g, 69.6 mmol) at 0 °C. The reaction was warmed and stirred at 40 °C for 2 h. The reaction mixture was quenched by addition of water (30 mL) then the mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxypyridine (3.30 g, 20.9 mmol, 90 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 7.97 (d, J=2.9 Hz, 1 H), 7.1 7 - 7.07 (m, 2H), 3.99 (q, J=7.0 Hz, 2H), 1 .36 (t, J=7.0 Hz, 3H).

Step 2: Preparation of 2-chloro-5-ethoxypyridine -oxide.

Hydrogen peroxide-urea adduct (3.82 g, 40.61 mmol) was added in one portion to a solution of 2- chloro-5-ethoxypyridine (3.20 g, 20.3 mmol) in dichloromethane (30 mL) at 0 °C, trifluoroacetic anhydride (7.68 g, 36.6 mmol, 5.08 mL) was added dropwise. The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched by addition of saturated aqueous sodium thiosulfate (30 mL). The mixture was extracted with dichloromethane (60 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxypyridine 1 -oxide (4.0 g) as a yellow oil. ¹ H NMR (400 MHz, CDCb) δ 8.35 - 8.28 (m, 1 H), 7.44 (dt, J=3.0, 6.0 Hz, 1 H), 7.13 - 7.04 (m, 1 H), 4.13 - 4.00 (m, 2H), 1 .50 - 1 .40 (m, 3H).

Step 3: Preparation of 2-chloro-5-ethoxy-4-nitro

To a stirred solution of 2-chloro-5-ethoxypyridine 1 -oxide (1 .80 g, 10.37 mmol) in concentrated sulfuric acid (12 mL) was added concentrated nitric acid (6.50 mL) at 0 °C, the mixture was stirred at 25 °C for 1 hrs, then heated to 1 10 and stirred for 16 hrs. After cooling to 20 °C, the mixture was poured onto ice, and then aqueous sodium hydroxide solution (40 wt.%) was added carefully to adjust the pH to 14. The mixture was extracted with dichloromethane (80 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-chloro-5-ethoxy-4-nitropyridine (810 mg, 4.00 mmol, 39 %) as a yellow solid. ¹ H NMR (400 MHz, CDCb) δ 8.32 (s, 1 H), 7.64 (s, 1 H), 4.30 (q, J=6.9 Hz, 2H), 1 .51 (t, J=7.0 Hz, 3H).

Step 4: Preparation of 2-chloro-5-ethoxy-4-methoxypyridine.

To a stirred solution of 2-chloro-5-ethoxy-4-nitro-pyridine (770 mg, 3.80 mmol) in methanol (8 mL) was added potassium tert-butoxide (644 mg, 4.18 mmol) at 0 °C, then the mixture was warmed and stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure then diluted with water (10 mL) of water. The mixture was extracted with dichloromethane (60 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxy-4-methoxypyridine (660 mg, 3.52 mmol, 93 %) as a yellow solid. ¹ H NMR (400 MHz, CDCb) δ 7.85 (s, 1 H), 6.80 (s, 1 H), 4.13 (q, J=7.0 Hz, 2H), 3.95 - 3.88 (m, 3H), 1 .47 (t, J=7.0 Hz, 3H).

Step 5: Preparation of 5-ethoxy-4-methoxypicoli

To a stirred solution of zinc cyanide (368 mg, 3.14 mmol) in N,N-dimethylformamide (8 mL) was added 2-chloro-5-ethoxy-4-methoxypyridine (590 mg, 3.14 mmol) and

tetrakis(triphenylphosphine)palladium(0) (362 mg, 314 μιτιοΙ) under nitrogen. The mixture was heated at 120 for 16 h. The reaction was cooled to 20 °C, water (20 mL) was added to the reaction, and then the mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :0 to 5:1 ) to give 5-ethoxy-4-methoxypicolinonitrile (320 mg, 1 .80 mmol, 57 %) as a white solid. Ή NMR (400 MHz, CDCb) δ 8.19 (s, 1 H), 7.1 8 (s, 1 H), 4.25 (q, J=6.9 Hz, 2H), 3.96 (s, 3H), 1 .52 (t, J=7.0 Hz, 3H).

Step 6: Preparation of (Z)-5-ethoxy-N'-hydroxy-4-methoxypicolinimidamide.

To a stirred solution of 5-ethoxy-4-methoxypicolinonitrile (320 mg, 1 .80 mmol) in ethanol (5 mL) was added hydroxylamine hydrochloride (250 mg, 3.60 mmol), triethylamine (364 mg, 3.60 mmol, 499 μί) and water (0.50 mL). The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure then diluted with water (10 mL). The mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL) then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (Z)-5- ethoxy-N'-hydroxy-4-methoxypicolinimidamide (330 mg, 1 .56 mmol, 87 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1 H), 8.1 0 (s, 1 H), 7.39 (s, 1 H), 5.75 (br s, 2H), 4.17 - 4.06 (m, 2H), 3.84 (s, 3H), 1 .34 (t, J=6.9 Hz, 3H).

Step 7: Preparation of 4-(4-(3-(5-ethoxy-4-methoxypyridin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidine- 1- carbonyl)- 1-phenylpyrrolidin- -one.

To a stirred solution of 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (90 mg, 285 μιηοΙ) in N,N-dimethylformamide (2 mL) was added (Z)-5-ethoxy-N'-hydroxy-4- methoxypicolinimidamide (60 mg, 285 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (107 mg, 285 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 10 mg, 854 μιτιοΙ, 149 μΙ_). The mixture was stirred at 20 for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled and then purified directly by prep-HPLC (column: Waters Xbridge 1 50x2.5mm 5μιη; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 30%-55%,12 min) to give 4-(4-(3- (5-ethoxy-4-methoxypyridin-2-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 -phenylpyrrolidin-2-one (34 mg, 70 μιτιοΙ, 24 %) as a yellow solid. Ή NMR (400 MHz, CDCb) δ 8.29 (s, 1 H), 7.68 - 7.57 (m, 3H), 7.44 - 7.33 (m, 2H), 7.22 - 7.13 (m, 1 H), 4.63 - 4.50 (m, 1 H), 4.36 - 4.22 (m, 3H), 4.04 - 3.90 (m, 5H), 3.59 (td, J=8.6, 16.7 Hz, 1 H), 3.43 - 3.30 (m, 2H), 3.12 - 2.93 (m, 2H), 2.88 - 2.79 (m, 1 H), 2.33 - 2.20 (m, 2H), 2.13 - 1 .93 (m, 2H), 1 .52 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 492.1 .

Example 119: (4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)((2S,5R)-5- phenylpyrrolidin-2-yl)methanone.

Step 1: Preparation of methyl 2-((tert-butoxycarbonyl)amino)-5-oxo-5-phenylpentanoate.

To a stirred solution of 01 -tert-butyl 02-methyl 5-oxopyrrolidine-1 ,2-dicarboxylate (1 .0 g, 4.1 1 mmol) in tetrahydrofuran (10 mL) was added phenylmagnesium bromide (1 M in THF, 4.93 mL) at -30 °C. The reaction mixture was slowly warmed to 20 °C and stirred for 16 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (1 0 mL), and then extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :0 to 20:1 ) to give methyl 2-((tert-butoxycarbonyl)amino)-5-oxo-5-phenylpentanoate (900 mg, 2.80 mmol, 68 %) as a white solid. ¹ H NMR (400 MHz, CDCb) δ 7.95 (d, J=8.0 Hz, 2H), 7.60 - 7.53 (m, 1 H), 7.50 - 7.43 (m, 2H), 5.17 (br s, 1 H), 4.40 (brs, 1 H), 3.75 (s, 3H), 3.19 - 2.99 (m, 2H), 2.37 - 2.26 (m, 1 H), 2.15 - 2.02 (m, 1 H), 1 .42 (s, 9H).

Step 2: Preparation of (2S/R,5R/S)- 1 -tert-butyl 2-methyl 5-phenylpyrrolidine- 1 ,2-dicarboxylate.

To a stirred solution of methyl 2-((tert-butoxycarbonyl)amino)-5-oxo-5-phenylpentanoate (800 mg, 2.49 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5.68 g, 49.8 mmol, 3.69 mL) at 20 °C. After 16 h, the solvent was removed under reduced pressure, then the residue was dissolved in methanol (10 mL) and cooled to 0 °C. Sodium borohydride (188 mg, 4.98 mmol) was slowly added, then the mixture was warmed and stirred at 20 °C for 16 h. The mixture was concentrated in vacuo and the resulting orange oil was diluted with methanol (20 mL) and concentrated again a total of four times. The residue was suspended in dichloromethane (1 0 mL), then di-tert-butyl dicarbonate (815 mg, 3.74 mmol, 858 μί), triethylamine (377 mg, 3.74 mmol, 517 μί), 4-dimethylaminopyridine (3 mg, 24.90 μιηοΙ) were added and stirred at 20 °C for 16 h. Sat. aq. ammonium chloride (20 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (50 mL x 3) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by prep-HPLC (column: Waters Xbridge 1 50x2.5mm 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 36%-66%,12min]) to give (2S/R,5R/S)-1 -tert-butyl 2-methyl 5- phenylpyrrolidine-1 ,2-dicarboxylate (230 mg, 753 μιτιοΙ, 30 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 7.56 (br d, J=7.5 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H), 7.26 - 7.19 (m, 1 H), 5.00 (br d, J=3.4 Hz, 0.4H), 4.75 (br t, J=7.0 Hz, 0.6H), 4.50 (br dd, J=4.7, 8.0 Hz, 0.6H), 4.36 (br t, J=7.4 Hz, 0.4H), 3.82 (s, 3H), 2.38 - 2.28 (m, 1 H), 2.20 (ddd, J=6.5, 7.8, 12.5 Hz, 1 H), 2.12 - 1 .91 (m, 2H), 1 .42 (s, 3.6H), 1 .15 (s, 5.4H).

Step 3: Preparation of (2S/R,5R/S)- 1-(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid.

To a stirred solution of (2S/R,5R/S)-1 -tert-butyl 2-methyl 5-phenylpyrrolidine-1 ,2-dicarboxylate (180 mg, 589 μιηοΙ) in tetrahydrofuran (2 mL) was added lithium hydroxide (2 M, 589 μί). The mixture was stirred at 20 for 16 h. The mixture was acidified to pH 1 by dropwise addition of concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (40 mL x 3). The organic layer was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (2S/R,5R/S)-1 -(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid (300 mg) as a white solid.

Step 4: Preparation of (2S/R,5R/S)-tert-butyl 2-(4-(3-(4-ethoxy-3-methoxyphenyl)- 1 ,2,4-oxadiazol-5- yl)piperidine- 1 -carbonyl) -5-phenylpyrrolidine- 1 -carboxylate.

To a stirred solution of (2S,5R)-1 -(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid (270 mg, 927 μιτιοΙ) in N,N-dimethylformamide (3 mL) was added 3-(4-ethoxy-3-methoxyphenyl)-5-(piperidin-4- yl)-1 ,2,4-oxadiazole (281 mg, 927 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium

hexafluorophosphate) (351 mg, 927 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (359 mg, 2.78 mmol, 485 μί). The mixture was stirred at 20 for 1 h. Water (15 mL) was added to the reaction, then the reaction mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (2S/R,5R/S)-tert-butyl 2-(4-(3-(4-ethoxy-3- methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-5-phenylpyrrolidine-1 -carboxylate (500 mg) as a yellow oil. This material was used directly without purficication.

Step 5: Preparation of (4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2 -oxadiazol-5-yl)piperidin- 1-yl)(

5-phenylpyrrolidin-2-yl)metha

To a stirred solution of (2S/R,5R/S)-tert-butyl 2-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4- oxadiazol-5-yl)piperidine-1 -carbonyl)-5-phenylpyrrolidine-1 -carboxylate (500 mg, 867 μιτιοΙ) in ethyl acetate (5 mL) was added 4N hydrochloric acid in ethyl acetate (20 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to provide the crude product. The crude product was purified by prep-HPLC (column : Waters Xbridge 150x2.5mm 5μιη; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 45%-65%,12 min) to give (4-(3-(4-ethoxy-3- methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 -yl)((2S/R,5R/S)-5-phenylpyrrolidin-2-yl)methanone (78 mg, 161 .6 μιτιοΙ, 19 %) as a yellow solid. Ή NMR (400 MHz, Methanol-d4) δ 7.66 (ddd, J=2.0, 3.5, 8.3 Hz, 1 H), 7.61 (br d, J=2.5 Hz, 1 H), 7.48 (br d, J=7.8 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.35 - 7.28 (m, 1 H), 7.1 1 - 7.04 (m, 1 H), 4.53 (br t, J=12.5 Hz, 1 H), 4.24 - 4.05 (m, 5H), 3.92 (d, J=1 .8 Hz, 3H), 3.49 - 3.38 (m, 2H), 3.1 8 - 3.06 (m, 1 H), 2.45 - 2.20 (m, 4H), 2.04 - 1 .66 (m, 4H), 1 .45 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 477.1 .

Example 120: 4-(4-(3-(1,3-dimethyl-1H^yrazolo[4,3-c]pyridin-6-yl)-1,2,4-o xa

carbonyl)-1-phenylpyrrolidin-2-one.

Step 1: Preparation of 4,6-dichloro-N-methoxy-N-methylnicotinamide.

A solution of 4,6-dichloropyridine-3-carboxylic acid (13.5 g, 70.3 mmol) and 1 ,1 '- carbonyldiimidazole (17.10 g, 105.5 mmol) in tetrahydrofuran (200 mL) was stirred for 0.5 h at 25 °C. N- ethyl-N-(propan-2-yl)propan-2-amine (18.1 7 g, 140.62 mmol, 24.55 mL) and Ν,Ο-dimethylhydroxylamine hydrochloride (8.23 g, 84.4 mmol) were added and the resulting solution was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (200 mL), then the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with water (50 mL x 3) then saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 4,6-dichloro-N-methoxy-N-methylnicotinamide (19.0 g) as a yellow oil. ¹ H NMR (400 MHz, CDC ) δ 8.35 (s, 1 H), 7.44 (d, J=0.6 Hz, 1 H), 3.49 (br s, 3H), 3.38 (br s, 3H).

Step 2: Preparation of 1-(4,6-dichloropyridin-3-

To a stirred solution of 4,6-dichloro-N-methoxy-N-methylnicotinamide (16.0 g, 68.1 mmol) in tetrahydrofuran (200 mL) was added a solution of methylmagnesium bromide in tetrahydrofuran (3 M, 57.6 mL) at 0 °C, the mixture was stirred at 0 °C for 2 h. After addition of saturated aqueous ammonium chloride (100 mL), the mixture was concentrated to ~ 200 mL and the residue was extracted with dichloromethane (200 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1 -(4,6-dichloropyridin-3-yl)ethanone (8.95 g, 47.1 mmol, 69 %) as a yellow oil. ¹ H NMR (400 MHz, CDCb) δ 8.62 (s, 1 H), 7.46 (s, 1 H), 2.68 (s, 3H). Step 3: Preparation of 6-chloro-3-methyl- 1H-pyrazolo[4,3-c]pyridine.

1 -(4,6-dichloropyridin-3-yl)ethanone (8.40 g, 44.2 mmol) in hydrazine hydrate (60 mL) was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (100 mL), then the mixture was extracted with dichloromethane (150 mL x 3). The separated organic layer was washed water (40 mL x 3) and saturated aqueous sodium chloride solution (50 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give 6-chloro-3-methyl-1 H-pyrazolo[4,3-c]pyridine (6.10 g, 36.4 mmol, 82 %) as a yellow solid. Ή NMR (400 MHz, DMSO-d6) δ 13.17 (br s, 1 H), 8.88 (s, 1 H), 7.53 (s, 1 H), 2.55 (s, 3H). Step 4: Preparation of 6-chloro- 1 ,3-dimethy - 1H-pyrazolo[4,3-c]pyridine.

To a stirred solution of 6-chloro-3-methyl-1 H-pyrazolo[4,3-c]pyridine (5.90 g, 35.2 mmol) in N,N- dimethylformamide (80 mL) was added iodomethane (9.99 g, 70.4 mmol, 4.38 mL), and potassium hydroxide (7.90 g, 140.8 mmol) at 0 °C. The reaction was stirred at 60 °C for 2 h. The reaction mixture was cooled then quenched by addition of water (100 mL). The mixture was extracted with ethyl acetate (150 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :0 to 5:1 )to give 6-chloro- 1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine (2.73 g, 15.0 mmol, 43 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 8.70 (s, 1 H), 7.22 (s, 1 H), 3.93 (s, 3H), 2.58 (s, 3H).

Step 5: Preparation of 1 ,3-dimethyl- 1 6-carbonitrile.

To a stirred solution of 6-chloro-1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine (1 .70 g, 9.36 mmol) in N,N-dimethylformamide (20 mL) was added zinc cyanide (1 .1 0 g, 9.36 mmol, 594 μί) and

tetrakis(triphenylphosphine)palladium(0) (1 .08 g, 936 μιηοΙ) under nitrogen. The mixture was stirred at 1 10 °C for 16 h. The reaction was cooled to 20 °C, water (30 mL) was added to the reaction, and then the reaction mixture was extracted with ethyl acetate (80 mL x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 50:1 to 1 :1 ) to give 1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine-6-carbonitrile (1 .06 g, 6.16 mmol, 66 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 9.03 (d, J=1 .0 Hz, 1 H), 7.73 (d, J=1 .0 Hz, 1 H), 4.07 (s, 3H), 2.67 (s, 3H).

Step 6: Preparation of (Z)Ή'-hydroxy- 1,3-dimethyl- 1H yrazolo[4,3-c]pyridine-6-carboximidamide.

To a stirred solution of 1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine-6-carbonitrile (1 .06 g, 6.16 mmol) in ethanol (15 mL) was added hydroxylamine hydrochloride (855 mg, 12.3 mmol), triethylamine (1 .25 g, 12.3 mmol, 1 .71 mL) and water (1 .50 mL). The mixture was heated at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure then the residue was triturated with water (5 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3- c]pyridine-6-carboximidamide (1 .0 g, 4.87 mmol, 79 %) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1 H), 9.02 (s, 1 H), 7.91 (s, 1 H), 5.91 (br s, 2H), 3.98 (s, 3H), 2.56 (s, 3H).

Step 7: Preparation of methyl 1-(5-ox - 1-phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylate.

To a stirred solution of 5-oxo-1 -phenylpyrrolidine-3-carboxylic acid (3.0 g, 14.6 mmol) in dichloromethane (30 mL) was added methyl piperidine-4-carboxylate (2.09 g, 14.6 mmol), 2,4,6-tripropyl- 1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (9.30 g, 14.6 mmol, 8.69 mL, 50% purity in ethyl acetate) and triethylamine (1 .48 g, 14.6 mmol, 2.03 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted by addition of water (20 mL) then extracted with dichloromethane (60 mL x 3). The combined organic layer was washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 1 -(5-oxo-1 -phenylpyrrolidine-3- carbonyl)piperidine-4-carboxylate (4.02 g, 12.2 mmol, 83 %) as a yellow oil. ¹ H NMR (400 MHz, CDC ) δ 7.59 (d, J=7.7 Hz, 2H), 7.38 (t, J=7.3 Hz, 2H), 7.21 - 7.12 (m, 1 H), 4.43 (m, 1 H), 4.29 (dd, J=7.3, 9.6 Hz, 1 H), 3.97 - 3.81 (m, 2H), 3.72 (s, 3H), 3.55 (m, 1 H), 3.28 - 3.17 (m, 1 H), 3.01 - 2.75 (m, 3H), 2.62 (dt, J=6.3, 10.4 Hz, 1 H), 2.08 - 1 .94 (m, 2H), 1 .80 - 1 .64 (m, 2H). Step 8: Preparation of 1-(5-oxo- 1-phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid.

To a stirred solution of methyl 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylate (4.0 g, 12.1 1 mmol) in tetrahydrofuran (30 mL) was added aqueous lithium hydroxide (2 M, 12.1 1 mL). After 1 h, the reaction mixture was cooled to 0 °C then acidified with 2 M hydrochloric acid (6 mL). The mixture was extracted with ethyl acetate (80 mL x 3). The combined organic extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (3.60 g, 1 1 .38 mmol, 94 %) as a yellow solid. Ή NMR (400 MHz, Methanol-d4) δ 7.59 (dd, J=4.0, 7.7 Hz, 2H), 7.38 (t, J=7.6 Hz, 2H), 7.23 - 7.1 5 (m, 1 H), 4.41 - 4.30 (m, 1 H), 4.15 - 3.96 (m, 3H), 3.85 - 3.75 (m, 1 H), 3.30 - 3.22 (m, 1 H), 2.99 - 2.77 (m, 3H), 2.63 (m, 1 H), 2.06 - 1 .93 (m, 2H), 1 .74 - 1 .53 (m, 2H).

Step 9: Preparation of 4-(4-(3-( 1 ,3-dimethyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)- 1 ,2,4-oxadiazol-5- yl)piperidine- 1 -carbonyl)- -phenylpyrrolidin-2-one.

To a stirred solution of (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridine-6-carboximidamide (84 mg, 410.9 μιηοΙ) in N,N-dimethylformamide (2 mL) was added 1 -(5-oxo-1 -phenylpyrrolidine-3- carbonyl)piperidine-4-carboxylic acid (130 mg, 410.9 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (155 mg, 410.9 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2- amine (159 mg, 1 .23 mmol, 215 iL). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-40%,12 min) to give 4-(4-(3-(1 ,3-dimethyl-1 H-pyrazolo[4,3-c]pyridin-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 - carbonyl)-1 -phenylpyrrolidin-2-one (78 mg, 155 μιτιοΙ, 38 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 9.13 (d, J=1 .0 Hz, 1 H), 8.12 (br d, J=3.9 Hz, 1 H), 7.60 (br d, J=7.8 Hz, 2H), 7.39 (br t, J=8.0 Hz, 2H), 7.18 (br t, J=7.4 Hz, 1 H), 4.59 (br t, J=13.8 Hz, 1 H), 4.36 - 4.27 (m, 1 H), 4.09 (d, J=3.8 Hz, 3H), 4.03 - 3.92 (m, 2H), 3.60 (m, 1 H), 3.39 (br s, 2H), 3.14 - 2.94 (m, 2H), 2.90 - 2.80 (m, 1 H), 2.68 (s, 3H), 2.37 - 2.23 (m, 2H), 2.12 - 1 .96 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 486.1 . Example 121: N-(2-(4-(3-(5-ethoxy-4-methoxypyridin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of 2-c ioro-5-et oxy pyridine.

To a stirred solution of 6-chloropyridin-3-ol (21 .0 g, 1 62.1 mmol) in N,N-dimethylformamide (200 mL) was added iodoethane (30.34 g, 194.5 mmol, 15.6 mL) and potassium carbonate (67.2 g, 486.3 mmol) at 0 °C, then the reaction was warmed and stirred at 40 °C for 2 h. The reaction mixture was quenched by addition of water (200 mL), then the mixture was extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxypyridine (26.0 g) as a yellow oil. This was used directly without further purification. ¹ H NMR (400 MHz, CDCI3) δ 7.95 (d, J=2.9 Hz, 1 H), 7.15 - 7.06 (m, 2H), 3.98 (q, J=7.0 Hz, 2H), 1 .35 (t, J=7.0 Hz, 3H).

Step 2: Preparation of 2-chloro-5-ethoxypy

Hydrogen peroxide-urea complex (31 .04 g, 330 mmol) was added in one portion to a solution of 2-chloro-5-ethoxypyridine (26.0 g, 165 mmol) in dichloromethane (250 mL) at 0 °C, then trifluoroacetic anhydride (62.4 g, 297 mmol, 41 .3 0 mL) was added dropwise. The mixture was stirred at 20 for 16 h. The reaction mixture was quenched by addition of saturated aqueous sodium thiosulfate (150 mL). The mixture was extracted with dichloromethane (200 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :0 to 1 :2) to give 2-chloro-5-ethoxypyridine 1 -oxide (22.0 g, 126.7 mmol, 77 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 8.05 (d, J=2.6 Hz, 1 H), 7.29 (d, J=9.0 Hz, 1 H), 6.81 (dd, J=2.6, 9.1 Hz, 1 H), 3.97 (q, J=6.9 Hz, 2H), 1 .37 (t, J=7.0 Hz, 3H).

Step 3: Preparation of 2-chloro-5-ethoxy-4-nitropyridine.

To a stirred solution of 2-chloro-5-ethoxypyridine 1 -oxide (5.0 g, 28.8 mmol) in concentrated sulfuric acid (30 mL) was added dropwise concentrated nitric acid (15 mL) at 0 °C, then the mixture was warmed, stirred at 25 °C for 1 h, and then heated to 1 1 0 °C for 16 h. After cooling to 20 °C, the mixture was poured onto ice, and then aqueous sodium hydroxide solution (40 wt.%) was added carefully to adjust the pH to 14. The mixture was extracted with dichloromethane (100 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxy-4-nitropyridine (3.10 g,

15.3 mmol, 53 %) as a yellow solid. Ή NMR (400 MHz, CDC ) δ 8.32 (s, 1 H), 7.64 (s, 1 H), 4.30 (q, J=7.0 Hz, 2H), 1 .50 (t, J=7.0 Hz, 3H).

Step 4: Preparation of 2-chloro-5-ethoxy-4-methoxypyridine.

To a stirred solution of 2-chloro-5-ethoxy-4-nitro-pyridine (3.1 0 g, 15.3 mmol) in methanol (32 mL) was added potassium tert-butoxide (2.60 g, 16.8 mmol) at 0 °C, the mixture was warmed and stirred at 20 °C for 2 h. The reaction was concentrated under reduced pressure then diluted with water (20 mL). The mixture was extracted with dichloromethane (60 mL x 3), then the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-chloro-5-ethoxy-4-methoxypyridine (2.68 g, 14.28 mmol, 93 %) as a yellow solid. Ή NMR (400 MHz, CDC ) δ 7.88 - 7.81 (m, 1 H), 6.83 - 6.76 (m, 1 H), 4.18 - 4.07 (m, 2H), 3.91 (dd, J=2.1 , 2.8 Hz, 3H), 1 .46 (m, 3H). Step 5: Preparation of 5-ethoxy-4-methoxypicolinonitrile.

To a stirred solution of zinc cyanide (1 .31 g, 1 1 .2 mmol) in N,N-dimethylformamide (25 mL) was added 2-chloro-5-ethoxy-4-methoxypyridine (2.10 g, 1 1 .2 mmol) and

tetrakis(triphenylphosphine)palladium(0) (1 .29 g, 1 .12 mmol) under nitrogen. The mixture was heated at 1 10 °C for 16 h. The reaction was cooled to 20 °C, then water (40 mL) was added and the reaction mixture extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue that was purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :0 to 5:1 ) to give 5-ethoxy-4-methoxypicolinonitrile (1 .20 g, 6.73 mmol, 60 %) as a white solid. Ή NMR (400 MHz, CDCb) δ 8.18 (s, 1 H), 7.18 (s, 1 H), 4.24 (q, J=7.0 Hz, 2H), 3.96 (s, 3H), 1 .51 (t, J=7.0 Hz, 3H).

Step 6: Preparation of (Z)-5-ethoxy-N'-hydroxy-4-methoxypicolinimidamide.

To a stirred solution of 5-ethoxy-4-methoxypicolinonitrile (1 .20 g, 6.73 mmol) in ethanol (15 mL) was added hydroxylamine hydrochloride (935 mg, 13.5 mmol), triethylamine (1 .36 g, 13.5 mmol, 1 .87 mL) and water (1 .50 mL). The mixture was heated at 80 °C for 2 h. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was triturated with water (5 mL), filtered and the filter cake was dried under reduced pressure to give (Z)-5-ethoxy-N'-hydroxy-4-methoxypicolinimidamide (1 .30 g, 6.15 mmol, 91 %) as a white solid. Ή NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1 H), 8.10 (s, 1 H), 7.38 (s, 1 H), 5.72 (s, 2H), 4.12 (q, J=7.0 Hz, 2H), 3.84 (s, 3H), 1 .34 (t, J=6.9 Hz, 3H). Step 7: Preparation of N-(2-(4-(3-(5-ethoxy-4-methoxypyridin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidin- 1-yl)-2- oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (150 mg, 51 6.7 μιτιοΙ) in N,N-dimethylformamide (2 mL) was added (Z)-5-ethoxy-N'-hydroxy-4-methoxypicolinimidamide (109 mg, 516.7 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (195 mg, 51 6.7 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (200 mg, 1 .55 mmol, 270 μί). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 for 1 h. The reaction mixture was cooled and then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-40%,12 min) to give N-(2-(4-(3-(5-ethoxy-4-methoxypyridin-2-yl)-1 ,2,4- oxadiazol-5-yl)piperidin-1 -yl)-2-oxoethyl)benzamide (32 mg, 67 μιτιοΙ, 13 %) as a yellow solid. ¹ H NMR (400 MHz, CDC ) δ 8.29 (s, 1 H), 7.90 - 7.82 (m, 2H), 7.64 (s, 1 H), 7.56 - 7.42 (m, 3H), 7.34 (br s, 1 H), 4.52 (br d, J=13.6 Hz, 1 H), 4.34 - 4.21 (m, 4H), 4.02 (s, 3H), 3.91 (br d, J=14.1 Hz, 1 H), 3.41 - 3.28 (m, 2H), 3.12 (br t, J=1 1 .0 Hz, 1 H), 2.33 - 2.21 (m, 2H), 2.13 - 1 .95 (m, 2H), 1 .52 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 466.3.

Example 122: N-[2-[4-[3-(1,3-dimethyl-2-oxo-benzimidazol-5-yl)-1,2,4-oxad iazo

oxo-ethyl]benzamide:

Step 1: Preparation of 3,4-diaminobenzo

To a stirred solution of 4-amino-3-nitro-benzonitrile (2.00 g, 12.3 mmol) in methanol (20 mL) was added Pd/C (500 mg, 10% purity), then the flask was degassed and filled with hydrogen three times, and the reaction mixture stirred vigorously under hydrogen (balloon) for 18 h at 25 °C. The mixture was evacuated and backfilled with nitrogen three times, then filtered through a pad of celite, and the filtrate concentrated in vacuo to give 3,4-diaminobenzonitrile (1 .47 g, 1 1 .04 mmol, 90 %) as a green oil that was used in next step directly.

Step 2: Preparation of 2-oxo- 1 ,3-dihydrobenzimidazole-5-carbonitrile

To a stirred solution of 3,4-diaminobenzonitrile (1 .40 g, 10.5 mmol) in tetrahydrofuran (70 mL) at 0 °C was added 1 ,1 '-carbonyldiimidazole (2.22 g, 13.7 mmol), then the mixture was warmed to 25 °C and stirred for 18 h. The mixture was treated with ethyl acetate (100 mL), washed with 1 N HCI (20 mL x 2) and saturated aqueous sodium chloride solution (30 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to give 2-oxo-1 ,3-dihydrobenzimidazole-5-carbonitrile (1 .50 g) as a pale yellow solid, which was used in next step directly.

Step 3: Preparation of 1,3-dimethyl-2-oxo-benzimidazole-5-carbonitrile.

To a stirred suspension of sodium hydride (1 .13 g, 28.29 mmol, 47.15 mL, 60% dispersion in mineral oil) in N,N-dimethylformamide (5 mL) was added 2-oxo-1 ,3-dihydrobenzimidazole-5-carbonitrile (1 .50 g, 9.43 mmol) in N,N-dimethylformamide (5 mL) at 25 °C. After 15 min, the mixture was cooled to 5 °C then methyl iodide (4.70 g, 33.1 mmol, 2.06 mL) was added dropwise. The reaction mixture was warmed to 25°C and stirred for 1 h. The mixture was poured into ice-water (1 00 mL), filtered and the residue dissolved in dichloromethane (10 mL). The phases were separated and the organic phase was washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1 ,3-dimethyl-2-oxo-benzimidazole-5-carbonitrile (1 .26 g, 6.73 mmol, 71 %) as pale yellow solid. Ή NMR (400MHz, CHLOROFORM-d) δ = 7.37 (dd, J=1 .4, 8.2 Hz, 1 H), 7.15 (s, 1 H), 6.95 (d, J=8.2 Hz, 1 H), 3.38 (d, J=3.3 Hz, 6H).

Step 4: Preparation of N'-hydroxy-1,3-dimethyl-2-oxo-benzimidazole-5-carboxamidine.

A mixture of 1 ,3-dimethyl-2-oxo-benzimidazole-5-carbonitrile (1 .25 g, 6.68 mmol), hydroxylamine hydrochloride (928 mg, 13.4 mmol) and triethylamine (1 .35 g, 13.4 mmol, 1 .85 mL) in ethanol (15 mL) and water (1 .50 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 70 °C for 5 h under a nitrogen atmosphere. The resulting suspension was filtered then the filter cake was dissolved in ethyl acetate (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give N'-hydroxy-1 ,3-dimethyl-2-oxo-benzimidazole-5-carboxamidine (1 .25 g, 5.68 mmol, 85 %) as a white solid.

Step 5: Preparation of N-[2-[4-[3-( 1,3-dimethyl-2-oxo-benzimidazol-5-yl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]- 2-oxo-ethyl]benzamide.

To a stirred solution of N'-hydroxy-1 ,3-dimethyl-2-oxo-benzimidazole-5-carboxamidine (80 mg, 363 μιηοΙ) and 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (105 mg, 363 μιηοΙ) in N,N- dimethylformamide (1 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium

hexafluorophosphate) (137 mg, 363 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (93 mg, 726.5 μιτιοΙ, 126 μΐ) at 25 °C. After stirring at 25 °C for 1 h, the mixture was warmed to 1 10 °C and stirred for 1 h. The mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-40%,12 min) to give N-[2-[4-[3-(1 ,3- dimethyl-2-oxo-benzimidazol-5-yl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]benzamide (38 mg, 78.7 μιτιοΙ, 22 %) as pale yellow solid. Ή NMR (400MHz, DMSO-d6) δ = 8.55 (t, J=5.7 Hz, 1 H), 7.89 - 7.83 (m, 2H), 7.75 (dd, J=1 .5, 8.2 Hz, 1 H), 7.67 (d, J=1 .3 Hz, 1 H), 7.55 - 7.42 (m, 3H), 7.29 (d, J=8.2 Hz, 1 H), 4.31 (br d, J=13.0 Hz, 1 H), 4.16 (dd, J=3.6, 5.4 Hz, 2H), 3.97 (br d, J=13.9 Hz, 1 H), 3.48 - 3.40 (m, 1 H), 3.37 (d, J=10.4 Hz, 6H), 3.29 - 3.22 (m, 1 H), 2.91 (br t, J=1 1 .2 Hz, 1 H), 2.13 (br t, J=12.9 Hz, 2H), 1 .89 - 1 .58 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 475.3. Example 123: 1,3-dimethyl-5-[5-[1-(5-oxo-1^henyl^yrrolidine-3-carbonyl)-4 ^iperidyl]-1,2,4- oxadiazol-3-yl]benzimidazol-2-one.

Step 1: Preparation of 1,3-dimet y\-5-[5-[1-(5-oxo- 1-p eny\-pyrro\idine-3-carbony\ ^

oxadiazol-3-yl]benzimidazol-2-one.

To a stirred solution of N'-hydroxy-1 ,3-dimethyl-2-oxo-benzimidazole-5-carboxamidine (120 mg, 544.9 μιτιοΙ) and 1 -(5-oxo-1 -phenyl-pyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (206 mg, 653.9 μιηοΙ) in N,N-dimethylformamide (2 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (206 mg, 544.9 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (140 mg, 1 .09 mmol, 190 μΙ_) at 25°C. After stirring at 25 °C for 2h, the mixture was heated at 120 °C for 1 h. The mixture was cooled then purified by prep-HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 25%-55%,12 min) to give 1 ,3-dimethyl-5-[5-[1 -(5- oxo-1 -phenyl-pyrrolidine-3-carbonyl)-4-piperidyl]-1 ,2,4-oxadiazol-3-yl]benzimidazol-2-one (57 mg, 1 10.5 μιτιοΙ, 20 %) as a yellow solid. ¹ H NMR (400MHz, DMSO-de) δ = 7.75 (td, J=1 .5, 8.2 Hz, 1 H), 7.69 - 7.62 (m, 3H), 7.38 - 7.32 (m, 2H), 7.29 (d, J=8.4 Hz, 1 H), 7.15 - 7.08 (m, 1 H), 4.35 (br d, J=12.8 Hz, 1 H), 4.07 - 3.91 (m, 3H), 3.77 - 3.68 (m, 1 H), 3.47 - 3.39 (m, 1 H), 3.39 - 3.34 (m, 6H), 3.34 - 3.32 (m, 1 H), 3.28 (s, 1 H), 2.98 - 2.88 (m, 1 H), 2.82 - 2.67 (m, 2H), 2.14 (br t, J=13.8 Hz, 2H), 1 .90 - 1 .63 (m, 2H).LCMS (ESI) m/z: [M+H] ⁺ = 501 .3.

Example 124: 1-[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1,3-dimethylindazol -6-yl)-1,2,4-oxadiazo yl]piperidine-1-carbonyl]pyrrolidin-2-one

Step 1: Preparation of 1-[1-[(2 -dimet oxyp enyi)met yi]-5-oxo-pyrroiidine-3-carbony^

carboxylic acid

To a stirred solution of methyl 1 -[1 -[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3- carbonyl]piperidine-4-carboxylate (200 mg, 494 μιτιοΙ) in tetrahydrofuran (2 ml_) was added aqueous lithium hydroxide (2 M, 494 μΙ_). The mixture was stirred at 20 °C for 2 h, then the mixture was acidified with 2N hydrochloric acid to pH 1 . The mixture was extracted with ethyl acetate (20 mL x 3), then the organic extracts were combined and washed with saturated aqueous sodium chloride solution (1 0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 1 -[1 -[(2,4- dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3-carbonyl]piperid ine-4-carboxylic acid (160 mg, 409.8 μιηοΙ, 83 %) as a yellow solid. Step 2: Preparation of 1-[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1,3-dimethylindazol -6-yl)- 1 _^

5-yl]piperidine- 1 -carbonyl]pyrrolidin-2-one.

To a stirred solution of N'-hydroxy-1 ,3-dimethyl-indazole-6-carboxamidine (78 mg, 384 μιτιοΙ) in N,N-dimethylformamide (2 mL) was added 1 -[1 -[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3- carbonyl]piperidine-4-carboxylic acid (150 mg, 384 μιτιοΙ), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (145 mg, 384 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2- amine (148 mg, 1 .15 mmol, 201 μΙ_). The mixture was stirred at 20 °C for 1 h, then heated at 1 10 °C for 1 h. The reaction mixture was cooled then purified directly by prep-HPLC (column: Waters Xbridge 150x2.5mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-50%,12 min) to give 1 -[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5- yl]piperidine-1 -carbonyl]pyrrolidin-2-one (35 mg, 64 μmol, 17 %) as a pink solid. ¹ H NMR (400 MHz, CDC ) δ 8.09 (d, J=4.1 Hz, 1 H), 7.85 - 7.80 (m, 1 H), 7.77 - 7.71 (m, 1 H), 7.17 (d, J=8.7 Hz, 1 H), 6.49 - 6.43 (m, 2H), 4.59 - 4.38 (m, 3H), 4.08 (d, J=1 .8 Hz, 3H), 3.98 - 3.86 (m, 1 H), 3.84 - 3.77 (m, 6H), 3.71 - 3.62 (m, 1 H), 3.46 - 3.24 (m, 4H), 3.13 - 2.96 (m, 1 H), 2.85 - 2.75 (m, 1 H), 2.67 (m, 1 H), 2.60 (s, 3H), 2.21 (br s, 2H), 2.04 - 1 .87 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 559.3.

Example 125: 1-cyclohexyl-4-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]piperidine-1- carbonyl]pyrrolidin-2-one

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (100 mg, 345.6 μιηοΙ) and 1 -cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid (73 mg, 345.6 μιηοΙ) in N,N- dimethylformamide (1 .00 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (131 mg, 345.63 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (89 mg, 691 μιηοΙ, 120 μΙ_) at 25 °C. The mixture was then stirred for an additional 2h at 25 °C. The reaction mixture was concentrated under reduced pressure to give a residue further purified by chromatography [Waters Xbridge 150x25 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-50%,12 min]. The title product, 1 -cyclohexyl-4-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 - carbonyl]pyrrolidin-2-one, was isolated as a white solid (97 mg, 201 .6 μιηοΙ, 58 %). ¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.69 (dd, J=1 .7, 8.3 Hz, 1 H), 7.57 (d, J=1 .8 Hz, 1 H), 6.97 (d, J=8.4 Hz, 1 H), 4.60 - 4.44 (dd, 1 H), 3.97 (d, J=7.9 Hz, 6H), 3.77 (br t, J=7.0 Hz, 1 H), 3.51 - 3.21 (m, 4H), 3.14 - 2.97 (m, 1 H), 2.77 - 2.61 (m, 2H), 2.28 - 2.17 (m, 2H), 2.03 - 1 .89 (m, 2H), 1 .88 - 1 .64 (m, 7H), 1 .48 - 1 .32 (m, 4H), 1 .23 - 1 .04 (m, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 483.3. Example 126: 4-[4-[3-(1,3-dimethylindazol-6-yl)-1,2,4-oxadiazol-5-ylJpipe ridine-1- carbonyl]pyrrolidin-2-one.

Step 1: Preparation of 1,3-dimethylindazol

To a stirred solution of 6-bromo-1 ,3-dimethyl-indazole (3.0 g, 13.33 mmol) in N,N- dimethylformamide (30 mL) was added, under a nitrogen atmosphere, zinc cyanide (1 .57 g, 13.33 mmol, 846 μί) and tetrakis(triphenylphosphine)palladium(0) (1 .54 g, 1 .33 mmol). The mixture was then stirred at 1 10 °C for 16 h and then cooled to 20 °C. Water (50 mL) was added to the reaction mixture which was extracted with ethyl acetate (80 mL x 3). The organic extracts were combined, washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product further purified by chromatography (silica, petroleum ether: ethyl acetate = 50 : 1 to 1 0:1 . The title compound, 1 ,3-dimethylindazole-6-carbonitrile was isolated as a white solid (1 .92 g, 1 1 .21 mmol, 84 %) ¹ H NMR (400 MHz, CDC ) δ 7.78 - 7.67 (m, 2H), 7.33 (dd, J=1 .0, 8.3 Hz, 1 H), 4.05 (s, 3H), 2.59 (s, 3H)

Step 2: Preparation of N'-hydroxy- 1 ,3-dimethyl-indazole-6-carboxamidine.

To a stirred solution of 1 ,3-dimethylindazole-6-carbonitrile (2.50 g, 14.60 mmol) in ethanol (30 mL) was added hydroxylamine hydrochloride (2.03 g, 29.20 mmol), triethylamine (2.95 g, 29.20 mmol, 4.05 mL) and water (3 mL). The mixture was stirred at 80 °C for 2 h, and then concentrated under reduced pressure. Water (5mL) was added to the residue, the resulting solid was collected by filtration and used for the next step without further purification. The title compound, N'-hydroxy-1 ,3-dimethyl- indazole-6-carboxamidine, was isolated as a white solid (2.86 g, 14.00 mmol, 96 %); ¹ H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1 H), 7.85 (s, 1 H), 7.63 (d, J=8.4 Hz, 1 H), 7.47 (dd, J=1 .2, 8.5 Hz, 1 H), 5.89 (s, 2H), 3.96 (s, 3H), 2.46 (s, 3H).

Step 3: Preparation of methyl 1-[1-[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3-carbo nyl]piperidine- 4-carboxylate.

To a stirred solution of 1 -[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3-carboxyli c acid (1 .0 g, 3.58 mmol) in dichloromethane (15 mL) was added methyl piperidine-4-carboxylate (512 mg, 3.58 mmol), 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (2.51 g, 3.94 mmol, 2.34 mL, 50% purity), triethylamine (724 mg, 7.16 mmol, 992 μί), and the reaction mixture was stirred at 20 °C for 2 h. Water (30 mL) was added to the mixture which was extracted with dichloromethane (50 mL x 3)). The organic extracts were combined, washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 1 -[1 -[(2,4-dimethoxyphenyl)methyl]-5- oxo-pyrroiidine-3-carbonyi]plperidine-4-carboxylafe isolated as a yellow oil (1 .37 g, 3,39 mmol, 95 %) and used for the next step without further purification. Ή NMR (400 MHz, CDCI3) δ 7.15 (br d, J=8.5 Hz, 1 H), 6.51 - 6.39 (m, 2H), 4.50 - 4.33 (m, 3H), 3.80 (s, 6H), 3.75 (br d, J=5.0 Hz, 1 H), 3.70 (s, 3H), 3.65 - 3.55 (m, 1 H), 3.42 - 3.29 (m, 2H), 3.19 - 3.05 (m, 1 H), 2.94 - 2.71 (m, 2H), 2.64 - 2.49 (m, 2H), 1 .94 (br dd, J=3.3, 13.3 Hz, 2H), 1 .62 (br s, 2H).

Step 4: Preparation of 1-[1-[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3-carbo nyl]piperidine-4- carboxylic acid.

To a stirred solution of methyl l -[l -[(2,4-dimethoxyphenyl)methyl]-5-oxo-pyrrolidine-3- carbonyl]piperidine-4-carboxylate (1 .1 7 g, 2.89 mmol) in tetrahydrofuran (15 mL) was added lithium hydroxide (2 M solution in tetrahydrofuran, 2.89 mL). The reaction mixture was stirred at 20 °C for 1 h, and then acidified until pH 1 using a 2M aqueous solution of hydrochloric acid. The resulting mixture was extracted with ethyl acetate (80 mL x 3). The organic extracts were combined, washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 1 -[1 -[(2 _: 4-dimethoxypheny!)methy!]~5-oxo-pyrro!idlne-3-carbony! ]piperldine-4-carboxylic acid Isolated as a white solid (1 .0 g, 2.56 mmol, 89 %) and used for the next step without further purification. ¹ H NMR (400 MHz, Methano!-d4) δ 7,09 (dd, J=2.9, 8.4 Hz, 1 H), 6,52 (d, J=2.2 Hz, 1 H), 6,47 (dd, J=2.3, 8.3 Hz, 1 H), 4,46 - 4.25 (m, 3H), 3.92 - 3.83 (m, 1 H), 3,80 (d, J=1 .3 Hz, 3H), 3,78 - 3.75 (m, 3H), 3.65 - 3.36 (m, 3H), 3,25 - 3.1 1 (m, 1 H), 2.92 - 2.80 (m, 1 H), 2,71 - 2.52 (m, 3H), 1 .97 - 1 .87 (m, 2H), 1 .68 - 1 ,42 (m, 2H), Step 5: Preparation of 1-[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-( 1 ,3-dimethylindazol-6-yl)- 1 ,2,4-oxadiazol- 5-yl]piperidine- 1 -carbonyl]pyrrolidin-2-one.

To a stirred solution of N'-hydroxy-1 ,3-d!methyi-indazo!e-6-carboxam!dlne (261 mg, 1 .28 mmoi) in N,N-dimethyiformamide (6 mL) was added 1 -[1 -[(2,4-dimethoxyphenyl)methyi]-5-oxo-pyrroiidine-3- carbonyi]plperidine-4-carboxy!ie acid (500 mg, 1 .28 mmoi), (2-(1 H-benzotr!azol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (485 mg, 1 .28 mmoi) and N-ethy!-N-(propan-2-yl)propan-2- amine (496 mg, 3.84 mmoi, 670 μί). The reaction mixture was stirred at 20 °C for 1 h, at 1 10 °C for 1 h. and then cooled to 20 °C. Water (10 mL) was added to the mixture, which was extracted with ethyl acetate (40 mL x 3). The organic extracts were combined, washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product further purified by chromatography (Dichloromethane : Methanol = 1 :0 to 10:1 ). The title compound, 1 -[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4- oxadiazol-5-yl]piperidine-1 -carbonyi]pyrrolidin-2-one was isolated as a yellow solid (500 mg, 895 μιηοΙ, 70 %). ¹ H NMR (400 MHz, CDC ) δ 8.1 1 (d, J=5.0 Hz, 1 H), 7.84 (d, J=8.5 Hz, 1 H), 7.79 - 7.73 (m, 1 H), 7,17 (d, J=8.9 Hz, 1 H), 6.50 - 6.44 (m, 2H), 4.58 - 4.41 (m, 3H), 4.10 (s, 3H), 3.97 - 3,88 (m, 1 H), 3.84 - 3.79 (m, 6H), 3.69 (br d, J=6.7 Hz, 1 H), 3.47 - 3.27 (m, 4H), 3.16 (q, J=7.5 Hz, 1 H), 2.83 - 2.76 (m, 1 H), 2.71 - 2.64 (m, 1 H), 2.62 (s, 3H), 2.25 (br s, 2H), 2.03 - 1 .88 (m, 2H)

Step 6: Preparation of 4-[4-[3-( 1 ,3-dimethylindazol-6-yl)- 1,2,4-oxadiazol-5-yl]piperidine- 1- carbonyl]pyrrolidin-2-one.

A mixture of 1 -[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5- yl]piperidine-1 -carbonyl]pyrrolidin-2-one (150 mg, 268.51 μιηοΙ), anisole (58 mg, 537 μιτιοΙ, 58 μί) in trifluoro acetic acid (2 mL) was degassed, purged with nitrogen three times, and then stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product further purified by chromatography (column: Waters Xbridge 150x25 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 15%-35%,12min). The title compound, 4- [4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -carbonyl]pyrrolidin-2-one, was isolated as a white solid (50 mg, 122.8 μιτιοΙ, 46 %) ¹ H NMR (400 MHz, CDC ) δ 8.10 (br s, 1 H), 7.86 - 7.80 (m, 1 H), 7.77 - 7.72 (m, 1 H), 5.74 (br s, 1 H), 4.55 (br t, J=14.1 Hz, 1 H), 4.08 (s, 3H), 3.95 (br d, J=9.0 Hz, 1 H), 3.82 - 3.75 (m, 1 H), 3.66 - 3.53 (m, 2H), 3.43 - 3.29 (m, 2H), 3.15 - 3.02 (m, 1 H), 2.77 - 2.67 (m, 1 H), 2.60 (s, 3H), 2.59 - 2.52 (m, 1 H), 2.33 - 2.18 (m, 2H), 2.08 - 1 .92 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 409.3.

Example 127: [4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-(4- isopropylphenyl)methanone.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (80 mg, 276.50 μιηοΙ) and 4-isopropylbenzoic acid (54 mg, 331 .80 μιηοΙ) in N,N-dimethylformamide (1 .00 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (125 mg, 331 .80 μιηοΙ) and N- ethyl-N-(propan-2-yl)propan-2-amine (71 mg, 553 μιηοΙ, 96 μΙ_) at 25 °C. The mixture was stirred at 25 °C for 2h and then concentrated under reduced pressure to provide a residue purified by

chromatography (Waters Xbridge 150x25 5μιη ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 40%-70%,12min. The title compound, [4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5- yl]-1 -piperidyl]-(4-isopropylphenyl)methanone was isolated as a yellow solid (83 mg, 191 .6 μιηοΙ, 69 %) ¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.71 (dd, J=1 .9, 8.3 Hz, 1 H), 7.59 (d, J=1 .9 Hz, 1 H), 7.40 - 7.36 (dd, 2H), 7.31 - 7.26 (t, 2H), 6.97 (d, J=8.4 Hz, 1 H), 4.65 (br s, 1 H), 3.97 (d, J=8.5 Hz, 6H), 3.36 - 3.15 (m, 3H), 2.95 (spt, J=6.9 Hz, 1 H), 2.33 - 1 .62 (m, 4H), 2.36 - 1 .62 (m, 1 H), 1 .28 (d, J=6.9 Hz, 6H); LCMS (ESI) m/z: [M+H] ⁺ = 436.3.

Example 128: 2-[2-[4-[3-(4-ethoxy-3-methoxy-phenyl)- 1,2,4-oxadiazol-5-ylJ-1-piperidylJ-1- (hydroxymethyl)-2-oxo-ethyl]isoindolin-1-one.

To a stirred solution of 3-hydroxy-2-(1 -oxoisoindolin-2-yl)propanoic acid (120 mg, 542 μιτιοΙ) in N,N-dlmethylformamide (2 mL) was added 3-(4-ethoxy-3-methoxy-phenyl)-5-(4-piperidyl)-1 ,2,4- oxadiazole (153 mg, 452 μιτιοΙ, 1 .00 eq, hydrochloric acid), (2-(1 H-benzotrlazol-1 -y!)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (205 mg, 542 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2- amine (175 mg, 1 .36 mmol, 236 μί). The mixture was stirred at 20 °C for 1 h, and then purified directly by prep-HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (l OmM ammonium carbonate)-acetonitrile]; B%: 30%-60%,12min). The title compound, 2-[2-[4-[3-(4-ethoxy-3-methoxy- phenyi)-1 _! 2,4-oxadiazoi-5-yi]-1 -piperidyl]-1 -(hydroxymethyi)-2-oxo-ethyi]isoindolin-1 -one was isolated as a white solid (139 mg, 274.8 μιτιαί, 61 %). ¹ H NMR (400 MHz, CDC ) δ 7.88 (t, J=6.8 Hz, 1 H), 7.68 - 7.44 (m, 5H), 6.92 (dd, J=8.4, 17.7 Hz, 1 H), 5.38 (t, J=4.6 Hz, 1 H), 4.84 (br d, J=17.2 Hz, 1 H), 4.48 - 4.35 (m, 2H), 4.21 - 3.98 (m, 5H), 3.94 (d, J=17.1 Hz, 3H), 3.77 - 3.41 (m, 1 H), 3.39 - 3.04 (m, 3H), 2.26 - 1 .78 (m, 4H), 1 .50 (q, J=6.8 Hz, 3H); LCMS (ESI) m/z: [M÷H] ⁺ = 507.3.

Example 129: 2-[2-[4-[3-(1,3-dimethylindazol-6-yl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-1- (hydroxymethyl)-2-oxo-ethyl]isoindolin-1-one.

To a stirred solution of 3-hydroxy-2-(1 -oxoisoindoiin-2-y!)propanoic acid (1 20 mg, 542 μιτιοΙ) in N,N-dlmethyiformamide (2 mL) was added 3-(1 ,3-dimethylindazol-6-yl)-5-(4-piperidyl)-1 ,2,4-oxadlazoie, hydrochloride (150 mg, 452 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium

hexafluorophosphate) (205 mg, 542 μmol) and N-ethyi-N-(propan-2-y!)propan-2-amine (175 mg, 1 .36 mmoi, 236 μί_). The reaction mixture was stirred at 20 °C for 1 h and then purified directly by prep-HPLC (column: Waters Xbrldge 150x25 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonltriiej; B%: 25%-55%,12min). The title compound, 2-[2-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-y!]-1 - piperidyl]-1 -(hydroxymethyl)-2-oxo-ethyl]isoindolin-1 -one was isolated as a white solid (68 mg, 137 μιηοΙ, 30 %) Ή NMR (400 MHz, CDCb) δ 8.1 0 - 7.97 (m, 1 H), 7.91 - 7.65 (m, 3H), 7.62 - 7.44 (m, 3H), 5.40 (t, J=4.9 Hz, 1 H), 4.82 (dd, J=3,0, 17,3 Hz, 1 H), 4.51 - 4,37 (m, 2H), 4.16 - 3.99 (m, 6H), 3.65 (br s, 1 H),

3.43 - 3.04 (m, 3H), 2.58 (d, J=6.7 Hz, 3H), 2,27 - 1 .93 (m, 3.6H), 1 ,62 - 1 .50 (m, 0.4H); LCMS (ESI) m/z: [M+H] ⁺ = 501 .3.

Example 130: 4-[4-[3-(6-ethoxy-5-methoxy-3-pyridyl)-1,2,4-oxadiazol-5-yl] piperidine-1 -carbonyl]-1- phenyl-pyrrolidin-2-one.

A solution of (Z)-6-ethoxy-N'-hydroxy-5-methoxynicotinimidamide (100 mg, 474 μιτιοΙ) in N,N- dimethylformamide (2.00 mL) was added 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (150 mg, 474 μιτιοΙ) N-ethyl-N-(propan-2-yl)propan-2-amine (183 mg, 1 .42 mmol, 248 μί), and (2- (1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (197 mg, 521 .58 μιηοΙ). The mixture was stirred at 25 °C for 12 h, and then at 1 10 °C for 1 h. The residue was purified directly by pre- HPLC (column: Waters Xbridge 150x2, 5mm 5μΓη ; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 30%-50%,12min) to give 4-[4-[3-(6-ethoxy-5-methoxy-3-pyridyl)-1 ,2,4-oxadiazol-5- yl]piperidine-1 -carbonyl]-1 -phenyl-pyrrolidin-2-one (96 mg, 194.7 μmol, 41 %), isolated as as a yellow solid. Ή NMR (400MHz, CHLOROFORM-d) δ = 8.44 (s, 1 H), 7.64 - 7.57 (m, 3H), 7.41 - 7.34 (m, 2H), 7,21 - 7.14 (m, 1 H), 4.61 - 4.46 (m, 3H), 4.37 - 4.28 (m, 1 H), 4.02 - 3.90 (m, 5H), 3.58 (td, J=8.4, 16.6 Hz, 1 H), 3.44 - 3,26 (m, 2H), 3.17 - 2.91 (m, 2H), 2.89 - 2.78 (m, 1 H), 2.31 - 2.17 (m, 2H), 2.06 - 1 .87 (m, 2H), 1 ,47 (t, J=7,2 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 492.1 .

Example 131: 2-(2-(4-(3-(6-ethoxy-5-methoxypyridin-3-yl)-1,2,4-oxadiazol- 5-yl)piperidin^ oxoethyl)isoindolin-1 -one.

A solution of 6-ethoxy-N'-hydroxy-5-methoxy-pyridine-3-carboxamidine (104 mg, 496 μιηοΙ) in N,N-dimethylformamide (2 ml_) was added 1 -[2-(1 -oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylic acid (150 mg, 496 μιτιοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (192 mg, 1 .49 mmol, 259 μΙ_) and (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (206 mg, 545.77 μιτιοΙ). The mixture was stirred at 25 for 12 h, and then at 1 10 °C for 1 h. The mixture was purified by pre-HPLC (column: Waters Xbridge 150x25 5μιη; mobile phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 25%- 50%,12min) to give 2-[2-[4-[3-(6-ethoxy-5-methoxy-3-pyridyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo- ethyl]isoindolin-1 -one (82 mg, 171 μιτιοΙ, 34 %), isolated as a pink solid. ¹ H NMR (400MHz,

CHLOROFORM-d) δ = 8.46 (d, J=1 .8 Hz, 1 H), 7.89 (d, J=7.8 Hz, 1 H), 7.65 (d, J=1 .5 Hz, 1 H), 7.62 - 7.56 (m, 1 H), 7.50 (t, J=6.7 Hz, 2H), 4.64 - 4.44 (m, 7H), 4.1 1 (br d, J=13.7 Hz, 1 H), 3.98 (s, 3H), 3.46 - 3.26 (m, 2H), 3.08 (br t, J=10.9 Hz, 1 H), 2.24 (br t, J=14.0 Hz, 2H), 2.09 - 1 .89 (m, 2H), 1 .50 (t, J=7.1 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 478.1 .

Example 132: N-(2-(4-(3-(6-ethoxy-5-methoxypyridin-3-yl)-1,2,4-oxadiazol- 5-yl)pip^

oxoethyl)benzamide.

Step 1: Preparation of 5-bromo-2-ethoxy-3-methox pyridine.

A solution of sodium (465 mg, 20.23 mmol, 479 μΙ_) in ethanol (5 mL) was stirred at 20 °C for 2 h. 5-Bromo-2-chloro-3-methoxypyridine (1 .50 g, 6.74 mmol) was then added to the mixture which was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was then added to the residue. The mixture was extracted with dichloromethane (60 mL x 3). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 5-bromo-2-ethoxy-3-methoxypyridinee, isolated as a white solid (1 .70 g, crude), and used for the next step without further purification. ¹ H NMR (400MHz, METHANOL-d4) δ = 7.70 (d, J=2.0 Hz, 1 H), 7.34 (d, J=2.2 Hz, 1 H), 4.34 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 1 .36 (t, J=7.1 Hz, 3H).

Step 2: Preparation of 6-ethoxy-5-methoxynicotinonitrile.

To a stirred solution of 5-bromo-2-ethoxy-3-methoxy-pyridine (1 .70 g, 7.33 mmol) in N,N- dimethylformamide (10 mL) was added zinc cyanide (860 mg, 7.33 mmol, 464 μί), and

tetrakis(triphenylphosphine)palladium(0) (847 mg, 733 μιηοΙ, 0.10 eq), the mixture was degassed with nitrogen for three times. The resulting mixture was stirred at 1 10 for 12 h under nitrogen atmosphere and then poured into water (30 mL). The mixture was then extracted with dichloromethane (50 mL x 3). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product purified by chromatography (silica, petroleum ether : ethyl acetate = 50:1 Rf= 0.6). The title compound, 6-ethoxy-5-methoxy-pyridine-3-carbonitrile was isolated as a white solid (820 mg, 4.60 mmol, 63 %) ¹ H NMR (400MHz, METHANOL-d4) δ = 8.08 (d, J=1 .8 Hz, 1 H), 7.49 (d, J=1 .8 Hz, 1 H), 4.48 (q, J=7.1 Hz, 2H), 3.92 - 3.88 (m, 3H), 1 .42 (t, J=7.1 Hz, 3H) .

Step 3: Preparation of (Z)-6-ethoxy-N'-hydroxy-5-methoxynicotinimidamide.

To a stirred solution of 6-ethoxy-5-methoxynicotinonitrile (820 mg, 4.60 mmol) in ethanol (20 mL) and water (2 mL) was added hydroxylamine hydrochloride (639 mg, 9.20 mmol) and triethylamine (931 mg, 9.20 mmol, 1 .28 mL). The mixture was stirred at 80 °C for 2 h, cooled to room temperature, concentrated under reduced pressure and poured into water (5 mL). The resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give (Z)-6-ethoxy-N'-hydroxy-5-methoxynicotinimidamide (1 .0 g, crude) as a white solid. ¹ H NMR (400MHz, METHANOL-d4) δ = 7.94 (d, J=2.0 Hz, 1 H), 7.44 (d, J=2.0 Hz, 1 H), 4.43 - 4.36 (m, 2H), 3.86 (s, 3H), 1 .38 (t, J=7.1 Hz, 3H).

To a stirred solution of (Z)-6-ethoxy-N'-hydroxy-5-methoxynicotinimidamide (109 mg, 516.69 μιτιοΙ) in N,N-dimethylformamide (2 ml_) was added 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (150 mg, 516.69 μιτιοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (200 mg, 1 .55 mmol, 270 μΙ_) and (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (215 mg, 568 μιηοΙ). The mixture was stirred at 25 for 12 h, and at 1 1 0 °C for 1 h. The residue was purified directly by chromatography (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 30%-50%,12min) to give N-(2-(4-(3-(6-ethoxy-5-methoxypyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1 - yl)-2-oxoethyl)benzamide (83 mg, 177.7 μιτιοΙ, 34 %) as a yellow solid. ¹ H NMR (400MHz,

CHLOROFORM-d) δ = 8.44 (d, J=1 .8 Hz, 1 H), 7.88 - 7.82 (m, 2H), 7.62 (d, J=2.0 Hz, 1 H), 7.55 - 7.49 (m, 1 H), 7.48 - 7.42 (m, 2H), 7.32 (br s, 1 H), 4.58 - 4.47 (m, 3H), 4.30 (d, J=4.0 Hz, 2H), 3.95 (s, 3H), 3.39 - 3.28 (m, 2H), 3.18 - 3.09 (m, 1 H), 2.30 - 2.19 (m, 2H), 2.07 - 1 .91 (m, 2H), 1 .47 (t, J=7.1 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 466.1 .

Example 133: 3-methyl-5-[5-[1-[2-(1-oxoisoindolin-2-yl)acetyl]-4^iperidyl ]-1^

benzimidazol-2-one.

A mixture of N'-hydroxy-3-methyl-2-oxo-1 H-benzimidazole-5-carboxamidine (81 .85 mg, 396.94 μιτιοΙ, 1 .20 eq), 1 -[2-(1 -oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylic acid (100.00 mg, 330.78 μιηοΙ, 1 .00 eq), (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (188.16 mg, 496.1 6 μιτιοΙ, 1 .50 eq), N-ethyl-N-(propan-2-yl)propan-2-amine (128.25 mg, 992.33 μιτιοΙ, 173.31 μΙ_, 3.00 eq) in N,N-dimethylformamide (2.00 mL) then the mixture was stirred at 20 °C for 15h then the mixture was stirred at 1 10 °C for 1 h. The product was purified by column: Waters Xbridge 150x25 5μιη; mobile phase: [water (1 0 mM NH ₄ HC0 ₃ )-acetonitrile]; B%: 20%-45%,12min to obtain compound 3-methyl-5-[5-[1 -[2-(1 - oxoisoindolin-2-yl)acetyl]-4-piperidyl]-1 ,2,4-oxadiazol-3-yl]-1 H-benzimidazol-2-one (53.58 mg, 1 13.40 μιτιοΙ, 34.28 %) as a pink solid. 1 H NMR (400MHz, CHLOROFORM-d) δ = 9.60 (br s, 1 H), 7.79 (t, J=9.0 Hz, 2H), 7.61 (s, 1 H), 7.51 - 7.46 (m, 1 H), 7.42 - 7.37 (m, 2H), 7.10 (d, J=8.2 Hz, 1 H), 4.52 (s, 2H), 4.45 - 4.37 (m, 3H), 4.02 (br d, J=13.6 Hz, 1 H), 3.42 (s, 3H), 3.37 - 3.19 (m, 2H), 3.00 (br t, J=1 1 .0 Hz, 1 H), 2.21 - 2.10 (m, 2H), 1 .99 - 1 .85 (m, 2H); LCMS (ESI) m/z [M+H] ⁺ = 473.3.

Example 134: 3-methyl-5-[5-[1-(5-oxo-1^henyl^yrrolidine-3-carbonyl)-4^ipe ridyl]-1,2,4-oxad -yl]-1H-benzimidazol-2-one.

Example 134 was synthesized according to the synthetic procedure reported for the preparation of Example 133. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.82 (br s, 1 H), 7.79 (br d, J=8.2 Hz, 1 H), 7.62 (br s, 1 H), 7.52 (d, J=8.2 Hz, 2H), 7.34 - 7.29 (m, 2H), 7.14 - 7.08 (m, 2H), 4.57 - 4.40 (m, 1 H), 4.26 (br t, J=7.3 Hz, 1 H), 3.97 - 3.84 (m, 2H), 3.52 (quin, J=8.4 Hz, 1 H), 3.42 (d, J=1 .6 Hz, 3H), 3.37 - 3.23 (m, 2H), 3.13 - 2.86 (m, 2H), 2.83 - 2.76 (m, 1 H), 2.19 (br t, J=12.5 Hz, 2H), 2.00 - 1 .82 (m, 2H). LCMS (ESI) m/z: [M+H] ⁺ = 487.3.

Example 135: N-[2-[4-[3-(3-methyl-1 ,2-benzoxazol-6-yl)-1 ,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo- ethyljbenzamide

To a stirred solution of 1 -(4-bromo-2-hydroxy-phenyl)ethanone (10.00 g, 46.50 mmol) and pyridine (49.66 g, 627.75 mmol, 50.67 mL) in ethanol (100 mL) was added hydroxylamine hydrochloride (16.16 g, 232.50 mmol) at 25 °C. The mixture was heated to 90°C for 4 h and was poured into a 2M aqueous solution of hydrochloric acid (250 mL). The mixture was then extracted with ethyl acetate (1 00 mL x 4), washed with saturated aqueous sodium chloride solution (25 mL x 1 ), dried with anhydrous Na2S04, filtered and concentrated under vacuum to give 1 -(4-bromo-2-hydroxy-phenyl)ethanone oxime (12.49 g, crude), isolated as pale yellow solid, and used for the next step without further purification. ( ¹ H NMR (400MHz, CHLOROFORM-d) δ = 1 1 .47 (br s, 1 H), 8.65 (br d, J=4.3 Hz, 1 H), 7.94 (br s, 1 H), 7.31 - 7.28 (d, 1 H), 7.1 7 (d, J=1 .9 Hz, 1 H), 7.06 (dd, J=2.0, 8.5 Hz, 1 H), 2.37 (s, 3H) Step 2: Preparation of [(E)- 1-(4-bromo-2-hydroxy-phenyl)ethylideneamino] acetate.

Acetic anhydride (25.50 mL) was added to 1 -(4-bromo-2-hydroxy-phenyl)ethanone oxime (12.49 g, 54.29 mmol, 1 .00 eq) one portion at 25 °C, then the mixture was stirred at 25 °C for 30 mins. Water (1 00 mL) was then added to the suspension (a solid precipitated from the reaction mixture after 30 min stirring at room temperature), further stirred for 30 min at 25 °C. The suspension was filtered and the resulting solid was washed with water (1 0 mL x 3) and dissolved in ethyl acetate (20 mL). The organic solution was then dried with anhydrous Na2S04, filtered and concentrated under vacuum to give [(E)-1 -(4- bromo-2-hydroxy-phenyl)ethylideneamino] acetate (1 2.1 8 g , 44.8 mmol, 82 %) as pale white solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 1 1 .48 (s, 1 H), 7.34 (d, J=8.7 Hz, 1 H), 7.24 (d, J=1 .9 Hz, 1 H), 7.07 (dd, J=1 .9, 8.6 Hz, 1 H), 2.45 (s, 3H), 2.28 (s, 3H).

Step 3: Preparation of 6-bromo-3-methyl- 1,2-benzoxazole

[(E)-1 -(4-bromo-2-hydroxy-phenyl)ethylideneamino] acetate (1 1 .00 g, 40.4 mmol) was added in one portion to pyridine (1 00 mL) and the resulting solution was refluxed at 1 30 for 1 5 h. The mixture was cooled to room temperature and poured into a 2M aqueous solution of hydrochloric acid (500 mL). The resulting mixture was extracted with methyl tert-butyl ether (200 mL x 3). The organic extracts were washed with saturated aqueous sodium chloride solution (20 mL x 1 ), dried with anhydrous Na2S04, filtered and concentrated under vaccum to give the crude product further purified by chromatography (silica, petroleum ether / ethyl acetate=200/1 to 1 00/1 ). The desired compound (6-bromo-3-methyl-1 ,2- benzoxazole) was obtained as a yellow solid (7.50 g). ¹ H NMR (400MHz, DMSO-de) δ = 8.05 (s, 1 H), 8.08 - 8.03 (d, 1 H), 8.08 - 8.03 (, 1 H), 7.82 (d, J=8.4 Hz, 1 H), 7.56 (dd, J=1 .1 , 8.3 Hz, 1 H), 2.56 (s, 3H). Step 4: Preparation of 3-methyl- 1 ,2-benzoxazol

To a stirred solution of 6-bromo-3-methyl-1 ,2-benzoxazole (2.50 g, 1 1 .8 mmol) and zinc cyanide (1 .38 g, 1 1 .8 mmol, 748 iL) in N,N-dimethylformamide (12 mL) was added

tetrakis(triphenylphosphine)palladium(0) (1 .36 g, 1 .1 8 mmol) at 25 °C ,the mixture was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 1 1 0 °C for 24 hrs under a nitrogen atmosphere. The suspension was filtered through a pad of Celite. The filtrate was then poured into water (50 mL), extracted with ethyl acetate (50 mL x 3) and the organic layer was washed with saturated aqueous sodium chloride solution (20 mL x 1 ), dried with anhydrous Na2S04, and concentrated in vacuo. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate=1 00/1 to 50:1 ) to give 3-methyl-1 ,2-benzoxazole-6-carbonitrile (240 mg, 1 .52 mmol, 13 %), isolated as awhite solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.89 (t, J=1 .0 Hz, 1 H), 7.76 (dd, J=0.7, 8.2 Hz, 1 H), 7.60 - 7.57 (m, 1 H), 2.63 (s, 3H).

Step 5: Preparation of N'-hydroxy-3-methyl- 1 ,2-benzoxazole-6-carboxamidine

To a stirred solution of 3-methyl-1 ,2-benzoxazole-6-carbonitrile (240 mg, 1 .52 mmol) in ethanol (4.00 mL) and water (400 μΙ_) was added hydroxylamine hydrochloride (21 0 mg, 3.03 mmol) and triethylamine (307 mg, 3.03 mmol, 420 μΙ_) at 25 °C. The mixture was then stirred at 70 °C for 5 h and concentrated in vacuo to give N'-hydroxy-3-methyl-1 ,2-benzoxazole-6-carboxamidine (265 mg, 1 .39 mmol, 91 .60 %) isolated as a white solid, and used for the next step without further purification.

Step 6: Preparation of N-[2-[4-[3-(3-methyl- 1 ,2-benzoxazol-6-yl)- 1 ,2,4-oxadiazol-5-yl]- 1 -piperidyl]-2-oxo- ethyljbenzamide.

To a stirred solution of N'-hydroxy-3-methyl-1 ,2-benzoxazole-6-carboxamidine (85 mg, 447.80 μιηοΙ) and 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (130 mg, 447.80 μιηοΙ) in N,N- dimethylformamide (2.00 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (169 mg, 447.80 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (1 15 mg,

895.60 μιτιοΙ, 156 μΙ_) at 25 °C. The mixture was then stirred at 25 °C for 4 h and warmed to 1 10 °C for 1 h. The mixture was concentrated in vacuo and the resulting residue was purified by chromatography (Boston Green ODS 150x30mm 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 26%-56%,1 1 .5 min) to give N-[2-[4-[3-(3-methyl-1 ,2-benzoxazol-6-yl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]-2-oxo-ethyl]benzamide (48 mg, 107.82 μιτιοΙ,24%, 99% purity), isolated as a pale yellow solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.28 (s, 1 H), 8.05 (d, J=8.3 Hz, 1 H), 7.85 (d, J=7.5 Hz, 2H), 7.74 (d, J=7.9 Hz, 1 H), 7.55 - 7.42 (m, 3H), 7.34 (br s, 1 H), 4.51 (br d, J=13.6 Hz, 1 H), 4.31 (d, J=3.9 Hz, 2H), 3.93 (br d, J=14.0 Hz, 1 H), 3.41 - 3.32 (m, 2H), 3.16 (br t, J=10.7 Hz, 1 H), 2.63 (s, 3H), 2.33 - 2.22 (m, 2H), 2.09 - 1 .93 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ :446.2. Example 136: 4-[4-[3-(3-methyl- 1 ,2-benzoxazol-6-yl)- 1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]-1- phenyl-pyrrolidin-2-one.

To a stirred solution of N'-hydroxy-3-methyl-1 ,2-benzoxazole-6-carboxamidine (78 mg, 410.94 μιηοΙ) and 1 -(5-oxo-1 -phenyl-pyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (130 mg, 410.94 μιτιοΙ) in N,N-dimethylformamide (2.00 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (155 mg, 410.94 μιτιοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (106 mg, 821 .88 μιτιοΙ, 143 μΐ) at 25 °C. The mixture was then stirred at 25 °C for 4 h and warmed to 1 10 for 1 h. The mixture was concentrated in vacuo and the resulting residue was purified by chromatography (Boston Green ODS 150x30 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,1 1 .5 min) to give 4-[4-[3-(3-methyl-1 ,2-benzoxazol-6-yl)-1 ,2,4-oxadiazol-5-yl]piperidine-1 - carbonyl]-1 -phenyl-pyrrolidin-2-one (42 mg, 89.8 μιηοΙ, 22 %) isolated as a yellow solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.28 (s, 1 H), 8.06 (d, J=8.3 Hz, 1 H), 7.74 (d, J=8.3 Hz, 1 H), 7.60 (d, J=7.9 Hz, 2H), 7.38 (t, J=7.9 Hz, 2H), 7.20 - 7.14 (t, 1 H), 4.61 - 4.48 (t, 1 H), 4.35 - 4.29 (t, 1 H), 4.04 - 3.92 (dd, 2H), 3.59 (quin, J=8.4 Hz, 1 H), 3.46 - 3.31 (m, 2H), 3.20 - 3.05 (m, 1 H), 3.03 - 2.92 (m, 1 H), 2.89 - 2.80 (m, 1 H), 2.63 (s, 3H), 2.28 (br t, J=12.3 Hz, 2H), 2.08 - 1 .91 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 472.2.

Example 137: N-(2-(4-(3-(1,3-dimethyl-1H-pyrazolo[4,3-b]pyridm-6-yl)-1,2, 4-oxad^ ^'

1-yl)-2-oxoethyl)benzamide.

Step 1: Preparation of 1-(5-bromo-3-fluoropyridin-2-yl)ethanone.

A 3M solution of ethylmagnesium bromide in tetrahydrofuran (4.97 mL) was added at 0 °C to stirred solution of 5-bromo-3-fluoropicolinonitrile (2.0 g, 9.95 mmol) in tetrahydrofuran (20 mL). The mixture was then stirred at 25 °C for 1 h, and quenched by addition of an aqueous solution of ammonium hydroxide ammonium chloride solution (20 mL). The resulting mixture was extracted with ethyl acetate (2 X 20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the crude product further purified by chromatography (silica, petroleum ether : ethyl acetate = 20:1 to 1 :1 ). The desired compound (1 -(5-bromo-3-fluoropyridin-2-yl)ethanone) was isolated as a yellow solid (580 mg, 1 .49 mmol, 15 %). ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.56 (s, 1 H), 7.74 (dd, J=1 ,8, 9.8 Hz, 1 H), 2.68 (s, 3H). Step 2 preparation of 6-bromo- 1 ,3-dimethyl- -pyrazolo[4,3-b]pyridine

To a stirred solution of 1 -(5-bromo-3-fluoropyridin-2-yl)ethanone (570 mg, 1 .46 mmol) in ethanol (5 mL), was added methylhydrazine (1 .68 g, 14.60 mmol, 1 .91 mL), and the resulting mixture was heated at 80 °C for 2 h. The reaction mixture was then quenched with water (5 mL) and extracted with ethyl acetate (2X5 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the crude product further purified by prep-TLC (silica, petroleum ether : ethyl acetate = 3:1 ). The title compound (6-bromo-1 ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridine) was isolated as a yellow solid (280 mg, 1 .23 mmol, 84 %) ^¾ H NMR (400MHz, CHLOROFORM-d) δ 8.54 (d, J=1 .9 Hz, 1 H), 7.86 (d, J=1 .9 Hz, 1 H), 3.99 (s, 3H), 2.64 (s, 3H).

Step 3 preparation of 1 ,3-dimethyl- 1 H-pyrazolo[4,3-b]pyridine-6-carbonitrile.

A solution of 6-bromo-1 ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridine (280 mg, 1 .24 mmol), tetrakis(triphenylphosphine)palladium(0) (214 mg, 186 μιηοΙ), and zinc cyanide (87 mg, 744 μιτιοΙ, 47 μί) in N,N-dimethylformamide (2 mL) under nitrogen was heated to 100 °C and stirred for 12 h at 100 °C. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated to give a residue poured into water (3 mL). The aqueous phase was extracted with ethyl acetate (3 mL x 3). The combined organic extracts were then washed with saturated aqueous sodium chloride solution (5 mL x 1 ), dried over anhydrous anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-TLC (silica, petroleum ether : ethyl acetate = 1 :1 ) to give 1 ,3-dimethyl-1 H-pyrazolo[4,3- b]pyridine-6-carbonitrile (190 mg, 805.5 μιτιοΙ, 65 %) as a light yellow solid. Ή NMR (400MHz,

CHLOROFORM-d) δ 8.72 (d, J=1 .5 Hz, 1 H), 8.04 (d, J=1 .5 Hz, 1 H), 4.09 (s, 3H), 2.69 (s, 3H). Step 4: Preparation of (Z)Ή'-hydroxy- 1,3- e-6-carboximidamide.

To a stirred solution of 1 ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridine-6-carbonitrile (170 mg, 987 μιτιοΙ) in ethanol (2 ml_) was added hydroxylamine hydrochloride (137 mg, 1 .97 mmol), triethylamine (199 mg, 1 .97 mmol, 273 μΙ_) and water (200 μΙ_). The reaction mixture was then stirred at 80 °C for 2 h. and concentrated under reduced pressure. The residue was diluted with water (5 mL). The resulting solid was filtered to give (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridine-6-carboximidamide (160 mg, 779.7 μιτιοΙ, 79 %) isolated as a light yellow solid, and used for the next step without further purification. 1 H NMR (400MHz, DMSO-de) δ 9.93 (s, 1 H), 8.82 (d, J=1 .8 Hz, 1 H), 8.29 (d, J=2.0 Hz, 1 H), 6.07 (br s, 2H), 4.00 (s, 3H), 2.51 (s, 3H).

Step 5: Preparation of N-(2-(4-(3-(1,3-dimethyl- 1H-pyrazolo[4,3-b]pyridin-6-yl)- 1 ,2,4-oxadiazol-5- yl)piperidin- 1-yl)-2-oxoethyl)benzamide.

To a stirred solution of 1 -(2-benzamidoacetyl)piperidine-4-carboxylic acid (150 mg, 51 6.69 μιηοΙ) in N,N-dimethylformamide (1 .50 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (215 mg, 568 μιηοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (200 mg, 1 .55 mmol, 270 μΙ_) and (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridine-6-carboximidamide (106 mg, 516.69 μιτιοΙ). The reaction mixture was stirred at 25 °C for 1 h, and then warmed to 1 10 °C for 1 h. The reaction mixture was concentrated under vacuum and the resulting residue was purified by prep-HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-45%,12min) to give N-(2-(4-(3-(1 ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridin-6-yl)-1 ,2,4-oxadiazol-5- yl)piperidin-1 -yl)-2-oxoethyl)benzamide (1 16 mg, 252.7 μιτιοΙ, 49 %) isolated as a brown solid. ¹ H NMR (400MHz, DMSO-de) δ 9.05 (d, J=1 .8 Hz, 1 H), 8.64 (d, J=1 .8 Hz, 1 H), 8.61 - 8.54 (m, 1 H), 7.88 (br d, J=7.1 Hz, 2H), 7.57 - 7.45 (m, 3H), 4.35 (br d, J=13.0 Hz, 1 H), 4.19 (br t, J=5.6 Hz, 2H), 4.1 0 (s, 3H), 4.01 (br d, J=13.2 Hz, 1 H), 3.53 (br t, J=1 0.9 Hz, 1 H), 3.58 - 3.48 (m, 1 H), 3.32 - 3.24 (m, 1 H), 2.96 (br t, J=1 1 .8 Hz, 1 H), 2.56 (s, 3H), 2.18 (br t, J=13.7 Hz, 2H), 1 .88 (br d, J=10.1 Hz, 1 H), 1 .81 - 1 .57 (m, 1 H); LCMS (ESI) m/z: [M+H] ⁺ = 460.3. Example 138: 4-(4-(3-(1,3-dimethyl-1H^yrazolo[4,3-b]pyridin-6-yl)-1,2,4-o xadiazol-5-yl^

carbonyl)-1-phenylpyrrolidin-2-one.

To a stirred solution of 1 -(5-oxo-1 -phenylpyrrolidine-3-carbonyl)piperidine-4-carboxylic acid (150 mg, 474 μιτιοΙ) in N,N-dimethylformamide (1 .50 mL) was added (2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate) (197 mg, 521 .58 μιηοΙ), N-ethyl-N-(propan-2-yl)propan-2-amine (183 mg, 1 .42 mmol, 248 μΙ_) and (Z)-N'-hydroxy-l ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridine-6- carboximidamide (97 mg, 474 μιτιοΙ). The reaction mixture was stirred at 25 °C for 1 h and then warmed to 1 10 for 1 h. The reaction mixture was concentrated under vacuum and the resulting residue was purified by prep-HPLC (column: Waters Xbridge 1 50x25 5μιη; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 20%-50%,12min) to give 4-(4-(3-(1 ,3-dimethyl-1 H-pyrazolo[4,3-b]pyridin-6- yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-1 -phenylpyrrolidin-2-one (121 mg, 249 μιτιοΙ, 52 %) isolated as a yellow solid. ¹ H N R (400MHz, DMSG-de) δ 9.05 (s, 1 H), 8.64 (br s, 1 H), 7.66 (br d, J=8,2 Hz, 2H), 7.41 - 7.34 (m, 2H), 7.17 - 7.1 1 (m, 1 H), 4.39 (br d, J=13.5 Hz, 1 H), 4.10 (s, 3H), 4.06 (br d, J=9,0 Hz, 2H), 4.00 - 3,93 (m, 1 H), 3.80 - 3.71 (m, 1 H), 3.52 (br t, J=10.9 Hz, 1 H), 3,40 - 3.34 (m, 1 H), 3.03 - 2.92 (m, 1 H), 2.85 - 2,71 (m, 2H), 2.56 (s, 3H), 2.19 (t, J=14,3 Hz, 2H), 1 .95 - 1 .82 (m, 1 H), 1 ,80-1 .70 (m, 1 H); LCMS (ES!) m/z: [M+H] ⁺ = 486,3.

Example 139: 4-[4-[4-[3-(1,3-dimethylindazol-6-yl)-1,2,4-oxadiazol-5-yl]p iperidi

oxo-pyrrolidin-1-yl]benzonitrile.

Step 1: Preparation of 4-[4-[3-( 1 ,3-dimethylindazol-6-yl)- 1,2,4-oxadiazol-5-yl]piperidine- 1- carbonyl]pyrrolidin-2-one.

A mixture of 1 -[(2,4-dimethoxyphenyl)methyl]-4-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5- yl]piperidine-1 -carbonyl]pyrrolidin-2-one (350 mg, 626.53 μιηοΙ), anisole (135 mg, 1 .25 mmol, 135 μΙ_) in trifluoroacetic acid (5 mL) was degassed and purged with nitrogen three times. The reaction mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere and then concentrated under reduced pressure to to provide the crude product (500 mg) isolated as a yellow oil and used for the next step without further purification. Step 2: Preparation of 4-[4-[4-[3-(1,3-dimethylindazol-6-yl)- 1,2,4-oxadiazol-5-yl]piperM

oxo-pyrrolidin- 1 -yljbenzonitrile.

A mixture of 4-[4-[3-(1 ,3-dimethyiindazoi-6-yi)-1 ,2,4-oxadiazol-5-yl]piperidine-1 -earbonyljpyrro!idin- 2-orie (200 mg, 489.66 μπηοΙ), 4-iodobenzonitriie (1 12 mg, 489.66 μιηοΙ), potassium phosphate tribasic (1 87 mg, 881 μιηοΙ), copper iodide (18 mg, 97.93 μιηοΙ) and (1 S,2S)-eyciohexane-1 ,2-diamine (55 mg, 489.66 μηηοΙ, 60 μΙ_) in dioxane (1 mL) and N,N-dimethyiformamide (1 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 1 10 °C for 1 6 h under a nitrogen atmosphere. After the reaction cooled to 20 °C, water (10 mL) was added to the mixture which was extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude product further purified by prep-HPLC (column: Waters Xbridge 150x2.5mm δμηι; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 15%-40%,12min). The title compound (4-[4-[4-[3-(1 ,3- dimethy!indazoi-6-yl)-1 ,2,4-oxad!azoi-5-yl]piperid!ne-1 -carbonyl]-2-oxo-pyrroi!d!n-1 -yljbenzonitrile) was Isolated as a pale yellow solid (1 7 mg, 34 μιτιοΙ, 7 %). ¹ H NMR (400 MHz, CDC ) δ 8.10 (br s, 1 H), 7.87 - 7.72 (m, 4H), 7.67 (d, J=8.8 Hz, 2H), 4.63 - 4.47 (m, 1 H), 4.36 (dd, J=7,1 , 9.5 Hz, 1 H), 4.09 (s, 3H), 4.03 - 3.93 (m, 2H), 3.62 (m, 1 H), 3.48 - 3.32 (m, 2H), 3.20 - 3.04 (m, 1 H), 3.02 - 2.88 ( , 2H), 2.61 (s, 3H), 2.30 (br t, J=14,4 Hz, 2H), 2.10 - 1 .96 ( , 2H); LCMS (ESI) m/z: [M+H] ⁺ = 51 0.3. Example 140: 2-[2-[4-[3-(4-ethoxy-3-methoxy-phenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-1-methyl-2- oxo-ethyl]isoindolin-1-one.

Step 1: Preparation of 2-[2-[4-[3-(4-ethoxy-3- ethoxy-phenyl)- 1,2,4-oxadiazol-5-yl]- 1-piperidyl]- 1- 2-oxo-ethyl]isoindolin- 1-one.

To a stirred solution of 3-(4-ethoxy-3-methoxy-phenyl)-5-(4-plperidyi)-1 ,2,4-oxadiazole (130 mg, 382.56 μιτιοΙ, 1 .00 eq, hydrochloric acid) in N,N-dimethylformamlde (2 mL) was added 2-(1 -oxoisoindolin- 2-yi)propanoic acid (78 mg, 382.56 μηηοΙ), (2-(1 H-benzotriazo!-1 -y!)-1 ,1 ,3,3-tetramethy!uronium hexafiuorophosphate) (174 mg, 459 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (148 mg, 1 .15 mmoi, 200 μΙ_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under vacuum and the residue was purified by prep-HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phas [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 40%-70%,12min) to give 2-[2-[4-[3-(4-ethoxy-3- methoxy-phenyl}-1 ,2,4-oxadiazoi-5-yi]-1 -piperidyi]-1 -methyi-2-oxo-ethyi]isoindolin-1 -one (132 mg, 266 μπηοΙ, 70 %), isolated as a yellow solid. Ή NMR (400 MHz, CDC ) δ 7.86 (br t, J=6.2 Hz, 1 H), 7.69 - 7.43 (m, 5H), 6.93 (dd, J=8.4, 15.4 Hz, 1 H), 5.55 (q, J=6.8 Hz, 1 H), 4.57 - 4.36 (m, 3H), 4.29 - 4.1 1 (m, 3H), 3.95 (d, J=13.5 Hz, 3H), 3.42 - 3.19 (m, 2H), 3.14 - 3.00 (m, 1 H), 2.1 6 (br dd, J=4.4, 8.8 Hz, 2H), - 1 .67 (m, 2H), 1 .54 - 1 .47 (m, 6H); LCMS (ESI) m/z: [M+H] ⁺ = 491 .1 .

To a stirred solution of 2-(1 -oxoisoindoiin-2-yl)propanoic acid (79 mg, 389 μmol} in N,N- dimethylformamide (2 mL) was added 3-(1 ,3-dimethylindazol-6-yl)-5-(4-piperidyl)-1 ,2,4-oxadiazoie (130 mg, 389 μιηοΙ}, (2-(1 H-benzotriazoi-1 -yl)-1 ,1 ,3,3-tetramethyiuronium hexafiuorophosphate) (177 mg, 467 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2-amine (150 mg, 1 .17 mmoi, 204 μί_). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under vacuum and the residue was purified by prep-HPLC (column: Waters Xbridge 150x25 5μιη ; mobile phase: [water (10mM ammonium carbonate)- acetonitrilej; B%: 40%-70%,12min) to give 2-[2-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazoi-5-yij-1 - piperidyl]-1 -methyl-2-oxo-ethyl]isoindolin-1 -one (1 18 mg, 243.5 μηιοΙ, 63 %) isolated as a white solid. ¹ H NMR (400 MHz, CDCia) δ 8.12 - 8.01 (m, 1 H), 7.90 - 7.67 (m, 3H), 7.60 - 7.44 (m, 3H), 5.56 (q, J=6,6 Hz, 1 H), 4.58 - 4.40 (m, 3H), 4.27 (br t, J=13.7 Hz, 1 H), 4.07 (d, J=9.9 Hz, 3H), 3.45 - 3.24 (m, 2H), 3.14 - 3.03 (m, 1 H), 2.59 (d, J=6.6 Hz, 3H), 2.21 (br d, J=12.8 Hz, 2H), 2.10 - 1 .70 (m, 2H), 1 .52 (br dd, J=4.3, 6.3 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 485.1 .

Example 142: 2-(2-(4-(3-(5-ethoxy-6-methoxypyridin-2-yl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)isoindolin-1 -one

Example 142 was synthesized according to the synthetic procedure reported for the preparation of Example 147. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.87 (d, J=7.5 Hz, 1 H), 7.67 (d, J=8.3 Hz, 1 H), 7.58 - 7.53 (m, 1 H), 7.47 (t, J=6.8 Hz, 2H), 7.10 (d, J=7.9 Hz, 1 H), 4.58 (d, J=5.7 Hz, 2H), 4.52 (s, 1 H), 4.48 - 4.41 (m, 2H), 4.19 - 4.12 (m, 5H), 4.04 (s, 1 H), 3.44 - 3.26 (m, 2H), 3.05 (br t, J=1 1 .0 Hz, 1 H), 2.26 - 2.13 (m, 2H), 1 .96 (br dd, J=10.1 , 19.7 Hz, 2H), 1 .52 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z:

[M+H] ⁺ :478.1 .

Example 143: N-[2-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-2- ethyl]piperidine-1-carboxamide

Step 1: Preparation of tert-butyl N-[2-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]- 1-piperidyl]-2-oxo- ethyljcarbamate.

To a stirred solution of 3-(3,4-dimethoxyphenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole hydrochloride (1 .00 g, 3.07 mmol, 1 .00 eq) and 2-(tert-butoxycarbonylamino) acetic acid (537 mg, 3.07 mmol), (2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (1 .16 g, 3.07 mmol) in N,N- dimethylformamide (10.00 mL) was added N-ethyl-N-(propan-2-yl)propan-2-amine (793 mg, 6.14 mmol, 1 .07 mL) at 25 °C. The mixture was then stirred at 25 °C for 1 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried with anhydrous Na2S04, filtered and concentrated under vacuum to provide the crude product further purified by chromatography (silica, petroleum ether / ethyl acetate=1 00/1 to 50:1 to 1 :1 ). The title compound (tert-butyl N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4- oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]carbamate)was isolated as a pale yellow oil (1 .70 g, crude) (contained some residual ethyl acetate and dimethylformamide, and was used without further purification).

Step 2: 2-amino- 1-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]- 1-piperidyl]ethanone.

To a stirred solution of tert-butyl N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]-2-oxo-ethyl]carbamate (800 mg, 1 .79 mmol) in ethyl acetate (5.00 mL) was added a 4M hydrochloric acid in ethyl acetate (1 5.00 mL). The mixture was then stirred at 25 °C fori h, and then concentrated under vacuum to give 2-amino-1 -[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]ethanone hydrochloride (660 mg, crude), isolated as a white solid and used for the next step without further purification.

Step 3: Preparation of N-[2-[4-[3-(3 -dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]- 1-piperidyl]-2-oxo- ethyljpiperidine- 1 -carb

To a stirred solution of 2-amino-1 -[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]ethanone (200 mg, 522 μιτιοΙ) and piperidine-1 -carbonyl chloride (77 mg, 522 μιτιοΙ, 65 μί) in dichloromethane (3.00 mL) was added triethylamine (158 mg, 1 .57 mmol, 217 μί) at 25 °C. The mixture was then stirred at 25 °C for 5 h. The reaction mixture was poured into 5mL water and extracted with dichloromethane (5 mL x 3). The combined organic extracts were concentrated under vacuum, dissolved in N,N-dimethylformamide (3 mL)and purified by chromatography (Boston Green ODS 150x30

phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 30%-70%,1 1 .5min to give N- [2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]piperidine-1 -carboxamide (1 13 mg, 248 μιτιοΙ, 48 %) isolated as a white solid. Ή NMR (400MHz, CHLOROFORM-d) δ = 7.68 (dd, J=1 .8, 8.3 Hz, 1 H), 7.56 (d, J=1 .8 Hz, 1 H), 6.95 (d, J=8.8 Hz, 1 H), 5.57 (br s, 1 H), 4.46 (br d, J=13.6 Hz, 1 H), 4.1 0 (d, J=3.5 Hz, 2H), 3.95 (d, J=7.5 Hz, 6H), 3.86 (br d, J=14.0 Hz, 1 H), 3.40 - 3.35 (m, 4H), 3.32 - 3.23 (m, 2H), 3.08 (br t, J=1 1 .0 Hz, 1 H), 2.25 - 2.1 5 (m, 2H), 2.03 - 1 .88 (m, 2H), 1 .62 - 1 .51 (m, 6H); LCMS (ESI) m/z: [M+H] ⁺ = 458.1 .

Example 144: N-[2-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-2-oxo-ethyl]-2- methoxy-benzamide.

To a stirred solution of 2-amino-1 -[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]ethanone hydrochloride (200 mg, 522 μιτιοΙ) and 2-methoxybenzoic acid (79 mg, 522 μιτιοΙ) in dichloromethane (3.00 mL) was added 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (661 .8 mg,1 .04 mmol, 681 .51 μΐ, 50% purity) and triethylamine (158 mg, 1 .57 mmol, 217 μί) at 25 °C. The mixture was then stirred at 25 °C for 5 h. The reaction mixture was poured into water (5mL) and extracted with dichloromethane (5 mL x 3). The combined organic extracts were concentrated under vacuum. The resulting residue, dissolved in dimethylsulphoxide (3mL), was purified by chromatography (Boston Green ODS 150 ^* 30mm δμιη ιιτιοοϋβ phase: [water (1 0mM ammonium carbonate)-acetonitrile]; B%: 42%-72%,1 1 .5 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4- oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]-2-methoxy-benzamide (83 mg, 169.3 μιηοΙ, 32 %) isolated as a white solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.01 (br s, 1 H), 8.21 (dd, J=1 .8, 7.9 Hz, 1 H), 7.68 (dd, J=2.2, 8.3 Hz, 1 H), 7.56 (d, J=1 .8 Hz, 1 H), 7.49 - 7.43 (m, 1 H), 7.1 1 - 6.93 (m, 3H), 4.51 (br d, J=13.6 Hz, 1 H), 4.36 (d, J=3.9 Hz, 2H), 4.04 (s, 3H), 3.95 (t, J=7.9 Hz, 7H), 3.38 - 3.26 (m, 2H), 3.13 (br t, J=1 1 .0 Hz, 1 H), 2.28 - 2.17 (d, 2H), 2.07 - 1 .91 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 481 .1 .

Example 145: N-[2-[4-[3-(3,4-dimethoxyphenyl)- 1,2,4-oxadiazol-5-yl]-1-piperidyl]-2- ethyl]pyridine-2-carboxamide.

To a stirred solution of 2-amino-1 -[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]ethanone (200 mg, 522 μιτιοΙ,1 .00 eg, HCI) and pyridine-2-carboxylic acid (64 mg, 522 μιτιοΙ) in dichloromethane (3.00 mL) was added 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (661 .81 mg,1 .04 mmol, 681 .51 μΙ_, 50% purity, 2eq) and triethylamine (158 mg, 1 .57 mmol, 217 μΙ_) at 25 °C, then the mixture was stirred at 25 °C for 5 h. The reaction mixture was poured into water (5ml_) and extracted with dichloromethane (5 mL x 3). The combined organic extracts were concentrated under vacuum. The resulting residue, dissolved in dimethylsulphoxide (3ml_), was purified by prep-HPLC (Boston Green ODS 150x30mm 5μιη ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 35%-65%,1 1 .5 min) to give N-[2-[4-[3-(3,4-dimethoxyphenyl)-1 ,2,4- oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]pyridine-2-carboxamide (85 mg, 182.18 μιηοΙ, 35 %) isolated as a white solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.91 (br s, 1 H), 8.61 (d, J=3.9 Hz, 1 H), 8.17 (d, J=7.9 Hz, 1 H), 7.84 (dt, J=1 .8, 7.7 Hz, 1 H), 7.68 (dd, J=1 .8, 8.3 Hz, 1 H), 7.56 (d, J=1 .8 Hz, 1 H), 7.46 - 7.40 (dd, 1 H), 6.95 (d, J=8.3 Hz, 1 H), 4.53 (br d, J=13.6 Hz, 1 H), 4.33 (d, J=4.4 Hz, 2H), 3.95 (d, J=7.9 Hz, 6H), 3.91 (br s, 1 H), 3.39 - 3.26 (m, 2H), 3.12 (br t, J=1 1 .0 Hz, 1 H), 2.29 - 2.1 8 (t, 2H), 2.07 - 1 .91 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 452.1 .

Example 146: 2-[2-[4-[3-(1,3-dimethylpyrazolo[3,4-b]pyridin-6-yl)-1,2,4-o xadiazol-5^

2-oxo-ethyl]isoindolin-1-one.

Example 146 was synthesized according to the synthetic procedure reported for the preparation of Example 147. ¹ H NMR (400MHz, CHLOROFORM-d) 0 = 8.1 1 (d, J=8.4 Hz, 1 H), 7.89 (d, J=8.2 Hz, 1 H), 7.85 (d, J=8.2 Hz, 1 H), 7.56 - 7.50 (m, 1 H), 7.47 - 7.41 (m, 2H), 4.60 - 4.41 (m, 5H), 4.16 (s, 3H), 4.12 - 4.05 (m, 1 H), 3.41 - 3.31 (m, 2H), 3.06 - 2.98 (m, 1 H), 2.62 - 2.57 (m, 3H), 2.25 (br t, J=14.6 Hz, 2H), 2.05 - 1 .94 (m, 2H); LCMS(ESI) m/z: [M+H] ⁺ :472.3.

Example 147: 2-[2-[4-[3-(5-ethoxy-4-methoxy-2-pyridyl)- 1,2,4-oxadiazol-5-yl]- 1-piperidyl]-2- ethyl]isoindolin-1 -one.

Step 1: methyl 1 -[2-(1 -oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylate.

A mixture of 2-(1 -oxoisoindolin-2-yl)acetic acid (3.0 g, 15.69 mmol), methyl piperidine-4- carboxylate (2.47 g, 17.26 mmol), 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (12.98 g, 20.40 mmol, 12.13 mL, 50% purity) and triethylamine (31 .76 g, 313.80 mmol, 43.51 mL) in dichloromethane (60 mL), was stirred at 20 for 16 h. The reaction mixture was then diluted with water (20 mL) and extracted with dichloromethane (60 mL). The organic layers were combined, washed with saturated aqueous sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to give the crude product further purified by chromatography (silica, petroleum ether / ethyl acetate=1 :2). The title compound methyl 1 -[2-(1 - oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylate was isolated as a yellow solid (4.30 g, 13.6 mmol, 87 %).

Step 2: Preparation of 1 -[2-(1 -oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylic acid.

A mixture of methyl 1 -[2-(1 -oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylate (4.30 g, 13.59 mmol), Lithium hydroxide monohydrate (1 M, 13.59 mL) in tetrahydrofuran (50 mL) was stirred at 20 °C for 1 h, and then acidified to pH 3 by addition of a 1 M aqueous hydrochloric acid solution. The mixture was extracted with dichloromethane 20 mL. The organic layers were combined, washed with saturated aqueous sodium chloride solution (25 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1 -[2-(1 -oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylic acid (2.50 g, 8.27 mmol, 60.85 %) isolated as a white solid, and used for the next step without further purification. Step 3: 2-[2-[4-[3-(5-ethoxy-4-methoxy-2-pyridyl)- 1 ,2,4-oxadiazol-5-yl]- 1 -piperidyl]-2-oxo-ethyl]isoindolin- 1-one.

A mixture of 1 -[2-(1 -oxoisoindolin-2-yl)acetyl]piperidine-4-carboxylic acid (150 mg, 496 μιηοΙ), 5- ethoxy-N'-hydroxy-4-methoxy-pyridine-2-carboxamidine (125 mg, 595 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)- 1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) (282 mg, 744 μιτιοΙ) and N-ethyl-N-(propan-2- yl)propan-2-amine (192 mg, 1 .49 mmol, 259 μΙ_) in N,N-dimethylformamide (2 mL) was stirred at 20 °C for 5 h, and at 1 10°C for 1 h. The mixture was then cooled to room temperature and concentrated under vacuum to give a residue purified by chromatography (Boston Green ODS 150x30 5μιη; mobile phase: [water (1 OmM ammonium carbonate)-acetonitrile]; B%: 25%-45%,1 1 .5min). The title compound 2-[2-[4- [3-(5-ethoxy-4-methoxy-2-pyridyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]isoindolin-1 -one was isolated as a white solid (76 mg, 160 μιτιοΙ, 32 %) as a white solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.26 (s, 1 H), 7.88 - 7.82 (m, 1 H), 7.62 (s, 1 H), 7.56 - 7.52 (m, 1 H), 7.48 - 7.43 (m, 2H), 4.56 (d, J=9.3 Hz, 2H), 4.52 - 4.40 (m, 3H), 4.24 (q, J=7.1 Hz, 2H), 4.07 (br d, J=13.7 Hz, 1 H), 4.00 (s, 3H), 3.40 - 3.26 (m, 2H), 3.05 - 2.97 (m, 1 H), 2.27 - 2.16 (m, 2H), 2.07 - 1 .93 (m, 2H), 1 .50 (t, J=6.9 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 478.3.

Example 148: (R)-5-(4-(3-(4-ethoxy-3-methoxyphenyl)-1,2,4-oxadiazol-5-yl) piperidine-1-carbon phenyloxazolidin-2-one.

To a stirred solution of (R)-2-oxo-3-phenyloxazolidine-5-carboxylic acid (100 mg, 482.67 μιτιοΙ) in dichloromethane (2 mL) was added 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 1 1 mg, 579 μιτιοΙ), HOBt (78 mg, 579 μιτιοΙ), triethylamine (146 mg, 1 .45 mmol, 200 iL) and 3-(4-ethoxy-3-methoxyphenyl)- 5-(piperidin-4-yl)-1 ,2,4-oxadiazole hydrochloride (164 mg, 482.67 μιτιοΙ). The reaction mixture was stirred at 25 °C for 12 h and then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Boston Green ODS 150x30 5μιη; mobile phase: [water (10mM ammonium carbonate)- acetonitrile]; B%: 45%-75%,1 1 .5min) to give (R)-5-(4-(3-(4-ethoxy-3-methoxyphenyl)-1 ,2,4-oxadiazol-5- yl)piperidine-1 -carbonyl)-3-phenyloxazolidin-2-one (139 mg, 280 μιηοΙ, 58 %) as a pale yellow solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ 7,67 (d, J=8.3 Hz, 1 H), 7,59 - 7.55 (m, 3H), 7.40 (t, J=7.7 Hz, 2H), 7,17 (t, J=6.9 Hz, 1 H), 6.95 (dd, J=1 ,1 , 8.6 Hz, 1 H), 5.25 (ddd, J=3,1 , 6.2, 9.1 Hz, 1 H), 4.81 (dd, J=6.8, 8,6 Hz, 1 H), 4,58 (br d, J=14.0 Hz, 0.5H), 4.37 - 4.21 (m, 1 H), 4.17 (q, J=7.0 Hz, 2H), 4.07 (dt, J=2.6, 9.0 Hz, 1 ,5H), 3.96 (d, J=2.2 Hz, 3H), 3.59 (ddd, J=3.3, 10.3, 14.0 Hz, 0.5H), 3,41 - 3.17 (m, 2H), 3.09 - 3.00 (m, 0,5H), 2.34 - 1 .95 (m, 4H), 1 .54 - 1 .47 (m, 3H) ; LCMS (ESI) m/z: [M+H] ⁺ = 493,3.

Example 149: (S)-5-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5 -yl)piperidi

3- hen loxazolidin-2-one. "

Step 1: Preparation of benzyl phe

To a stirred solution of aniline (5.0 g, 53.69 mmol, 4.90 mL) in tetrahydrofuran (100 mL) at 0 °C was added saturated aqueous sodium hydrogen carbonate (4.96 g, 59.06 mmol, 2.30 mL) followed by benzyl chloroformate (10.07 g, 59.06 mmol, 8.39 mL). The reaction mixture was stirred for 0.25h at 0 °C, warmed to 25 °C and stirring was continued for 0.75 h at 25 °C. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic extracts were dried over anhydrous anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide benzyl phenylcarbamate (12.98 g, 53.7 mmol, 100 %) isolated as a white solid, and used for the next step without further purification Ή NMR (400MHz, DMSO-de) δ 9.76 (s, 1 H), 7.53 - 7.23 (m, 9H), 6.99 (t, J=7,1 Hz, 1 H), 5.15 (s, 2H).

Step 2: Preparation of (S)-5-(hydroxymethyl)-3-phenyloxazolidin-2-one.

A solution of benzyl phenylcarbamate (3.0 g, 13.20 mmol) in dry tetrahydrofuran (30 mL) was cooled to -78 °C under dry nitrogen atmosphere. A solution of n-butyl lithium in tetrahydrofuran (2.5 M, 7.92 mL) was slowly added to the reaction mixture which was stirred for 0.75h at -78 °C. A solution of (S)-oxiran-2-ylmethyl butyrate (2.28 g, 15.84 mmol) in dry tetrahydrofuran (1 0 mL) was slowly added to the mixture which was stirred at -78 °C for 2 h and then slowly warmed to 25 °C. Stirring was continued for 12h at room temperature and the reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (30 mL). Ethyl acetate (30 mL) and water (30 mL) were added to the mixture and the layers were separated. The aqueous layer was further extracted with ethyl acetate (3 X30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product purified by chromatography (silica, petroleum ether : ethyl acetate = 1 :1 ). The title compound (S)-5-(hydroxymethyl)-3-phenyloxazolidin-2-one was isolated as a white solid (1 .70 g, 8.80 mmol, 67 %). ¹ H NMR (400MHz, METHANOLS) δ 7.57 (d, J=7.8 Hz, 2H), 7.43 - 7.31 (m, 2H), 7,14 (t, J=7.2 Hz, 1 H), 4.78 - 4.71 (m, 1 H), 4.13 (t, J=9.0 Hz, 1 H), 3,94 (dd, J=6.6, 8.8 Hz, 1 H), 3,85 (dd, J=3.4, 12.5 Hz, 1 H), 3.70 (dd, J=4.2, 12.6 Hz, 1 H).

Step 3: Preparation of (S)-2-oxo-3-phenyloxazolidine-5-carboxylic acid.

To an ice-cooled solution of NalC (3.88 g, 18.13 mmol, 1 .01 mL) in water (30 mL) was added a solution of (S)-5-(hydroxymethyl)-3-phenyloxazolidin-2-one (1 .0 g, 5.1 8 mmol) in a mixture of acetonitrile (20 mL) and carbon tetrachloride (20 mL). Solid RUCI3.H2O (58 mg, 259 μιηοΙ) was added to the reaction mixture which was stirred at 0 °C for 0.5 h, warmed to 25 °C and then stirred at 25 °C for an additional 12 h. The suspension was then filtered and the filtered solid was washed thoroughly with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure to provide a residue further dissolved in ethyl acetate (50mL). The organic solution was washed with saturated aqueous sodium carbonate (2 X 20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 X 30 mL). The combined organic phases were dried over anhydrous anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (850 mg) crude. 500 mg of this crude product was purified by prep-HPLC (column: Luna C18 1 50x25mm 5μιτι ; mobile phase: [water (0.225%FA)-acetonitrile]; B%: 30%-50%,12min) to give 1 50 mg of (S)-2-oxo-3-phenyloxazolidine-5-carboxylic acid as an off-white solid. ¹ H NMR (400MHz,

CHLOROFORM-d) δ 7.57 - 7.45 (m, 2H), 7.44 - 7.34 (m, 2H), 7.24 - 7.1 0 (m, 1 H), 5.12 (dd, J=5.3, 9.8 Hz, 1 H), 4.37 (t, J=9.6 Hz, 1 H), 4.19 (dd, J=5.3, 9.4 Hz, 1 H).

Step 4: Preparation of (S)-5-(4-(3-(1,3-dimethyl- 1H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidine- 1^ carbonyl)-3-phenyloxazolidin- -one.

To a stirred solution of (S)-2-oxo-3-phenyloxazolidine-5-carboxylic acid (80 mg, 386 μιηοΙ) in hydroxybenzotriazole (62 mg, 463 μιηοΙ), triethylamine (1 17 mg, 1 .1 6 mmol, 160 μί) and 3-(1 ,3-dimethyl- 1 H-indazol-6-yl)-5-(piperidin-4-yl)-1 ,2,4-oxadiazole, hydrochloride (128 mg, 386 μιηοΙ, hydrochloric acid). The reaction mixture was stirred at 25 °C for 12 h and was then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Boston Green ODS 1 50x30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 43%-73%,1 1 .5min) to give (S)-5-(4-(3-(1 ,3-dimethyl-1 H- indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidine-1 -carbonyl)-3-phenyloxazolidin-2-one (82 mg, 168.7 μιτιοΙ, 44 %) isolated as a white solid. ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.1 1 (d, J=7.9 Hz, 1 H), 7.84 (d, J=8.8 Hz, 1 H), 7.74 (dd, J=3.5, 8.3 Hz, 1 H), 7.58 (d, J=8.3 Hz, 2H), 7.41 (t, J=7.7 Hz, 2H), 7.20 - 7.16 (m, 1 H), 5.26 (dd, J=7.5, 8,3 Hz, 1 H), 4.83 (dd, J=6.4, 9,0 Hz, 1 H), 4.66 - 4,57 (m, 0.5H), 4.38 - 4,27 (m, 1 H), 4,09 (d, J=3.1 Hz, 4.5H), 3.66 - 3,59 (m, 0.5H), 3.45 - 3,32 (m, 2H), 3.08 (br t, J=1 1 .2 Hz, 0.5H), 2.60 (s, 3H), 2.39 - 2.25 (m, 2H), 2.24 - 1 .97 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 487.3.

Example 150: N-[2-[4-[3-(1,3-dimethylindazol-6-yl)-1,2,4-oxadiazol-5-yl]- ^

methoxy-pyridine-2-carboxamide.

To a stirred solution of 2-amino-1 -[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazoi-5-yi]-1 - piper!dyi]ethanone (130 mg, 366.81 moi) in dichloromethane (3 mL) was added 4-methoxypyridine-2- carboxyiic acid (56 mg, 366.81 μηΊθΙ), 2,4,6-trlpropyi-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-triox!de in ethyl acetate (256 mg, 403 μιηοΙ, 239 μί, 50% purity) and triethyiamine (1 1 1 mg, 1 .10 mmol, 152 μΙ_). The mixture was stirred at 20 °C for 1 h and then concentrated under reduced pressure. The resulting residue was purified by chromatography (column: Luna C18 100x30 5μηι ; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 20%-6Q%,1 Omin) to give N-[2-[4-[3-(1 ,3-dimethylindazoi~6-yl)- 1 ,2,4-oxadlazol-5~y!]~1 -piperidyi]-2-oxo~ethyi]-4-methoxy-pyridine-2-carboxamide (18 mg, 35 μιηοΙ, 10 %) as a white solid. Ή NMR (400 MHz, CDCb) δ 8.93 (br s, 1 H), 8.41 (d, J=5.5 Hz, 1 H), 8.10 (s, 1 H), 7.86 - 7.80 (m, 1 H), 7,77 - 7.69 (m, 2H), 6.93 (dd, J=2.4, 5.5 Hz, 1 H), 4.56 (br d, J=14.1 Hz, 1 H), 4.34 (d, J=4.4 Hz, 2H), 4.08 (s, 3H), 3.96 (br d, J=13.9 Hz, 1 H), 3.92 (s, 3H), 3.41 - 3.31 (m, 2H), 3.14 (br t, J=1 1 .6 Hz, 1 H), 2.60 (s, 3H), 2.33 - 2.22 (m, 2H), 2,1 1 - 1 .95 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 490.2.

Example 151: N-(2-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)-5-methoxypicolinamide.

Example 151 was synthesized according to a procedure similar to the one described in Example 154. ¹ H NMR (400 MHz, CDCb) δ 8.72 (br s, 1 H), 8.27 (d, J=2.6 Hz, 1 H), 8.13 (d, J=8.6 Hz, 1 H), 8.09 (s, 1 H), 7.85 - 7.79 (m, 1 H), 7.77 - 7.68 (m, 1 H), 7.29 (d, J=2.6 Hz, 1 H), 4.55 (br d, J=13.7 Hz, 1 H), 4.33 (d, J=4.2 Hz, 2H), 4.08 (s, 3H), 3.96 (br d, J=13.9 Hz, 1 H), 3.91 (s, 3H), 3.40 - 3.30 (m, 2H), 3.13 (br t, J=10.9 Hz, 1 H), 2.60 (s, 3H), 2.27 (br t, J=1 1 .8 Hz, 2H), 2.09 - 1 .95 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ 490.2.

Example 152: N-(2-(4-(3-(1 ,3-dimethyl-1 H-indazol-6-yl)-1 ,2,4-oxadiazol-5-yl)piperidin-1^

oxoethyl)-2-methoxybenzamide.

Example 152 was synthesized according to a procedure similar to the one described in Example 154. ¹ H NMR (400 MHz, CDCb) δ 9.03 (br s, 1 H), 8.22 (dd, J=1 .4, 7.8 Hz, 1 H), 8.10 (s, 1 H), 7.87 - 7.80 (m, 1 H), 7.77 - 7.71 (m, 1 H), 7.51 - 7.43 (m, 1 H), 7.09 (t, J=7.6 Hz, 1 H), 7.01 (d, J=8.2 Hz, 1 H), 4.55 (br d, J=13.9 Hz, 1 H), 4.38 (d, J=4.0 Hz, 2H), 4.08 (s, 3H), 4.05 (s, 3H), 3.96 (br d, J=14.1 Hz, 1 H), 3.41 - 3.31 (m, 2H), 3.15 (br t, J=1 1 .4 Hz, 1 H), 2.60 (s, 3H), 2.28 (br t, J=10.6 Hz, 2H), 2.10 - 1 .96 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 489.3.

Example 153: N-(2-(4-(3-(1,3-dimethyl-1H-indazol-6-yl)-1,2,4-oxadiazol-5- yl)piperid

oxoethyl)picolinamide.

Example 153 was synthesized according to a procedure similar to the one described in Example 154. ¹ H NMR (400 MHz, CDCb) δ 8.93 (br s, 1 H), 8.63 (d, J=4.0 Hz, 1 H), 8.19 (d, J=7.7 Hz, 1 H), 8.10 (s, 1 H), 7.89 - 7.80 (m, 2H), 7.76 - 7.71 (m, 1 H), 7.47 - 7.41 (m, 1 H), 4.56 (br d, J=13.7 Hz, 1 H), 4.35 (d, J=4.4 Hz, 2H), 4.09 (s, 3H), 3.96 (br d, J=13.9 Hz, 1 H), 3.44 - 3.31 (m, 2H), 3.15 (br t, J=10.7 Hz, 1 H), 2.60 (s, 3H), 2.34 - 2.23 (m, 2H), 2.1 1 - 1 .95 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 460.2.

Example 154: N-[2-[4-[3-(1,3-dimethylindazol-6-yl)-1,2,4-oxadiazol-5-yl]- 1^ipe

methoxy-pyridine-2-carboxamide. c

Step 1: Preparation of tert-butyl N-[2-[4-[3-(1,3-dimethylindazol-6-yl)- 1,2,4-oxadiazol-5-yl]- 1-piperidyl]-2- oxo-ethyl]carbamate.

BocHN

To a stirred solution of 3-(1 ,3-dimethylindazol-6-yl)-5-(4-piperidyl)-1 ,2,4-oxadiazole (1 .0 g, 3.00 mmol, 1 .00 eq, hydrochloric acid salt) in dichloromethane (20 mL) was added 2-(tert- butoxycarbonylamino)acetic acid (525 mg, 3.00 mmol), 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (2.86 g, 4.50 mmol, 2.68 mL, 50% purity) and triethylamine (1 .82 g, 18.00 mmol, 2.49 mL, 6.00 eq). The mixture was stirred at 20 for 16 h. Water (30 mL) was then added to the reaction mixture which was extracted with dichloromethane (60 mL x 3). The combined organic extracts were washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product further purified by chromatography (silica, petroleum ether : ethyl acetate = 20:1 to 1 :4). The title compound (tert-butyl N-[2- [4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]carbamate) was isolated as a white solid (1 .0 g, 2.20 mmol, 73 %). ¹ H NMR (400 MHz, CDC ) δ 8.1 0 (s, 1 H), 7.86 - 7.80 (m, 1 H), 7.77 - 7.72 (m, 1 H), 5.53 (br s, 1 H), 4.50 (br d, J=12.3 Hz, 1 H), 4.09 (s, 3H), 4.02 (br d, J=3.5 Hz, 2H), 3.83 (br d, J=12.7 Hz, 1 H), 3.38 - 3.23 (m, 2H), 3.10 (br t, J=1 1 .6 Hz, 1 H), 2.60 (s, 3H), 2.23 (br s, 2H), 2.06 - 1 .94 (m, 2H), 1 .47 (s, 9H).

Step 2: Preparation of 2-amino- 1-[4-[3-( 1 ,3-dimethylindazol-6-yl)- 1,2,4-oxadiazol-5-yl]- 1- piperidyljethanone.

To a stirred solution of tert-butyl N-[2-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]-2-oxo-ethyl]carbamate (980 mg, 2.16 mmol) in ethyl acetate (5 mL) was added a 4M solution of hydrochloric acid in ethyl acetate (50 mL). The mixture was stirred at 20 °C for 0.5 h and then concentrated under reduced pressure to give 2-amino-1 -[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol- 5-yl]-1 -piperidyl]ethanone, hydrochloride (940 mg, crude)) isolated as a white solid and used for the next step without further purification. ¹ H NMR (400 MHz, Methanoi-d4) δ 8.19 (s, 1 H), 7.83 (d, J=0.9 Hz, 2H), 4.48 (br d, J=13.9 Hz, 1 H), 4.06 (s, 3H), 4.04 - 3.95 (m, 2H), 3.86 (br d, J=13.9 Hz, 1 H), 3.53 - 3.43 (m, 1 H), 3.38 (br t, J=1 1 .5 Hz, 1 H), 3.13 (br t, J=1 1 .2 Hz, 1 H), 2.58 (s, 3H), 2.28 (br t, J=9.3 Hz, 2H), 2.01 - 1 .84 (m, 2H).

Step 3: Preparation of N-[2-[4-[3-(1 ,3-dimet yiindazoi-6-yi)- 1 ,2 -oxadiazoi-5-yi]- ^

6-methoxy-pyridine-2-carboxa

To a stirred solution of 2-amino-1 -[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]-1 - piperidyl]ethanone (130 mg, 366.81 μιηοΙ) in N,N-dimethylformamide (2 mL) was added 6- methoxypyridine-2-carboxylic acid (56 mg, 366.81 μιηοΙ), (2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (166 mg, 440 μιηοΙ) and N-ethyl-N-(propan-2-yl)propan-2- amine (142 mg, 1 .10 mmol, 192 μΙ_). The mixture was stirred at 20 °C for 1 h and concentrated under reduced pressure. The resulting residue was purified by chromatography (column: Luna C18 100x30 5μιη; mobile phase: [water (10mM ammonium carbonate)-acetonitrile]; B%: 25%-65%,10min) to give N- [2-[4-[3-(1 ,3-dimethylindazol-6-yl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]-6-methoxy-pyridine-2- carboxamide (92 mg, 187.6 μιτιοΙ, 51 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 8.82 (br s, 1 H), 8.10 (s, 1 H), 7.86 - 7.69 (m, 4H), 6.92 (d, J=8.2 Hz, 1 H), 4.55 (br d, J=13.9 Hz, 1 H), 4.34 (d, J=4.2 Hz, 2H), 4.08 (s, 3H), 4.05 (s, 3H), 4.01 - 3.92 (m, 1 H), 3.43 - 3.32 (m, 2H), 3.17 (br t, J=1 1 .1 Hz, 1 H), 2.60 (s, 3H), 2.34 - 2.23 (m, 2H), 2.12 - 1 .97 (m, 2H); LCMS (ESI) m/z: [M+H] ⁺ = 490.3. Example 155: N-(2-(4-(3-(4-ethoxy-3-methoxyphenyl)- 1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2- oxoethyl)benzamide.

Step 1: Preparation of 4-ethoxy-3-methoxy-benzonitrile.

To a 0 °C stirred solution of 4-hydroxy-3-methoxy-benzonitrile (20g, 134.09 mmol) in N,N- dimethylformamide (200 mL) was added iodoethane (25.1 0 g, 160.91 mmol, 12.87 mL), potassium carbonate (37.07 g, 268.18 mmol). The reaction mixture was stirred at 40 °C for 16 h and then quenched by addition of water (300 mL). The mixture was extracted with ethyl acetate (200mL x 3) and the combined organic extracts were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-ethoxy-3- methoxy-benzonitrile (25.0 g, crude), isolated as a yellow solid and used for the next step without further purification. ¹ H NMR (400 MHz, CDC ) δ 7.30 - 7.20 (m, 1 H), 7.07 (d, J=1 .8 Hz, 1 H), 6.88 (d, J=8.4 Hz, 1 H), 4.14 (q, J=7.0 Hz, 2H), 3.88 (s, 3H), 1 .49 (t, J=7.0 Hz, 3H).

Step 2: Preparation of 4-ethoxy-N'-hydro -3-methoxy-benzamidine.

To a stirred solution of 4-ethoxy-3-methoxy-benzonitrile (25.0 g, 141 .08 mmol) in ethanol (200 mL) was added hydroxylamine hydrochloride (19.61 g, 282.17 mmol), triethylamine (28.55 g, 282.17 mmol, 39.1 1 mL) and water (20 mL). The mixture was stirred at 80 °C for 2 h and then concentrated under reduced pressure. The resulting residue was diluted with water (30 mL) and filtered to provide 4- ethoxy-N'-hydroxy-3-methoxy-benzamidine isolated as a white solid (24.0 g, 1 14.2 mmol, 81 %) and used for the next step without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 9.47 (br s, 1 H), 7.25 (d, J=2.0 Hz, 1 H), 7.20 (dd, J=2.0, 8.4 Hz, 1 H), 6.92 (d, J=8.4 Hz, 1 H), 5.75 (br s, 2H), 4.01 (q, J=7.0 Hz, 2H), 3.76 (s, 3H), 1 .32 (t, J=7.0 Hz, 3H).

Step 3: Preparation of tert-butyl 4-[3-(4-ethoxy-3-methoxy-phenyl)- 1,2,4-oxadiazol-5-yl]piperidine- 1- carboxylate.

To a stirred solution of 4-ethoxy-N'-hydroxy-3-methoxy-benzamidine (10.0 g, 47.57 mmol) in N,N- dimethylformamide (100 mL) was added 1 -tert-butoxycarbonylpiperidine-4-carboxylic acid (1 0.91 g, 47.57 mmol), 2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexaf!uorophosphate (18.04 g, 47.57 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (18.44 g, 142.71 mmol, 24.92 mL). The mixture was stirred at 20 °C for 16 h and at 1 10 °C for 1 h. The reaction mixture was then cooled to room temperature, quenched by addition of water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product further was purified by chromatography (silica, petroleum ethe : ethyl acetate = 1 :0 to 10:1 ), The title compound, tert-butyi 4-[3- (4-ethoxy-3-methoxy-phenyi)-1 ,2,4-oxadiazoi-5-yi]piperidine-1 -carboxyiate, was isolated as a yellow solid (13.30 g, 33.0 mmol, 69 %). Step 4: Preparation of 3-(4-ethoxy-3-methoxy-phenyl)-5-(4-piperidyl)- 1 ,2,4-oxadiazole.

To a stirred solution of tert-buty! 4-[3-(4-ethoxy-3-methoxy-phenyl)-1 ,2,4-oxadiazai-5-yi]piperidine- 1 -earboxy!ate (13.30 g, 32.96 mmol) in ethyl acetate (300 mL) was added a 4M solution of hydrochloric acid in methanol (30 mL). The mixture was stirred at 20 ^* C for 2 h and filtered to give 3-(4-ethoxy-3- methoxy-phenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole hydrochloride (10.0 g, 29.4 mmol, 89 %), isolated as a white solid and used for the next step without further purification.

Step 5: Preparation of N-[2-[4-[3-(4-ethoxy-3-methoxy-phenyl)- 1,2,4-oxadiazol-5-yl]- 1-piperidyl]-2-oxo- ethyl enzamide.

To a stirred solution of 2-benzamidoacetic acid (1 .16 g, 6.48 mmol) in dichloromethane (20 mL) was added 3-(4-ethoxy-3-methoxy-phenyl)-5-(4-piperidyl)-1 ,2,4-oxadiazole hydrochloride (2.0 g, 5.89 mmol), 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide in ethyl acetate (4.87 g, 7.65 mmol, 4.55 mL, 50% in ethyl acetate) and triethylamine (2.38 g, 23.5 mmol, 3.26 mL). The mixture was stirred at 20 °C for 16 h. Water (20 mL) was then added to the mixture which was extracted with dichloromethane (80 mL x 2). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue dissolved in with ethyl acetate (40 mL). The organic solution was washed with 1 N aqueous hydrochloric acid solution (15 mL x 2), saturated sodium carbonate (15 mL x 2), saturated aqueous sodium chloride solution (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. To a solution of the crude product in methyl tert-butyl ether (20 mL) was added petroleum ether (2 mL). The precipitate, formed after 2 h stirring at room temperature, was collected by filtration, washed with methyl tert-butyl ether (5 mL x 2) and dried under reduced pressure to give N-[2-[4-[3-(4-ethoxy-3-methoxy- phenyl)-1 ,2,4-oxadiazol-5-yl]-1 -piperidyl]-2-oxo-ethyl]benzamide (1 .68 g, 3.60 mmol, 61 %) as a white solid. ¹ H NMR (400 MHz, CDC ) δ 7.89 - 7.83 (m, 2H), 7.66 (dd, J=1 .9, 8.3 Hz, 1 H), 7.58 - 7.42 (m, 4H), 7.35 (br s, 1 H), 6.95 (d, J=8.4 Hz, 1 H), 4.50 (td, J=3.8, 13.6 Hz, 1 H), 4.30 (d, J=4.0 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 3.96 (s, 3H), 3.94 - 3.87 (m, 1 H), 3.38 - 3.27 (m, 2H), 3.19 - 3.08 (m, 1 H), 2.24 (m, 2H), 2.07 - 1 .91 (m, 2H), 1 .50 (t, J=7.0 Hz, 3H); LCMS (ESI) m/z: [M+H] ⁺ = 465.2. Example 156. Characterization Data of Compounds of the Invention

The following compounds were synthesized by methods similar to those described above.

¹ H NMR (400 MHz, DMSO-de) δ 8.10-7.71 (m, 5H), 7.65-7.30 (m, 7H), 4.87 (br s, 2H), 4.26 (s, 2H), 3.69 (br s, 2H), 1 .23 (br s, 3H); LCMS (ESI) [M+H]+: 372.1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.07-8.00 (m, 1 H), 7.99-7.91 (m, 1 H), 7.86 (d, J = 6.2 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.58-7.52 (m, 3H), 7.49 (br s, 2H), 7.20 (d, J = 8.4 Hz, 1 H), 4.92 (br s, 2H), 4.32 (s, 2H), 3.91 (d, J = 6.2 Hz, 6H), 3.74 (br s, 2H), 1 .28 (br s, 3H); LCMS (ESI) [M+H]+: 432.1 .

¹ H NMR (400 MHz, DMSO-de) δ 7.71 -7.59 (m, 1 H), 7.33 (br d, J = 8.6 Hz, 1 H), 7.1 8 (d, J = 8.4 Hz, 1 H), 6.89 (br d, J = 8.6 Hz, 2H), 4.76 (s, 2H), 4.06-3.91 (m, 2H), 3.74 (s, 3H), 1 .60-1 .49 (m, 2H), 1 .34 (br d, J 2.2 Hz, 2H), 1 .16 (br t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 392.2.

¹ H NMR (400 MHz, DMSO-de) δ 7.73-7.63 (m, 2H), 7.44-7.39 (m, 2H), 7.37-7.25 (m, 3H), 7.21 -7.15 (m, 1 H), 4.84-4.69 (s, 2H), 4.05-3.91 (m, 2H), 1 .62-1 .54 (m, 2H), 1 .43-1 .36 (m, 2H), 1 .16 (s, 3H); LCMS (ESI) [M+H]+: 362.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.71 (dd, J = 1 .8, 8.3 Hz, 1 H), 7.63 (d, J = 1 .9 Hz, 1 H), 7.37- 7.31 (m, 2H), 7.27 (t, J = 7.5 Hz, 2H), 7.22-7.16 (m, 2H), 7.00 (d, J = 8.3 Hz, 1 H), 4.60 (s, 2H), 4.28 (q, J = 7.2 Hz, 1 H), 3.99 (q, J = 7.1 Hz, 2H), 1 .69 (d, J = 7.2 Hz, 3H), 1 .25 (t, J = 7.2 Hz, 3H); LCMS (ESI) [M+H]+: 350.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09-8.1 1 (m, 2H), 7.51 -7.53 (m, 5H), 7.25-7.40 (m, 3H), 1 .72- 1 .74 (t, 2H), 1 .43-1 .46 (t, 2H); LCMS (ESI) [M+H]+: 263.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.06 (br s, 1 H), 7.88-7.80 (m, 3H), 7.69 (s, 1 H), 7.53-7.44 (m, 3H), 7.40-7.30 (m, 1 H), 7.1 8-7.16 (d, J = 8.4 Hz, 1 H), 4.54-4.50 (m, 1 H), 4.33-4.32 (d, J = 4.0 Hz, 2H), 3.95-3.91 (m, 1 H), 3.49 (s, 3H), 3.39-3.13 (m, 1 H), 2.30-2.23 (m, 2H), 2.05-1 .98 (m, 2H); LCMS (ESI) [M+H]+: 461 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.64 (t, J = 1 .1 Hz, 1 H), 8.1 1 (dd, J = 1 .2, 9.4 Hz, 1 H), 7.96 (dd, J = 1 .0, 9.4 Hz, 1 H), 7.87-7.81 (m, 2H), 7.54-7.48 (m, 1 H), 7.47-7.41 (m, 2H), 7.31 (br s, 1 H), 4.57-4.48 (m, 1 H), 4.30 (d, J = 3.7 Hz, 2H), 3.92 (br d, J = 14.1 Hz, 1 H), 3.41 -3.31 (m, 2H), 3.20-3.09 (m, 1 H), 2.27 (dt, J = 3.7, 13.2 Hz, 2H), 2.00 (ddq, J = 4.1 , 1 0.6, 14.4 Hz, 2H); LCMS (ESI) [M+H]+: 433.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.63 (s, 1 H), 8.10 (d, J = 9.3 Hz, 1 H), 7.95 (d, J = 9.3 Hz, 1 H), 7.57 (d, J = 7.9 Hz, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.18-7.12 (m, 1H), 4.63-4.43 (m, 1H), 4.30 (br t, J = 7.9 Hz, 1 H), 4.06-3.87 (m, 2H), 3.57 (quin, J = 8.6 Hz, 1 H), 3.45-3.28 (m, 2H), 3.17-2.75 (m, 3H), 2.36-2.20 (m, 2H), 2.07-1.89 (m, 2H); LCMS (ESI) [M+H]+: 459.2.

¹ H NMR (400 MHz, METHANOLS) δ 8.14 (s, 1H), 7.77-7.70 (m, 3H), 7.62-7.47 (m, 2H), 7.51-7.46 (m, 1 H), 4.64-4.42 (m, 5H), 4.09-4.01 (m, 1 H), 4.01 (s, 3H), 3.48-3.37 (m, 2H), 3.06 (br t, J = 11.0 Hz, 1 H), 2.53 (s, 3H), 2.32-2.18 (m, 2H), 2.07-1.84 (m, 2H); LCMS (ESI) [M+H]+: 471.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (s, 1 H), 7.85 (d, J = 7.0 Hz, 2H), 7.54-7.42 (m, 3H), 7.32 (brs, 1H), 4.51 (brd, J = 13.6 Hz, 1H), 4.29 (t, J = 4.8 Hz, 2H), 4.26-4.17 (m, 5H), 3.90 (br d, J = 14.0 Hz, 1H), 3.42-3.28 (m, 2H), 3.10 (br t, J = 11.0 Hz, 1H), 2.33-2.22 (m, 2H), 2.13-1.95 (m, 2H), 1.52 (t, J = 7.0 Hz, 3H); LCMS (ESI) [M+H]+: 467.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.68 (dd, J = 1.8, 8.3 Hz, 1 H), 7.56 (d, J = 1.8 Hz, 1 H), 7.36- 7.27 (m, 3H), 7.24-7.20 (m, 1H), 6.95 (d, J = 8.3 Hz, 1H), 4.76-4.53 (m, 1H), 3.86-3.93 (m, 1H), 3.94-3.96 (d, J = 8.3 Hz, 6H), 3.34-3.14 (m, 2H), 3.34-3.11 (m, 1H), 2.93 (quin, J = 7.0 Hz, 1H), 2.97-2.89 (m, 1H), 2.34-1.88 (m, 4H), 1.26 (d, J = 7.0 Hz, 6H); LCMS (ESI) [M+H]+: 436.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (d, J = 3.1 Hz, 1 H), 8.01 -7.88 (m, 2H), 7.87-7.80 (m, 1 H), 7.78-7.71 (m, 1 H), 7.53-7.42 (m, 2H), 4.63-4.49 (m, 1 H), 4.34 (dd, J = 7.1 , 8.8 Hz, 1 H), 4.09 (d, J = 2.6 Hz, 3H), 4.04-3.92 (m, 2H), 3.63 (quin, J = 8.2 Hz, 1 H), 3.48-3.34 (m, 2H), 3.21 -2.85 (m, 3H), 2.61 (s, 3H), 2.30 (br t, J = 14.3 Hz, 2H), 2.1 1 -1 .94 (m, 2H); LCMS (ESI) [M+H]+: 51 0.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.69 (br s, 1 H), 8.32 (dd, J = 1 .5, 4.2 Hz, 1 H), 8.1 0 (s, 1 H), 7.86- 7.80 (m, 1 H), 7.77-7.71 (m, 1 H), 7.45-7.36 (m, 2H), 4.54 (br d, J = 13.9 Hz, 1 H), 4.37 (br d, J = 3.5 Hz, 2H), 4.09 (s, 3H), 4.00 (s, 3H), 3.96 (br s, 1 H), 3.41 -3.31 (m, 2H), 3.14 (br t, J = 1 1 .1 Hz, 1 H), 2.60 (s, 3H), 2.33-2.22 (m, 2H), 2.1 1 -1 .94 (m, 2H); LCMS (ESI) [M+H]+: 490.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (br d, J = 7.1 Hz, 1 H), 7.87-7.79 (m, 1 H), 7.78-7.63 (m, 3H), 7.56-7.48 (m, 1 H), 7.46-7.38 (m, 1 H), 4.56 (br t, J = 13.6 Hz, 1 H), 4.32-4.22 (m, 1 H), 4.17-3.96 (m, 5H), 3.74 (quin, J = 8.2 Hz, 1 H), 3.48-3.31 (m, 2H), 3.20-3.04 (m, 1 H), 3.01 -2.84 (m, 2H), 2.60 (s, 3H), 2.36- 2.21 (m, 2H), 2.1 0- 1 .93 (m, 2H); LCMS (ESI) [M+H]+: 510.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.05 (s, 1 H), 7.87-7.78 (m, 4H), 7.54-7.42 (m, 2H), 7.35 (br s, 1 H), 5.00-4.91 (spt, J = 6.8 Hz, 1 H), 4.52-4.50 (br d, J = 13.7 Hz, 1 H), 4.35-4.27 (d, J = 3.7 Hz, 2H), 3.94-3.91 (br d, J = 13.9 Hz, 1 H), 3.38-3.32 (m, 2H), 3.18-3.12 (br t, J = 1 1 .0 Hz, 1 H), 2.35-2.21 (m, 2H), 2.09-1 .96 (m, 2H), 1 .63-1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 473.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (br d, J = 8.2 Hz, 1 H), 7.60-7.55 (m, 3H), 7.40 (t, J = 7.7 Hz, 2H), 7.18 (t, J = 6.9 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 5.28-5.22 (m, 1 H), 4.84-4.79 (m, 1 H), 4.59 (br d, J = 13.5 Hz, 0.5H), 4.36-4.22 (m, 1 H), 4.1 8 (q, J = 7.1 Hz, 2H), 4.13-4.03 (m, 1 .5H), 3.97 (d, J = 2.2 Hz, 3H), 3.64-3.54 (m, 0.5H), 3.41 -3.27 (m, 2H), 3.09-3.01 (m, 0.5H), 2.35-2.15 (m, 2.5H), 2.1 1 -1 .93 (m, 1 .5H), 1 .51 (t, J = 6.8 Hz, 3H); LCMS (ESI) [M+H]+: 492.8.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (d, J = 7.5 Hz, 1 H), 7.84 (dd, J = 1 .3, 8.3 Hz, 1 H), 7.74 (dd, J = 3.9, 8.3 Hz, 1 H), 7.58 (d, J = 7.9 Hz, 2H), 7.40 (t, J = 7.7 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1 H), 5.26 (t, J = 7.7 Hz, 1 H), 4.83 (dd, J = 6.6, 8.8 Hz, 1 H), 4.62 (d, J = 13.6 Hz, 0.5H), 4.38-4.26 (m, 1 H), 4.13-4.05 (m, 4.5H), 3.66-3.58 (m, 0.5H), 3.45-3.31 (m, 2H), 3.1 1 -3.04 (m, 0.5H), 2.60 (s, 3H), 2.40-2.25 (m, 2H), 2.24- 1 .96 (m, 2H); LCMS (ESI) [M+H]+: 487.3.

¹ H NMR (400 MHz, DMSO-de) δ 8.28 (s, 1 H), 8.1 7 (s, 1 H), 7.92-7.90 (d, J = 8.4 Hz, 1 H), 7.75-7.73 (d, J = 8.4 Hz, 1 H), 7.66-7.64 (br d, J = 8.2 Hz, 2H), 7.38-7.33 (dt, J = 3.7, 7.8 Hz, 2H), 7.13-7.1 1 (m, 1 H), 5.15- 5.1 1 (dt, J = 3.5, 6.5 Hz, 1 H), 4.39-4.35 (br d, J = 13.2 Hz, 1 H), 4.06-3.93 (m, 3H), 3.78-3.70 (m, 1 H), 3.50-3.45 (br t, J = 10.7 Hz, 1 H), 3.36-3.33 (m, 1 H), 2.98-2.93 (m, 1 H), 2.81 -2.71 (m, 2H), 2.20-2.13 (br t, J = 14.0 Hz, 2H), 1 .89-1 .65 (m, 2H), 1 .49-1 .48 (d, J = 6.4 Hz, 6H); LCMS (ESI) [M+H]+: 499.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.69-7.62 (m, 2H), 7.55 (d, J = 1 .8 Hz, 1 H), 7.45 (dt, J = 4.6, 7.7 Hz, 1 H), 7.27-7.24 (m, 1 H), 7.27-7.19 (m, 1 H), 6.94 (d, J = 8.6 Hz, 1 H), 4.63 (d, J = 2.9 Hz, 2H), 4.55-4.39 (m, 3H), 4.16 (q, J = 6.9 Hz, 2H), 4.02 (br d, J = 13.7 Hz, 1 H), 3.95 (s, 3H), 3.43-3.23 (m, 2H), 3.06 (br t, J = 10.9 Hz, 1 H), 2.29-2.15 (m, 2H), 2.08-1 .88 (m, 2H), 1 .50 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 495.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.85 (dd, J = 5.3, 8.4 Hz, 1 H), 7.65 (dd, J = 1 .8, 8.4 Hz, 1 H), 7.56 (d, J = 1 .8 Hz, 1 H), 7.20-7.13 (m, 2H), 6.95 (d, J = 8.4 Hz, 1 H), 4.57 (d, J = 3.7 Hz, 2H), 4.51 -4.41 (m, 3H), 4.18 (q, J = 7.0 Hz, 2H), 4.05 (br d, J = 13.9 Hz, 1 H), 3.96 (s, 3H), 3.42-3.24 (m, 2H), 3.07 (br t, J = 1 0.9 Hz, 1 H), 2.29-2.15 (m, 2H), 2.07-1 .89 (m, 2H), 1 .51 (t, J = 6.9 Hz, 3H); LCMS (ESI) [M+H]+: 495.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.53 (dd, J = 2.0, 8.4 Hz, 1 H), 7.46-7.39 (m, 2H), 7.30 (dd, J = 4.4, 8.2 Hz, 1 H), 7.18-7.10 (m, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 4.52-4.27 (m, 5H), 4.05 (q, J = 7.0 Hz, 2H), 3.92 (br d, J = 13.7 Hz, 1 H), 3.84 (s, 3H), 3.32-3.10 (m, 2H), 2.94 (br t, J = 10.8 Hz, 1 H), 2.1 0 (br t, J = 15.0 Hz, 2H), 1 .95-1 .76 (m, 2H), 1 .39 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 495.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.66 (dd, J = 2.0, 8.4 Hz, 1 H), 7.58-7.49 (m, 2H), 7.24 (d, J = 7.5 Hz, 1 H), 7.10 (t, J = 8.8 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 4.59 (d, J = 5.1 Hz, 2H), 4.53-4.38 (m, 3H), 4.17 (q, J = 6.9 Hz, 2H), 4.07 (br d, J = 13.9 Hz, 1 H), 3.96 (s, 3H), 3.45-3.22 (m, 2H), 3.12-3.02 (m, 1 H), 2.22 (br dd, J = 14.2, 18.2 Hz, 2H), 2.09-1 .88 (m, 2H), 1 .51 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 495.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (dd, J = 2.3, 7.2 Hz, 1 H), 8.13-8.02 (m, 2H), 7.86-7.79 (m, 1 H), 7.77-7.71 (m, 1 H), 7.1 7 (d, J = 8.6 Hz, 1 H), 4.64-4.47 (m, 1 H), 4.32 (ddd, J = 3.3, 6.6, 9.5 Hz, 1 H), 4.08 (d, J = 2.2 Hz, 3H), 4.04-3.91 (m, 2H), 3.63 (quin, J = 8.3 Hz, 1 H), 3.46-3.32 (m, 2H), 3.19-3.04 (m, 1 H), 3.01 -2.81 (m, 2H), 2.60 (s, 3H), 2.54 (s, 3H), 2.28 (br t, J = 13.3 Hz, 2H), 2.1 1 -1 .95 (m, 2H); LCMS (ESI) [M+H]+: 500.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.51 (s, 1 H), 7.98 (s, 1 H), 7.73 (s, 2H), 7.59-7.57 (br d, J = 8.2 Hz, 2H), 7.38-7.34 (t, J = 7.9 Hz, 2H), 7.17-7.13 (m, 1 H), 4.85-4.77 (m, 1 H), 4.50-4.42 (br t, J = 14.9 Hz, 1 H), 4.33-4.23 (m, 1 H), 4.01 -3.89 (m, 2H), 3.62-3.54 (quin, J = 8.5 Hz, 1 H), 3.45-3.27 (m, 2H), 3.22-2.90 (m, 2H), 2.87-2.75 (m, 1 H), 2.31 -2.17 (m, 2H), 2.07-1 .91 (m, 2H), 1 .67-1 .66 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 499.3.

¹ H NMR (400 MHz, DMSO-de) δ 8.57-8.52 (m, 2H), 8.27 (s, 1 H), 7.88-7.84 (t, J = 7.6 Hz, 3H), 7.62-7.60 (dd, J = 1 .2, 8.7 Hz, 1 H), 7.55-7.43 (m, 3H), 4.92-4.82 (spt, J = 6.7 Hz, 1 H), 4.34-4.31 (br d, J = 13.5 Hz, 1 H), 4.1 8-4.1 6 (d, J = 5.5 Hz, 2H), 4.00-3.96 (br d, J = 13.9 Hz, 1 H), 3.50-3.43 (m, 1 H), 3.29-3.25 (m, 1 H), 2.95-2.90 (br t, J = 1 1 .2 Hz, 1 H), 2.18-2.12 (br t, J = 12.3 Hz, 2H), 1 .88-1 .80 (q, J = 1 0.6 Hz, 1 H), 1 .73- 1 .63 (m, 1 H), 1 .60-1 .55 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 473.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.63 (t, J = 1 .1 Hz, 1 H), 8.1 1 (dd, J = 1 .3, 9.3 Hz, 1 H), 7.96 (dd, J = 1 .0, 9.4 Hz, 1 H), 7.88-7.83 (m, 1 H), 7.59-7.53 (m, 1 H), 7.50-7.43 (m, 2H), 4.58 (s, 2H), 4.53-4.43 (m, 3H), 4.1 1 (br d, J = 14.1 Hz, 1 H), 3.45-3.28 (m, 2H), 3.12-3.01 (m, 1 H), 2.25 (br t, J = 14.1 Hz, 2H), 2.07- 1 .87 (m, 2H); LCMS (ESI) [M+H]+: 445.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.44 (br d, J = 5.5 Hz, 1 H), 8.09 (s, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.71 (m, 1 H), 7.50 (br s, 1 H), 7.40 (br d, J = 5.3 Hz, 1 H), 4.64-4.48 (m, 1 H), 4.29 (dd, J = 6.9, 9.6 Hz, 1 H), 4.08 (s, 3H), 4.04-3.90 (m, 2H), 3.61 (quin, J = 8.4 Hz, 1 H), 3.40 (br d, J = 10.8 Hz, 2H), 3.21 -3.04 (m, 1 H), 3.02-2.82 (m, 2H), 2.60 (s, 3H), 2.56 (s, 3H), 2.29 (br t, J = 14.7 Hz, 2H), 2.1 1 -1 .96 (m, 2H); LCMS (ESI) [M+H]+: 500.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.27 (br dd, J = 4.7, 8.3 Hz, 1 H), 8.1 5 (br s, 1 H), 8.10 (br s, 1 H), 7.86-7.79 (m, 1 H), 7.78-7.71 (m, 1 H), 7.52 (br d, J = 8.4 Hz, 1 H), 4.57 (br t, J = 12.7 Hz, 1 H), 4.41 (dd, J = 9.0, 1 0.8 Hz, 1 H), 4.22-4.14 (m, 1 H), 4.09 (s, 3H), 4.04 (br d, J = 14.1 Hz, 1 H), 3.57 (quin, J = 8.2 Hz, 1 H), 3.47-3.32 (m, 2H), 3.25 (br dd, J = 7.7, 17.2 Hz, 1 H), 3.16-3.04 (m, 1 H), 2.86-2.76 (m, 1 H), 2.60 (s, 3H), 2.36-2.21 (m, 5H), 2.12-1 .93 (m, 2H); LCMS (ESI) [M+H]+: 500.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.85-7.80 (m, 2H), 7.66 (br t, J = 8.8 Hz, 1 H), 7.58-7.49 (m, 3H), 7.47-7.41 (m, 2H), 6.94 (t, J = 7.9 Hz, 1 H), 5.1 8 (br d, J = 2.6 Hz, 1 H), 4.54-4.38 (m, 1 H), 4.18 (br t, J = 14.0 Hz, 1 H), 3.97-3.92 (m, 7H), 3.89-3.83 (m, 1 H), 3.46-3.36 (m, 1 H), 3.34-3.23 (m, 1 H), 3.19-3.03 (m, 1 H), 2.23 (br s, 2H), 2.1 1 -1 .92 (m, 2H); LCMS (ESI) [M+H]+: 481 .3.

¹ H NMR (400 MHz, METHANOLS) δ 8.14 (br d, J = 1 1 .0 Hz, 1 H), 7.89-7.84 (m, 2H), 7.77 (br d, J = 7.0 Hz, 2H), 7.55-7.43 (m, 3H), 5.23 (t, J = 6.1 Hz, 1 H), 4.58-4.45 (m, 1 H), 4.28 (br t, J = 14.9 Hz, 1 H), 4.02 (br d, J = 5.3 Hz, 3H), 3.93-3.82 (m, 2H), 3.54-3.40 (m, 2H), 3.16-3.03 (m, 1 H), 2.54 (s, 3H), 2.34-2.18 (m, 2H), 2.08-1 .86 (m, 2H); LCMS (ESI) [M+H]+: 489.3.

1 H NMR (400 MHz, CHLOROFORM-d) δ 7.86 (d, J = 7.1 Hz, 2H), 7.58-7.42 (m, 3H), 7.35 (br s, 1 H), 7.23 (d, J = 2.2 Hz, 2H), 6.61 (t, J = 2.2 Hz, 1 H), 4.50 (br d, J = 13.7 Hz, 1 H), 4.31 (d, J = 4.0 Hz, 2H), 3.91 (br d, J = 14.3 Hz, 1 H), 3.86 (s, 6H), 3.39-3.29 (m, 2H), 3.1 5 (br t, J = 10.7 Hz, 1 H), 2.30-2.20 (m, 2H), 2.08- 1 .93 (m, 2H); LCMS (ESI) [M+H]+: 451 .3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (d, J = 4.9 Hz, 1 H), 7.87-7.80 (m, 1 H), 7.79-7.72 (m, 1 H), 7.57 (br dd, J = 4.6, 8.6 Hz, 2H), 7.08 (t, J = 8.6 Hz, 2H), 4.65-4.48 (m, 1 H), 4.36-4.29 (m, 1 H), 4.09 (d, J = 3.3 Hz, 3H), 4.05-3.87 (m, 2H), 3.60 (quin, J = 8.3 Hz, 1 H), 3.48-3.32 (m, 2H), 3.20-3.03 (m, 1 H), 3.01 - 2.82 (m, 2H), 2.61 (s, 3H), 2.29 (br t, J = 13.7 Hz, 2H), 2.10-1 .94 (m, 2H); LCMS (ESI) [M+H]+: 503.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.34 (d, J = 0.9 Hz, 1 H), 7.93 (d, J = 1 .1 Hz, 1 H), 7.83-7.75 (m, 4H), 7.49-7.35 (m, 3H), 7.27 (br s, 1 H), 4.52-4.43 (m, 1 H), 4.25 (dd, J = 2.4, 3.7 Hz, 2H), 4.02 (br d, J = 6.4 Hz, 2H), 3.91 -3.81 (m, 2H), 3.34-3.24 (m, 2H), 3.1 1 -3.02 (m, 1 H), 2.21 (dt, J = 3.4, 13.2 Hz, 2H), 2.05- 1 .87 (m, 2H), 1 .69 (s, 6H); LCMS (ESI) [M+H]+: 503.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.83-7.78 (m, 2H), 7.67 (br t, J = 8.6 Hz, 1 H), 7.58-7.47 (m, 2H), 7.46-7.40 (m, 2H), 7.16 (br d, J = 6.6 Hz, 1 H), 6.97-6.90 (m, 1 H), 5.09-4.96 (m, 1 H), 4.59-4.38 (m, 1 H), 4.23-4.06 (m, 1 H), 3.99-3.91 (m, 6H), 3.49-3.25 (m, 2H), 3.21 -3.04 (m, 1 H), 2.34-2.13 (m, 2H), 2.10-1 .90 (m, 2H), 1 .25 (br d, J = 5.7 Hz, 1 H), 0.74-0.43 (m, 4H); LCMS (ESI) [M+H]+: 491 .0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.08 (br d, J = 6.6 Hz, 1 H), 7.85-7.77 (m, 3H), 7.75-7.67 (m, 1 H), 7.53-7.46 (m, 1 H), 7.45-7.40 (m, 2H), 7.18 (br s, 1 H), 5.09-4.96 (m, 1 H), 4.59-4.43 (m, 1 H), 4.23- 4.10 (m, 1 H), 4.06 (br d, J = 5.3 Hz, 3H), 3.52-3.30 (m, 2H), 3.21 -3.05 (m, 1 H), 2.58 (d, J = 2.2 Hz, 3H), 2.37-2.19 (m, 2H), 2.13-1 .97 (m, 1 H), 2.13-1 .97 (m, 1 H), 1 .27 (br s, 1 H), 0.63-0.43 (m, 4H); LCMS (ESI) [M+H]+: 499.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.04 (d, J = 5.7 Hz, 2H), 7.88-7.78 (m, 4H), 7.55-7.40 (m, 3H), 7.33 (br s, 1 H), 4.51 (br d, J = 13.7 Hz, 1 H), 4.30 (d, J = 3.7 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.90 (br d, J = 14.1 Hz, 1 H), 3.39-3.28 (m, 2H), 3.12 (br t, J = 1 1 .1 Hz, 1 H), 2.32-2.17 (m, 2H), 1 .99 (s, 8H), 1 .15 (t, J = 7.2 Hz, 3H); LCMS (ESI) [M+H]+: 545.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.53 (s, 1 H), 8.12 (s, 1 H), 7.76-7.71 (m, 2H), 7.58 (br d, J = 7.9 Hz, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1 H), 4.51 -4.37 (m, 1 H), 4.28 (q, J = 8.3 Hz, 1 H), 4.17 (q, J = 7.2 Hz, 2H), 4.01 -3.89 (m, 2H), 3.57 (quin, J = 8.4 Hz, 1 H), 3.45-3.28 (m, 2H), 3.23-3.09 (m, 1 H), 3.02-2.91 (m, 1 H), 2.86-2.76 (m, 1 H), 2.31 -2.1 6 (m, 2H), 2.00 (s, 8H), 1 .17 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 571 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.55 (s, 1 H), 8.15 (s, 1 H), 7.86 (d, J = 7.1 Hz, 2H), 7.76 (s, 2H), 7.56-7.42 (m, 3H), 7.36 (br s, 1 H), 4.45 (br d, J = 13.7 Hz, 1 H), 4.32 (br s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.91 (br d, J = 14.1 Hz, 1 H), 3.42-3.29 (m, 2H), 3.22 (br t, J = 10.6 Hz, 1 H), 2.26 (br t, J = 10.8 Hz, 2H), 2.10-1 .94 (m, 8H),1 .20 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 545.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.44-8.31 (m, 2H), 8.1 1 (s, 1 H), 7.87-7.81 (m, 1 H), 7.78-7.66 (m, 2H), 7.06 (br s, 1 H), 4.64-4.52 (m, 1 H), 4.44 (dd, J = 9.0, 1 1 .0 Hz, 1 H), 4.25-4.17 (m, 1 H), 4.09 (s, 3H), 4.04 (br d, J = 13.0 Hz, 1 H), 3.58 (quin, J = 8.2 Hz, 1 H), 3.48-3.32 (m, 2H), 3.27 (dd, J = 7.7, 17.4 Hz, 1 H), 3.17-3.05 (m, 1 H), 2.88-2.78 (m, 1 H), 2.61 (s, 3H), 2.36-2.22 (m, 2H), 2.14-1 .94 (m, 2H); LCMS (ESI) [M+H]+: 486.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.08-8.02 (m, 2H), 7.88-7.79 (m, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.19-7.12 (m, 1 H), 4.60-4.47 (m, 1 H), 4.36-4.26 (m, 1 H), 4.20 (br dd, J = 3.4, 6.9 Hz, 2H), 3.94 (q, J = 9.3 Hz, 2H), 3.58 (quin, J = 8.4 Hz, 1 H), 3.43-3.27 (m, 2H), 3.16-2.89 (m, 2H), 2.88- 2.79 (m, 1H), 2.25 (br t, J = 12.8 Hz, 2H), 1.99 (s, 8H), 1.18-1.10 (m, 3H); LCMS (ESI) [M+H]+: 571.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.09 (d, J = 1.6 Hz, 1H), 8.76 (dd, J = 1.6, 4.9 Hz, 1H), 8.16 (td, J = 2.0, 8.0 Hz, 1 H), 8.10 (s, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.71 (m, 1 H), 7.46-7.37 (m, 2H), 4.58-4.48 (m, 1H), 4.33 (d, J = 3.9 Hz, 2H), 4.08 (s, 3H), 3.93 (brd, J = 13.8 Hz, 1H), 3.44-3.33 (m, 2H), 3.23-3.13 (m, 1H), 2.60 (s, 3H), 2.36-2.24 (m, 2H), 2.13-1.97 (m, 2H); LCMS (ESI) [M+H]+: 460.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.81-8.76 (m, 2H), 8.09 (s, 1H), 7.86-7.80 (m, 1H), 7.77-7.67 (m, 3H), 7.48 (br s, 1H), 4.58-4.48 (m, 1H), 4.31 (d, J = 3.9 Hz, 2H), 4.08 (s, 3H), 3.92 (brd, J = 14.1 Hz, 1H), 3.38 (ddd, J = 3.4, 10.6, 14.0 Hz, 2H), 3.23-3.13 (m, 1H), 2.60 (s, 3H), 2.36-2.24 (m, 2H), 2.12-1.96 (m,2H); LCMS (ESI) [M+H]+: 460.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.89-7.83 (m, 2H), 7.67 (dd, J = 1.9, 8.3 Hz, 1 H), 7.60-7.42 (m, 4H), 7.35 (br s, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 4.55-4.46 (m, 1 H), 4.31 (d, J = 3.9 Hz, 2H), 4.20 (q, J = 7.0 Hz, 2H), 3.94 (s, 3H), 3.93-3.87 (m, 1 H), 3.40-3.27 (m, 2H), 3.20-3.09 (m, 1 H), 2.25 (dt, J 2H), 2.08-1 .92 (m, 2H), 1 .51 (t, J = 7.0 Hz, 3H); LCMS (ESI) [M+H]+: 465.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.16 (br d, J = 1 .8 Hz, 1 H), 8.33 (d, J = 1 .5 Hz, 1 H), 7.82 (br d, J = 7.5 Hz, 1 H), 7.55-7.48 (m, 1 H), 7.45-7.39 (m, 2H), 4.54 (s, 2H), 4.49-4.41 (m, 3H), 4.05 (s, 4H), 3.41 - 3.24 (m, 2H), 3.03 (br t, J = 1 1 .8 Hz, 1 H), 2.65 (s, 3H), 2.22 (br t, J = 15.8 Hz, 2H), 2.07-1 .86 (m, 4H); LCMS (ESI) [M+H]+: 472.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.48 (s, 1 H), 8.08 (s, 1 H), 7.74 (s, 2H), 7.58 (d, J = 7.7 Hz, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.18-7.1 1 (m, 1 H), 4.53-4.40 (m, 1 H), 4.33-4.24 (m, 1 H), 4.00-3.89 (m, 4H), 3.57 (quin, J = 8.4 Hz, 1 H), 3.44-3.28 (m, 2H), 3.20-3.06 (m, 1 H), 3.03-2.90 (m, 1 H), 2.86-2.77 (m, 1 H), 2.30- 2.18 (m, 2H), 2.07-1 .88 (m, 3H), 1 .71 (s, 6H); LCMS (ESI) [M+H]+: 529.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.50 (d, J = 0.9 Hz, 1 H), 8.10 (d, J = 0.7 Hz, 1 H), 7.86 (d, J = 7.3 Hz, 2H), 7.77 (s, 2H), 7.56-7.50 (m, 1 H), 7.49-7.43 (m, 2H), 7.36 (br s, 1 H), 4.47 (br d, J = 13.5 Hz, 1 H), 4.31 (d, J = 2.6 Hz, 2H), 4.06 (br s, 1 H), 3.99-3.87 (m, 3H), 3.43-3.31 (m, 2H), 3.21 (br t, J = 10.7 Hz, 1 H), 2.33-2.21 (m, 2H), 2.1 1 -1 .94 (m, 2H), 1 .73 (s, 6H); LCMS (ESI) [M+H]+: 503.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.39 (s, 1 H), 7.99 (s, 1 H), 7.88-7.79 (m, 1 H), 7.88-7.79 (m, 1 H),

7.58 (d, J = 7.9 Hz, 2H), 7.36 (t, J = 7.8 Hz, 2H), 7.19-7.12 (m, 1 H), 4.64-4.49 (m, 1 H), 4.36-4.27 (m, 1 H), 4.07 (br s, 2H), 4.02-3.85 (m, 3H), 3.57 (quin, J = 8.5 Hz, 1 H), 3.43-3.29 (m, 2H), 3.16-2.89 (m, 2H), 2.88- 2.78 (m, 1 H), 2.34-2.19 (m, 2H), 2.05-1 .96 (m, 2H), 1 .74 (d, J = 2.0 Hz, 6H); LCMS (ESI) [M+H]+: 529.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (s, 1 H), 8.01 (s, 1 H), 7.87-7.78 (m, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.24 (s, 1 H), 4.64 (br s, 1 H), 4.14 (s, 3H), 4.09-3.71 (m, 1 H), 3.37-3.27 (m, 1 H), 3.20 (br s, 2H), 2.97- 2.87 (m, 1 H), 2.28-1 .96 (m, 4H), 1 .24 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 430.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (s, 1 H), 8.01 (d, J = 0.7 Hz, 1 H), 7.87-7.78 (m, 2H), 7.34- 7.26 (m, 3H), 7.21 (br d, J = 7.3 Hz, 1 H), 4.66 (br s, 1 H), 4.14 (s, 3H), 3.97-3.78 (m, 1 H), 3.36-3.12 (m, 3H), 2.96-2.87 (m, 1 H), 2.32-1 .90 (m, 4H), 1 .25 (d, J = 7.1 Hz, 6H); LCMS (ESI) [M+H]+: 430.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (br d, J = 4.9 Hz, 1 H), 7.86-7.81 (m, 1 H), 7.77-7.72 (m, 1 H), 7.49 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.64-4.51 (m, 1 H), 4.30 (br s, 1 H), 4.09 (d, J = 3.5 Hz, 3H), 3.99 (br s, 1 H), 3.91 (br t, J = 8.8 Hz, 1 H), 3.81 (s, 3H), 3.59 (quin, J = 8.2 Hz, 1 H), 3.47-3.31 (m, 2H), 3.1 9-3.03 (m, 1 H), 3.00-2.79 (m, 2H), 2.61 (s, 3H), 2.34-2.23 (m, 2H), 2.01 (br d, J = 10.8 Hz, 2H); LCMS (ESI) [M+H]+: 515.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (s, 1 H), 7.84 (d, J = 7.1 Hz, 2H), 7.79-7.66 (m, 2H), 7.55- 7.41 (m, 3H), 7.22 (br s, 1 H), 4.29-4.13 (m, 2H), 4.06 (s, 3H), 4.04-3.96 (m, 2H), 3.96-3.84 (m, 2H), 3.69- 3.56 (m, 3H), 3.50 (dd, J = 5.1 , 10.8 Hz, 1 H), 3.31 -3.22 (m, 1 H), 3.20-3.1 1 (m, 1 H), 2.59 (s, 3H); LCMS (ESI) [M+H]+: 486.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.79 (d, J = 4.8 Hz, 1 H), 8.16 (s, 1 H), 8.05-7.99 (m, 3H), 7.87- 7.80 (m, 2H), 7.75 (s, 1 H), 7.52-7.44 (m, 3H), 7.25 (d, J = 4.8 Hz, 1 H), 4.67 (br d, J = 1 1 .4 Hz, 1 H), 4.16 (s, 3H), 3.83 (br d, J = 14.0 Hz, 1 H), 3.41 -3.21 (m, 3H), 2.34 (br s, 1 H), 2.22-1 .97 (m, 3H); LCMS (ESI) [M+H]+: 465.0.

Ή NMR (400 MHz, CHLOROFORM-d) δ 8.12-8.08 (m, 1 H), 7.89-7.80 (m, 3H), 7.77-7.72 (m, 1 H), 7.56- 7.42 (m, 3H), 7.25 (br d, J = 3.1 Hz, 1 H), 4.33-4.24 (m, 2H), 4.17-3.99 (m, 5H), 3.97-3.68 (m, 3H), 2.68- 2.38 (m, 5H); LCMS (ESI) [M+H]+: 445.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (s, 1 H), 7.79-7.74 (m, 1 H), 7.73-7.67 (m, 1 H), 7.46-7.30 (m, 5H), 4.71 -4.51 (m, 1 H), 4.44 (br d, J = 10.4 Hz, 1 H), 4.39-4.25 (m, 2H), 4.15 (br d, J = 1 1 .7 Hz, 1 H), 4.07 (s, 3H), 3.90-3.65 (m, 2H), 3.51 -3.1 7 (m, 3H), 2.98-2.70 (m, 2H), 2.59 (s, 3H), 2.1 1 -1 .79 (m, 4H) ; LCMS (ESI) [M+H]+: 487.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (s, 1 H), 7.79-7.73 (m, 1 H), 7.72-7.65 (m, 1 H), 7.47-7.30 (m, 5H), 4.71 -4.51 (m, 1 H), 4.44 (br d, J = 10.4 Hz, 1 H), 4.39-4.25 (m, 2H), 4.15 (br d, J = 1 1 .7 Hz, 1 H), 4.06 (s, 3H), 3.90-3.66 (m, 2H), 3.51 -3.1 7 (m, 3H), 2.98-2.71 (m, 2H), 2.59 (s, 3H), 2.1 1 -1 .79 (m, 4H) ; LCMS (ESI) [M+H]+: 487.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.01 (t, J = 1 .0 Hz, 1 H), 7.89-7.80 (m, 2H), 7.72 (dq, J = 1 .0, 8.6 Hz, 2H), 7.60-7.50 (m, 1 H), 7.50-7.43 (m, 2H), 6.98 (br s, 1 H), 4.52 (s, 4H), 4.49 (s, 2H), 4.34 (s, 2H), 4.08 (d, J = 4.6 Hz, 2H), 4.07 (s, 3H), 2.59 (s, 3H); LCMS (ESI) [M+H]+: 472.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.00 (s, 1 H), 7.91 (d, J = 0.9 Hz, 1 H), 7.59 (dd, J = 8.5, 12.0 Hz, 3H), 7.43-7.32 (m, 2H), 7.22-7.13 (m, 1 H), 6.85 (td, J = 1 .5, 8.6 Hz, 1 H), 4.71 -4.53 (m, 1 H), 4.27 (ddd, J = 6.8, 9.6, 18.8 Hz, 1 H), 4.03 (s, 3H), 4.00-3.91 (m, 2H), 3.57 (quin, J = 8.3 Hz, 1 H), 3.25- 3.1 1 (m, 1 H), 3.04-2.90 (m, 1 H), 2.87-2.76 (m, 2H), 2.57 (dt, J = 4.1 , 1 0.9 Hz, 1 H), 2.08-1 .94 (m, 2H), 1 .89-1 .80 (m, 1 H), 1 .89-1 .79 (m, 1 H); LCMS (ESI) [M+H]+: 446.1 .

¹ H NMR (400 MHz, METHANOLS) δ 7.93-7.70 (m, 4H), 7.55-7.35 (m, 3H), 7.25-7.10 (m, 1 H), 5.23-5.19 (t, J = 6.0 Hz, 1 H), 4.60-4.40 (m, 1 H), 4.30-4.1 5 (m, 1 H), 3.90-3.75 (m, 2H), 3.55-3.35 (m, 8H), 3.20-2.95 (m, 1 H), 2.30-2.10 (m, 2H), 2.10-1 .95 (m, 1 H), 1 .95-1 .75 (m, 1 H); LCMS (ESI) [M+H]+: 505.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.47 (s, 1 H), 7.84 (d, J = 7.3 Hz, 2H), 7.54-7.41 (m, 4H), 7.38 (s, 1 H), 7.26-7.22 (t, 2H), 4.53 (br d, J = 13.9 Hz, 1 H), 4.30 (t, J = 3.7 Hz, 2H), 3.91 (br d, J = 13.7 Hz, 1 H), 3.38-3.27 (m, 2H), 3.1 1 (br t, J = 1 1 .1 Hz, 1 H), 2.73 (s, 3H), 2.31 -2.19 (t, 2H), 2.07-1 .90 (m, 2H); LCMS (ESI) [M+H]+: 445.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.42 (br d, J = 4.4 Hz, 1 H), 7.53 (br d, J = 8.2 Hz, 2H), 7.43 (d, J = 9.5 Hz, 1 H), 7.36-7.28 (dd, 3H), 7.20 (m, 1 H), 7.14-7.07 (t, 1 H), 4.59-4.43 (dd, 1 H), 4.31 -4.23 (m, 1 H), 3.98-3.82 (m, 2H), 3.52 (quin, J = 8.4 Hz, 1 H), 3.39-3.21 (m, 2H), 3.15-2.73 (m, 3H), 2.68 (d, J = 5.7 Hz, 3H), 2.27-2.13 (t, 2H), 1 .99-1 .81 (m, 2H); LCMS (ESI) [M+H]+: 471 .3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (br d, J = 8.3 Hz, 1 H), 7.49 (s, 1 H), 7.43-7.31 (m, 5H), 6.90 (d, J = 8.3 Hz, 1 H), 4.65 (br d, J = 13.6 Hz, 1 H), 4.53 (br d, J = 12.7 Hz, 1 H), 4.42 (br d, J = 10.5 Hz, 1 H), 4.34-4.21 (m, 2H), 4.14 (q, J = 7.0 Hz, 3H), 3.93 (s, 3H), 3.86-3.64 (m, 2H), 3.43 (br t, J = 1 1 .4 Hz, 1 H), 3.27-3.16 (m, 2H), 2.91 (br t, J = 1 1 .4 Hz, 1 H), 2.81 -2.67 (m, 2H), 2.07-1 .77 (m, 4H), 1 .48 (t, J = 7.0 Hz, 3H); LCMS (ESI) [M+H]+: 493.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (br d, J = 8.3 Hz, 1 H), 7.49 (s, 1 H), 7.43-7.32 (m, 5H), 6.90 (d, J = 8.3 Hz, 1 H), 4.66 (br d, J = 13.6 Hz, 0.5H), 4.54 (br d, J = 13.6 Hz, 0.5H), 4.42 (br d, J = 10.1 Hz, 1 H), 4.34-4.22 (m, 2H), 4.1 5 (q, J = 7.0 Hz, 3H), 3.93 (s, 3H), 3.87-3.65 (m, 2H), 3.44 (br t, J = 1 1 .6 Hz, 0.5H), 3.27-3.17 (m, 2H), 2.91 (br t, J = 1 1 .8 Hz, 0.5H), 2.81 -2.69 (m, 2H), 2.06-1 .78 (m, 4H), 1 .48 (t, J = 7.0 Hz, 3H); LCMS (ESI) [M+H]+: 493.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.01 (s, 1 H), 7.88 (d, J = 7.5 Hz, 1 H), 7.78-7.67 (m, 2H), 7.61- 7.55 (m, 1H), 7.52-7.46 (m, 2H), 4.59 (s, 2H), 4.52 (s, 2H), 4.06 (s, 3H), 3.83-3.73 (m, 8H), 2.59 (s, 3H); LCMS (ESI) [M+H]+: 472.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (br d, J = 7.5 Hz, 1 H), 7.95 (br s, 1 H), 7.59 (d, J = 7.9 Hz, 2H), 7.41-7.33 (m, 3H), 7.19-7.14 (m, 1H), 5.16 (s, 4H), 4.58-4.47 (m, 1H), 4.31 (dd, J = 7.2, 9.4 Hz, 1H), 4.00-3.89 (m, 2H), 3.62-3.55 (m, 1H), 3.44-3.28 (m, 2H), 3.18-2.92 (m, 2H), 2.87-2.80 (m, 1H), 2.32-2.18 (m, 2H), 2.06-1.90 (m, 2H); LCMS (ESI) [M+H]+: 459.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.75 (d, J = 5.3 Hz, 1 H), 8.57 (br t, J = 5.7 Hz, 1 H), 8.06-8.00 (m, 1 H), 7.96 (s, 1H), 7.89 (d, J = 7.0 Hz, 2H), 7.58-7.52 (m, 1H), 7.52-7.44 (m, 2H), 7.29 (d, J = 5.3 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 4.51 (brd, J = 12.3 Hz, 1H), 4.27-4.12 (m, 2H), 4.06 (brd, J = 13.6 Hz, 1H), 3.84 (d, J = 4.4 Hz, 6H), 3.23 (br t, J = 12.1 Hz, 1H), 3.04 (br t, J = 11.8 Hz, 1H), 2.79 (br t, J = 12.1 Hz, 1H), 2.00 (brt, J = 12.1 Hz, 2H), 1.86-1.73 (m, 1H), 1.70-1.56 (m, 1H); LCMS (ESI) [M+H]+: 461.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1H), 7.95 (dd, J = 1.2, 2.8 Hz, 1H), 7.86-7.80 (m, 1H), 7.78-7.72 (m, 1 H), 7.46 (dd, J = 1.1 , 5.1 Hz, 1 H), 7.36 (dd, J = 3.1 , 5.1 Hz, 1 H), 7.15 (br s, 1 H), 4.53 (br d, J = 13.7 Hz, 1H), 4.29 (d, J = 4.0 Hz, 2H), 4.09 (s, 3H), 3.93 (brd, J = 14.3 Hz, 1H), 3.42-3.32 (m, 2H), 3.16 (br t, J = 10.8 Hz, 1 H), 2.60 (s, 3H), 2.29 (br t, J = 10.9 Hz, 2H), 2.1 1 -1 .95 (m, 2H); LCMS (ESI) [M+H]+: 465.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.99 (d, J = 7.9 Hz, 1 H), 7.94 (s, 1 H), 7.86 (d, J = 8.3 Hz, 1 H), 7.57-7.52 (m, 1 H), 7.49-7.43 (m, 2H), 7.34 (d, J = 7.9 Hz, 1 H), 5.16 (s, 4H), 4.60-4.39 (m, 5H), 4.07 (br d, J = 14.0 Hz, 1 H), 3.43-3.24 (m, 2H), 3.07 (br t, J = 1 1 .2 Hz, 1 H), 2.21 (br t, J = 13.8 Hz, 2H), 2.03-1 .88 (m, 2H); LCMS (ESI) [M+H]+: 445.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.99 (d, J = 7.9 Hz, 1 H), 7.94 (s, 1 H), 7.85 (d, J = 7.0 Hz, 2H), 7.54-7.48 (m, 1 H), 7.48-7.42 (m, 2H), 7.35 (br d, J = 7.9 Hz, 2H), 5.16 (s, 4H), 4.49 (br d, J = 14.0 Hz, 1 H), 4.30 (d, J = 3.9 Hz, 2H), 3.90 (br d, J = 14.0 Hz, 1 H), 3.40-3.26 (m, 2H), 3.21 -3.13 (m, 1 H), 2.32-2.18 (m, 2H), 2.07-1 .91 (m, 2H); LCMS (ESI) [M+H]+: 433.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.87 (d, J = 7.5 Hz, 1 H), 7.59-7.54 (m, 2H), 7.51 -7.45 (m, 3H), 6.91 (d, J = 8.4 Hz, 1 H), 4.58 (s, 2H), 4.51 (s, 2H), 4.1 5 (q, J = 6.9 Hz, 2H), 3.94 (s, 3H), 3.79-3.68 (m, 8H), 1 .49 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 478.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.70 (d, J = 4.6 Hz, 1 H), 8.23 (br s, 1 H), 8.10 (s, 1 H), 7.89-7.80 (m, 2H), 7.77-7.70 (m, 1 H), 4.55 (br d, J = 14.1 Hz, 1 H), 4.32 (d, J = 4.4 Hz, 2H), 4.09 (s, 3H), 3.93 (br d, J = 13.5 Hz, 1 H), 3.41 -3.32 (m, 2H), 3.15 (br t, J = 1 1 .4 Hz, 1 H), 2.60 (s, 3H), 2.34-2.22 (m, 2H), 2.12- 1 .95 (m, 2H); LCMS (ESI) [M+H]+: 466.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.88-7.81 (m, 3H), 7.78-7.72 (m, 1 H), 7.55-7.50 (m, 1 H), 7.49-7.43 (m, 2H), 7.35 (br s, 1 H), 4.42-4.31 (m, 2H), 4.28-4.19 (m, 1 H), 4.10 (s, 3H), 3.76 (br d, J = 14.3 Hz, 1 H), 3.46-3.36 (m, 1 H), 3.21 -3.1 1 (m, 1 H), 2.61 (s, 3H), 2.58-2.45 (m, 2H), 1 .84-1 .74 (m, 2H), 1 .61 (s, 3H); LCMS (ESI) [M+H]+: 473.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.49 (s, 1 H), 8.1 1 -8.04 (m, 2H), 7.87-7.83 (m, 2H), 7.54-7.49 (m, 2H), 7.47-7.42 (m, 2H), 7.35 (br s, 1 H), 4.88 (td, J = 6.7, 13.3 Hz, 1 H), 4.53-4.46 (m, 1 H), 4.31 (d, J = 3.7 Hz, 2H), 3.96-3.88 (m, 1 H), 3.40-3.28 (m, 2H), 3.22-3.12 (m, 1 H), 2.26 (dt, J = 3.6, 13.0 Hz, 2H), 2.09- 1 .93 (m, 2H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 473.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.45 (s, 1 H), 8.06 (s, 1 H), 7.95 (dd, J = 1 .3, 9.0 Hz, 1 H), 7.85 (d, J = 7.3 Hz, 2H), 7.79 (d, J = 9.0 Hz, 1 H), 7.54-7.49 (m, 1 H), 7.47-7.42 (m, 2H), 7.35 (br s, 1 H), 4.82 (quin, J = 6.7 Hz, 1 H), 4.49 (td, J = 4.0, 13.7 Hz, 1 H), 4.30 (d, J = 4.0 Hz, 2H), 3.95-3.87 (m, 1 H), 3.38-3.27 (m, 2H), 3.21 -3.13 (m, 1 H), 2.25 (dt, J = 3.7, 12.9 Hz, 2H), 2.07-1 .95 (m, 2H), 1 .68 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 473.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.93 (br s, 1 H), 8.64 (br d, J = 4.3 Hz, 1 H), 8.20 (d, J = 7.9 Hz, 1H), 7.94-7.84 (m, 2H), 7.70 (s, 1H), 7.49-7.41 (m, 1H), 7.07 (d, J = 8.2 Hz, 1H), 4.56 (brd, J = 13.6 Hz, 1 H), 4.36 (br d, J = 4.4 Hz, 2H), 3.97 (br d, J = 14.3 Hz, 1 H), 3.50 (d, J = 8.3 Hz, 6H), 3.43-3.32 (m, 2H), 3.16 (brt, J = 11.2 Hz, 1H), 2.27 (br t, J = 12.1 Hz, 2H), 2.11-1.91 (m, 2H); LCMS (ESI) [M+H]+: 476.3.

¹ HNMR (400 MHz, CHLOROFORM-d) δ 7.60-7.54 (m, 2H), 7.36 (t, J = 7.8 Hz, 2H), 7.19-7.10 (m, 1H), 4.81 (s, 4H), 4.52-4.39 (m, 1H), 4.27 (dd, J = 7.3, 9.7 Hz, 1H), 4.20 (s, 4H), 3.95-3.84 (m, 2H), 3.53 (quin, J = 8.4 Hz, 1 H), 3.34-3.23 (m, 1 H), 3.15-2.87 (m, 3H), 2.84-2.75 (m, 1 H), 2.16-2.04 (m, 2H), 1.90-1.75 (m, 2H); LCMS (ESI) [M+H]+: 438.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.94 (br s, 1 H), 8.63 (br s, 1 H), 8.36-8.27 (m, 1 H), 8.19 (br d, J = 7.3 Hz, 1 H), 8.08 (br d, J = 7.9 Hz, 1 H), 7.90-7.81 (m, 1 H), 7.73 (br d, J = 7.7 Hz, 1 H), 7.52-7.40 (m, 1H), 4.75 (brd, J = 12.1 Hz, 1H), 4.36 (brs, 2H), 4.10 (brs, 3H), 4.02 (brd, J = 12.6 Hz, 1H), 3.51 (brs, 1H), 3.36 (brt, J = 11.2 Hz, 1H), 3.08-2.94 (m, 1H), 2.61 (brs, 3H), 2.32 (brd, J = 14.8 Hz, 2H), 1.96 (br d, J = 10.8 Hz, 2H); LCMS (ESI) [M+H]+: 476.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.10 (dd, J = 0.7, 2.3 Hz, 1H), 8.77 (dd, J = 1.7, 4.9 Hz, 1H), 8.17 (td, J = 2.0, 7.9 Hz, 1H), 7.89 (dd, J = 1.5, 8.2 Hz, 1H), 7.69 (d, J = 1.3 Hz, 1H), 7.42 (ddd, J = 0.8, 4.9, 7.9 Hz, 2H), 7.07 (d, J = 8.2 Hz, 1H), 4.53 (td, J = 3.8, 13.8 Hz, 1H), 4.33 (d, J = 3.9 Hz, 2H), 3.96- 3.89 (m, 1H), 3.49 (d, J = 7.6 Hz, 6H), 3.42-3.32 (m, 2H), 3.18 (ddd, J = 3.1, 10.9, 13.6 Hz, 1H), 2.29 (dt, J = 3.8, 13.8 Hz, 2H), 2.12-1.95 (m, 2H); LCMS (ESI) [M+H]+: 476.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.67-7.58 (m, 1 H), 7.55-7.46 (m, 3H), 7.42-7.32 (m, 3H), 6.91 (br d, J = 8.4 Hz, 1 H), 4.57-4.39 (m, 1 H), 4.13 (q, J = 7.1 Hz, 2H), 4.05-3.97 (m, 1 H), 3.96-3.91 (m, 3H), 3.90-3.61 (m, 3H), 3.58-3.42 (m, 1 H), 3.39-3.1 8 (m, 3H), 3.08-2.91 (m, 1 H), 2.34-1 .82 (m, 6H), 1 .47 (t, J = 6.9 Hz, 3H); LCMS (ESI) [M+H]+: 505.3.

Ή NMR (400 MHz, CHLOROFORM-d) δ 7.63 (br s, 1 H), 7.54 (br s, 1 H), 7.45-7.39 (m, 2H), 7.38-7.34 (m, 2H), 7.32-7.27 (m, 1 H), 6.93 (br d, J = 8.4 Hz, 1 H), 4.67 (br s, 1 H), 4.45-4.39 (m, 1 H), 4.26 (br dd, J = 8.5, 12.7 Hz, 1 H), 4.15 (q, J = 6.6 Hz, 2H), 3.94 (br s, 3H), 3.77 (br d, J = 12.8 Hz, 1 H), 3.47 (br t, J = 1 1 .5 Hz, 0.5H), 3.35-3.15 (m, 2H), 2.97 (br t, J = 12.1 Hz, 0.5H), 2.23 (br s, 2H), 2.12-1 .87 (m, 2H), 1 .49 (br t, J = 6.9 Hz, 3H); LCMS (ESI) [M+H]+: 507.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (br d, J = 8.6 Hz, 1 H), 7.82 (br s, 1 H), 7.77-7.70 (m, 1 H), 7.65 (d, J = 7.1 Hz, 2H), 7.51 -7.38 (m, 3H), 4.75 (br s, 1 H), 4.63-4.27 (m, 4H), 4.08 (br d, J = 4.6 Hz, 3H), 3.70-3.59 (m, 2H), 3.39-2.99 (m, 3H), 2.60 (s, 3H), 2.24 (br d, J = 1 1 .0 Hz, 2H), 2.05-1 .91 (m, 2H); LCMS (ESI) [M+H]+: 485.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.65 (br d, J = 7.1 Hz, 3H), 7.56 (br s, 1 H), 7.51 -7.39 (m, 3H), 6.95 (br d, J = 8.2 Hz, 1 H), 4.74 (br t, J = 7.1 Hz, 1 H), 4.59-4.25 (m, 4H), 4.17 (q, J = 7.1 Hz, 2H), 3.97 (br s, 3H), 3.68-3.57 (m, 2H), 3.35-2.97 (m, 3H), 2.20 (br d, J = 12.1 Hz, 2H), 2.03-1.87 (m, 2H), 1.51 (t, J = 6.9 Hz, 3H); LCMS (ESI) [M+H]+: 491.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.80-8.74 (m, 2H), 7.87 (dd, J = 1.5, 8.2 Hz, 1 H), 7.70-7.66 (m, 3H), 7.46 (brs, 1 H), 7.07-7.02 (m, 1H), 7.05 (d, J = 8.2 Hz, 1H), 4.51 (td, J = 3.7, 13.7 Hz, 1H), 4.30 (d, J = 3.7 Hz, 2H), 3.93-3.86 (m, 1H), 3.47 (d, J = 7.1 Hz, 6H), 3.40-3.29 (m, 2H), 3.21-3.13 (m, 1H), 2.27 (dt, J = 3.5, 13.3 Hz, 2H), 2.09-1.94 (m, 2H); LCMS (ESI) [M+H]+: 476.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.11-8.04 (m, 1H), 7.84-7.76 (m, 1H), 7.74-7.70 (m, 1H), 7.56- 7.48 (m, 2H), 7.43-7.35 (m, 3H), 4.62-4.46 (m, 1H), 4.10-4.02 (m, 4H), 4.00-3.67 (m, 3H), 3.62-3.45 (m, 1 H), 3.41 -3.20 (m, 3H), 3.12-2.94 (m, 1 H), 2.58 (s, 3H), 2.38-1.86 (m, 6H); LCMS (ESI) [M+H]+: 499.3.

¹ H NMR (400 MHz, DMSO-de) δ 8.22-8.17 (m, 1H), 7.91-7.86 (m, 1H), 7.76-7.64 (m, 3H), 7.41-7.34 (m, 2H), 7.18-7.11 (m, 1H), 4.99-4.34 (m, 1H), 4.13-3.86 (m, 6H), 3.77-3.64 (m, 1H), 3.49 (brs, 1H), 2.90- 2.62 (m, 3H), 2.52-2.52 (m, 3H), 2.38-2.03 (m, 4H), 1.42-0.87 (m, 3H); LCMS (ESI) [M+H]+: 499.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (br s, 1 H), 7.85 (br d, J = 8.4 Hz, 1 H), 7.80-7.71 (m, 1 H), 7.60 (br d, J = 7.0 Hz, 2H), 7.47-7.33 (m, 2H), 7.1 9 (br d, J = 5.1 Hz, 1 H), 4.76-4.1 6 (m, 3H), 4.09 (br s, 3H), 4.03-3.39 (m, 5H), 3.08-2.80 (m, 2H), 2.61 (s, 3H), 2.52-2.23 (m, 2H); LCMS (ESI) [M+H]+: 521 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.59 (d, J = 8.2 Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.21 -7.14 (m, 1 H), 4.56-4.42 (m, 1 H), 4.33-4.23 (m, 3H), 3.97-3.83 (m, 4H), 3.56 (quin, J = 8.5 Hz, 1 H), 3.37-3.27 (m, 1 H), 3.1 9-2.90 (m, 4H), 2.87-2.78 (m, 1 H), 2.75 (d, J = 7.1 Hz, 2H), 2.14 (br t, J = 12.5 Hz, 2H), 1 .93-1 .78 (m, 2H); LCMS (ESI) [M+H]+: 435.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.59 (d, J = 8.2 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.32 (s, 1 H), 7.22-7.13 (m, 1 H), 4.55-4.41 (m, 3H), 4.31 (br t, J = 8.3 Hz, 1 H), 3.96-3.79 (m, 4H), 3.76 (s, 3H), 3.56 (quin, J = 8.5 Hz, 1 H), 3.38-3.27 (m, 1 H), 3.18-2.90 (m, 3H), 2.89-2.74 (m, 3H), 2.14 (br t, J = 13.0 Hz, 2H), 1 .94-1 .79 (m, 2H); LCMS (ESI) [M+H]+: 476.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.85 (t, J = 7.3 Hz, 3H), 7.78-7.73 (m, 1 H), 7.58- 7.51 (m, 1 H), 7.50-7.43 (m, 2H), 7.22 (br s, 1 H), 4.65-4.49 (m, 0.5H), 4.44-4.1 8 (m, 3H), 4.09 (s, 3H), 4.07-4.01 (m, 0.5H), 3.94-3.70 (m, 2H), 3.67-3.50 (m, 1 H), 2.61 (s, 3H), 2.47-2.31 (m, 2H); LCMS (ESI) [M+H]+: 495.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.88-7.80 (d, J = 2, 1 H), 7.60 (dd, J = 1 .1 , 8.4 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 4.40-4.26 (m, 1 H), 3.88-3.84 (s, 3H), 3.80-3.64 (m, 2H), 3.40 (t, J = 9.2 Hz, 1 H), 3.25 (td, J = 8.4, 16.6 Hz, 1 H), 3.18-3.08 (m, 2H), 3.03-2.78 (m, 3H), 2.57-2.41 (m, 2H), 2.38 (s, 3H), 2.1 1 -1 .96 (m, 2H), 1 .85-1 .67 (m, 2H), 0.76-0.66 (m, 1 H), 0.36-0.29 (m, 2H), 0.02 (q, J = 4.8 Hz, 2H); LCMS (ESI)

[M+H]+: 463.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.13 (d, J = 1 .8 Hz, 1 H), 8.28 (d, J = 1 .8 Hz, 1 H), 7.61 -7.55 (m, 2H), 7.37 (t, J = 7.9 Hz, 2H), 7.19-7.14 (m, 1 H), 4.32 (dd, J = 7.2, 9.4 Hz, 1 H), 4.07 (s, 3H), 3.95 (t, J = 9.2 Hz, 1 H), 3.86-3.67 (m, 8H), 3.63-3.54 (m, 1 H), 2.97-2.81 (m, 2H), 2.68 (s, 3H) ; LCMS (ESI) [M+H]+: 487.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.75 (br s, 1 H), 7.64 (d, J = 3.7 Hz, 1 H), 7.58 (d, J = 7.9 Hz, 2H), 7.37 (t, J = 7.9 Hz, 2H), 7.20-7.13 (m, 1 H), 4.61 -4.46 (m, 1 H), 4.30 (br t, J = 8.4 Hz, 1 H), 4.01 -3.88 (m, 2H), 3.56 (quin, J = 8.4 Hz, 1 H), 3.43-3.25 (m, 2H), 3.12-2.88 (m, 2H), 2.87-2.79 (m, 1 H), 2.23 (br t, J = 12.8 Hz, 2H), 2.01 -1 .86 (m, 2H); LCMS (ESI) [M+H]+: 448.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.54-7.43 (m, 3H), 7.34-7.26 (m, 2H), 7.12-7.03 (m, 2H), 4.44 (br t, J = 15.5 Hz, 1 H), 4.22 (br d, J = 2.3 Hz, 1 H), 3.94-3.83 (m, 2H), 3.55-3.45 (m, 1 H), 3.35-3.15 (m, 2H), 3.05-2.83 (m, 2H), 2.81 -2.71 (m, 1 H), 2.15 (br t, J = 13.6 Hz, 2H), 1 .95-1 .78 (m, 2H); LCMS (ESI) [M+H]+: 501 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.93-7.82 (m, 2H), 7.69 (dd, J = 1 .9, 8.4 Hz, 1 H), 7.61 -7.42 (m, 4H), 7.38-7.31 (m, 2H), 4.57-4.45 (m, 1 H), 4.31 (d, J = 3.8 Hz, 2H), 3.94 (s, 3H), 3.93-3.86 (m, 1 H), 3.85- 3.78 (m, 1 H), 3.41 -3.26 (m, 2H), 3.22-3.09 (m, 1 H), 2.34-2.18 (m, 2H), 2.10-1 .92 (m, 2H), 0.95-0.81 (m, 4H); LCMS (ESI) [M+H]+: 477.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.31 (s, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 7.3 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1 H), 7.56-7.50 (m, 1 H), 7.49-7.44 (m, 2H), 7.36 (br s, 1 H), 4.72 (br d, J = 13.4 Hz, 1 H), 4.40-4.27 (m, 2H), 4.1 0 (s, 3H), 4.00 (br d, J = 13.9 Hz, 1 H), 3.52 (tt, J = 3.7, 1 1 .0 Hz, 1 H), 3.41 -3.31 (m, 1 H), 3.04 (br t, J = 1 1 .3 Hz, 1 H), 2.61 (s, 3H), 2.35 (br t, J = 15.7 Hz, 2H), 1 .95 (dquin, J = 3.9, 12.1 Hz, 2H); LCMS (ESI) [M+H]+: 475.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.31 (s, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.22-7.15 (m, 1 H), 4.75 (br t, J = 14.6 Hz, 1 H), 4.35 (q, J = 8.1 Hz, 1 H), 4.10 (d, J = 2.2 Hz, 3H), 4.04 (br s, 1 H), 3.96 (dt, J = 3.1 , 9.0 Hz, 1 H), 3.60 (quin, J = 8.5 Hz, 1 H), 3.51 (dt, J = 4.0, 1 1 .0 Hz, 1 H), 3.46-3.33 (m, 1 H), 3.07-2.92 (m, 2H), 2.91 -2.82 (m, 1 H), 2.61 (s, 3H), 2.43-2.28 (m, 2H), 2.01 -1 .87 (m, 2H); LCMS (ESI) [M+H]+: 501 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.24 (s, 1 H), 8.53 (br d, J = 8.1 Hz, 1 H), 8.35 (d, J = 8.1 Hz, 1 H), 8.07 (br s, 1 H), 7.62 (d, J = 8.1 Hz, 2H), 7.40 (t, J = 7.9 Hz, 2H), 7.22-7.1 7 (m, 1 H), 4.64-4.50 (m, 1 H), 4.37-4.30 (m, 1 H), 4.05-3.94 (m, 2H), 3.61 (quin, J = 8.4 Hz, 1 H), 3.47-3.33 (m, 2H), 3.09 (d, J = 5.1 Hz, 4H), 3.04-2.94 (m, 1 H), 2.91 -2.82 (m, 1 H), 2.35-2.22 (m, 2H), 2.07-1 .92 (m, 2H); LCMS (ESI) [M+H]+: 475.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.89-7.83 (m, 2H), 7.73-7.67 (m, 2H), 7.57-7.50 (m, 1 H), 7.50- 7.43 (m, 2H), 7.38-7.31 (m, 2H), 4.53 (br d, J = 14.6 Hz, 1 H), 4.32 (d, J = 3.3 Hz, 2H), 3.98 (s, 3H), 3.92 (br d, J = 13.5 Hz, 1 H), 3.40-3.30 (m, 2H), 3.19-3.09 (m, 1 H), 2.32-2.20 (m, 2H), 2.08-1 .93 (m, 2H); LCMS (ESI) [M+H]+: 505.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.60 (d, J = 8.2 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.21 -7.14 (m, 1 H), 4.49 (br t, J = 14.6 Hz, 1 H), 4.30 (dd, J = 7.3, 9.7 Hz, 1 H), 4.21 -4.13 (m, 2H), 4.05-3.98 (m, 2H), 3.93 (br t, J = 8.7 Hz, 2H), 3.57 (quin, J = 8.5 Hz, 1 H), 3.39-3.27 (m, 1 H), 3.18-2.92 (m, 3H), 2.88-2.79 (m, 2H), 2.20-2.08 (m, 2H), 1 .88 (br d, J = 12.1 Hz, 2H), 1 .35 (s, 6H); LCMS (ESI) [M+H]+: 463.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (d, J = 4.4 Hz, 1 H), 7.86-7.79 (m, 1 H), 7.77-7.71 (m, 1 H), 4.87-4.78 (m, 2H), 4.61 -4.45 (m, 3H), 4.09 (d, J = 2.6 Hz, 3H), 3.92 (br d, J = 8.4 Hz, 1 H), 3.87-3.79 (m, 1 H), 3.77-3.69 (m, 1 H), 3.63-3.56 (m, 1 H), 3.50-3.42 (m, 2H), 3.41 -3.23 (m, 3H), 3.15-3.00 (m, 1 H), 2.79- 2.63 (m, 2H), 2.61 (s, 3H), 2.26 (br s, 2H), 2.06-1 .90 (m, 2H); LCMS (ESI) [M+H]+: 479.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.35-8.25 (m, 2H), 7.82 (br d, J = 8.2 Hz, 1 H), 7.66-7.59 (m, 2H), 7.02-6.95 (m, 2H), 4.52-4.42 (m, 1 H), 4.35 (dd, J = 8.9, 1 1 .0 Hz, 1 H), 4.18-4.08 (m, 1 H), 3.95 (br d, J = 13.6 Hz, 1 H), 3.54-3.47 (m, 1 H), 3.41 (d, J = 8.8 Hz, 6H), 3.36-3.23 (m, 2H), 3.18 (dd, J = 7.8, 1 7.2 Hz, 1 H), 3.1 0-2.97 (m, 1 H), 2.81 -2.69 (m, 1 H), 2.22-2.1 5 (m, 2H), 2.07-1 .84 (m, 2H); LCMS (ESI) [M+H]+: 502.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.71 (m, 1 H), 7.43-7.29 (m, 5H), 4.63 (s, 2H), 4.51 (br d, J = 13.0 Hz, 1 H), 4.23 (d, J = 2.8 Hz, 2H), 4.08 (s, 3H), 4.02 (br d, J = 13.6 Hz, 1 H), 3.36-3.23 (m, 2H), 3.04 (br t, J = 1 1 .8 Hz, 1 H), 2.61 (s, 3H), 2.21 (br s, 2H), 2.04-1 .92 (m, 2H); LCMS (ESI) [M+H]+: 446.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.66 (m, 1 H), 4.43 (br d, J = 13.8 Hz, 2H), 4.08 (s, 3H), 3.36-3.26 (m, 1 H), 3.16 (br t, J = 1 1 .8 Hz, 2H), 2.60 (s, 3H), 2.26-2.1 8 (m, 2H), 2.03-1 .92 (m, 2H), 1 .33 (s, 9H); LCMS (ESI) [M+H]+: 382.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (s, 1 H), 7.77-7.70 (m, 1 H), 7.67-7.62 (m, 1 H), 7.30-7.23 (m, 2H), 7.23-7.16 (m, 3H), 4.48 (br d, J = 13.4 Hz, 1H), 4.00 (s, 3H), 3.87 (br d, J = 13.7 Hz, 1H), 3.72 (s, 2H), 3.22-3.12 (m, 2H), 2.97 (br t, J = 11.1 Hz, 1H), 2.52 (s, 3H), 2.12 (br d, J = 10.8 Hz, 1H), 1.97 (brd, J = 10.8 Hz, 1 H), 1.91 -1.80 (m, 1 H), 1.71 -1.60 (m, 1 H); LCMS (ESI) [M+H]+: 416.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1H), 7.87-7.80 (m, 1H), 7.77-7.70 (m, 1H), 4.55 (br s, 1 H), 4.31 (br s, 1 H), 4.08 (s, 3H), 3.49-3.27 (m, 2H), 3.01 (br s, 1 H), 2.60 (s, 3H), 2.24 (br s, 2H), 2.01 (br s, 2H), 1.85-1.75 (m, 1 H), 1.02 (br s, 2H), 0.80 (br dd, J = 2.8, 7.6 Hz, 2H); LCMS (ESI) [M+H]+: 366.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.04 (s, 1 H), 7.80-7.70 (m, 2H), 7.53-7.45 (m, 5H), 4.08 (s, 3H), 3.96-3.65 (m, 8H), 2.61 (s, 3H); LCMS (ESI) [M+H]+: 403.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.03 (s, 1H), 7.81-7.67 (m, 2H), 7.52-7.32 (m, 4H), 4.19-4.06 (m, 4H), 3.94-3.70 (m, 5H), 3.55-3.35 (m, 2H), 2.61 (s, 3H); LCMS (ESI) [M+H]+: 437.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.78-7.70 (m, 1H), 4.62 (brd, J = 13.1 Hz, 1H), 4.08 (s, 3H), 4.05 (brd, J = 15.3 Hz, 1H), 3.36-3.25 (m, 2H), 2.97 (br t, J = 11.7 Hz, 1 H), 2.60 (s, 3H), 2.32 (s, 2H), 2.22 (br d, J = 12.2 Hz, 2H), 2.05-1.88 (m, 2H), 1.09 (s, 9H); LCMS (ESI) [M+H]+: 396.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.87-7.79 (m, 1 H), 7.77-7.69 (m, 1 H), 4.59 (br d, J = 13.1 Hz, 1 H), 4.08 (s, 3H), 4.02-3.90 (m, 1 H), 3.38-3.23 (m, 2H), 3.00 (br t, J = 1 1 .5 Hz, 1 H), 2.60 (s, 3H), 2.34 (d, J = 6.8 Hz, 2H), 2.23 (br d, J = 13.1 Hz, 2H), 2.06-1 .89 (m, 2H), 1 .15-1 .02 (m, 1 H), 0.66-0.53 (m, 2H), 0.25-0.18 (m, 2H); LCMS (ESI) [M+H]+: 380.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.06 (s, 1 H), 7.90-7.77 (m, 2H), 5.10-4.88 (m, 1 H), 4.30-4.01 (m, 2H), 3.32-3.15 (m, 1 H), 3.02 (t, J = 12.0 Hz, 2H), 2.29-2.06 (m, 2H), 2.04 -1 .87 (m, 2H), 1 .63 (d, J = 6.8 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 412.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.69 (m, 1 H), 7.32 (t, J 7.7 Hz, 2H), 7.05-6.94 (m, 3H), 4.74 (s, 2H), 4.49 (br d, J = 13.3 Hz, 1 H), 4.14 (br s, 1 H), 4.08 (s, 3H), 3.46-3.25 (m, 2H), 3.10 (br t, J = 1 1 .4 Hz, 1 H), 2.60 (s, 3H), 2.22 (br s, 2H), 2.1 0-1 .91 (m, 2H); LCMS (ESI) [M+H]+: 432.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.98 (d, J = 8.2 Hz, 2H), 7.87-7.83 (m, 1 H), 7.81 - 7.74 (m, 3H), 7.42 (br s, 1 H), 4.54 (br d, J = 13.6 Hz, 1 H), 4.33 (d, J = 3.7 Hz, 2H), 4.10 (s, 3H), 3.93 (br d, J = 14.1 Hz, 1 H), 3.40 (br t, J = 1 0.7 Hz, 2H), 3.27-3.16 (m, 1 H), 2.62 (s, 3H), 2.37-2.25 (m, 2H), 2.14- 2.00 (m, 2H); LCMS (ESI) [M+H]+: 484.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.19 (s, 1 H), 8.12-8.06 (m, 2H), 7.86-7.81 (m, 2H), 7.74 (s, 1 H), 7.64-7.58 (m, 1 H), 7.43 (br s, 1 H), 4.58-4.50 (m, 1 H), 4.33 (d, J = 3.8 Hz, 2H), 4.1 0 (s, 3H), 3.98-3.89 (m, 1 H), 3.46-3.33 (m, 2H), 3.28-3.15 (m, 1 H), 2.62 (s, 3H), 2.31 (dt, J = 3.3, 13.3 Hz, 2H), 2.14-1 .98 (m, 2H); LCMS (ESI) [M+H]+: 484.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.88-7.79 (m, 3H), 7.78-7.74 (m, 1 H), 7.45 (d, J = 8.3 Hz, 2H), 7.33 (br s, 1 H), 4.54 (br d, J = 13.4 Hz, 1 H), 4.32 (d, J = 3.5 Hz, 2H), 4.10 (s, 3H), 3.94 (br d, J = 14.1 Hz, 1 H), 3.39 (br t, J = 10.6 Hz, 2H), 3.19 (br t, J = 10.8 Hz, 1 H), 2.62 (s, 3H), 2.35-2.23 (m, 2H), 2.13-1 .99 (m, 2H); LCMS (ESI) [M+H]+: 493.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (s, 1 H), 7.70-7.60 (m, 2H), 7.41 -7.32 (m, 1 H), 7.17-7.07 (m, 3H), 3.98 (s, 3H), 3.89-3.55 (m, 8H), 2.51 (s, 3H); LCMS (ESI) [M+H]+: 421 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (s, 1 H), 7.88 (d, J = 8.3 Hz, 1 H), 7.81 -7.72 (m, 2H), 7.66- 7.55 (m, 3H), 7.03 (br s, 1 H), 4.52 (br d, J = 13.4 Hz, 1 H), 4.34 (d, J = 3.9 Hz, 2H), 4.13 (s, 3H), 3.92 (br d, J = 13.7 Hz, 1 H), 3.38 (br t, J = 1 0.6 Hz, 2H), 3.17 (br t, J = 1 1 .0 Hz, 1 H), 2.65 (s, 3H), 2.30 (br t, J = 13.9 Hz, 2H), 2.14-1 .99 (m, 2H); LCMS (ESI) [M+H]+: 527.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (s, 1H), 7.85 (dd, J = 1.0, 8.4 Hz, 1H), 7.78-7.71 (m, 1H), 7.43-7.34 (m, 2H), 7.25-7.19 (m, 1H), 7.14 (d, J = 7.7 Hz, 2H), 4.43-4.25 (m, 2H), 4.09 (s, 3H), 3.32 (tt, J = 3.9, 10.7 Hz, 2H), 3.20 (brs, 1H), 2.61 (s, 3H), 2.28 (brdd, J = 3.3, 13.4 Hz, 2H), 2.09 (brd, J = 10.8 Hz, 2H); LCMS (ESI) [M+H]+: 418.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.78-7.69 (m, 1H), 4.20 (br s, 2H), 4.08 (s, 3H), 3.74 (s, 3H), 3.29-3.19 (m, 1 H), 3.10 (br t, J = 11.6 Hz, 2H), 2.60 (s, 3H), 2.18 (br d, J = 11.0 Hz, 2H), 2.03-1.90 (m, 2H); LCMS (ESI) [M+H]+: 356.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.86 (d, J = 7.2 Hz, 2H), 7.67 (dd, J = 1.8, 8.3 Hz, 1 H), 7.60 (d, J = 1.8 Hz, 1 H), 7.56-7.50 (m, 1 H), 7.49-7.43 (m, 2H), 7.34 (br s, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 4.66 (spt, J = 6.1 Hz, 1 H), 4.55-4.45 (m, 1 H), 4.31 (d, J = 3.9 Hz, 2H), 3.92 (s, 3H), 3.90 (br d, J = 3.7 Hz, 1 H), 3.39- 3.27 (m, 2H), 3.21-3.10 (m, 1H), 2.24 (dt, J = 3.5, 12.9 Hz, 2H), 2.08-1.92 (m, 2H), 1.41 (d, J = 6.0 Hz, 6H); LCMS (ESI) [M+H]+: 479.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.45-8.39 (m, 1H), 8.18 (brs, 1H), 8.09 (s, 1H), 7.86-7.80 (m, 1 H), 7.76-7.72 (m, 1 H), 7.44 (br t, J = 8.3 Hz, 1 H), 4.61 -4.51 (m, 1 H), 4.41 -4.34 (m, 1 H), 4.20 (td, J = 5.9, 1 1 .3 Hz, 1 H), 4.08 (s, 3H), 4.02 (br d, J = 14.3 Hz, 1 H), 3.57 (quin, J = 8.0 Hz, 1 H), 3.47-3.31 (m, 2H), 3.22 (dd, J = 7.6, 17.3 Hz, 1 H), 3.1 6-3.04 (m, 1 H), 2.88-2.78 (m, 1 H), 2.60 (s, 3H), 2.37-2.21 (m, 2H), 2.12-1 .92 (m, 2H); LCMS (ESI) [M+H]+: 504.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (dd, J = 4.9, 7.9 Hz, 1 H), 8.10 (s, 1 H), 7.85-7.80 (m, 1 H), 7.76-7.72 (m, 1 H), 7.57 (t, J = 7.9 Hz, 1 H), 6.89 (d, J = 7.5 Hz, 1 H), 4.64-4.49 (m, 1 H), 4.47-4.39 (m, 1 H), 4.20 (dd, J = 7.1 , 1 1 .2 Hz, 1 H), 4.08 (s, 3H), 4.03 (br s, 1 H), 3.55 (quin, J = 8.3 Hz, 1 H), 3.47-3.31 (m, 2H), 3.26-3.01 (m, 2H), 2.85-2.76 (m, 1 H), 2.60 (s, 3H), 2.46 (d, J = 2.2 Hz, 3H), 2.26 (br d, J = 14.1 Hz, 2H), 2.12-1 .91 (m, 2H); LCMS (ESI) [M+H]+: 500.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.53 (s, 1 H), 8.00 (s, 1 H), 7.79-7.70 (m, 2H), 4.91 -4.77 (m, 1 H), 4.22-4.05 (m, 2H), 3.26-3.14 (m, 1 H), 3.03 (br t, J = 1 1 .2 Hz, 2H), 2.22-2.08 (m, 2H), 1 .98-1 .85 (m, 2H), 1 .69 (d, J = 6.8 Hz, 6H), 1 .94 (s, 9H); LCMS (ESI) [M+H]+: 412.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (s, 1 H), 7.70-7.60 (m, 2H), 7.35 (dd, J = 4.8, 8.8 Hz, 1 H), 7.06-6.96 (m, 2H), 4.07-3.96 (m, 4H), 3.88-3.60 (m, 5H), 3.45-3.28 (m, 2H), 2.51 (s, 3H); LCMS (ESI) [M+H]+: 455.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.78-7.69 (m, 1H), 4.09 (s, 3H), 3.89 (br d, J = 13.1 Hz, 2H), 3.28-3.14 (m, 4H), 2.60 (s, 3H), 2.26 (brdd, J = 2.9, 13.4 Hz, 2H), 2.17- 2.05 (m, 2H), 1.38 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 404.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1H), 7.90-7.81 (m, 1H), 7.78-7.70 (m, 1H), 7.44 (s, 5H), 4.82-4.37 (m, 1 H), 4.09 (s, 3H), 3.91 (br s, 1 H), 3.40-3.30 (m, 1 H), 3.30-3.17 (m, 2H), 2.61 (s, 3H), 2.37- 1.96 (m, 4H); LCMS (ESI) [M+H]+: 402.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1H), 7.89-7.84 (m, 2H), 7.83-7.78 (m, 1H), 7.75-7.70 (m, 1H), 7.55-7.49 (m, 1 H), 7.49-7.42 (m, 2H), 7.33 (br s, 1H), 4.88 (m, 1 H), 4.53 (m, J = 3.7, 13.5 Hz, 1H), 4.32 (d, J = 3.9 Hz, 2H), 3.99-3.87 (m, 1H), 3.43-3.29 (m, 2H), 3.23-3.09 (m, 1H), 2.61 (s, 3H), 2.28 (m, 2H), 2.13-1.92 (m, 2H), 1.60 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 487.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77-7.70 (m, 1H), 4.35 (brs, 1H), 4.08 (s, 3H), 3.96 (brd, J = 13.4 Hz, 2H), 3.26-3.16 (m, 1H), 3.08-2.99 (m, 2H), 2.60 (s, 3H), 2.19 (br d, J = 10.3 Hz, 2H), 2.04-1.92 (m, 2H), 1.38 (s, 9H); LCMS (ESI) [M+H]+: 397.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.88-7.80 (m, 1 H), 7.74 (br d, J = 7.9 Hz, 2H), 7.68-7.60 (m, 1H), 7.59-7.52 (m, 1H), 7.38 (dd, J = 7.5, 17.2 Hz, 1H), 4.78-4.63 (m, 1H), 4.09 (s, 3H), 3.58-3.46 (m, 1 H), 3.39-3.14 (m, 3H), 2.61 (s, 3H), 2.38-2.30 (m, 1 H), 2.16-1 .86 (m, 3H); LCMS (ESI) [M+H]+: 470.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.84 (dd, J = 1 .0, 8.4 Hz, 1 H), 7.79-7.70 (m, 1 H), 7.48-7.37 (m, 1 H), 7.22 (d, J = 7.6 Hz, 1 H), 7.19-7.1 0 (m, 2H), 4.65 (br s, 1 H), 4.09 (s, 3H), 3.91 (br s, 1 H), 3.45-3.1 6 (m, 3H), 2.61 (s, 3H), 2.42-1 .91 (m, 4H); LCMS (ESI) [M+H]+: 420.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.67 (s, 1 H), 8.10 (s, 1 H), 7.54 (s, 1 H), 7.38-7.33 (m, 2H), 7.29- 7.26 (m, 2H), 4.62 (br s, 1 H), 4.10 (s, 1 H), 3.93 (s, 3H), 3.34 (tt, J = 4.0, 10.8 Hz, 1 H), 3.19 (br s, 2H), 2.94 (spt, J = 6.9 Hz, 1 H), 2.18 (br d, J = 4.6 Hz, 2H), 1 .98 (br d, J = 9.5 Hz, 2H), 1 .27 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 423.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.27 (s, 1 H), 7.89-7.82 (m, 3H), 7.72 (d, J = 8.6 Hz, 1 H), 7.56- 7.50 (m, 1 H), 7.49-7.43 (m, 2H), 7.35 (br s, 1 H), 4.59-4.49 (m, 1 H), 4.32 (d, J = 3.7 Hz, 2H), 3.94 (br d, J = 13.9 Hz, 1 H), 3.58 (tt, J = 3.6, 6.9 Hz, 1 H), 3.44-3.30 (m, 2H), 3.23-3.10 (m, 1 H), 2.58 (s, 3H), 2.29 (dt, J = 3.2, 13.1 Hz, 2H), 2.15-1 .95 (m, 2H), 1 .28-1 .1 7 (m, 4H); LCMS (ESI) [M+H]+: 485.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.52 (s, 1 H), 7.49 (d, J = 1 .8 Hz, 1 H), 7.38-7.34 (m, 2H), 7.28 (d, J = 7.7 Hz, 2H), 6.43 (d, J = 1 .8 Hz, 1 H), 4.84-4.39 (m, 1 H), 4.35-3.91 (m, 1 H), 3.85 (s, 3H), 3.37 (tt, J = 4.0, 1 0.9 Hz, 1 H), 3.28-3.10 (m, 2H), 2.95 (spt, J = 6.9 Hz, 1 H), 2.19 (br d, J = 9.9 Hz, 2H), 2.08-1 .87 (m, 2H), 1 .27 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 423.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (d, J = 2.6 Hz, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.70 (m, 1 H), 7.43 (br d, J = 5.4 Hz, 1 H), 7.40-7.28 (m, 3H), 4.80-4.63 (m, 1 H), 4.08 (s, 3H), 3.67-3.53 (m, 1 H), 3.41 - 3.12 (m, 3H), 2.60 (s, 3H), 2.34 (br d, J = 13.1 Hz, 1 H), 2.20-1 .87 (m, 3H); LCMS (ESI) [M+H]+: 436.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.50 (s, 1 H), 7.85 (br d, J = 7.3 Hz, 2H), 7.66 (m, 2H), 7.55-7.41 (m, 3H), 7.35 (br s, 1 H), 4.78 (td, J = 6.7, 13.3 Hz, 1 H), 4.44 (br d, J = 13.2 Hz, 1 H), 4.30 (m, 2H), 3.90 (br d, J = 13.5 Hz, 1 H), 3.43-3.28 (m, 2H), 3.22 (br t, J = 1 1 .4 Hz, 1 H), 2.72-2.56 (s, 3H), 2.33-2.17 (m, 2H), 2.13-1 .91 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 487.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.79-7.67 (m, 1 H), 7.39 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 4.63 (br s, 1 H), 4.10 (s, 3H), 3.92 (br s, 1 H), 3.45-3.13 (m, 3H), 2.96 (quind, J = 6.8, 13.8 Hz, 1 H), 2.62 (s, 3H), 2.38-1 .94 (m, 4H), 1 .28 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 444.2.

¹ Η NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.88-7.81 (m, 1 H), 7.78-7.71 (m, 1 H), 7.46-7.37 (m, 4H), 4.60 (br s, 1 H), 4.09 (s, 3H), 3.91 (br s, 1 H), 3.44-3.13 (m, 3H), 2.61 (s, 3H), 2.40-1 .88 (m, 4H); LCMS (ESI) [M+H]+: 436.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.88-7.80 (m, 1 H), 7.78-7.69 (m, 2H), 7.27-7.20 (m, 1 H), 7.09 (br dd, J = 7.9, 16.6 Hz, 1 H), 4.78-4.55 (m, 1 H), 4.09 (s, 3H), 3.58-3.46 (m, 1 H), 3.41 -3.16 (m, 3H), 2.61 (s, 3H), 2.43-2.26 (m, 1 H), 2.19-1 .90 (m, 3H); LCMS (ESI) [M+H]+: 488.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.93 (s, 1 H), 7.72-7.60 (m, 3H), 7.21 (br d, J = 2.3 Hz, 1 H), 7.17 (d, J = 2.2 Hz, 1 H), 7.02 (dd, J = 2.4, 7.9 Hz, 1 H), 4.05-3.96 (m, 4H), 3.86-3.69 (m, 3H), 3.65-3.55 (m, 2H), 3.30 (t, J = 5.2 Hz, 2H), 2.51 (s, 3H); LCMS (ESI) [M+H]+: 489.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09-8.00 (m, 2H), 7.95 (d, J = 7.8 Hz, 1 H), 7.78-7.65 (m, 3H), 7.56-7.50 (m, 1 H), 7.32 (br s, 1 H), 4.49-4.41 (m, 1 H), 4.25 (d, J = 3.9 Hz, 2H), 4.01 (s, 3H), 3.89-3.81 (m, 1 H), 3.34-3.26 (m, 2H), 3.1 6-3.07 (m, 1 H), 2.52 (s, 3H), 2.22 (dt, J = 3.5, 13.5 Hz, 2H), 2.04-1 .90 (m, 2H); LCMS (ESI) [M+H]+: 527.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (s, 1 H), 7.82-7.69 (m, 3H), 7.69-7.57 (m, 2H), 7.39 (d, J 7.5 Hz, 1 H), 4.15-4.06 (m, 4H), 3.96-3.79 (m, 3H), 3.71 -3.61 (m, 2H), 3.40-3.33 (m, 2H), 2.60 (s, 3H); LCMS (ESI) [M+H]+: 471 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) 8.02-7.83 (m, 2H), 7.66 (br d, J = 8.4 Hz, 1 H), 7.58 (s, 1 H), 7.51 - 7.40 (m, 2H), 6.95 (d, J = 8.6 Hz, 1 H), 4.67-4.62 (m, 1 H), 4.58-4.44 (m, 1 H), 4.37-4.27 (m, 1 H), 4.01 -3.93 (m, 2H), 3.91 (s, 3H), 3.64-3.56 (m, 1 H), 3.45-3.24 (m, 2H), 3.19-3.02 (m, 1 H), 3.01 -2.83 (m, 2H), 2.24 (br t, J = 14.4 Hz, 2H), 2.09-1 .88 (m, 2H), 1 .40 (br d, J = 5.7 Hz, 6H); LCMS (ESI) [M+H]+: 530.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (s, 1 H), 8.08 (d, J = 8.8 Hz, 1 H), 7.44-7.33 (m, 3H), 7.27 (d, J = 7.9 Hz, 2H), 4.63 (br s, 1 H), 4.03 (s, 4H), 3.32 (br t, J = 10.7 Hz, 1 H), 3.21 (br s, 2H), 2.97-2.90 (m, 1 H), 2.62 (s, 3H), 2.36-1 .87 (m, 4H), 1 .26 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 444.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.86 (d, J = 7.1 Hz, 2H), 7.75 (dd, J = 1 .5, 8.4 Hz, 1 H), 7.65 (d,

J = 1 .3 Hz, 1 H), 7.57-7.50 (m, 1 H), 7.49-7.43 (m, 2H), 7.35 (br s, 1 H), 6.76 (d, J = 8.4 Hz, 1 H), 4.52 (br d,

J = 13.7 Hz, 1 H), 4.31 (d, J = 3.7 Hz, 2H), 4.1 7-4.05 (m, 2H), 3.92 (br d, J = 14.1 Hz, 1 H), 3.85 (s, 2H), 3.42-3.28 (m, 2H), 3.19-3.07 (m, 1 H), 2.92 (s, 3H), 2.33-2.19 (m, 2H), 2.10-1 .91 (m, 2H), 1 .32 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 503.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.42 (s, 1 H), 8.07 (dd, J = 0.9, 8.8 Hz, 1 H), 7.87 (d, J = 7.3 Hz, 2H), 7.56-7.51 (m, 1 H), 7.45 (dd, J = 8.4, 17.2 Hz, 3H), 7.35 (br s, 1 H), 4.53 (br d, J = 13.7 Hz, 1 H), 4.43- 4.37 (m, 2H), 4.32 (d, J = 3.7 Hz, 2H), 3.94 (br d, J = 13.9 Hz, 1 H), 3.41 -3.32 (m, 1 H), 3.36 (dt, J = 4.1 , 10.3 Hz, 1 H), 3.17 (br t, J = 10.9 Hz, 1 H), 2.63 (s, 3H), 2.35-2.22 (m, 2H), 2.12-1 .96 (m, 2H), 1 .52 (t, J = 7.3 Hz, 3H; LCMS (ESI) [M+H]+: 473.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.31 (s, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 4.26 (br s, 2H), 4.09 (s, 3H), 3.41 -3.31 (m, 1 H), 2.98 (br t, J = 12.0 Hz, 2H), 2.60 (s, 3H), 2.23 (br d, J = 12.0 Hz, 2H), 1 .85 (dq, J = 4.0, 12.0 Hz, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 414.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.34 (s, 1 H), 7.99 (dd, J = 1 .2, 8.7 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 4.31 (q, J = 7.3 Hz, 2H), 4.08 (br d, J = 10.1 Hz, 2H), 3.15-3.08 (m, 1 H), 2.94 (br t, J = 1 1 .7 Hz, 2H), 2.55 (s, 3H), 2.07 (br dd, J = 2.9, 13.2 Hz, 2H), 1 .93-1 .82 (m, 2H), 1 .46-1 .43 (m, 3H), 1 .41 (s, 9H); LCMS (ESI) [M+H]+: 412.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.28-8.24 (m, 1H), 8.14 (br s, 1H), 8.09 (d, J = 3.5 Hz, 1H), 7.85-7.80 (m, 1 H), 7.74-7.72 (m, 1 H), 7.51 (br d, J = 8.8 Hz, 1 H), 4.56 (br t, J = 13.4 Hz, 1 H), 4.40 (dd, J = 9.2, 11.0 Hz, 1H), 4.21-4.12 (m, 1H), 4.08 (s, 3H), 4.03 (brd, J = 13.6 Hz, 1H), 3.62-3.51 (m, 1H), 3.46- 3.30 (m, 2H), 3.25 (dd, J = 7.9, 17.1 Hz, 1H), 3.15-3.01 (m, 1H), 2.86-2.74 (m, 1H), 2.59 (s, 3H), 2.35- 2.20 (m, 5H), 2.12-1.91 (m, 2H); LCMS (ESI) [M+H]+: 500.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.28-8.24 (m, 1H), 8.14 (br s, 1H), 8.09 (d, J = 3.5 Hz, 1H), 7.85-7.80 (m, 1H), 7.76-7.71 (m, 1H), 7.51 (brd, J = 8.3 Hz, 1H), 4.56 (br t, J = 12.7 Hz, 1H), 4.40-4.37 (m, 1H), 4.21-4.13 (m, 1H), 4.08 (s, 3H), 4.03 (brd, J = 13.2 Hz, 1H), 3.62-3.51 (m, 1H), 3.46-3.30 (m, 2H), 3.25 (dd, J = 7.7, 17.3 Hz, 1H), 3.15-3.01 (m, 1H), 2.86-2.75 (m, 1H), 2.59 (s, 3H), 2.35-2.20 (m, 5H), 2.11 -1.91 (m, 2H); LCMS (ESI) [M+H]+: 500.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (s, 1 H), 7.75 (dd, J = 0.9, 8.4 Hz, 1 H), 7.69-7.62 (m, 2H), 7.22 (dd, J = 2.4, 8.1 Hz, 1 H), 7.19-7.14 (m, 1H), 6.97 (br s, 1 H), 4.46-4.36 (m, 1H), 4.23 (d, J = 4.0 Hz, 2H), 4.01 (s, 3H), 3.81 (brd, J = 13.9 Hz, 1H), 3.34-3.24 (m, 2H), 3.13-3.04 (m, 1H), 2.53 (s, 3H), 2.27- 2.15 (m, 2H), 2.05-1.91 (m, 2H); LCMS (ESI) [M+H]+: 545.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.11 (d, J = 2.3 Hz, 1 H), 8.02-7.89 (m, 2H), 7.87-7.82 (m, 1 H), 7.79-7.73 (m, 1 H), 7.54-7.43 (m, 2H), 4.66-4.48 (m, 1 H), 4.35 (dd, J = 6.6, 9.4 Hz, 1 H), 4.10 (d, J = 2.1 Hz, 3H), 4.06-3.92 (m, 2H), 3.64 (m, 1H), 3.52-3.33 (m, 2H), 3.25-3.07 (m, 1H), 3.06-2.86 (m, 2H), 2.62 (s, 3H), 2.39-2.23 (m, 2H), 2.15-1.95 (m, 2H); LCMS (ESI) [M+H]+: 510.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (d, J = 2.3 Hz, 1 H), 8.00-7.87 (m, 2H), 7.86-7.80 (m, 1 H), 7.77-7.70 (m, 1 H), 7.53-7.40 (m, 2H), 4.62-4.47 (m, 1 H), 4.33 (dd, J = 6.7, 9.4 Hz, 1 H), 4.08 (d, J = 2.3 Hz, 3H), 4.03-3.90 (m, 2H), 3.61 (td, J = 8.3, 1 6.1 Hz, 1 H), 3.51 -3.31 (m, 2H), 3.13 (m, 1 H), 3.02-2.83 (m, 2H), 2.60 (s, 3H), 2.38-2.20 (m, 2H), 2.12-1 .92 (m, 2H); LCMS (ESI) [M+H]+: 510.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1 H), 7.85-7.71 (m, 4H), 7.66 (d, J = 8.8 Hz, 2H), 4.62- 4.47 (m, 1 H), 4.35 (dd, J = 6.8, 9.6 Hz, 1 H), 4.08 (s, 3H), 4.03-3.91 (m, 2H), 3.61 (m, 1 H), 3.48-3.30 (m, 2H), 3.22-3.05 (m, 1 H), 3.03-2.84 (m, 2H), 2.60 (s, 3H), 2.29 (br t, J = 13.2 Hz, 2H), 2.12-1 .92 (m, 2H); LCMS (ESI) [M+H]+: 510.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1 H), 7.85-7.72 (m, 4H), 7.66 (d, J = 8.8 Hz, 2H), 4.65- 4.47 (m, 1 H), 4.35 (dd, J = 6.8, 9.6 Hz, 1 H), 4.08 (s, 3H), 4.03-3.89 (m, 2H), 3.61 (m, 1 H), 3.48-3.31 (m, 2H), 3.22-3.05 (m, 1 H), 3.03-2.85 (m, 2H), 2.60 (s, 3H), 2.29 (br t, J = 13.3 Hz, 2H), 2.14-1 .92 (m, 2H); LCMS (ESI) [M+H]+: 510.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.90-7.77 (m, 4H), 7.57-7.45 (m, 3H), 7.36 (br s, 1 H), 4.59-4.50 (m, 1 H), 4.33 (d, J = 3.8 Hz, 2H), 4.1 0 (s, 3H), 3.95 (br d, J = 14.1 Hz, 1 H), 3.38 (ddd, J 3.3, 10.6, 14.0 Hz, 2H), 3.22-3.12 (m, 1 H), 3.07-3.00 (m, 1 H), 3.04 (q, J = 7.6 Hz, 1 H), 2.30 (dt, J = 3.3, 13.0 Hz, 2H), 2.1 1 -1 .97 (m, 2H), 1 .44 (t, J = 7.6 Hz, 3H); LCMS (ESI) [M+H]+: 473.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.86 (br d, J = 6.8 Hz, 2H), 7.60 (dd, J = 1 .6, 8.4 Hz, 1 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.46 (t, J = 7.2 Hz, 1 H), 7.38 (d, J = 1 .2 Hz, 1 H), 7.37-7.31 (m, 1 H), 7.05 (d, J = 8.4 Hz, 1 H), 4.52 (td, J = 3.6, 13.6 Hz, 1 H), 4.31 (d, J = 8.0 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 3.92 (d, J = 13.6 Hz, 1 H), 3.42-3.27 (m, 2H), 3.20-3.07 (m, 1 H), 2.93 (s, 3H), 2.34-2.17 (m, 2H), 2.08-1 .90 (m, 2H), 1 .31 (t, J = 7.2 Hz, 3H); LCMS (ESI) [M+H]+: 503.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1 H), 7.87-7.79 (m, 1 H), 7.78-7.66 (m, 1 H), 4.08 (s, 3H), 3.79 (br d, J = 13.4 Hz, 2H), 3.74-3.64 (m, 4H), 3.37-3.28 (m, 4H), 3.28-3.18 (m, 1 H), 3.04 (br t, J = 1 1 .6 Hz, 2H), 2.60 (s, 3H), 2.20 (br d, J = 10.9 Hz, 2H), 2.09-1 .95 (m, 2H); LCMS (ESI) [M+H]+: 41 1 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.87-7.80 (m, 1 H), 7.78-7.70 (m, 1 H), 7.45-7.32 (m, 1 H), 7.16-6.98 (m, 2H), 4.76-4.60 (m, 1 H), 4.09 (s, 3H), 3.59 (br t, J = 12.8 Hz, 1 H), 3.41 -3.16 (m, 3H), 2.60 (s, 3H), 2.34 (br d, J = 1 1 .1 Hz, 1 H), 2.24-1 .87 (m, 3H); LCMS (ESI) [M+H]+: 454.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.77-7.68 (m, 1 H), 4.08 (s, 3H), 3.75 (br d, J = 13.4 Hz, 2H), 3.30-3.15 (m, 5H), 2.99 (br t, J = 1 1 .8 Hz, 2H), 2.60 (s, 3H), 2.18 (br d, J = 1 0.9 Hz, 2H), 2.08-1 .95 (m, 2H), 1 .60 (br s, 6H); LCMS (ESI) [M+H]+: 409.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.79 (br s, 1 H), 8.55 (s, 1 H), 8.14-8.07 (m, 2H), 7.81 (br d, J = 8.4 Hz, 2H), 7.75-7.70 (m, 1 H), 4.54 (br d, J = 13.7 Hz, 1 H), 4.32 (br d, J = 4.2 Hz, 2H), 4.07 (s, 3H), 3.93 (br d, J = 13.7 Hz, 1 H), 3.41 -3.30 (m, 2H), 3.13 (br t, J = 1 1 .6 Hz, 1 H), 2.59 (s, 3H), 2.32-2.19 (m, 2H), 2.10-1 .93 (m, 2H); LCMS (ESI) [M+H]+: 494.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.59 (br d, J = 7.7 Hz, 2H), 7.38 (br t, J = 7.4 Hz, 2H), 7.22-7.13 (m, 1 H), 4.83 (s, 4H), 4.49 (br t, J = 15.0 Hz, 1 H), 4.33-4.27 (m, 1 H), 4.22 (s, 4H), 3.97-3.87 (m, 2H), 3.61 -3.50 (m, 1 H), 3.31 (br d, J = 8.2 Hz, 1 H), 3.16-2.90 (m, 3H), 2.87-2.77 (m, 1 H), 2.19-2.07 (m, 2H), 1 .86 (br d, J = 10.4 Hz, 2H); LCMS (ESI) [M+H]+: 438.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.59 (br d, J = 7.5 Hz, 2H), 7.38 (br t, J = 7.2 Hz, 2H), 7.22-7.13 (m, 1 H), 4.83 (br s, 4H), 4.49 (br t, J = 15.0 Hz, 1 H), 4.30 (br t, J = 8.2 Hz, 1 H), 4.22 (br s, 4H), 3.97-3.87 (m, 2H), 3.61 -3.51 (m, 1 H), 3.31 (br d, J = 6.8 Hz, 1 H), 3.17-2.90 (m, 3H), 2.87-2.77 (m, 1 H), 2.19-2.07 (m, 2H), 1 .86 (br d, J = 10.6 Hz, 2H); LCMS (ESI) [M+H]+: 438.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.99 (d, J = 8.1 Hz, 2H), 7.84 (dd, J = 0.9, 8.4 Hz, 1 H), 7.75 (dd, J = 5.0, 8.1 Hz, 3H), 7.43 (br s, 1 H), 4.60-4.50 (m, 1 H), 4.34 (d, J = 3.8 Hz, 2H), 4.1 0 (s, 3H), 3.94 (br d, J = 14.1 Hz, 1 H), 3.45-3.33 (m, 2H), 3.25-3.14 (m, 1 H), 2.62 (s, 3H), 2.37-2.25 (m, 2H), 2.14-1 .99 (m, 2H); LCMS (ESI) [M+H]+: 527.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.29 (s, 1 H), 7.86 (dd, J = 1 .5, 9.0 Hz, 1 H), 7.61 (d, J = 9.0 Hz, 1 H), 7.29 (d, J = 8.0, 2H), 7.20 (d, J = 7.6 Hz, 2H), 4.54 (br s, 1 H), 4.05 (s, 4H), 4.26-3.24 (m, 1 H), 3.15 (br t, J = 1 1 .4 Hz, 2H), 2.90-2.81 (m, 1 H), 2.60 (s, 3H), 2.22-1 .86 (m, 4H), 1 .19 (d, J = 7.0 Hz, 6H); LCMS (ESI) [M+H]+: 444.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (s, 1 H), 7.86-7.83 (m, 1 H), 7.79-7.76 (m, 1 H), 4.16 (br s, 2H), 4.09 (s, 3H), 3.10-2.91 (m, 3H), 2.61 (s, 3H), 2.08 (br d, J = 10.6 Hz, 2H), 1 .94-1 .82 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 398.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.38 (s, 1 H), 7.95 (br d, J = 9.2 Hz, 1 H), 7.88 (br d, J = 7.6 Hz, 2H), 7.72 (d, J = 8.9 Hz, 1 H), 7.57-7.44 (m, 3H), 7.36 (br s, 1 H), 4.58-4.40 (m, 3H), 4.33 (br d, J = 3.5 Hz, 2H), 3.94 (br d, J = 13.6 Hz, 1 H), 3.43-3.32 (m, 2H), 3.19 (br t, J = 1 1 .1 Hz, 1 H), 2.70 (s, 3H), 2.33-2.23 (m, 2H), 2.13-1 .99 (m, 2H), 1 .60 (t, J = 7.2 Hz, 3H); LCMS (ESI) [M+H]+: 473.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.43 (s, 1 H), 7.88 (br d, J = 7.7 Hz, 2H), 7.71 (s, 2H), 7.57-7.51 (m, 1 H), 7.51 -7.45 (m, 2H), 7.36 (br s, 1 H), 4.51 (br d, J = 13.8 Hz, 1 H), 4.33 (br d, J = 2.3 Hz, 2H), 4.18 (s, 3H), 3.94 (br d, J = 13.9 Hz, 1 H), 3.42-3.33 (m, 2H), 3.21 (br t, J = 10.7 Hz, 1 H), 3.13-3.07 (m, 2H), 2.34-2.24 (m, 2H), 2.12-2.00 (m, 2H), 1 .40 (t, J = 7.6 Hz, 3H); LCMS (ESI) [M+H]+: 473.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.18 (s, 1 H), 8.1 1 -8.00 (m, 2H), 7.81 (d, J = 7.6 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 7.42 (br s, 1 H), 4.90 (br d, J = 13.2 Hz, 1 H), 4.43- 4.22 (m, 2H), 4.10 (s, 3H), 3.97 (d, J = 14.0 Hz, 1 H), 3.60-3.46 (m, 1 H), 3.37 (t, J = 12.0 Hz, 1 H), 3.06 (t, J = 1 1 .6 Hz, 1 H), 2.61 (s, 3H), 2.37 (t, J = 1 1 .6 Hz, 2H), 2.05-1 .86 (m, 2H); LCMS (ESI) [M+H]+: 500.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (br s, 1 H), 7.53 (br t, J = 6.0 Hz, 1 H), 7.30 (t, J = 8.2 Hz, 1 H), 7.1 5 (br d, J = 7.9 Hz, 1 H), 4.56-4.38 (m, 1 H), 4.28 (dd, J = 7.1 , 9.5 Hz, 1 H), 4.01 -3.86 (m, 2H), 3.84- 3.76 (m, 4H), 3.60-3.52 (m, 1 H), 3.44 (br t, J = 4.3 Hz, 4H), 3.39-3.28 (m, 1 H), 3.20-2.90 (m, 3H), 2.89- 2.78 (m, 1 H), 2.23-2.08 (m, 2H), 1 .96-1 .77 (m, 2H); LCMS (ESI) [M+H]+: 460.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (s, 1 H), 7.56-7.49 (m, 1 H), 7.30 (t, J = 8.2 Hz, 1 H), 7.1 5 (d, J = 8.2 Hz, 1 H), 4.56-4.41 (m, 1 H), 4.28 (dd, J = 7.1 , 9.5 Hz, 1 H), 4.19-4.03 (m, 2H), 3.91 (br t, J = 7.9 Hz, 2H), 3.63-3.46 (m, 3H), 3.40-3.27 (m, 1 H), 3.21 -2.90 (m, 5H), 2.89-2.76 (m, 1 H), 2.15 (br t, J = 13.2 Hz, 2H), 1 .96-1 .77 (m, 2H), 1 .27 (d, J = 6.4 Hz, 6H); LCMS (ESI) [M+H]+: 488.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (br s, 1 H), 7.53 (br d, J = 6.0 Hz, 1 H), 7.30 (t, J = 8.2 Hz, 1 H), 7.1 5 (br d, J = 7.1 Hz, 1 H), 4.48 (s, 5H), 4.28 (dd, J = 7.1 , 9.5 Hz, 1 H), 3.91 (br t, J = 7.9 Hz, 2H), 3.56 (quin, J = 8.3 Hz, 1 H), 3.43-3.28 (m, 5H), 3.1 8-2.89 (m, 3H), 2.87-2.77 (m, 1 H), 2.20-2.07 (m, 2H), 1 .98-1 .92 (m, 4H), 1 .91 -1 .76 (m, 2H); LCMS (ESI) [M+H]+: 500.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (s, 1 H), 7.89-7.82 (m, 3H), 7.80-7.75 (m, 1 H), 7.55-7.49 (m, 1 H), 7.48-7.42 (m, 2H), 7.36 (br s, 1 H), 4.57 (br d, J = 13.8 Hz, 1 H), 4.31 (d, J = 3.8 Hz, 2H), 4.09 (s, 3H), 3.92 (br d, J = 13.9 Hz, 1 H), 3.37-3.28 (m, 1 H), 3.26-3.17 (m, 1 H), 3.13-3.04 (m, 1 H), 2.60 (s, 3H), 2.26-2.15 (m, 2H), 2.05-1 .90 (m, 2H); LCMS (ESI) [M+H]+: 459.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.89-7.84 (m, 1 H), 7.79-7.75 (m, 1 H), 4.20 (s, 3H), 3.81 -3.73 (m, 4H), 3.44-3.36 (m, 4H), 3.27 (br s, 4H), 2.71 (s, 3H); LCMS (ESI) [M+H]+: 410.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (s, 1 H), 7.76 (d, J = 8.3 Hz, 1 H), 7.70-7.65 (m, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.54-7.42 (m, 2H), 6.97 (br s, 1 H), 4.42 (br d, J = 13.6 Hz, 1 H), 4.23 (d, J = 3.9 Hz, 2H), 4.01 (s, 3H), 3.81 (br d, J = 14.2 Hz, 1 H), 3.34-3.23 (m, 2H), 3.09 (br t, J = 1 1 .1 Hz, 1 H), 2.53 (s, 3H), 2.21 (br t, J = 13.4 Hz, 2H), 2.05-1 .91 (m, 2H); LCMS (ESI) [M+H]+: 561 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.17-7.97 (m, 1 H), 7.87-7.77 (m, 1 H), 7.75-7.66 (m, 1 H), 7.24 (br d, J = 6.6 Hz, 2H), 7.20-7.12 (m, 3H), 4.89 (s, 1 H), 4.06 (s, 3H), 3.99 (br d, J = 13.5 Hz, 2H), 3.21 (br t, J = 10.8 Hz, 1 H), 3.06 (br t, J = 1 1 .5 Hz, 2H), 2.85 (br s, 1 H), 2.58 (s, 3H), 2.18 (br d, J = 1 1 .5 Hz, 2H), 2.09-1 .87 (m, 3H), 1 .25-1 .20 (m, 1 H), 1 .17-1 .1 0 (m, 1 H); LCMS (ESI) [M+H]+: 457.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.31 (s, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 4.26 (br s, 2H), 4.09 (s, 3H), 3.41 -3.31 (m, 1 H), 2.98 (br t, J = 12.0 Hz, 2H), 2.60 (s, 3H), 2.23 (br d, J = 12.0 Hz, 2H), 1 .85 (dq, J = 4.0, 12.0 Hz, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 414.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (d, J = 4.3 Hz, 1 H), 8.00 (br d, J = 4.6 Hz, 1 H), 7.94 (br t, J = 7.6 Hz, 1 H), 7.89-7.84 (d, 1 H), 7.83-7.77 (d, 1 H), 7.54-7.43 (m, 2H), 4.61 (m, 1 H), 4.35 (m, 1 H), 4.12 (d, J = 1 .7 Hz, 3H), 4.05-3.92 (m, 2H), 3.65 (m, 1 H), 3.47-3.34 (m, 1 H), 3.31 -3.1 9 (m, 1 H), 3.16-2.86 (m, 3H), 2.63 (s, 3H), 2.31 -2.16 (m, 2H), 2.09-1 .89 (m, 2H); LCMS (ESI) [M+H]+: 51 0.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.96 (brd, J = 10.6 Hz, 1H), 7.90 (br t, J = 9.0 Hz, 1H), 7.52- 7.41 (m, 2H), 4.83 (s, 4H), 4.47 (br t, J = 14.4 Hz, 1H), 4.35-4.27 (m, 1H), 4.22 (s, 4H), 3.99-3.84 (m, 2H), 3.58 (quin, J = 8.2 Hz, 1H), 3.40-3.26 (m, 1H), 3.19-2.82 (m, 4H), 2.14 (br t, J = 14.0 Hz, 2H), 1.96-1.72 (m, 2H); LCMS (ESI) [M+H]+: 463.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (dd, J = 3.9, 8.3 Hz, 1H), 8.13 (s, 1H), 7.50 (dd, J = 1.8, 8.3 Hz, 1 H), 4.82 (s, 4H), 4.52-4.41 (m, 1 H), 4.36 (t, J = 9.9 Hz, 1 H), 4.21 (s, 4H), 4.13 (br t, J = 7.7 Hz, 1 H), 3.93 (brd, J = 13.2 Hz, 1H), 3.51 (quin, J = 8.1 Hz, 1H), 3.32 (br t, J = 11.2 Hz, 1H), 3.21 (brdd, J = 7.5, 17.1 Hz, 1H), 3.14-2.93 (m, 2H), 2.77 (brdd, J = 9.2, 18.9 Hz, 1H), 2.29 (s, 3H), 2.18-2.05 (m, 2H), 1.94- 1.74 (m, 2H); LCMS (ESI) [M+H]+: 453.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.48-7.36 (m, 5H), 4.83 (s, 4H), 4.74-4.45 (m, 1H), 4.22 (s, 4H), 3.81 (br d, J = 15.4 Hz, 1 H), 3.27-3.00 (m, 3H), 2.30-1.94 (m, 2H), 1.87 (br s, 2H); LCMS (ESI) [M+H]+: 355.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.49-7.35 (m, 5H), 4.59 (br s, 1 H), 4.13 (d, J = 8.6 Hz, 2H), 4.01 (d, J = 8.6 Hz, 2H), 3.87 (t, J = 6.8 Hz, 2H), 3.84-3.67 (m, 1 H), 3.26-3.02 (m, 3H), 2.25-2.11 (m, 3H), 2.02- 1.73 (m, 5H); LCMS (ESI) [M+H]+: 369.2.

¹ H NMR (400 MHz, METHANOL-cU) δ 7.39-7.29 (m, 4H), 4.52 (br s, 1 H), 4.08-3.97 (m, 4H), 3.86 (t, J = 6.8 Hz, 3H), 3.23 (tt, J = 4.0, 10.8 Hz, 3H), 2.96 (td, J = 6.9, 13.8 Hz, 1 H), 2.25-2.02 (m, 4H), 1 .95 (quin, J = 7.1 Hz, 2H), 1 .81 (br s, 2H), 1 .27 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 41 1 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.38-7.31 (m, 2H), 7.27-7.24 (m, 2H), 4.83 (s, 4H), 4.71 -4.40 (m, 1 H), 4.22 (s, 4H), 4.09-3.68 (m, 1 H), 3.31 -3.03 (m, 3H), 2.94 (spt, J = 6.9 Hz, 1 H), 2.06 (br d, J = 7.1 Hz, 2H), 1 .88 (br s, 2H), 1 .26 (d, J = 7.1 Hz, 6H); LCMS (ESI) [M+H]+: 397.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.05-7.92 (m, 2H), 7.71 -7.60 (m, 1 H), 7.50 (br t, J = 7.4 Hz, 1 H), 7.28 (t, J = 8.2 Hz, 1 H), 7.13 (dd, J = 1 .0, 8.0 Hz, 1 H), 4.64-4.40 (m, 2H), 4.26 (dd, J = 7.1 , 9.3 Hz, 1 H), 4.00-3.85 (m, 2H), 3.60-3.51 (m, 1 H), 3.41 -3.20 (m, 2H), 3.15-2.99 (m, 1 H), 2.99-2.77 (m, 2H), 2.21 (br t, J = 13.6 Hz, 2H), 2.02-1 .84 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 483.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.68-7.64 (m, 1 H), 7.52 (br t, J = 6.2 Hz, 1 H), 7.30 (t, J = 8.2 Hz, 1 H), 7.1 5 (d, J = 7.9 Hz, 1 H), 4.84 (s, 4H), 4.56-4.39 (m, 1 H), 4.30-4.24 (m, 1 H), 4.22 (s, 4H), 3.90 (dt, J = 3.5, 8.9 Hz, 2H), 3.60-3.51 (m, 1 H), 3.40-3.25 (m, 1 H), 3.18-2.97 (m, 2H), 2.97-2.88 (m, 1 H), 2.87-2.78 (m, 1 H), 2.13 (t, J = 12 Hz, 2H), 1 .96-1 .72 (m, 2H) ; LCMS (ESI) [M+H]+: 472.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.51 (d, J = 2.0 Hz, 1 H), 8.06 (s, 1 H), 7.86-7.80 (m, 1 H), 7.55 (br d, J = 8.2 Hz, 1 H), 7.37 (dt, J = 2.3, 8.1 Hz, 1 H), 7.17 (br d, J = 8.2 Hz, 1 H), 5.68-5.61 (m, 1 H), 4.96-4.83 (m, 4H), 4.31 (br d, J = 12.6 Hz, 1 H), 4.08-4.01 (m, 1 H), 3.97 (br d, J = 13.9 Hz, 1 H), 3.91 (dd, J = 5.7, 9.7 Hz, 1 H), 3.76-3.65 (m, 1 H), 3.44-3.34 (m, 1 H), 3.29-3.21 (m, 1 H), 2.90 (br t, J = 13.8 Hz, 1 H), 2.79-2.68 (m, 2H), 2.09 (br t, J = 14.0 Hz, 2H), 1 .87-1 .56 (m, 2H); LCMS (ESI) [M+H]+: 497.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (t, 1 H), 7.79 (m, 2H), 4.38 (m, 2H), 4.09 (s, 3H), 3.59 (m, 1 H), 2.61 (s, 3H), 2.06 (m, 5H), 1 .81 (d, J = 8Hz, 2H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 424.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.29 (s, 1 H), 7.86 (dd, J = 1 .5, 9.0 Hz, 1 H), 7.62 (d, J = 9.0 Hz, 1 H), 4.35 (q, J = 7.3 Hz, 2H), 4.06 (br s, 2H), 3.1 1 (tt, J = 3.6, 1 0.8 Hz, 1 H), 2.93 (br t, J = 1 1 .7 Hz, 2H), 2.60 (s, 3H), 2.06 (br dd, J = 2.7, 13.1 Hz, 2H), 1 .90-1 .81 (m, 2H), 1 .50 (t, J = 7.3 Hz, 3H), 1 .41 (s, 9H); LCMS (ESI) [M+H]+: 412.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1 H), 7.84-7.78 (m, 1 H), 7.75-7.69 (m, 1 H), 4.88 (m, 1 H), 4.16 (br s, 2H), 3.25-3.15 (m, 1 H), 3.07-2.94 (m, 2H), 2.60 (s, 3H), 2.20-2.10 (m, 2H), 2.00-1 .87 (m, 2H), 1 .59 (d, J = 6.6 Hz, 6H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 426.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.07 (s, 1 H), 7.95-7.78 (m, 2H), 7.49-7.36 (m, 1 H), 7.25-7.20 (m, 1 H), 7.19-7.10 (m, 2H), 5.06-4.89 (m, 1 H), 4.86-4.50 (m, 1 H), 4.05-3.72 (m, 1 H), 3.46-3.32 (m, 1 H), 3.30-3.15 (m, 2H), 2.46-1 .92 (m, 4H), 1 .64 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 434.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.07 (s, 1 H), 7.90-7.74 (m, 2H), 7.49-7.27 (m, 4H), 5.09-4.98 (m, 1 H), 4.82-4.68 (m, 1 H), 3.70-3.52 (m, 1 H), 3.44-3.10 (m, 3H), 2.43-2.27 (m, 1 H), 2.22-1 .81 (m, 3H), 1 .64 (d, J = 6.4 Hz, 6H); LCMS (ESI) [M+H]+: 450.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.07 (s, 1 H), 7.84 (q, J = 8.4 Hz, 2H), 7.45 (s, 5H), 5.06-4.90 (m, 1 H), 4.77-4.54 (m, 1 H), 4.10-3.77 (m, 1 H), 3.45-3.30 (m, 1 H), 3.30-3.07 (m, 2H), 2.45-1 .93 (m, 4H), 1 .64 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 416.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 1 1 .23-10.26 (m, 1 H), 8.16 (s, 2H), 7.72-7.63 (m, 1 H), 7.53 (br t, J = 7.3 Hz, 1 H), 7.31 (t, J = 8.1 Hz, 1 H), 7.15 (d, J = 7.9 Hz, 1 H), 4.66-4.44 (m, 1 H), 4.35-4.23 (m, 1 H), 4.02-3.89 (m, 2H), 3.63-3.54 (m, 1 H), 3.44-3.26 (m, 2H), 3.21 -2.77 (m, 3H), 2.24 (br t, J = 13.5 Hz, 2H), 2.06-1 .87 (m, 2H); LCMS (ESI) [M+H]+: 441 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (br d, J = 10.1 Hz, 1H), 7.52 (br t, J = 8.7 Hz, 1H), 7.30 (t, J = 8.2 Hz, 1H), 7.15 (brd, J = 7.9 Hz, 1H), 4.50 (brdd, J = 14.2, 18.4 Hz, 1H), 4.34-4.18 (m, 1H), 4.04- 3.85 (m, 2H), 3.60-3.52 (m, 1H), 3.44-3.22 (m, 2H), 3.16-3.00 (m, 1H), 3.00-2.77 (m, 2H), 2.31-2.13 (m, 2H), 2.03-1.79 (m, 2H); LCMS (ESI) [M+H]+: 409.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (s, 1 H), 8.03 (s, 1 H), 7.77 (s, 2H), 4.94 (spt, J = 6.6 Hz, 1 H), 3.70 (br d, J = 5.1 Hz, 4H), , 3.62-3.55 (m, 4H), 1.61 (d, J = 6.8 Hz, 6H), 1.49 (s, 9H); LCMS (ESI) [M+H]+: 413.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.03-7.94 (m, 1H), 7.89 (br dd, J = 8.2, 19.2 Hz, 1H), 7.54-7.41 (m, 2H), 4.50 (br t, J = 14.3 Hz, 1H), 4.36-4.24 (m, 1H), 4.02-3.87 (m, 2H), 3.60 (s, J = 8.2 Hz, 1H), 3.46- 3.24 (m, 2H), 3.18-3.01 (m, 1H), 3.00-2.82 (m, 2H), 2.22 (br t, J = 14.0 Hz, 2H), 2.03-1.79 (m, 2H); LCMS (ESI) [M+H]+: 400.1.

Ή NMR (400 MHz, CHLOROFORM-d) δ 7.49-7.34 (m, 5H), 4.61 (br s, 1H), 3.86 (br s, 1H), 3.31-3.10 (m, 3H), 2.27 -1.92 (m, 4H); LCMS (ESI) [M+H]+: 292.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.38-7.32 (m, 2H), 7.29-7.25 (m, 2H), 4.60 (br s, 1 H), 3.94 (br s, 1 H), 3.35-3.08 (m, 3H), 2.94 (spt, J = 6.8 Hz, 1 H), 2.15 (br s, 2H), 1.93 (br s, 2H), 1.26 (d, J = 7.1 Hz, 6H); LCMS (ESI) [M+H]+: 334.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.26 (t, J = 8.6 Hz, 1 H), 8.14 (br s, 1 H), 7.51 (br d, J = 7.9 Hz, 1 H), 4.50 (br s, 1 H), 4.38 (br t, J = 1 0.1 Hz, 1 H), 4.13 (dd, J = 7.2, 1 1 .2 Hz, 1 H), 3.98 (br d, J = 13.6 Hz, 1 H), 3.57-3.48 (m, 1 H), 3.37 (br t, J = 1 1 .8 Hz, 1 H), 3.31 -3.1 7 (m, 2H), 3.09-2.98 (m, 1 H), 2.78 (dd, J = 9.2, 17.1 Hz, 1 H), 2.30 (s, 3H), 2.18 (br d, J = 14.0 Hz, 2H), 1 .99-1 .83 (m, 2H); LCMS (ESI) [M+H]+: 390.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (s, 1 H), 7.86-7.82 (d, J = 1 .2 Hz, 1 H), 7.78-7.74 (d, J = 8.4 Hz, 1 H), 7.34-7.27 (m, 5H), 4.86 (d, J = 14.7 Hz, 1 H), 4.52 (d, J = 14.7 Hz, 1 H), 4.10 (s, 3H), 3.63 (tdd, J = 3.6, 7.3, 13.5 Hz, 1 H), 3.40-3.34 (m, 2H), 3.05 (d, J = 7.5 Hz, 2H), 2.62 (s, 3H), 2.45-2.36 (m, 1 H), 2.29- 2.19 (m, 1 H); LCMS (ESI) [M+H]+: 402.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.05 (s, 1 H), 7.90-7.75 (m, 2H), 4.95 (spt, J = 6.6 Hz, 1 H), 4.18 (br s, 2H), 3.72 (s, 3H), 3.22 (tt, J = 3.9, 10.7 Hz, 1 H), 3.08 (br t, J = 1 1 .7 Hz, 2H), 2.16 (br d, J = 1 1 .0 Hz, 2H), 2.03-1 .86 (m, 2H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 370.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (s, 1 H), 8.03 (s, 1 H), 7.77 (s, 2H), 4.94 (spt, J = 6.6 Hz, 1 H), 3.76 (s, 3H), 3.72 (br s, 4H), 3.65 (br s, 4H), 1 .61 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 371 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.06 (s, 1 H), 7.83 (q, J = 8.4 Hz, 2H), 5.07-4.87 (m, 2H), 4.20 (br s, 2H), 3.23 (tt, J = 4.0, 1 0.8 Hz, 1 H), 3.06 (br t, J = 1 1 .6 Hz, 2H), 2.25-2.09 (m, 2H), 2.05- 1 .87 (m, 2H), 1 .64 (d, J = 6.8 Hz, 6H), 1 .28 (d, J = 6.0 Hz, 6H); LCMS (ESI) [M+H]+: 398.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.07 (s, 1 H), 7.93-7.77 (m, 2H), 7.32 (br t, J = 7.2 Hz, 2H), 7.09-6.92 (m, 3H), 5.09-4.90 (m, 1 H), 4.74 (s, 2H), 4.49 (br d, J = 13.6 Hz, 1 H), 4.13 (br d, J = 13.6 Hz, 1 H), 3.57-3.25 (m, 2H), 3.10 (br t, J = 1 1 .6 Hz, 1 H), 2.35-2.17 (m, 2H), 2.12-1 .87 (m, 2H), 1 .64 (d, J = 5.6 Hz, J = 6H); LCMS (ESI) [M+H]+: 446.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (s, 1 H), 8.04 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 1 H), 4.26-4.08 (m, 5H), 3.27-3.16 (m, 1 H), 3.03 (br t, J = 1 1 .6 Hz, 2H), 2.16 (br d, J = 10.0 Hz, 2H), 2.03-1 .87 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 384.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.34 (s, 1 H), 7.98 (s, 1 H), 7.92-7.84 (m, 1 H), 7.83-7.75 (m, 1 H), 4.24-4.07 (m, 2H), 3.72-3.62 (m, 1 H), 3.27-3.1 5 (m, 1 H), 3.09-2.93 (m, 2H), 2.16 (br d, J = 1 1 .0 Hz, 2H), 2.01 -1 .87 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 410.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.05 (s, 1 H), 7.82 (q, J = 8.5 Hz, 2H), 4.96 (spt, J = 6.7 Hz, 1 H), 4.16 (q, J = 7.2 Hz, 4H), 3.22 (tt, J = 3.9, 10.8 Hz, 1 H), 3.07 (br t, J = 1 1 .7 Hz, 2H), 2.22-2.1 1 (m, 2H), 2.02-1 .89 (m, 2H), 1 .62 (d, J = 6.6 Hz, 6H), 1 .28 (t, J = 7.2 Hz, 3H); LCMS (ESI) [M+H]+: 384.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.17 (s, 1 H), 8.12 (s, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.67 (dd, J = 1 .0, 8.5 Hz, 1 H), 7.53-7.41 (m, 4H), 5.06 (quin, J = 6.5 Hz, 1 H), 3.78-3.62 (m, 8H), 1 .53 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 417.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.09 (s, 1 H), 7.91 -7.81 (m, 2H), 7.47-7.39 (m, 4H), 5.07-4.92 (m, 1 H), 4.65 (br s, 1 H), 3.89 (br s, 1 H), 3.44-3.15 (m, 3H), 2.40-1 .94 (m, 4H), 1 .65 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 450.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 8.04 (s, 1 H), 7.77 (s, 2H), 7.47-7.30 (m, 4H), 5.01 - 4.86 (m, 1 H), 4.16-4.07 (m, 1 H), 3.95-3.64 (m, 5H), 3.52-3.31 (m, 2H), 1 .61 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 451 .0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1 H), 7.89-7.81 (d, J = 8.4 Hz, 1 H), 7.78-7.69 (d, J = 8.4 Hz, 1 H), 4.48-4.33 (m, 4H), 4.15-4.02 (m, 4H), 2.61 (s, 3H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 370.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.19 (s, 1 H), 8.05 (s, 1 H), 7.87 (d, J = 7.2 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 1 H), 4.52 (q, J = 7.2 Hz, 2H), 4.30-4.12 (m, 2H), 3.24-3.18 (m, 1 H), 3.01 (t, J = 5.6 Hz, 2H), 2.18- 2.14 (m, 2H), 1 .98-1 .92 (m, 2H), 1 .57 (t, J = 7.2 Hz, 3H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 398.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.17 (s, 1 H), 8.04 (s, 1 H), 7.92-7.85 (d, J = 8.4 Hz, 1 H), 7.84- 7.78 (d, J = 8.4 Hz, 1 H), 5.36-5.26 (m, 1 H), 4.36-4.06 (m, 5H), 4.00-3.82 (m, 4H), 3.29-3.18 (m, 1 H), 3.16- 3.00 (m, 2H), 2.30-2.17 (m, 3H), 2.1 1 -1 .88 (m, 3H); LCMS (ESI) [M+H]+: 398.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.86-7.80 (d, J = 8.4 Hz, 1 H), 7.78-7.72 (d, J Hz, 1 H), 4.08 (s, 3H), 3.98-3.46 (m, 5H), 2.60 (s, 3H), 2.50-2.35 (m, 2H), 1 .50 (s, 9H); LCMS (ESI)

[M+H]+: 384.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.23 (s, 1 H), 8.1 1 (s, 1 H), 7.90 (d, J = 8.6 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.49 (d, J = 8.4 Hz, 2H), 7.39 (s, 0.2H), 7.25-7.22 (d, J = 8.4 Hz, 2H), 7.22-7.20 (s, 0.6H), 7.03 (s, 0.2H), 4.14-3.93 (m, 5H), 3.54-3.43 (m, 1 H), 3.23 (br t, J = 1 1 .2 Hz, 2H), 2.17 (br dd, J = 2.5, 13.1 Hz, 2H), 1 .93-1 .82 (m, 2H); LCMS (ESI) [M+H]+: 454.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.50 (s, 1 H), 7.97 (s, 1 H), 7.79-7.71 (m, 2H), 4.51 (q, J = 7.6 Hz, 2H), 4.13 (br d, J = 8.8 Hz, 2H), 3.19 (tt, J = 4.0, 10.8 Hz, 1 H), 3.01 (br t, J = 1 1 .6 Hz, 2H), 2.14 (br dd, J = 2.8, 13.2 Hz, 2H), 2.00-1 .86 (m, 2H), 1 .66 (t, J = 7.6 Hz, 3H), 1 .48 (s, 9H); LCMS (ESI) [M+H-56]+: 342.2, LCMS (ESI) [M+23]+: 420.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1 H), 7.85-7.80 (d, J = 8.4 Hz, 1 H), 7.76-7.71 (d, J = 8.4 Hz, 1H), 4.51 (brd, J = 13.0 Hz, 1H), 4.19 (d, J = 6.8 Hz, 2H), 4.08 (s, 4H), 3.64-3.56 (m, 2H), 3.37-3.25 (m, 2H), 3.03 (br t, J = 11.5 Hz, 1H), 2.60 (s, 3H), 2.24 (brd, J = 12.3 Hz, 2H), 2.07-1.91 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 384.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.10 (s, 1H), 7.85-7.81 (d, J = 8.4 Hz, 1H), 7.77-7.72 (d, J = 8.4 Hz, 1H), 4.55 (brd, J = 13.5 Hz, 1H), 4.09 (s, 3H), 3.91 (brd, J = 14.3 Hz, 1H), 3.46-3.25 (m, 4H), 3.20-3.07 (m, 1 H), 2.61 (s, 3H), 2.33-2.21 (m, 2H), 2.11-1.95 (m, 2H); LCMS (ESI) [M+H]+: 408.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 2H), 8.10 (s, 1H), 7.83 (dd, J = 1.1, 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1 H), 4.76 (td, J = 3.5, 13.5 Hz, 2H), 4.07 (s, 3H), 3.32 (tt, J = 4.0, 11.0 Hz, 1 H), 3.25-3.15 (m, 2H), 2.59 (s, 3H), 2.49 (q, J = 7.5 Hz, 2H), 2.25 (br dd, J = 3.0, 13.6 Hz, 2H), 2.07-1.95 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H); LCMS (ESI) [M+H]+: 404.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.18 (s, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 1.3 Hz, 1 H), 6.59 (d, J = 1.3 Hz, 1 H), 4.04 (s, 3H), 3.45 (s, 3H), 3.38-3.32 (m, 1 H), 3.27-3.24 (m, 2H), 2.92 (br t, J = 10.7 Hz, 2H), 2.21-2.12 (m, 2H), 2.08-1.96 (m, 2H); LCMS (ESI) [M+H]+: 378.3.

¹ H NMR (400 MHz, DMSO-de) δ 8.18 (s, 1 H), 7.88-7.86 (d, J = 8 Hz, 1 H), 4.71 - 4.73 (d, J = 8 Hz, 1 H), 4.05 (s, 3H), 3.95-9.32 (m, 2H), 3.49-3.53 (m, 1 H), 3.32-3.48 (m, 1 H), 2.25-2.22 (m, 2H), 1 .99-1 .96 (m, 2H); LCMS (ESI) [M+H]+: 380.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.05 (s, 1 H), 7.82 (q, J = 8.5 Hz, 2H), 5.05-4.90 (m, 1 H), 4.62 (br d, J = 13.7 Hz, 1 H), 4.03 (br d, J = 13.2 Hz, 1 H), 3.36-3.22 (m, 2H), 2.95 (br t, J = 1 1 .1 Hz, 1 H), 2.31 (s, 2H), 2.21 (br d, J = 1 0.8 Hz, 2H), 2.07-1 .86 (m, 2H), 1 .62 (d, J = 6.6 Hz, 6H), 1 .08 (s, 9H); LCMS (ESI) [M+H]+: 410.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.06 (s, 1 H), 7.98 (s, 1 H), 7.70 (s, 2H), 4.88 (spt, J = 6.6 Hz,

1 H), 3.75 (br d, J = 4.8 Hz, 2H), 3.67 (br d, J = 4.9 Hz, 4H), 3.62 (br d, J = 5.3 Hz, 2H), 2.26 (s, 2H), 1 .55 (d, J = 6.7 Hz, 6H), 1 .02 (s, 9H); LCMS (ESI) [M+H]+: 41 1 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (s, 1 H), 7.87-7.81 (d, J = 8.4 Hz, 1 H), 7.78-7.72 (d, J = 8.4 Hz, 1 H), 4.65-4.40 (m, 4H), 4.17-4.1 1 (m, 1 H), 4.09 (s, 3H), 2.61 (s, 3H), 2.06 (s, 2H), 1 .09 (s, 9H); LCMS (ESI) [M+H]+: 368.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.19 (s, 1 H), 8.07 (s, 1 H), 7.83 (q, J = 8.4 Hz, 2H), 4.72-4.62 (m, 1 H), 4.1 6 (br s, 2H), 3.25-3.16 (m, 1 H), 3.01 (br t, J = 1 1 .7 Hz, 2H), 2.20-2.08 (m, 3H), 2.00-1 .87 (m, 3H), 1 .60 (d, J = 6.6 Hz, 3H), 1 .48 (s, 9H), 0.80 (t, J = 7.4 Hz, 3H); LCMS (ESI) [M+H]+: 426.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.53 (s, 1 H), 7.96 (s, 1 H), 7.77-7.70 (m, 2H), 4.54 (qd, J = 6.9, 14.0 Hz, 1 H), 4.10 (br s, 2H), 3.22-3.13 (m, 1 H), 3.02 (br t, J = 1 1 .4 Hz, 2H), 2.17-2.04 (m, 3H), 2.00-1 .85 (m, 3H), 1 .66 (d, J = 6.8 Hz, 3H), 1 .48 (s, 9H), 0.84 (t, J = 7.4 Hz, 3H); LCMS (ESI) [M+H]+: 426.2, LCMS (ESI) [M-55]+: 370.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.51 (s, 1 H), 8.15 (s, 1 H), 8.04 (d, J = 8.6 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.66 (s, 0.2H), 7.51 (s, 0.5H), 7.36 (s, 0.3H), 4.15 (br s, 2H), 3.26-3.1 6 (m, 1 H), 3.01 (br t, J 12.8 Hz, 2H), 2.15 (br d, J = 1 0.4 Hz, 2H), 1 .99-1 .87 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 420.2, LCMS (ESI) [M+23]+: 442.1 , LCMS (ESI) [M-100+23]+: 342.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.08 (s, 1 H), 7.82-7.80 (d, J = 8.4 Hz, 1 H), 7.76-7.69 (d, J = 8.4 Hz, 1 H), 4.57-4.37 (m, 1 H), 4.07 (s, 3H), 3.65-3.47 (m, 1 H), 3.04-2.87 (m, 1 H), 2.59 (s, 3H), 2.36-2.14 (m, 4H), 1 .82 (dq, J = 2.9, 12.9 Hz, 2H), 1 .46 (s, 9H), 1 .29 (dq, J = 3.0, 12.5 Hz, 2H); LCMS (ESI) [M+H]+: 412.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.53 (s, 1 H), 8.39 (s, 1 H), 7.87-7.78 (m, 2H), 7.65 (s, 0.2H), 7.49 (s, 0.5H), 7.34 (s, 0.3H), 4.13 (br s, 2H), 3.24-3.15 (m, 1 H), 3.07-2.96 (m, 2H), 2.15 (br d, J = 10.8 Hz, 2H), 1 .98-1 .86 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+23]+: 442.1 , LCMS (ESI) [M-100]+: 320.0, LCMS (ESI) [M-55]+: 364.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.42 (s, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 8.04 (s, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 4.99 (td, J = 6.7, 13.3 Hz, 1 H), 4.35-4.14 (m, 2H), 3.43-3.29 (m, 1 H), 2.97 (br t, J = 12.0 Hz, 2H), 2.22 (br d, J = 1 1 .7 Hz, 2H), 1 .85 (m, 2H), 1 .63 (d, J = 6.6 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 428.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1 H), 7.85-7.79 (m, 1 H), 7.77-7.70 (m, 1 H), 4.08 (d, J 1 .8 Hz, 3H), 4.06-3.92 (m, 2H), 3.88-3.73 (m, 2H), 3.71 -3.62 (m, 1 H), 2.60 (s, 3H), 2.56-2.35 (m, 2H), 2.30-2.20 (m, 2H), 1 .10 (d, J = 1 .8 Hz, 9H); LCMS (ESI) [M+H]+: 382.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12-8.08 (m, 1 H), 7.83 (dd, J = 1 .1 , 8.6 Hz, 1 H), 7.76-7.72 (m, 1 H), 4.09 (s, 3H), 3.99-3.49 (m, 5H), 2.60 (s, 3H), 2.50-2.34 (m, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 384.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.87-7.81 (m, 1 H), 7.74 (d, J = 8.3 Hz, 1 H), 4.64- 4.62 (m, 1 H), 4.09 (s, 3H), 3.77-3.74 (m, 1 H), 3.23-3.20 (m, 1 H), 2.61 (s, 3H), 2.15 (br s, 2H), 2.01 (dt, J = 4.2, 8.9 Hz, 2H), 1 .85 (br d, J = 4.4 Hz, 2H), 1 .73 (br s, 2H), 1 .46 (s, 9H); LCMS (ESI) [M+H]+: 412.2.

¹ H NMR (400 MHz, METHANOL-cU) δ 8.16 (s, 1 H), 7.85-7.74 (m, 2H), 4.04 (s, 3H), 3.27-3.06 (m, 2H), 2.56 (s, 3H), 2.44-2.30 (m, 2H), 2.21 (br d, J = 10.6 Hz, 2H), 1 .83 (m, 2H), 1 .70-1 .51 (m, 2H); LCMS (ESI) [M+H]+: 312.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.06 (s, 1 H), 7.94-7.78 (m, 2H), 4.97 (td, J = 6.7,

13.3 Hz, 1 H), 4.59 (br d, J = 13.7 Hz, 1 H), 3.95 (br d, J = 13.9 Hz, 1 H), 3.39-3.21 (m, 2H), 3.00 (br t, J =

1 1 .4 Hz, 1 H), 2.34 (d, J = 6.8 Hz, 2H), 2.28-2.13 (m, 2H), 2.07-1 .88 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .14-1 .00 (m, 1 H), 0.67-0.52 (m, 2H), 0.21 (q, J = 4.9 Hz, 2H); LCMS (ESI) [M+H]+: 394.3.

¹ H NMR (400 MHz, METHANOLS) δ 8.24 (s, 1 H), 7.86 (s, 2H), 4.08 (s, 3H), 3.47 (br t, J = 4.3 Hz, 1 H), 3.36-3.32 (m, 1 H), 2.60 (s, 3H), 2.49-2.39 (m, 2H), 2.12-1 .98 (m, 4H), 1 .84-1 .68 (m, 2H); LCMS (ESI) [M+H]+: 312.2.

¹ H NMR (400 MHz, METHANOLS) δ 8.40 (br s, 1 H), 8.22 (s, 1 H), 7.83 (s, 2H), 4.63-4.45 (m, 5H), 4.05 (s, 3H), 2.57 (s, 3H); LCMS (ESI) [M+H]+: 270.1 .

¹ H NMR (400 MHz, METHANOLS) δ 8.25 (s, 1 H), 7.87 (s, 2H), 4.15 (quin, J = 7.2 Hz, 1 H), 4.09 (s, 3H), 3.91 -3.80 (m, 2H), 3.63-3.50 (m, 2H), 2.72-2.62 (m, 1 H), 2.61 (s, 3H), 2.50 (qd, J = 6.9, 13.8 Hz, 1 H); LCMS (ESI) [M+H]+: 284.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.06 (s, 1 H), 7.87-7.79 (m, 2H), 4.96 (quind, J = 6.7, 13.3 Hz, 1 H), 4.52 (dq, J = 2.0, 8.5 Hz, 2H), 4.19 (br t, J = 17.3 Hz, 2H), 3.33-3.08 (m, 3H), 2.21 (br d, J = 1 1 .5 Hz, 2H), 2.07-1 .92 (m, 2H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 438.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.05 (s, 1 H), 7.90-7.75 (m, 2H), 4.95 (spt, J = 6.6 Hz, 1 H), 4.18 (br s, 2H), 3.72 (s, 3H), 3.22 (tt, J = 3.9, 10.7 Hz, 1 H), 3.08 (br t, J = 1 1 .7 Hz, 2H), 2.16 (br d, J = 1 1 .0 Hz, 2H), 2.03-1 .86 (m, 2H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 370.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.08 (s, 1 H), 7.91 -7.79 (m, 2H), 4.99 (td, J = 6.7,

13.3 Hz, 1 H), 4.62 (br t, J = 12.5 Hz, 2H), 4.31 -4.08 (m, 2H), 3.36-3.09 (m, 4H), 2.23 (br s, 2H), 2.02 (br s, 2H), 1 .65 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 488.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.08 (s, 1 H), 7.91 -7.80 (m, 2H), 5.81 (spt, J = 6.1 Hz, 1 H), 4.99 (spt, J = 6.6 Hz, 1 H), 4.34-4.07 (m, 2H), 3.42-3.14 (m, 3H), 2.26 (br d, J = 3.5 Hz, 2H), 2.13- 1 .94 (m, 2H), 1 .65 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 506.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.72 (d, J = 6.0 Hz, 2H), 8.20 (s, 1 H), 8.06 (s, 1 H), 7.91 -7.77 (m, 2H), 7.32 (d, J = 6.0 Hz, 2H), 4.96 (spt, J = 6.6 Hz, 1 H), 4.64 (br d, J = 1 1 .2 Hz, 1 H), 3.76 (br d, J = 1 1 .9 Hz, 1 H), 3.44-3.32 (m, 1 H), 3.26 (br d, J = 1 0.8 Hz, 2H), 2.32 (br s, 1 H), 2.23-1 .88 (m, 3H), 1 .63 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 417.1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.27 (s, 1 H), 8.1 5 (s, 1 H), 7.91 (d, J = 8.6 Hz, 1 H), 7.75 (d, J = 8.6 Hz, 1 H), 5.1 1 (spt, J = 6.7 Hz, 1 H), 4.14-4.00 (m, 1 H), 3.94 (br d, J = 13.5 Hz, 2H), 3.49-3.36 (m, 1 H), 3.49- 3.36 (m, 1 H), 3.13-3.08 (m, 2H), 2.13 (br dd, J = 3.3, 13.2 Hz, 2H), 1 .86-1 .70 (m, 2H), 1 .53 (d, J = 6.4 Hz, 6H), 0.72-0.60 (m, 4H); LCMS (ESI) [M+H]+: 396.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.68-8.63 (m, 2H), 8.28 (s, 1 H), 8.16 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.86 (d, J = 7.9 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.48 (dd, J = 4.9, 7.7 Hz, 1 H), 5.1 1 (spt, J = 6.6 Hz, 1 H), 4.06 (br s, 2H), 3.59-3.46 (m, 1 H), 3.29 (br t, J = 1 1 .2 Hz, 2H), 2.25-2.15 (m, 2H), 1 .98-1 .83 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 41 7.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.60 (br d, J = 4.4 Hz, 1 H), 8.21 (s, 1 H), 8.05 (s, 1 H), 7.88-7.78 (m, 3H), 7.67 (br d, J = 7.7 Hz, 1 H), 7.40-7.33 (m, 1 H), 4.96 (td, J = 6.6, 13.2 Hz, 1 H), 4.68 (br d, J = 13.2 Hz, 1 H), 4.1 1 (br d, J = 13.2 Hz, 1 H), 3.36 (br t, J = 10.5 Hz, 2H), 3.24 (br t, J = 1 1 .5 Hz, 1 H), 2.32 (br d, J = 1 1 .7 Hz, 1 H), 2.24-2.01 (m, 3H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 417.1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.26 (s, 1H), 8.13 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1 H), 7.32 (q, J = 8.2 Hz, 4H), 5.09 (spt, J = 6.5 Hz, 1 H), 4.06 (br s, 2H), 3.58-3.42 (m, 1 H), 3.27-3.11 (m, 2H), 2.94 (spt, J = 6.8 Hz, 1H), 2.16 (br dd, J = 2.9, 13.0 Hz, 2H), 1.93-1.77 (m, 2H), 1.52 (d, J = 6.6 Hz, 6H), 1.23 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 458.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.09-8.06 (m, 1 H), 7.90-7.76 (m, 2H), 5.52 (br s, 1H), 4.96 (dq, J = 4.2, 6.5 Hz, 1H), 4.49 (brd, J = 13.2 Hz, 1H), 4.01 (brs, 2H), 3.82 (br d, J = 13.5 Hz, 1H), 3.39-3.22 (m, 2H), 3.08 (br t, J = 12.0 Hz, 1H), 2.21 (brs, 2H), 2.06-1.89 (m, 2H), 1.63 (dd, J = 2.6, 6.6 Hz, 6H), 1.46 (d, J = 2.0 Hz, 9H); LCMS (ESI) [M+H]+: 349.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.49 (d, J = 1.7 Hz, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.91-7.82 (m, 2H), 7.70-7.62 (m, 2H), 4.71 (br d, J = 13.4 Hz, 1 H), 4.18 (s, 4H), 3.45-3.33 (m, 2H), 3.25 (br t, J = 11.1 Hz, 1H), 3.02 (spt, J = 6.9 Hz, 1H), 2.34 (brd, J = 10.9 Hz, 1H), 2.23-2.11 (m, 3H), 1.33 (d, J = 7.0 Hz, 6H); LCMS (ESI) [M+H]+: 431.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.06 (s, 1 H), 7.89-7.81 (m, 2H), 4.35 (d, J = 6.8 Hz, 2H), 4.25-4.11 (m, 2H), 3.25-3.18 (m, 1H), 3.09-2.97 (m, 2H), 2.21-2.12 (m, 2H), 2.01-1.89 (m, 2H), 1.50 (s, 9H), 1.41 (br d, J = 4.9 Hz, 1 H), 0.65-0.59 (m, 2H), 0.49-0.44 (m, 2H); LCMS (ESI) [M+H]+: 424.1.

¹ H NMR (400 MHz, DMSO-de) δ 8.30 (s, 1 H), 8.1 9 (s, 1 H), 7.93 (d, J = 8.4 Hz, 1 H), 7.75 (dd, J = 1 .1 , 8.4 Hz, 1 H), 5.14 (quin, J = 6.6 Hz, 1 H), 3.93 (br d, J = 7.3 Hz, 1 H), 3.78 (br d, J = 8.2 Hz, 1 H), 3.68-3.60 (m, 1 H), 3.52-3.44 (m, 1 H), 3.40 (br d, J = 7.5 Hz, 1 H), 2.40 (br s, 1 H), 2.24 (br d, J = 6.8 Hz, 1 H), 1 .50 (d, J = 6.4 Hz, 6H), 1 .42 (s, 9H); LCMS (ESI) [M+H]+: 398.2.

¹ H NMR (400 MHz, DMSO-de) δ 9.05 (br s, 2H), 7.85 (d, J = 1 .3 Hz, 1 H), 7.80 (dd, J = 1 .5, 8.4 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 4.58 (spt, J = 6.9 Hz, 1 H), 3.52 (tt, J = 3.8, 10.9 Hz, 1 H), 3.38-3.33 (m, 2H), 3.07 (br t, J = 1 1 .2 Hz, 2H), 2.27 (br dd, J = 2.9, 14.1 Hz, 2H), 2.10-1 .98 (m, 2H), 1 .49 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 329.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.08 (s, 1 H), 7.85-7.79 (d, J = 8.4 Hz 1 H), 7.75-7.68 (d, J = 8.4 Hz 1 H), 7.42-7.29 (m, 5H), 5.1 1 (s, 2H), 4.68 (br d, J = 5.5 Hz, 1 H), 4.07 (s, 3H), 3.73-3.55 (m, 1 H), 3.05- 2.90 (m, 1 H), 2.59 (s, 3H), 2.36-2.16 (m, 4H), 1 .94-1 .75 (m, 2H), 1 .43-1 .24 (m, 2H); LCMS (ESI) [M+H]+: 446.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.52 (s, 2H), 8.10 (s, 1 H), 7.86-7.81 (d, J = 8.4 Hz, 1 H), 7.76- 7.72 (d, J = 8.4 Hz, 1 H), 4.85 (td, J = 3.7, 13.6 Hz, 2H), 4.08 (s, 3H), 3.45-3.25 (m, 3H), 2.60 (s, 3H), 2.29 (br dd, J = 3.3, 13.6 Hz, 2H), 2.1 1 -1 .94 (m, 2H); LCMS (ESI) [M+H]+: 444.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.08 (s, 1 H), 7.82-7.80 (d,J = 8.0 Hz, 1 H) 7.73- 7.70 (d,J = 8.0 Hz, 1 H), 5.40-5.30 (m, 1 H), 4.07 (s, 3H), 3.89 (m, 1 H), 2.97 (tt, J = 3.5, 12.2 Hz, 1 H), 2.59 (s, 3H), 2.34- 2.15 (m, 4H), 1 .99 (s, 3H), 1 .86 (m, 2H), 1 .39-1 .20 (m, 2H); LCMS (ESI) [M+H]+: 354.2.

1 H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.78-7.70 (m, 1 H), 5.50 5.47 (br s, 1 H), 4.09 (s, 3H), 4.08-3.99 (m, 1 H), 3.31 -3.23 (m, 1 H), 2.61 (s, 3H), 2.27-2.1 6 (m, 2H), 2.08 2.00 (m, 2H), 1 .99 (s, 3H), 1 .95-1 .84 (m, 2H), 1 .73-1 .64 (m, 2H); LCMS (ESI) [M+H]+: 354.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (s, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.79-7.71 (m, 3H), 7.54- 7.40 (m, 3H), 6.10 (br d, J = 7.1 Hz, 1 H), 4.26 (tt, J = 4.1 , 7.9 Hz, 1 H), 4.09 (s, 3H), 3.32 (quin, J = 5.2 Hz, 1 H), 2.61 (s, 3H), 2.35-2.23 (m, 2H), 2.15-1 .98 (m, 4H), 1 .86-1 .73 (m, 2H); LCMS (ESI) [M+H]+: 416.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (s, 1 H), 8.07 (s, 1 H), 7.85 (q, J = 8.4 Hz, 2H), 4.98 (quin, = 6.7 Hz, 1 H), 4.48-4.32 (m, 4H), 4.16-4.02 (m, 1 H), 1 .64 (d, J = 6.8 Hz, 6H), 1 .50-1 .45 (m, 9H); LCMS (ESI) [M+H]+: 384.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.28 (s, 1 H), 8.14 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 4.41 (d, J = 6.8 Hz, 2H), 3.93 (br d, J = 13.5 Hz, 2H), 3.45-3.32 (m, 1 H), 3.04-2.95 (m, 2H), 2.1 1 (br dd, J = 3.2, 13.8 Hz, 2H), 1 .84-1 .67 (m, 2H), 1 .51 (s, 3H), 1 .39-1 .26 (m, 1 H), 0.89-0.77 (m, 2H), 0.64-0.59 (m, 2H), 0.56-0.50 (m, 2H), 0.44-0.38 (m, 2H); LCMS (ESI) [M+H]+: 422.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.86-7.82 (m, 1 H), 7.80-7.71 (m, 3H), 7.55-7.42 (m, 3H), 5.99 (br d, J = 7.8 Hz, 1 H), 4.20-4.03 (m, 4H), 3.03 (tt, J = 3.2, 12.2 Hz, 1 H), 2.60 (s, 3H), 2.41 - 2.28 (m, 4H), 2.03-1 .84 (m, 2H), 1 .52-1 .36 (m, 2H); LCMS (ESI) [M+H]+: 41 6.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.86-7.81 (m, 1 H), 7.77-7.70 (m, 1 H), 4.08 (s, 3H), 3.96-3.49 (m, 5H), 2.60 (s, 3H), 2.51 -2.32 (m, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 384.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1 H), 7.83 (dd, J = 1 .0, 8.4 Hz, 1 H), 7.76-7.72 (d,J = 8.4 Hz, 1 H), 4.61 (t, J = 12.7 Hz, 2H), 4.27-4.1 0 (m, 2H), 4.08 (s, 3H), 3.32-3.10 (m, 3H), 2.60 (s, 3H), 2.24- 2.15 (m, 2H), 2.00 (br d, J = 4.9 Hz, 2H); LCMS (ESI) [M+H]+: 474.1 .

1 H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.86-7.81 (m, 1 H), 7.77-7.71 (m, 1 H), 5.79 (spt, J = 6.2 Hz, 1 H), 4.25-4.15 (m, 2H), 4.09 (s, 3H), 3.37-3.20 (m, 3H), 2.61 (s, 3H), 2.32-2.21 (m, 2H), 2.12-1 .97 (m, 2H); LCMS (ESI) [M+H]+: 492.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.27 (s, 1 H), 8.07 (s, 1 H), 7.92-7.86 (m, 1 H), 7.85-7.80 (m, 1 H), 5.01 -4.91 (m, 1 H), 4.80 (s, 2H), 3.60 (s, 3H), 1 .63 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 273.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.29 (s, 1 H), 8.06 (s, 1 H), 7.93-7.86 (m, 1 H), 7.83-7.77 (m, 1 H), 4.96 (spt, J = 6.8 Hz, 1 H), 4.83 (dd, J = 2.8, 10.7 Hz, 1 H), 4.24 (br d, J = 1 1 .7 Hz, 1 H), 3.84-3.62 (m, 1 H), 2.22-2.1 1 (m, 1 H), 2.09-1 .91 (m, 2H), 1 .86-1 .74 (m, 2H), 1 .73-1 .65 (m, 1 H), 1 .62 (dd, J = 1 .1 , 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 313.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (s, 1 H), 8.06 (s, 1 H), 7.91 -7.85 (m, 1 H), 7.84-7.78 (m, 1 H), 5.29 (dd, J = 5.4, 7.8 Hz, 1 H), 4.97 (spt, J = 6.7 Hz, 1 H), 4.27-4.14 (m, 1 H), 4.1 1 -3.99 (m, 1 H), 2.55-2.42 (m, 1 H), 2.40-2.31 (m, 1 H), 2.28-2.04 (m, 2H), 1 .63 (dd, J = 1 .1 , 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 299.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.16 (s, 1 H), 8.02 (s, 1 H), 7.88-7.79 (m, 2H), 4.80 (d, J = 7.0 Hz, 2H), 4.50 (d, J = 7.0 Hz, 2H),4.21 -4.08 (m, 5H), 3.29-3.20 (m, 1 H), 3.21 -3.09 (m, 2H), 2.18 (br d, J = 13.6 Hz, 2H), 2.02-1 .92 (m, 2H), 1 .75 (s, 3H); LCMS (ESI) [M+H]+: 398.1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.28 (d, J = 0.9 Hz, 1 H), 8.17 (d, J = 0.9 Hz, 1 H), 7.94 (dd, J = 0.6, 8.4 Hz, 1 H), 7.77 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.69-7.64 (m, 2H), 7.60-7.56 (m, 2H), 7.24-6.96 (t, J = 55.6 Hz, 1 H), 4.55-4.45 (m, 1 H), 4.1 5 (s, 3H), 3.67-3.48 (m, 2H), 3.29-3.08 (m, 2H), 2.33-2.00 (m, 2H), 1 .91 -1 .75 (m, 2H); LCMS (ESI) [M+H]+: 438.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.16 (s, 1H), 8.02 (s, 1H), 7.87-7.78 (m, 2H), 4.31-3.96 (m, 5H), 3.26-3.16 (m, 1 H), 3.03 (br t, J = 11.1 Hz, 2H), 2.15 (br d, J = 11.5 Hz, 2H), 1.92 (br d, J = 9.3 Hz, 2H), 1.56 (s, 3H), 0.91 -0.84 (m, 2H), 0.67-0.55 (m, 2H); LCMS (ESI) [M+H]+: 382.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.76-7.69 (d, J = 8.4 Hz, 1 H), 7.42-7.32 (m, 2H), 7.25-7.08 (m, 3H), 4.96 (br d, J = 7.6 Hz, 1 H), 4.07 (s, 3H), 3.70 (br dd, J = 4.1 , 7.4 Hz, 1H), 3.01 (br t, J = 12.2 Hz, 1H), 2.59 (s, 3H), 2.40-2.25 (m, 4H), 1.95-1.81 (m, 2H), 1.49-1.36 (m, 2H); LCMS (ESI) [M+H]+: 432.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.51 (s, 1 H), 8.15 (s, 1 H), 8.03 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1H), 7.66- 7.36 (t,J = 59.2 Hz, 1H), 4.62 (brd, J = 13.6 Hz, 1H), 4.04 (br d, J = 13.9 Hz, 1H), 3.35- 3.24 (m, 2H), 3.01-2.90 (m, 1H), 2.31 (s, 2H), 2.22 (brd, J = 12.7 Hz, 2H), 2.04-1.86 (m, 2H), 1.08 (s, 9H); LCMS (ESI) [M+H]+: 418.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.51 (s, 1H), 8.15 (s, 1H), 8.07-8.01 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1 H), 7.67-7.37(t, J = 59.6 Hz,1 H), 7.45-7.40 (m, 1 H), 7.36-7.27(m, 3H), 4.78-4.63 (m, 1 H), 3.64-3.53 (m, 1H), 3.40-3.13 (m, 3H), 2.34 (br dd, J = 3.3, 13.6 Hz, 1H), 2.20-1.85 (m, 3H); LCMS (ESI) [M+H]+: 458.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.97 (br s, 1 H), 7.82 (br d, J = 6.4 Hz, 1 H), 7.66-7.50 (m, 2H), 4.78-4.64 (m, 1 H), 3.87-3.34 (m, 5H), 2.35-2.09 (m, 2H), 2.06-1.93 (m, 2H), 1.45-1.31 (m, 6H), 0.95-0.75 (m, 9H);LCMS (ESI) [M+H]+: 396.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.31-8.21 (m, 1H), 8.15-8.04 (m, 1H), 7.91-7.77 (m, 2H), 4.99 (quind, J = 6.6, 13.3 Hz, 1H), 4.69-4.39 (m, 4H), 4.14 (tt, J = 6.0, 8.9 Hz, 1H), 2.14-2.00 (m, 2H), 1.65 (d, J = 6.6 Hz, 6H), 1.15-1.03 (m, 9H); LCMS (ESI) [M+H]+: 382.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.80 (br s, 1H), 8.57 (s, 1H), 8.21 (s, 1 H), 8.14 (br d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 7.90-7.76 (m, 3H), 4.97 (td, J = 6.6, 13.1 Hz, 1H), 4.56 (br d, J = 13.0 Hz, 1H), 4.33 (br s, 2H), 3.94 (br d, J = 14.1 Hz, 1H), 3.44-3.26 (m, 2H), 3.15 (br t, J = 11.5 Hz, 1H), 2.28 (br t, J = 12.5 Hz, 2H), 2.14-1.94 (m, 2H), 1.63 (br d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 508.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.26 (s, 1 H), 8.14 (s, 1H), 7.90 (d, J = 8.4 Hz, 1 H), 7.79-7.71 (m, 1H), 7.08 (d, J = 5.1 Hz, 1 H), 5.09 (spt, J = 6.7 Hz, 1 H), 4.03 (br d, J = 10.8 Hz, 2H), 3.56-3.45 (m, 1 H), 3.36- 3.22 (m, 2H), 2.21 (br dd, J = 3.1 , 13.2 Hz, 2H), 1.96-1.78 (m, 2H), 1.52 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 456.1.

¹ H NMR (400 MHz, DMSO-de) δ 8.30 (s, 1H), 8.20 (br s, 2H), 8.14-8.08 (m, 1H), 7.94 (br d, J = 8.3 Hz, 1H), 7.75 (brd, J = 8.3 Hz, 1H), 5.14 (td, J = 6.3, 12.8 Hz, 1H), 4.36 (brd, J = 12.8 Hz, 1H), 4.02-3.74 (m, 3H), 3.63-3.47 (m, 1 H), 3.30-3.21 (m, 1H), 3.01 (br t, J = 11.7 Hz, 1H), 2.18 (brd, J = 12.1 Hz, 2H), 2.00- 1.83 (m, 1 H), 1.78-1.61 (m, 1 H), 1.51 (br d, J = 6.4 Hz, 6H); LCMS (ESI) [M+H]+: 369.1.

¹ H NMR (300 MHz, CHLOROFORM-d) δ 8.74 (s, 1H), 8.46 (s, 2H), 8.12 (s, 1H), 7.91-7.80 (m, 1H), 7.76 (d, J = 8.5 Hz, 1H), 4.10 (s, 3H), 3.83 (d, J = 12.8 Hz, 2H), 3.12 (t, J = 10.3 Hz, 2H), 2.61 (s, 3H), 2.37 (d, J = 12.7 Hz, 2H), 2.29-2.16 (m, 2H); LCMS (ESI) [M+H]+: 376.1.

¹ H NMR (300 MHz, CHLOROFORM-d) δ 8.21 (d, J = 14.0 Hz, 2H), 7.96-7.82 (m, 2H), 5.91 (t, J = 7.1 1H), 5.35 (t, J = 6.5 Hz, 2H), 5.17 (t, J = 7.2 Hz, 2H), 4.16 (s,2H), 3.02 (t, J = 12.0 Hz, 2H), 2.17 (d, J 13.4 Hz, 2H), 2.07-1.77 (m, 2H), 1.50 (s, 8H); LCMS (ESI) [M+H]+: 426.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.16 (s, 1H), 7.86 (dd, J = 1.3, 8.4 Hz, 1H), 7.75 (d, J

1 H), 4.80 (s, 2H), 4.08 (s, 3H), 3.60 (s, 3H), 2.60 (s, 3H); LCMS (ESI) [M+H]+: 259.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (s, 1H), 7.87 (dd, J = 1.1, 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1 H), 4.83 (dd, J = 2.6, 10.5 Hz, 1 H), 4.24 (br d, J = 11.8 Hz, 1 H), 4.07 (s, 3H), 3.75-3.67 (m, 1 H), 2.60 (s, 3H), 2.16 (br d, J = 15.8 Hz, 1 H), 2.08-1.91 (m, 2H), 1.84-1.64 (m, 3H); LCMS (ESI) [M+H]+: 299.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (s, 1 H), 7.85 (dd, J = 1 .3, 8.3 Hz, 1 H), 7.76-7.70 (m, 1 H), 5.29 (dd, J = 5.3, 7.9 Hz, 1 H), 4.24-4.15 (m, 1 H), 4.08 (s, 3H), 4.07-4.02 (m, 1 H), 2.60 (s, 3H), 2.54-2.43 (m, 1 H), 2.41 -2.32 (m, 1 H), 2.26-2.06 (m, 2H); LCMS (ESI) [M+H]+: 285.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.40 (s, 1 H), 8.30 (dd, J = 1 .5, 8.8 Hz, 1 H), 7.69-7.61 (m, 1 H), 4.20-4.05 (m, 2H), 3.20 (tt, J = 3.9, 1 0.9 Hz, 1 H), 3.02 (br t, J = 1 1 .3 Hz, 2H), 2.66 (s, 3H), 2.15 (br d, J = 10.8 Hz, 2H), 1 .98-1 .88 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 385.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.86-7.78 (m, 1 H), 7.71 (s, 1 H), 7.44-7.28 (m, 3H), 7.25-7.19

(m, 2H), 4.70-4.57 (m, 1 H), 4.52 (td, J = 7.0, 13.9 Hz, 1 H), 3.51 (br t, J = 13.9 Hz, 1 H), 3.28-3.19 (m, 2H), 3.16-3.05 (m, 1 H), 2.25 (br d, J = 13.4 Hz, 1 H), 2.08-1 .99 (m, 2H), 1 .90-1 .74 (m, 1 H), 1 .53 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 467.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.88 (d, J = 8.4 Hz, 1 H), 7.78 (s, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 4.59 (spt, J = 6.9 Hz, 1 H), 4.32-3.96 (m, 2H), 3.25-3.13 (m, 1 H), 3.05-3.00 (m, 2H), 2.18-2.10 (m, 2H), 1 .95-1 .89 (m, 2H), 1 .64-1 .56 (m, 9H), 0.92-0.86 (m, 2H), 0.69-0.61 (m, 2H); LCMS (ESI) [M+H]+: 427.1 .

¹ H NMR (400 MHz, METHANOL-cU) δ 8.32 (s, 1 H), 8.10 (s, 1 H), 7.96-7.78 (m, 2H), 4.39 (d, J = 6.8 Hz, 2H), 3.60-3.50 (m, 3H), 3.29-3.21 (m, 2H), 2.47 (br dd, J = 3.3, 14.5 Hz, 2H), 2.29-2.10 (m, 2H), 1 .44-1 .28 (m, 1 H), 0.64-0.53 (m, 2H), 0.46 (m, 2H); LCMS (ESI) [M+H]+: 324.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.06 (s, 1 H), 7.92-7.78 (m, 2H), 4.61 (br d, J = 14.1 Hz, 1 H), 4.36 (d, J = 6.8 Hz, 2H), 3.98 (br d, J = 13.4 Hz, 1 H), 3.37-3.22 (m, 2H), 3.05-2.90 (m, 1 H), 2.40 (d, J = 4.0 Hz, 2H), 2.23 (br d, J = 13.3 Hz, 2H), 2.06-1 .86 (m, 2H), 1 .40 (br d, J = 7.2 Hz, 1 H), 1 .1 8 (s, 3H), 0.67-0.55 (m, 2H), 0.49-0.40 (m, 6H); LCMS (ESI) [M+H]+: 420.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.85 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.75 (s, 1 H), 7.36-7.30 (m, 2H), 7.24 (m, 3H), 4.60-4.50 (m, 2H), 3.98-3.94 (m, 1 H), 3.33-3.08 (m, 3H), 2.91 (td, J = 6.9, 13.8 Hz, 1 H), 2.30-1 .90 (m, 4H), 1 .56 (d, J = 7.0 Hz, 6H), 1 .23 (d, J = 7.0 Hz, 6H); LCMS (ESI) [M+H]+: 475.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.81 (dd, J = 1 .1 , 8.3 Hz, 1 H), 7.71 (s, 1 H), 7.22 (d, J = 8.3 Hz, 1 H), 4.59-4.48 (m, 2H), 3.96 (br d, J = 13.8 Hz, 1 H), 3.28-3.15 (m, 2H), 2.87 (br t, J = 1 1 .2 Hz, 1 H), 2.24 (d, J = 1 .7 Hz, 2H), 2.12 (br d, J = 13.2 Hz, 2H), 1 .94-1 .79 (m, 2H), 1 .52 (d, J = 7.0 Hz, 6H), 1 .00 (s, 9H); LCMS (ESI) [M+H]+: 427.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.06 (s, 1 H), 7.87-7.80 (m, 2H), 4.96 (spt, J = 6.7 Hz, 1 H), 4.57 (br d, J = 13.6 Hz, 1 H), 3.93 (br d, J = 14.5 Hz, 1 H), 3.66-3.51 (m, 1 H), 3.30-3.22 (m, 1 H), 2.43-2.21 (m, 6H), 1 .62 (d, J = 7.0 Hz, 6H), 1 .08 (s, 9H); LCMS (ESI) [M+H]+: 428.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (s, 1 H), 8.08 (s, 1 H), 7.90-7.82 (m, 2H), 5.02-4.95 (m, 1 H), 4.08-4.00 (m, 2H), 3.40 (br d, J = 9.8 Hz, 2H), 2.40-2.24 (m, 4H), 1 .65 (d, J = 6.7 Hz, 6H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 430.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.47 (s, 1 H), 8.45 (s, 1 H), 8.36-8.07 (t, J = 58.8, 1 H), 8.09-8.05 (m, 1 H), 7.99-7.95 (m, 1 H), 7.36-7.28 (m, 4H), 4.05 (br d, J = 4.6 Hz, 2H), 3.54-3.41 (m, 1 H), 3.26-3.17 (m, 2H), 2.98-2.88 (m, 1 H), 2.17 (br dd, J = 3.2, 13.3 Hz, 2H), 1 .91 -1 .80 (m, 2H), 1 .23 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 466.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.16 (s, 1 H), 8.05 (s, 1 H), 7.84-7.77 (m, 2H), 4.94 (m, 1 H), 3.92- 3.72 (m, 2H), 3.61 -3.48 (m, 2H), 2.40 (m, 2H), 2.17 (t, J = 3.1 Hz, 1 H), 1 .62 (d, J = 7.0 Hz, 6H), 1 .47 (s, 9H); LCMS (ESI) [M+H]+: 410.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.44 (s, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 8.04 (s, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 6.89 (br s, 1 H), 4.99 (td, J = 6.7, 13.3 Hz, 1 H), 4.21 (m, 2H), 3.71 (br t, J = 5.5 Hz, 2H), 2.77 (br s, J = 1 .6 Hz, 2H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 426.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.27 (s, 1 H), 8.08 (s, 1 H), 7.86 (m, 2H), 4.97 (td, J = 6.6, 13.2 Hz, 1 H), 4.20-4.12 (m, 2H), 3.12-2.87 (m, 3H), 2.08 (br d, J = 1 1 .2 Hz, 2H), 1 .95-1 .79 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 412.2.

¹ H NMR (400 MHz, METHANOLS) δ 8.36 (s, 1 H), 8.13 (s, 1 H), 7.97-7.82 (m, 2H), 5.08 (td, J = 6.

Hz, 1 H), 4.25-4.12 (m, 1 H), 3.92-3.80 (m, 2H), 3.70-3.49 (m, 2H), 2.79-2.64 (m, 1 H), 2.52 (qd, J = 13.6 Hz, 1 H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 298.1 .

¹ H NMR (400 MHz, DMSO-de) δ 9.33 (br s, 2H), 8.34 (s, 1 H), 8.21 (s, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 5.14 (td, J = 6.6, 13.0 Hz, 1 H), 4.64-4.45 (m, 1 H), 4.41 -4.28 (m, 4H), 1 .51 (d, J = 6.5 Hz, 6H); LCMS (ESI) [M+H]+: 284.1 .

¹ H NMR (400 MHz, DMSO-de) δ 9.04 (br s, 2H), 8.56 (s, 1 H), 8.50-8.21 (t, J = 58 Hz, 1 H), 8.47 (s, 1 H), 8.1 1 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 3.60-3.51 (m, 1 H), 3.36 (br d, J = 12.8 Hz, 2H), 3.09 (br t, J = 1 1 .0 Hz, 2H), 2.30 (br d, J = 14.3 Hz, 2H), 2.14-2.01 (m, 2H); LCMS (ESI) [M+H]+: 320.1 .

¹ H NMR (400 MHz, DMSO-de) δ 9.31 -8.98 (m, 2H), 8.36 (s, 1 H), 7.94 (br d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 4.08 (s, 3H), 3.62-3.58 (m, 1 H), 3.39-3.24 (m, 3H), 3.15-3.01 (m, 2H), 2.52 (s, 3H), 2.25-2.1 5 (m, 2H), 2.09-1 .95 (m, 2H); LCMS (ESI) [M+H]+: 298.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (s, 1 H), 7.86-7.82 (m, 1 H), 7.79-7.75 (m, 1 H), 4.66 (br d, J = 13.8 Hz, 1 H), 4.09 (s, 3H), 4.04 (br d, J = 15.0 Hz, 1 H), 3.26 (br t, J = 1 1 .7 Hz, 1 H), 3.18-3.08 (m, 1 H), 2.89 (br t, J = 1 1 .8 Hz, 1 H), 2.60 (s, 3H), 2.31 (s, 2H), 2.14 (br dd, J = 3.1 , 13.6 Hz, 2H), 1 .99-1 .80 (m, 2H), 1 .08 (s, 9H); LCMS (ESI) [M+H]+: 396.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.55 (s, 1 H), 8.49-8.21 (t, J = 58 Hz, 1 H), 8.48 (s, 1 H), 8.1 1 (d, J = 8.2 Hz, 1 H), 7.99 (dd, J = 1 .2, 8.4 Hz, 1 H), 4.05-3.80 (m, 2H), 3.41 (tt, J = 3.9, 1 1 .0 Hz, 1 H), 3.02 (br t, J = 10.8 Hz, 2H), 2.16-2.07 (m, 2H), 1 .79-1 .66 (m, 2H), 1 .49 (s, 3H), 0.83-0.78 (m, 2H), 0.67-0.57 (m, 2H); LCMS (ESI) [M+H]+: 418.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (s, 1 H), 8.10 (s, 1 H), 7.87 (m, 2H), 4.98 (td, J = 6.7, 13.3 Hz, 1 H), 4.67 (br d, J = 13.5 Hz, 1 H), 4.06-4.00 (m, 1 H), 3.27 (br t, J = 1 1 .6 Hz, 1 H), 3.18-3.07 (m, 1 H), 2.90 (br t, J = 1 1 .4 Hz, 1 H), 2.33 (d, J = 1 .1 Hz, 2H), 2.16 (br dd, J = 3.1 , 13.2 Hz, 2H), 2.02-1 .78 (m, 2H), 1 .65 (d, J = 6.8 Hz, 6H), 1 .09 (s, 9H); LCMS (ESI) [M+H]+: 410.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (s, 1 H), 7.85 (dd, J = 1 .2 ,8.4 Hz, 1 H), 7.78-7.72 (d,J = 8.4 Hz,1 H), 7.41 -7.32 (m, 2H), 7.24-7.17 (m, 1 H), 7.14 (d, J = 7.7 Hz, 2H), 5.1 1 (br d, J = 6.5 Hz, 1 H), 4.09 (s, 3H), 3.95-3.83 (m, 1 H), 3.31 -3.21 (m, 1 H), 2.61 (s, 3H), 2.29-2.18 (m, 2H), 2.1 1 -1 .92 (m, 4H), 1 .89-1 .78 (m, 2H); LCMS (ESI) [M+H]+: 432.2.

¹ H NMR (400 MHz, MATHANOL-d ₄ ) δ 8.27 (s, 1 H), 7.98-7.83 (m, 2H), 4.42-4.25 (m, 1 H), 4.11 (s, 3H), 3.99 (td, J = 8.6, 13.6 Hz, 1H), 3.88-3.74 (m, 1H), 3.69 (brd, J = 13.6 Hz, 1H), 3.46-3.35 (m, 1H), 2.72- 2.56 (m, 5H); LCMS (ESI) [M+H]+: 334.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1H), 7.84 (dd, J = 1.2, 8.4 Hz, 1H), 7.73 (dd, J = 0.6, 8.4 Hz, 1 H), 7.42-7.30 (m, 5H), 5.11 (s, 2H), 4.86-4.82 (m, 1 H), 4.08 (s, 3H), 3.86-3.82 (m, 1 H), 3.27-3.18 (m, 1 H), 2.60 (s, 3H), 2.22-2.10 (m, 2H), 2.07-1.97 (m, 2H), 1.91 -1.87 (m, 2H), 1.81 -1.69 (m, 2H); LCMS (ESI) [M+H]+: 446.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (d, J = 0.7 Hz, 1H), 7.99 (s, 1H), 7.82-7.77 (m, 1H), 7.76- 7.72 (m, 1H), 4.89 (spt, J = 6.7 Hz, 1H), 4.40-3.98 (m, 2H), 3.75-3.58 (m, 1H), 3.51-3.36 (m, 1H), 3.31- 3.13 (m, 1H), 2.39-2.12 (m, 2H), 1.56 (d, J = 6.6 Hz, 6H), 1.48-1.32 (m, 9H); LCMS (ESI) [M+H]+: 448.2.

¹ H NMR (300 MHz, CHLOROFORM-d) δ 8.39 (s, 1 H), 8.12 (s, 2H), 7.85 (dd, J = 8.4, 1.3 Hz, 1 H), 7.75 (dd, J = 8.4, 0.9 Hz, 1H), 7.26-7.14 (m, 1H), 4.09 (s, 3H), 3.80 (d, J = 12.7 Hz, 2H), 3.25 (m, 1H), 3.07 (d, J = 14.2 Hz, 2H), 2.61 (s, 3H), 2.32 (s, 2H), 2.26-2.16 (m, 1H); LCMS (ESI) [M+H]+: 375.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.07 (s, 1 H), 7.88-7.80 (m, 2H), 4.98 (td, J = 6.6, 13.4 Hz, 1 H), 4.65-4.50 (m, 1 H), 3.80-3.70 (m, 1 H), 3.21 (br d, J = 4.0 Hz, 1 H), 2.1 6 (br d, J = 7.9 Hz, 2H), 2.05-1 .97 (m, 2H), 1 .85 (br d, J = 4.4 Hz, 2H), 1 .75-1 .70 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .46 (s, 9H); LCMS (ESI) [M+H]+: 426.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.04 (s, 1 H), 7.79-7.76 (m, 1 H), 7.73-7.70 (m, 1 H), 4.08 (s, 3H), 3.76-3.70 (m, 4H), 3.65-3.59 (m, 4H), 2.61 (s, 3H), 1 .52 (s, 9H); LCMS (ESI) [M+H]+: 399.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.06 (s, 1 H), 7.88-7.78 (m, 2H), 5.50-5.35 (m, 1 H), 4.96 (spt, J = 6.7 Hz, 1 H), 4.04 (td, J = 3.9, 8.2 Hz, 1 H), 3.30-3.22 (m, 1 H), 2.25-2.16 (m, 2H), 2.03 (qd, J = 4.6, 9.2 Hz, 2H), 1 .98 (s, 3H), 1 .93-1 .84 (m, 2H), 1 .70-1 .60 (m, 8H); LCMS (ESI) [M+H]+: 368.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (d, J = 8.4 Hz, 1 H), 8.09 (s, 1 H), 7.95 (d, J = 8.2 Hz, 1 H), 5.52 (spt, J = 6.7 Hz, 1 H), 4.20-4.1 0 (m, 2H), 3.26 (tt, J = 3.8, 1 1 .1 Hz, 1 H), 2.99 (br t, J = 12.0 Hz, 2H), 2.16 (br d, J = 10.4 Hz, 2H), 2.00-1 .89 (m, 2H), 1 .59 (d, J = 6.6 Hz, 6H), 1 .48 (s, 9H); LCMS (ESI)

[M+H]+: 413.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (s, 2H), 8.10 (s, 1 H), 7.83 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.73 (dd, J = 0.6, 8.4 Hz, 1 H), 4.74 (td, J = 3.5, 13.6 Hz, 2H), 4.07 (s, 3H), 3.32 (tt, J = 4.0, 1 1 .0 Hz, 1 H), 3.20 (ddd, J = 2.8, 1 1 .3, 13.7 Hz, 2H), 2.60 (s, 3H), 2.24 (br dd, J = 3.2, 13.5 Hz, 2H), 2.07-1 .92 (m, 2H), 1 .73 (tt, J = 5.1 , 8.5 Hz, 1 H), 0.97-0.86 (m, 2H), 0.63-0.57 (m, 2H); LCMS (ESI) [M+H]+: 416.1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.29 (s, 1 H), 8.1 9 (s, 1 H), 7.92 (d, J = 8.3 Hz, 1 H), 7.75 (dd, J = 1 .0, 8.4 Hz, 1 H), 5.14 (spt, J = 6.5 Hz, 1 H), 3.93 (br d, J = 6.7 Hz, 1 H), 3.78 (br d, J = 7.2 Hz, 1 H), 3.68-3.61 (m, 1 H), 3.51 -3.44 (m, 1 H), 3.40 (br d, J = 6.6 Hz, 1 H), 2.46-2.33 (m, 1 H), 2.24 (br d, J = 7.1 Hz, 1 H), 1 .50 (d, J = 6.6 Hz, 6H), 1 .42 (s, 9H); LCMS (ESI) [M+H]+: 398.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.08 (s, 1 H), 7.92-7.81 (m, 2H), 4.98 (quind, J = 6.7, 13.3 Hz, 1 H), 4.83 (d, J = 7.1 Hz, 2H), 4.53 (d, J = 7.5 Hz, 2H), 4.1 7 (br s, 2H), 3.35-3.20 (m, 1 H), 3.13 (br s, 2H), 2.22 (br d, J = 1 1 .1 Hz, 2H), 2.06-1 .92 (m, 2H), 1 .78 (s, 3H), 1 .65 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 426.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.86-7.81 (m, 1 H), 7.77-7.72 (m, 1 H), 4.53 (dq, J 2.2, 8.4 Hz, 2H), 4.20 (br t, J = 16.1 Hz, 2H), 4.08 (s, 3H), 3.32-3.23 (m, 1 H), 3.22-3.10 (m, 2H), 2.60 (s, 3H), 2.22 (br d, J = 1 1 .9 Hz, 2H), 2.07-1 .94 (m, 2H); LCMS (ESI) [M+H]+: 424.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.84 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.73 (dd, J = 0.7, 8.4 Hz, 1 H), 4.08 (s, 3H), 3.60 (t, J = 5.9 Hz, 2H), 3.54 (q, J = 7.0 Hz, 2H), 3.10-2.99 (m, 3H), 2.65 (t, J = 6.0 Hz, 2H), 2.60 (s, 3H), 2.27 (dt, J = 2.3, 1 1 .3 Hz, 2H), 2.21 -2.03 (m, 4H), 1 .23 (t, J = 7.0 Hz, 3H); LCMS (ESI) [M+H]+: 370.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.06 (s, 1 H), 7.89-7.78 (m, 2H), 4.97 (td, J = 6.6, 13.4 Hz, 1H), 4.02-3.43 (m, 5H), 2.52-2.32 (m, 2H), 1.64 (d, J = 6.6 Hz, 6H), 1.50 (s, 9H); LCMS (ESI) [M+H]+: 398.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (s, 1H), 8.10 (s, 1H), 7.91-7.81 (m, 2H), 7.47-7.40 (m, 1H), 7.39-7.28 (m, 3H), 4.98 (td, J = 6.6, 13.5 Hz, 1H), 4.76 (br t, J = 12.5 Hz, 1H), 3.65-3.52 (m, 1H), 3.36- 3.10 (m, 3H), 2.28 (br dd, J = 3.5, 13.6 Hz, 1 H), 2.15-1.95 (m, 2.5H), 1.94-1.79 (m, 0.5H), 1.65 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 450.1.

¹ H NMR (400 MHz, DMSO-de) δ 9.13 (s, 2H), 8.49 (s, 1H), 8.25 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.80 (dd, J = 1.1, 8.6 Hz, 1H), 5.22 (spt, J = 6.4 Hz, 1H), 3.39-3.35 (m, 1H), 3.33-3.24 (m, 2H), 3.14-3.00 (m, 2H), 2.20 (br d, J = 11.8 Hz, 2H), 2.08-1.92 (m, 2H), 1.50 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 312.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.16 (s, 1H), 8.12 (s, 1H), 7.94-7.89 (m, 1H), 7.87-7.82 (m, 1H), 5.46 (q, J = 7.2 Hz, 1 H), 4.20-4.05 (m 2H), 3.72 (s, 3H), 3.21 (tt, J = 3.9, 10.8 Hz, 1 H), 3.02 (br t, J = 11.9 Hz, 2H), 2.15 (br d, J = 10.5 Hz, 2H), 1.98 (d, J = 7.2 Hz, 3H), 1.97-1.87 (m, 2H), 1.49 (s, 9H); LCMS (ESI) [M+H]+: 456.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1 H), 8.04 (s, 1 H), 7.77 (m, 2H), 4.95 (m, 1 H), 3.99-3.87 (m, 2H), 3.74-3.56 (m, 4H), 3.47-3.24 (m, 2H), 3.07 (br s, 2H), 1 .61 (d, J = 7.0 Hz, 6H), 1 .47 (s, 9H) LCMS (ESI) [M+H]+: 439.2.

¹ H NMR (400 MHz, METHANOLS) δ 8.22 (s, 1 H), 8.09 (s, 1 H), 7.84 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.73 (dd, J = 0.7, 8.4 Hz, 1 H), 5.03 (m, 1 H), 3.93 (br dd, J = 7.4, 1 1 .2 Hz, 2H), 3.75 (dd, J = 3.1 , 1 1 .2 Hz, 2H), 3.65 (br dd, J = 6.8, 1 1 .6 Hz, 2H), 3.41 -3.32 (m, 3H), 3.29 (m, 1 H), 1 .59 (d, J = 6.6 Hz, 6H); LCMS (ESI)

[M+H]+: 339.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.92-7.84 (m, 3H), 7.79 (d, J = 1 .1 Hz, 1 H), 7.56-7.51 (m, 1 H), 7.49-7.43 (m, 2H), 7.36-7.28 (m, 2H), 4.64-4.49 (m, 2H), 4.32 (t, J = 3.2 Hz, 2H), 3.93 (br d, J = 13.7 Hz, 1 H), 3.40-3.30 (m, 2H), 3.14 (br t, J = 1 1 .0 Hz, 1 H), 2.33-2.21 (m, 2H), 2.09-1 .94 (m, 2H), 1 .60 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 490.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.29 (s, 1 H), 8.04 (dd, J = 1 .2, 8.3 Hz, 1 H), 7.81 (dd, J = 0.6, 8.2 Hz, 1 H), 4.20-4.05 (m, 2H), 3.46 (spt, J = 7.0 Hz, 1 H), 3.21 (tt, J = 3.9, 10.9 Hz, 1 H), 3.02 (br t, J = 1 1 .6 Hz, 2H), 2.15 (br dd, J = 3.0, 13.3 Hz, 2H), 1 .92 (dtd, J = 4.2, 1 1 .1 , 13.5 Hz, 2H), 1 .53 (d, J = 7.0 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 413.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (s, 1 H), 8.05 (dd, J = 1 .1 , 8.2 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 4.20-4.05 (m, 2H), 3.20 (tt, J = 3.9, 10.9 Hz, 1 H), 3.01 (br t, J = 1 1 .9 Hz, 2H), 2.63 (s, 3H), 2.14 (br dd, J = 3.0, 13.3 Hz, 2H), 1 .97-1 .85 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M-55]+: 329.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.08 (s, 1 H), 7.91 -7.87 (m, 1 H), 7.86-7.81 (m, 1 H), 4.95-4.83 (m, 1 H), 4.27-4.02 (m, 4H), 3.21 (tt, J = 3.9, 10.9 Hz, 1 H), 3.02 (br t, J = 1 1 .6 Hz, 2H), 2.82-2.78 (m, 1 H), 2.16 (br dd, J = 2.6, 13.3 Hz, 2H), 2.00-1 .87 (m, 2H), 1 .60 (d, J = 6.7 Hz, 3H), 1 .49 (s, 9H) ; LCMS (ESI) [M+H]+: 428.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, 1 H), 8.06 (s, 1 H), 7.88-7.78 (m, 2H), 5.01 -4.93 (m, 1 H), 3.19-2.99 (m, 4H), 2.37-2.24 (m, 4H), 1 .63 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 330.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.69 (s, 1 H), 7.45-7.41 (m, 1 H), 7.36-7.32 (m, 1 H), 4.20 (br d, J = 13.5 Hz, 1 H), 3.68 (s, 3H), 3.57 (br d, J = 14.1 Hz, 1 H), 2.92-2.84 (m, 2H), 2.58 (br t, J = 1 1 .8 Hz, 1 H), 2.20 (s, 3H), 2.00 (d, J = 3.1 Hz, 2H), 1 .83 (br d, J = 13.2 Hz, 2H), 1 .62-1 .50 (m, 2H), 0.78 (s, 3H), 0.08- 0.03 (m, 4H); LCMS (ESI) [M+H]+: 394.2.

¹ H NMR (300 MHz, CHLOROFORM-d) δ 8.1 1 (s, J = 1 .0 Hz, 1 H), 7.85 (dd, J = 8.4, 1 .3 Hz, 1 H), 7.75 (dd, J = 8.4, 0.8 Hz, 1 H), 7.22 (d, J = 3.6 Hz, 1 H), 6.62 (d, J = 3.6 Hz, 1 H), 4.14 (m, 2H), 4.09 (s, 3H), 3.32 (td, J = 12.9, 1 1 .9, 3.1 Hz, 2H), 2.61 (s, 3H), 2.38-2.25 (m, 2H), 2.25-2.10 (m, 2H); LCMS (ESI) [M+H]+: 381 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1 H), 8.05 (s, 1 H), 7.78 (s, 2H), 4.95 (td, J = 6.6, 13.3 Hz, 1 H), 3.93-3.57 (m, 8H), 2.41 (s, 2H), 1 .63 (d, J = 6.7 Hz, 6H), 1 .18 (s, 3H), 0.58-0.37 (m, 4H); LCMS (ESI) [M+H]+: 409.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1 H), 8.05 (s, 1 H), 7.78 (d, J = 0.9 Hz, 2H), 5.03-4.86 (m, 1 H), 3.84-3.49 (m, 8H), 1 .62 (d, J = 6.7 Hz, 6H), 1 .59 (s, 3H), 0.95-0.88 (m, 2H), 0.72-0.64 (m, 2H);

LCMS (ESI) [M+H]+: 41 1 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1 H), 8.04 (s, 1 H), 7.79-7.75 (m, 2H), 5.01 -4.90 (m, 1 H), 3.96 (td, J = 7.9, 10.8 Hz, 2H), 3.88-3.77 (m, 2H), 3.68-3.50 (m, 3H), 3.45 (dd, J = 5.3, 10.7 Hz, 1 H), 3.23- 3.03 (m, 2H), 2.19 (s, 2H), 1 .61 (d, J = 6.6 Hz, 6H), 1 .06 (s, 9H); LCMS (ESI) [M+H]+: 437.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.04 (s, 1 H), 7.86-7.74 (m, 2H), 5.02-4.89 (m, 1 H), 4.02 (d, J = 1 1 .5 Hz, 1 H), 3.81 (d, J = 1 1 .5 Hz, 1 H), 3.50 (dt, J = 2.8, 1 1 .9 Hz, 2H), 2.32-2.16 (m, 3H), 1 .61 (dd, J = 6.7, 1 1 .7 Hz, 6H), 1 .1 9 (s, 9H); LCMS (ESI) [M+H]+: 410.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.62 (d, J = 4.2 Hz, 1 H), 8.29 (d, J = 0.9 Hz, 1 H), 8.10 (s, 1 H), 7.87 (s, 2H), 7.82 (dt, J = 1 .8, 7.7 Hz, 1 H), 7.67 (d, J = 7.7 Hz, 1 H), 7.36 (ddd, J = 1 .1 , 4.9, 7.7 Hz, 1 H), 4.99 (td, J = 6.6, 13.4 Hz, 1 H), 4.74 (br d, J = 13.9 Hz, 1 H), 4.08 (br d, J = 12.6 Hz, 1 H), 3.40-3.27 (m, 1 H), 3.26-3.1 0 (m, 2H), 2.26 (br d, J = 1 0.6 Hz, 1 H), 2.16-1 .95 (m, 3H), 1 .65 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 417.1 .

¹ H NMR (400 MHz, METHANOLS) δ 8.27 (s, 1 H), 8.08 (s, 1 H), 7.90-7.83 (m, 2H), 4.14 (s, 3H), 3.59-3.50 (m, 3H), 3.28-3.21 (m, 2H), 2.46 (br dd, J = 3.6, 14.9 Hz, 2H), 2.24-2.13 (m, 2H); LCMS (ESI) [M+H]+: 284.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.63 (d, J = 1 .8 Hz, 1 H), 8.10 (d, J = 0.6 Hz, 1 H), 7.96 (d, J = 0.7 Hz, 1 H), 7.81 -7.73 (m, 3H), 7.59 (d, J = 8.2 Hz, 1 H), 5.42 (s, 1 H), 5.19 (s, 1 H), 4.62 (br d, J = 13.4 Hz, 1 H), 4.09 (s, 4H), 3.36-3.27 (m, 2H), 3.22-3.1 1 (m, 1 H), 2.30-2.20 (m, 1 H), 2.14-2.03 (m, 6H); LCMS (ESI) [M+H]+: 429.2.

¹ H NMR (400 MHz, METHANOLS) δ 8.25-8.12 (m, 1 H), 7.83 (br s, 2H), 4.47 (br d, J = 13.4 Hz, 1 H), 4.14-4.01 (m, 6H), 3.63 (br s, 2H), 3.47-3.35 (m, 2H), 3.07-2.90 (m, 2H), 2.83 (br d, J = 5.7 Hz, 2H), 2.59 (s, 3H), 2.34-2.18 (m, 2H), 2.03-1 .83 (m, 2H), 1 .45 (s, 9H); LCMS (ESI) [M+H]+: 495.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.1 1 (s, 1 H), 7.92-7.86 (m, 1 H), 7.86-7.79 (m, 1 H), 5.17-5.02 (m, 1 H), 4.91 (dd, J = 8.0, 9.2 Hz, 0.5H), 4.84-4.74 (m, 1 H), 4.67 (dd, J = 4.9, 9.3 Hz, 0.5H), 4.16 (br s, 2H), 3.21 (tt, J = 3.9, 10.9 Hz, 1 H), 3.02 (br t, J = 1 1 .7 Hz, 2H), 2.22-2.09 (m, 2H), 2.02-1 .87 (m, 2H), 1 .66 (dd, J = 1 .6, 6.8 Hz, 3H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 430.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (s, 1 H), 7.89 (dd, J = 0.9, 8.4 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 4.31 (br s, 1 H), 4.22-4.14 (m, 1 H), 4.13 (s, 3H), 3.79-3.66 (m, 1 H), 3.48 (br d, J = 14.5 Hz, 1 H), 3.27 (br t, J = 10.6 Hz, 1 H), 2.65 (s, 3H), 2.42-2.30 (m, 1 H), 2.30-2.20 (m, 1 H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 434.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.44 (s, 1 H), 8.21 (s, 1 H), 7.98 (m, J = 8.4 Hz, 1 H), 7.80 (dd, J = 0.9, 8.4 Hz, 1 H), 7.53-7.48 (m, 2H), 7.47-7.42 (m, 2H), 5.18 (spt, J = 6.7 Hz, 1 H), 4.00-4.2 (m, 2H), 3.35-3.16 (m, 3H), 2.1 0 (br d, J = 10.8 Hz, 2H), 1 .90-1 .71 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 450.1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.44 (s, 1 H), 8.21 (s, 1 H), 7.98 (m, J = 8.6 Hz, 1 H), 7.81 (dd, J = 1 .0, 8.5 Hz, 1 H), 7.51 (dt, J = 5.7, 7.9 Hz, 1 H), 7.32-7.20 (m, 3H), 5.18 (spt, J = 6.6 Hz, 1 H), 4.00-4.20 (m, 2H), 3.36-3.16 (m, 3H), 2.1 1 (br d, J = 10.6 Hz, 2H), 1 .89-1 .75 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 434.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.89 (dd, J = 1 .5, 8.4 Hz, 1 H), 7.79 (s, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 4.96 (spt, J = 6.2 Hz, 1 H), 4.64-4.53 (m, 1 H), 4.19 (br d, J = 1 1 .9 Hz, 2H), 3.20 (tt, J = 3.9, 10.9 Hz, 1 H), 3.1 1 -2.99 (m, 2H), 2.1 5 (br dd, J = 3.1 , 13.2 Hz, 2H), 1 .99-1 .87 (m, 2H), 1 .60 (d, J = 6.8 Hz, 6H), 1 .27 (d, J = 6.2 Hz, 6H); LCMS (ESI) [M+H]+: 41 5.2.

¹ H NMR (400 MHz, METHANOLS) δ 8.35 (s, 1 H), 8.12 (s, 1 H), 7.93-7.84 (m, 2H), 5.13-5.02 (m, 1 H),

4.36-4.21 (m, 1 H), 3.99 (td, J = 8.5, 13.4 Hz, 1 H), 3.86-3.63 (m, 2H), 3.43-3.34 (m, 1 H), 2.68-2.56 (m,

2H), 1 .60 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 348.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (s, 1 H), 7.99 (s, 1 H), 7.80-7.72 (m, 2H), 7.03 (br d, J = 10.3 Hz, 1 H), 4.95-4.84 (m, 1 H), 4.1 1 (q, J = 5.0 Hz, 1 H), 3.98-3.78 (m, 1 H), 3.52-3.35 (m, 1 H), 2.35-2.14 (m, 2H), 1 .56 (d, J = 6.6 Hz, 6H), 1 .45 (s, 9H); LCMS (ESI) [M+H]+: 428.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.31 -8.23 (m, 1 H), 8.09 (s, 1 H), 7.94-7.89 (m, 1 H), 7.86-7.80 (m, 1 H), 5.08-4.93 (m, 1 H), 4.28 (br s, 2H), 3.69 (br d, J = 5.0 Hz, 2H), 2.85 (br s, 2H), 1 .65 (dd, J = 1 .3, 6.7 Hz, 6H), 1 .53 (d, J = 1 .3 Hz, 9H); LCMS (ESI) [M+H]+: 428.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.84 (s, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 6.40 (dd, J = 8.8, 2.0 Hz, 1 H), 6.22 (s, 1 H), 4.79-4.61 (m, 1 H), 3.71 (s, 4H), 3.43 (t, J = 5.6 Hz, 4H), 1 .81 (br t, J = 5.2 Hz, 4H), 1 .56 (d, J = 6.8 Hz, 6H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 385.2.

¹ H NMR (400 MHz, METHANOLS) δ 8.29 (s, 1 H), 7.97-7.85 (m, 2H), 4.80 (td, J = 9.1 , 13.6 Hz, 0.7H), 4.63 (br d, J = 14.2 Hz, 0.4H), 4.34-4.16 (m, 2.4H), 4.13 (s, 3H), 4.10-3.98 (m, 1 .5H), 3.96-3.79 (m, 0.6H), 3.66-3.48 (m, 1 H), 3.33-3.25 (m, 0.4H), 2.64 (s, 3H), 2.56-2.26 (m, 2H); LCMS (ESI) [M+H]+: 391 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (d, J = 0.9 Hz, 1 H), 8.03 (s, 1 H), 7.81 -7.74 (m, 2H), 5.03- 4.87 (m, 1 H), 4.03-3.90 (m, 2H), 3.84-3.67 (m, 2H), 3.43-3.32 (m, 2H), 3.13 (t, J = 10.3 Hz, 2H), 2.41 (m, 2H), 1 .61 (d, J = 6.7 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 439.2.

¹ H NMR (300 MHz, CHLOROFORM-d) δ 8.11 (s, 1 H), 7.85 (dd, J = 8.4, 1.3 Hz, 1 H), 7.75 (dd, J = 8.5, 0.8 Hz, 1 H), 7.39 (s, 1 H), 7.21 (d, J = 1.2 Hz, 1 H), 7.15-7.04 (m, 1 H), 4.45-4.32 (m, 2H), 4.09 (s, 3H), 3.53- 3.30 (m, 3H), 2.61 (s, 3H), 2.43-2.28 (m, 2H), 2.28-2.12 (m, 2H); LCMS (ESI) [M+H]+: 415.3.

¹ H NMR (300 MHz, CHLOROFORM-d) δ 7.98 (t, J = 0.7 Hz, 1 H), 7.88-7.77 (m, 1 H), 7.72 (d, J = 8.8 Hz 1H), 7.20 (d, J = 8.8, 1H), 4.90-4.76 (m, 1H), 3.95 (ms, 2H), 3.88 (s, 2H), 3.38 (t, J = 12.4 Hz, 2H), 2.02 (m, 2H), 1.84 (m, 2H), 1.60 (d, J = 6.7 Hz, 6H), 1.50 (s, 9H); LCMS (ESI) [M+H]+: 415.3.

¹ H NMR (300 MHz, DMSO-de) δ 8.31 (s, 1 H), 8.19 (s, 1 H), 7.93 (d, J = 8.4 Hz, 1 H), 7.75 (dd, J = 8.4, 1.2 Hz, 1H), 5.16 (p, J = 6.5 Hz, 1H), 3.71 (dt, J = 13.2, 3.8 Hz, 2H), 3.39 (tt, J = 10.9, 3.8 Hz, 1H), 3.13 (td, J = 12.4, 12.0, 2.7 Hz, 3H), 2.19 (dd, J = 13.7, 3.6 Hz, 2H), 2.01 (t, J = 11.9 Hz, 2H), 1.92-1.72 (m, 4H), 1.62 (d, J = 12.6 Hz, 1H), 1.50 (d, J = 6.5 Hz, 6H), 1.45-1.21 (m, 5H); LCMS (ESI) [M+H]+: 458.4.

¹ H NMR (300 MHz, DMSO-de) δ 8.31 (s, 1 H), 8.19 (d, J = 0.8 Hz, 1 H), 7.93 (dd, J = 8.4, 0.8 Hz, 1 H), 7.75 (dd, J = 8.5, 1.3 Hz, 1H), 5.15 (p, J = 6.5 Hz, 1H), 3.71 (d, J = 12.7 Hz, 3H), 3.47-3.35 (m, 2H), 3.21 (s, 2H), 3.13 (t, J = 11.4 Hz, 2H), 2.19 (dd, J = 13.9, 2.4 Hz, 3H), 1.95 (d, J = 13.7 Hz, 2H), 1.88-1.60 (m, 7H), 1.50 (d, J = 6.5 Hz, 6H), 1.44 (d, J = 2.9 Hz, 1 H); LCMS (ESI) [M+H]+: 488.4..

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1 H), 7.85-7.81 (m, 1 H), 7.76-7.72 (m, 1 H), 4.54 (br d, J = 13.9 Hz, 1 H), 4.08 (s, 3H), 3.99-3.89 (m, 1 H), 3.39-3.28 (m, 2H), 3.10-2.99 (m, 1 H), 2.66-2.61 (m, 2H), 2.60 (s, 3H), 2.59-2.50 (m, 2H), 2.31 -2.1 7 (m, 2H), 2.09-1 .90 (m, 2H); LCMS (ESI) [M+H]+: 422.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (s, 1 H), 8.00 (s, 1 H), 7.83-7.72 (m, 4H), 7.50-7.43 (m, 1 H), 7.42-7.34 (m, 2H), 7.14 (br s, 1 H), 4.90 (td, J = 6.6, 13.3 Hz, 1 H), 4.51 (dt, J = 6.7, 14.7 Hz, 0.5H), 4.38- 4.08 (m, 3H), 3.96 (br s, 0.5H), 3.86-3.63 (m, 2H), 3.61 -3.41 (m, 1 H), 2.40-2.1 8 (m, 2H), 1 .56 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 509.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, 1 H), 8.10 (s, 1 H), 7.94-7.83 (m, 4H), 7.31 -7.23 (m, 1 H), 7.15 (br t, J = 8.6 Hz, 2H), 5.07-4.93 (m, 1 H), 4.70-4.50 (m, 0.5H), 4.45-4.16 (m, 3H), 4.06 (br d, J = 13.4 Hz, 0.5H), 3.95-3.69 (m, 2H), 3.67-3.49 (m, 1 H), 2.51 -2.26 (m, 2H), 1 .66 (br d, J = 6.5 Hz, 6H); LCMS (ESI) [M+H]+: 527.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.28-8.22 (m, 1 H), 8.13 (br s, 1 H), 7.95-7.79 (m, 4H), 7.49 (br d, J = 8.2 Hz, 2H), 7.35-7.1 8 (m, 1 H), 5.02 (br d, J = 6.7 Hz, 1 H), 4.62 (br s, 0.5H), 4.46-4.18 (m, 3H), 4.07 (br s, 0.5H), 3.99-3.50 (m, 3H), 2.56-2.28 (m, 2H), 1 .69 (br d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 543.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (s, 1 H), 8.00 (s, 1 H), 7.86-7.71 (m, 3H), 7.64 (br d, J = 7.6 Hz, 1 H), 7.43 (br d, J = 7.7 Hz, 1 H), 7.37-7.28 (m, 1 H), 4.98-4.80 (m, 1 H), 4.50 (dt, J = 6.2, 14.5 Hz, 0.5H), 4.37-4.22 (m, 2.5H), 4.22-4.08 (m, 0.5H), 3.96 (br d, J = 13.6 Hz, 0.5H), 3.87-3.62 (m, 2H), 3.60- 3.38 (m, 1 H), 2.42-2.18 (m, 2H); LCMS (ESI) [M+H]+: 543.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (s, 1 H), 8.09 (br d, J = 4.6 Hz, 1 H), 8.02-7.95 (m, 2H), 7.83-7.68 (m, 3H), 7.52 (br t, J = 7.7 Hz, 1 H), 7.38-7.21 (m, 1 H), 4.90 (td, J = 6.6, 13.2 Hz, 1 H), 4.60-4.41 (m, 0.5H), 4.37-4.21 (m, 2.5H), 4.20-4.08 (m, 0.5H), 3.97 (br d, J = 13.4 Hz, 0.5H), 3.89-3.62 (m, 2H), 3.61 -3.42 (m, 1 H), 2.42-2.22 (m, 2H), 1 .56 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 534.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.50 (s, 1 H), 8.25 (s, 1 H), 7.99 (m, J = 8.4 Hz, 1 H), 7.81 (dd, J = 1 .2, 8.5 Hz, 1 H), 5.23 (spt, J = 6.6 Hz, 1 H), 3.78-3.66 (m, 2H), 3.60-3.52 (m, 1 H), 3.52-3.43 (m, 1 H), 3.38 (br t, J = 8.4 Hz, 1 H), 2.33 (br s, 1 H), 2.25-2.07 (m, 1 H), 1 .50 (d, J = 6.6 Hz, 6H), 1 .42 (s, 9H); LCMS (ESI)

[M+H]+: 398.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.06 (s, 1 H), 7.88-7.79 (m, 2H), 5.51 -5.37 (m, 1 H), 4.97 (td, J = 6.6, 13.2 Hz, 1 H), 4.60-4.48 (m, 0.5H), 4.30 (m, 0.5H), 4.20-4.01 (m, 2.5H), 3.93 (m, 0.5H), 3.89-3.59 (m, 2H), 3.56-3.37 (m, 1 H), 2.46-2.21 (m, 2H), 1 .63 (d, J = 6.6 Hz, 6H), 1 .46 (s, 9H); LCMS (ESI) [M-55]+: 449.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (s, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.68-7.63 (m, 1 H), 4.00 (s, 3H), 3.69 (br t, J = 10.3 Hz, 1 H), 2.93 (tt, J = 3.7, 1 1 .8 Hz, 1 H), 2.52 (s, 3H), 2.26-2.18 (m, 2H), 2.1 0 (br dd, J = 3.3, 13.0 Hz, 2H), 1 .79-1 .69 (m, 2H), 1 .45-1 .34 (m, 2H); LCMS (ESI) [M+H]+: 313.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1 H), 7.86-7.81 (m, 1 H), 7.77-7.70 (m, 1 H), 5.55-5.39 (m, 1 H), 4.55 (dt, J = 6.6, 14.4 Hz, 0.5H), 4.35-4.26 (m, 0.5H), 4.22-4.1 0 (m, 1 H), 4.08 (s, 3H), 4.07-3.90 (m, 2H), 3.89-3.60 (m, 2H), 3.58-3.39 (m, 1 H), 2.60 (s, 3H), 2.43-2.25 (m, 2H), 1 .47 (s, 9H); LCMS (ESI) [M+H]+: 435.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (br s, 1 H), 8.09 (s, 1 H), 8.02-7.82 (m, 4H), 7.54-7.44 (m, 2H), 5.05-4.92 (m, 1 H), 4.66-4.51 (m, 1 H), 4.36 (dd, J = 6.6, 9.5 Hz, 1 H), 4.06-3.93 (m, 2H), 3.69-3.60 (m, 1 H), 3.49-3.35 (m, 2H), 3.23-3.07 (m, 1 H), 3.02-2.90 (m, 2H), 2.31 (br t, J = 14.1 Hz, 2H), 2.13-1 .96 (m, 2H), 1 .65 (dd, J = 1 .2, 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 524.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (br s, 1 H), 7.99 (s, 1 H), 7.93-7.73 (m, 4H), 7.43-7.34 (m, 2H), 4.89 (qd, J = 6.6, 13.3 Hz, 1 H), 4.55-4.41 (m, 1 H), 4.26 (dd, J = 7.0, 8.9 Hz, 1 H), 3.96-3.84 (m, 2H), 3.55 (td, J = 8.3, 16.0 Hz, 1 H), 3.40-3.26 (m, 2H), 3.13-2.97 (m, 1 H), 2.94-2.81 (m, 2H), 2.22 (br t, J = 14.3 Hz, 2H), 2.03-1 .89 (m, 2H), 1 .56 (br d, J = 5.9 Hz, 6H); LCMS (ESI) [M+H]+: 524.2.

¹ H NMR (400 MHz, METHANOLS) δ 8.23 (s, 1 H), 8.1 1 (s, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 5.12-4.98 (m, 1 H), 4.07-3.96 (m, 2H), 3.63 (br dd, J = 5.9, 1 0.5 Hz, 2H), 3.51 (br t, J = 9.7 Hz, 2H), 3.1 7 (br t, J = 10.8 Hz, 2H), 2.81 -2.65 (m, 2H), 1 .61 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 339.1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.51 (s, 1 H), 8.25 (s, 1 H), 8.01 (m, J = 8.4 Hz, 1 H), 7.82 (dd, J = 1 .1 , 8.6 Hz, 1 H), 5.20 (spt, J = 6.5 Hz, 1 H), 3.86 (quin, J = 7.6 Hz, 1 H), 3.68 (dd, J = 8.2, 1 1 .7 Hz, 1 H), 3.46 (dd, J = 7.5, 1 1 .7 Hz, 1 H), 3.41 -3.26 (m, 2H), 2.47-2.37 (m, 1 H), 2.29-2.15 (m, 1 H), 1 .50 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 298.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.07 (s, 1 H), 7.88-7.79 (m, 2H), 7.47-7.39 (m, 2H), 7.26-7.22 (m, 1 H), 7.16-7.10 (m, 1 H), 4.98 (td, J = 6.7, 13.3 Hz, 1 H), 4.71 (br d, J = 12.8 Hz, 1 H), 3.72 (br d, J = 13.6 Hz, 1 H), 3.42-3.17 (m, 3H), 2.33 (br dd, J = 3.3, 13.6 Hz, 1 H), 2.23-2.03 (m, 3H), 1 .64 (d, J = 6.7 Hz, 5H), 1 .66-1 .62 (m, 1 H). ; LCMS (ESI) [M+H]+: 434.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.07 (s, 1 H), 7.88-7.80 (m, 2H), 7.41 -7.36 (m, 1 H), 7.25 (dd, J = 1 .8, 8.3 Hz, 1 H), 7.18 (dd, J = 1 .9, 9.2 Hz, 1 H), 4.97 (spt, J = 6.7 Hz, 1 H), 4.67 (br d, J = 13.4 Hz, 1 H), 3.70 (br d, J = 13.8 Hz, 1 H), 3.42-3.18 (m, 3H), 2.33 (br dd, J = 3.4, 13.6 Hz, 1 H), 2.24-1 .95 (m, 3H), 1 .66-1 .62 (m, 1 H), 1 .64 (d, J = 6.7 Hz, 5H); LCMS (ESI) [M+H]+: 468.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.85 (s, 1 H), 7.54 (d, J = 8.7 Hz, 1 H), 7.46-7.40 (m, 1 H), 7.38- 7.28 (m, 3H), 6.40 (dd, J = 1 .6, 8.7 Hz, 1 H), 6.23 (s, 1 H), 4.70 (spt, J = 6.6 Hz, 1 H), 3.92-3.70 (m, 6H), 3.38-3.17 (m, 2H), 2.06-1 .87 (m, 3H), 1 .82-1 .73 (m, 1 H), 1 .56 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 423.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1 H), 7.98 (s, 1 H), 7.80-7.71 (m, 2H), 5.27 (br d, J = 7.9 Hz, 1 H), 4.94-4.84 (m, 1 H), 3.90-3.78 (m, 1 H), 2.91 (tt, J = 3.5, 12.2 Hz, 1 H), 2.25-2.1 1 (m, 4H), 1 .93 (s, 3H), 1 .79 (dq, J = 3.2, 13.0 Hz, 2H), 1 .56 (d, J = 6.7 Hz, 6H), 1 .24 (dq, J = 3.3, 12.5 Hz, 2H); LCMS (ESI) [M+H]+: 368.1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.30 (s, 1 H), 8.1 9 (s, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.77 (dd, J = 1 .1 , 8.4 Hz, 1 H), 5.17-5.07 (m, 1 H), 3.43 (br t, J = 4.5 Hz, 1 H), 3.25-3.16 (m, 1 H), 2.25 (br dd, J = 4.6, 9.2 Hz, 2H), 1 .97-1 .88 (m, 4H), 1 .66-1 .57 (m, 2H), 1 .50 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 326.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.07 (s, 1 H), 7.89-7.81 (m, 2H), 4.99 (td, J = 6.7, 13.3 Hz, 1 H), 4.48 (br s, 1 H), 3.57 (br s, 1 H), 2.99 (tt, J = 3.4, 12.2 Hz, 1 H), 2.33-2.20 (m, 4H), 1 .85 (dq, J = 3.0, 13.0 Hz, 2H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .48 (s, 9H), 1 .38-1 .26 (m, 2H); LCMS (ESI) [M+H]+: 426.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.84 (s, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 6.40 (dd, J = 8.8, 2.0 Hz, 1 H), 6.22 (s, 1 H), 4.79-4.61 (m, 1 H), 3.69 (s, 4H), 3.10-2.66 (m, 5H), 1 .83 (br t, J = 5.2 Hz, 4H), 1 .56 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 285.1 .

¹ H NMR (300 MHz, DMSO-de) δ 8.27 (d, J = 1 .2 Hz, 1 H), 8.19 (s, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 7.91 (d, J = 2.3 Hz, 1 H), 7.79 (dd, J = 8.7, 2.3 Hz, 1 H), 7.72 (dd, J = 8.5, 1 .3 Hz, 1 H), 7.37 (d, J = 8.8 Hz, 1 H), 5.14 (p, J = 6.6 Hz, 1 H), 3.96 (s, 3H), 3.69 (d, J = 1 1 .9 Hz, 3H), 2.22 (d, J

Hz, 2H), 1 .50 (d, J = 6.5 Hz, 6H); LCMS (ESI) [M+H]+: 560.2, 562.1 .

¹ H NMR (300 MHz, DMSO-de) δ 8.29 (d, J = 1 .1 Hz, 1 H), 8.19 (s, 1 H), 8.02 (dd, J = 7.7, 1 .6 Hz, 1 H), 7.92 (dd, J = 8.5, 0.8 Hz, 1 H), 7.76-7.66 (m, 3H), 7.59 (ddd, J = 7.9, 6.8, 1 .9 Hz, 1 H), 5.15 (p, J = 6.5 Hz, 1 H), 3.78 (d, J = 12.8 Hz, 2H), 3.39 (d, J = 15.0 Hz, 1 H), 3.09-2.93 (m, 2H), 2.21 (dd, J = 13.4, 3.5 Hz, 2H), 1 .93-1 .74 (m, 1 H), 1 .50 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 486.3, 488.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.28 (s, 1 H), 8.1 5 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.48 (dd, J = 1 .9, 9.6 Hz, 1 H), 7.30 (d, J = 8.2 Hz, 1 H), 5.10 (td, J = 6.6, 13.2 Hz, 1 H), 4.03 (br s, 1 H), 4.20-3.86 (m, 1 H), 3.58-3.43 (m, 1 H), 3.25 (br t, J = 1 1 .2 Hz, 2H), 2.19 (br d, J = 9.9 Hz, 2H), 1 .99-1 .81 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 468.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.29 (s, 1 H), 8.1 1 (d, J = 3.4 Hz, 1 H), 7.88 (d, J = 5.4 Hz, 2H), 5.07-4.90 (m, 1 H), 4.09-3.95 (m, 1 H), 3.94-3.77 (m, 2H), 3.76-3.57 (m, 2H), 2.55-2.31 (m, 2H), 2.29-2.24 (m, 2H), 1 .66 (d, J = 6.6 Hz, 6H), 1 .1 1 (d, J = 1 .8 Hz, 9H); LCMS (ESI) [M+H]+: 396.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.08 (d, J = 2.9 Hz, 1 H), 7.82 (br dd, J = 2.6, 8.4 Hz, 1 H), 7.72 (dd, J = 3.4, 8.3 Hz, 1 H), 4.24-4.13 (m, 2H), 4.07 (d, J = 3.7 Hz, 3H), 3.44-3.25 (m, 3H), 2.59-2.57 (m, 3H), 2.29-2.27 (m, 2H), 2.23 (d, J = 4.0 Hz, 3H), 2.1 6-2.04 (m, 2H); LCMS (ESI) [M+H]+: 380.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.28 (s, 1 H), 8.1 6 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.76 (dd, J = 1 .0, 8.5 Hz, 1 H), 7.55-7.47 (m, 2H), 7.30-7.22 (m, 2H), 5.1 1 (quin, J = 6.6 Hz, 1 H), 4.06 (br s, 2H), 3.57-3.45 (m, 1 H), 3.32-3.1 8 (m, 2H), 2.1 9 (br dd, J = 3.4, 13.1 Hz, 2H), 1 .97-1 .81 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 434.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (d, J = 0.9 Hz, 1 H), 8.01 (d, J = 0.9 Hz, 1 H), 7.79-7.77 (m, 2H), 4.14 (s, 3H), 3.74-3.68 (m, 4H), 3.62-3.56 (m, 4H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 385.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (s, J = 0.7 Hz, 1 H), 8.10 (s, 1 H), 7.91 -7.82 (m, 2H), 4.98 (spt, J = 6.6 Hz, 1 H), 4.64 (br d, J = 13.6 Hz, 1 H), 3.98 (br d, J = 13.6 Hz, 1 H), 3.32-3.20 (m, 1 H), 3.1 5 (tt, J = 3.9, 10.9 Hz, 1 H), 2.91 (br t, J = 1 1 .2 Hz, 1 H), 2.40 (d, J = 4.2 Hz, 2H), 2.16 (br d, J = 1 1 .1 Hz, 2H), 1 .99-1 .80 (m, 2H), 1 .65 (d, J = 6.7 Hz, 6H), 1 .18 (s, 3H), 0.55-0.31 (m, 4H); LCMS (ESI) [M+H]+: 408.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.17 (d, J = 10.8 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1 H), 7.67 (dd, J = 1 .1 , 8.4 Hz, 1 H), 7.61 -7.49 (m, 1 H), 7.41 -7.24 (m, 3H), 5.10 (td, J = 6.6, 13.1 Hz, 1 H), 3.94-3.43 (m, 8H), 1 .50 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 435.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.09 (s, 1 H), 7.84 (d, J = 0.7 Hz, 2H), 4.97 (qui = 6.7 Hz, 1 H), 3.57 (br d, J = 5.5 Hz, 8H), 1 .65 (d, J = 6.6 Hz, 6H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 413.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.06 (s, 1 H), 7.92 (d, J = 3.1 Hz, 1 H), 7.88-7.77 (m, 2H), 7.57 (d, J = 3.3 Hz, 1 H), 5.43 (br d, J = 13.7 Hz, 1 H), 4.97 (spt, J = 6.7 Hz, 1 H), 4.67 (br d, J = 12.6 Hz, 1 H), 3.80-3.60 (m, 1 H), 3.48-3.36 (m, 1 H), 3.34-3.18 (m, 1 H), 2.31 (br s, 2H), 2.15 (br s, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 423.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.84 (dd, J = 1 .2, 8.4 Hz, 1 H), 7.77-7.71 (m, 1 H), 4.76 (br s, 1 H), 4.09 (s, 3H), 3.81 (br s, 1 H), 3.68 (s, 3H), 3.28-3.16 (m, 1 H), 2.61 (s, 3H), 2.25-2.12 (m, 2H), 2.07-1 .97 (m, 2H), 1 .88 (dt, J = 4.0, 8.7 Hz, 2H), 1 .79-1 .69 (m, 2H); LCMS (ESI) [M+H]+: 370.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (br s, 1 H), 8.06 (br s, 1 H), 7.91 -7.77 (m, 2H), 7.65-7.55 (m, 2H), 7.43 (br d, J = 5.7 Hz, 1 H), 7.33-7.15 (m, 2H), 5.04-4.91 (m, 0.8H), 4.57 (br s, 0.4H), 4.44-4.31 (m, 2H), 4.28-4.14 (m, 0.5H), 4.02 (br s, 0.5H), 3.93-3.68 (m, 2H), 3.68-3.46 (m, 1 H), 2.50-2.25 (m, 2H), 1 .63 (br d, J = 6.4 Hz, 6H); LCMS (ESI) [M+H]+: 527.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.07 (s, 1 H), 7.96-7.94 (d, J = 8.0 Hz, 2H), 7.87- 7.81 (m, 2H), 7.80-7.60 (d, J = 8.0 Hz, 2H), 7.33-7.25 (m, 1 H), 5.00-4.93 (m, 1 H), 4.65-4.50 (m, 0.5H), 4.45-4.25 (m, 2.6H, 4.25-4.15 (m, 0.5 h), 4.08-3.98 (m, 0.5H), 3.95-3.80 (m, 1 .5H), 3.80 -3.05 (m, 0.5H), 3.65-3.50 (m, 1 H), 2.50-2.33 (m, 2H), 1 .64-1 .62 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 534.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.73 (br d, J = 15.2 Hz, 1 H), 8.57 (d, J = 2.3 Hz, 1 H), 8.20-8.1 1 (m, 2H), 7.92 (d, J = 8.6 Hz, 1 H), 7.87-7.78 (m, 2H), 4.64 (dt, J = 6.8, 14.3 Hz, 0.5H), 4.39 (br t, J = 5.4 Hz, 2.4H), 4.30-4.22 (m, 0.6H), 4.18 (s, 3H), 4.06 (br d, J = 14.4 Hz, 0.6H), 3.93-3.70 (m, 2H), 3.62-3.49 (m, 1 H), 2.69 (s, 3H), 2.50-2.29 (m, 2H); LCMS (ESI) [M+H]+: 530.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.17 (s, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 7.84 (d, J = 8.3 Hz, 1 H), 7.79 (d, J = 8.3 Hz, 2H), 7.48-7.39 (m, 2H), 7.28-7.19 (m, 1 H), 4.64 (dt, J = 7.3, 14.2 Hz, 0.5H), 4.48-4.32 (m, 2.3H), 4.26 (br s, 0.6H), 4.22 (s, 3H), 4.06 (br d, J = 8.8 Hz, 0.7H), 3.95-3.69 (m, 2H), 3.61 -3.47 (m, 1 H), 2.73 (s, 3H), 2.50-2.30 (m, 2H); LCMS (ESI) [M+H]+: 529.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (d, J = 0.8 Hz, 1 H), 8.04 (s, 1 H), 7.77 (d, J = 0.8 Hz, 2H), 5.05-4.85 (m, 1 H), 4.06 (s, 4H), 3.42 (t, J = 5.6 Hz, 4H), 1 .85 (t, J = 5.6 Hz, 4H), 1 .61 (d, J = 6.4 Hz, 6H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 453.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.19 (s, 1 H),8.16 (s, 1 H), 8.08-8.04 (m, 2H), 7.87-7.78 (m, 3H), 7.59 (t, J = 7.8 Hz, 1 H), 7.41 -7.35 (m, 1 H), 4.96 (quin, J = 6.7 Hz, 1 H), 4.52 (br d, J = 13.7 Hz, 1 H), 4.31 (d, J = 3.7 Hz, 2H), 3.91 (br d, J = 13.9 Hz, 1 H), 3.37 (ddd, J = 3.3, 10.5, 13.9 Hz, 2H), 3.25-3.1 1 (m, 1 H), 2.37-2.21 (m, 2H), 2.13-1 .94 (m, 2H), 1 .63 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 498.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.11 (s, 1H), 7.93-7.81 (m, 3H), 7.79-7.72 (m, 1H), 7.25-7.10 (m, 3H), 4.59 (dt, J = 6.7, 14.9 Hz, 0.5H), 4.43-4.30 (m, 2.5H), 4.24 (dt, J = 6.3, 14.6 Hz, 0.5H), 4.10 (s, 3H), 4.05 (brd, J = 13.9 Hz, 0.5H), 3.95-3.70 (m, 2H), 3.68-3.50 (m, 1H), 2.61 (s, 3H), 2.49-2.31 (m, 2H); LCMS (ESI) [M+H]+: 513.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.06-7.90 (m, 2H), 7.75-7.57 (m, 2H), 5.76-5.60 (m, 1H), 5.12 (t, J = 6.5 Hz, 2H), 4.95 (t, J = 7.3 Hz, 2H), 4.38 (m, 1H), 3.74 (m, 1H), 3.17-2.98 (m, 2H), 2.86-2.69 (m, 1H), 2.12 (d, J = 6.8 Hz, 2H), 2.07-1.95 (m, 2H), 1.84-1.66 (m, 2H), 0.93-0.80 (m, 1H), 0.44-0.33 (m, 2H), 0.05- -0.05 (m, 2H); LCMS (ESI) [M+H]+: 408.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (d, J = 0.7 Hz, 1H), 8.17 (s, 1H), 7.93-7.81 (m, 2H), 5.96 5.83 (m, 1H), 5.33 (t, J = 6.6 Hz, 2H), 5.16 (t, J = 7.3 Hz, 2H), 4.60 (brd, J = 13.4 Hz, 1H), 3.97 (brd, J 13.9 Hz, 1H), 3.36-3.20 (m, 2H), 2.96 (br t, J = 11.2 Hz, 1H), 2.39 (m, 2H), 2.22 (brd, J = 13.4 Hz, 2H), 2.05-1.85 (m, 2H), 1.17 (s, 3H), 0.55-0.32 (m, 4H); LCMS (ESI) [M+H]+: 422.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.85-7.80 (m, 1H), 7.73 (d, J = 8.3 Hz, 1H), 4.32 (brd, J = 13.2 Hz, 2H), 4.08 (s, 3H), 3.36-3.27 (m, 1H), 3.23-3.11 (m, 2H), 2.72 (q, J = 7.7 Hz, 2H), 2.60 (s, 3H), 2.34-2.25 (m, 2H), 2.15-2.03 (m, 2H), 1.28 (t, J = 7.7 Hz, 3H); LCMS (ESI) [M+H]+: 404.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.51 (s, 1 H), 8.15 (d, J = 0.7 Hz, 1 H), 8.04 (dd, J = 1.1 , 8.4 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 1 H), 7.68-7.35 (t, J = 59.2 Hz, 1 H), 4.19 (br s, 2H), 3.73 (s, 3H), 3.23 (tt, J = 3.9, 10.9 Hz, 1 H), 3.08 (br t, J = 11.6 Hz, 2H), 2.17 (br d, J = 10.9 Hz, 2H), 2.01 -1.89 (m, 2H); LCMS (ESI) [M+H]+: 378.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (s, 1H), 8.10 (s, 1H), 7.85-7.82 (m, 1H), 7.80-7.75 (m, 1H), 7.40-7.33 (m, 1H), 7.32-7.20 (m, 3H), 5.92-5.74 (m, 1H), 5.26 (t, J = 6.6 Hz, 2H), 5.09 (t, J = 7.0 Hz, 2H), 4.76-4.55 (m, 1 H), 3.61 -3.44 (m, 1 H), 3.36-3.01 (m, 3H), 2.27 (m, 1 H), 2.15-1.93 (m, 2H), 1.93-1.77 (m, 1 H); LCMS (ESI) [M+H]+: 464.1.

¹ H NMR (400 MHz, DMSO-de) δ 8.25 (s, 1 H), 8.14 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 5.11-5.05 (m, 1H), 4.07-3.99 (m, 1H), 3.66-3.56 (m, 1H), 3.49 (br dd, J = 9.2, 13.3 Hz, 1H), 3.32-3.15 (m, 2H), 2.22-2.13 (m, 1H), 1.98-1.93 (m, 1H), 1.84-1.75 (m, 1H), 1.60-1.45 (m, 7H), 1.38 (s, 9H); LCMS (ESI) [M+H]+: 412.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.29-8.16 (m, 2H), 7.97-7.84 (m, 2H), 7.46 (m, 5H), 5.99-5.85 (m, 1 H), 5.36 (t, J = 6.7 Hz, 2H), 5.18 (t, J = 7.3 Hz, 2H), 4.86-4.54 (m, 1 H), 3.94 (m, 1 H), 3.46-3.31 (m, 1 H), 3.25 (br s, 2H), 2.39-1.82 (m, 4H); LCMS (ESI) [M+H]+: 430.1.

¹ H NMR (300 MHz, DMSO-de) δ 8.31 (d, J = 1.1 Hz, 1H), 8.19 (s, OH), 7.93 (dd, J = 8.4, 0.8 Hz, 1H), 7.75 (dd, J = 8.5, 1.3 Hz, 1 H), 5.16 (h, J = 6.6 Hz, 1 H), 3.65 (dt, J = 11.7, 3.3 Hz, 3H), 3.43-3.27 (m, 1 H), 3.02 (td, J = 12.6, 2.7 Hz, 3H), 2.95 (d, J = 6.6 Hz, 2H), 2.23 (dd, J = 13.6, 3.7 Hz, 2H), 2.12 (dq, J = 13.3, 6.7 Hz, 1 H), 1.97-1.78 (m, 2H), 1.50 (d, J = 6.6 Hz, 6H), 1.05 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 432.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (dd, J = 1.1 , 7.7 Hz, 1 H), 7.67 (s, 1 H), 7.35 (d, J = 7.7 Hz, 1H), 4.68 (spt, J = 7.0 Hz, 1H), 4.14 (m, 2H), 3.56 (s, 2H), 3.19 (tt, J = 4.0, 10.9 Hz, 1H), 3.01 (br t, J = 11.6 Hz, 2H), 2.14 (br dd, J = 2.8, 13.3 Hz, 2H), 1.98-1.84 (m, 2H), 1.54 (d, J = 7.1 Hz, 6H), 1.49 (s, 9H); LCMS (ESI) [M+H]+: 427.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.86-7.81 (m, 1 H), 7.74 (d, J = 8.4 Hz, 1H),4.42 (dd, J = 7.2, 9.2 Hz, 1H), 4.16 (dd, J = 5.3, 9.3 Hz, 1H), 4.08 (s, 3H), 3.09-2.89 (m, 3H), 2.87-2.76 (m, 1H), 2.68-2.61 (m, 1H), 2.60 (s, 3H), 2.45 (d, J = 7.9 Hz, 2H), 2.37 (dd, J = 5.7, 17.6 Hz, 1H), 2.31-2.13 (m, 4H), 2.11-1.98 (m, 2H)

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (d, J = 0.7 Hz, 1H), 8.04 (s, 1H), 7.77 (m, 2H), 4.95 (m, 1 H), 3.99 (m, 2H), 3.84 (dd, J = 6.3, 9.8 Hz, 1 H), 3.80-3.71 (m, 4H), 3.39 (m, 2H), 3.17 (q, J = 10.4 Hz, 2H), 2.53-2.34 (m, 2H), 1.61 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 397.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (d, J = 0.9 Hz, 1H), 8.04 (s, 1H), 7.81-7.73 (m, 2H), 4.95 (m, 1H), 4.07-3.93 (m, 3H), 3.84 (dd, J = 6.6, 8.9 Hz, 1H), 3.45-3.36 (m, 2H), 3.30 (dd, J = 9.2, 10.8 Hz, 1H), 3.16 (t, J = 11.0 Hz, 1H), 2.57-2.32 (m, 2H), 2.26-2.15 (m, 2H), 1.61 (d, J = 6.6 Hz, 6H), 1.12-1.04 (m, 9H); LCMS (ESI) [M+H]+: 437.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (s, 1 H), 8.04 (s, 1 H), 7.77 (s, 2H), 5.00-4.88 (m, 1 H), 4.07 (s, 4H), 3.71 (s, 3H), 3.47 (t, J = 4.8 Hz, 4H), 1 .86 (t, J = 5.6 Hz, 4H), 1 .61 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 41 1 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (s. 1 H), 8.05 (s, 1 H), 7.76 (s, 2H), 5.01 -4.90 (m, 1 H), 4.15- 4.04 (m, 4H), 3.61 (t, J = 5.2 Hz, 2H), 3.45 (t, J = 5.6 Hz, 2H), 2.13 (s, 3H), 1 .89 (dt, J = 16.6, 4.4 Hz, 4H), 1 .61 (d, J = 6.4 Hz, 6H); LCMS (ESI) [M+H]+: 395.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.83 (s, 1 H), 7.71 (dd, J = 1 .2, 7.6 Hz, 1 H), 7.28 (d, J = 7.6 Hz, 1 H), 4.73 (spt, J = 6.9 Hz, 1 H), 4.25-4.00 (m, 2H), 3.18 (tt, J = 3.9, 10.9 Hz, 1 H), 3.00 (br t, J = 1 1 .7 Hz, 2H), 2.91 -2.85 (m, 2H), 2.60 (dd, J = 5.8, 8.3 Hz, 2H), 2.13 (br dd, J = 2.8, 13.1 Hz, 2H), 1 .96-1 .85 (m, 2H), 1 .58 (d, J = 7.1 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M-55]+: 385.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.82 (d, J = 2.2 Hz, 1 H), 8.22 (s, 1 H), 8.06 (s, 1 H), 8.03 (d, J = 2.2 Hz, 1 H), 7.92-7.77 (m, 2H), 4.97 (spt, J = 6.7 Hz, 1 H), 4.63 (br d, J = 7.3 Hz, 2H), 3.47 (br s, 1 H), 3.38 (tt, J = 4.2, 10.5 Hz, 1 H), 3.24 (br s, 1 H), 2.29 (br s, 2H), 2.19-2.07 (m, 2H), 1 .63 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 423.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.07 (s, 1 H), 7.90-7.79 (m, 2H), 7.48 (dd, J = 1 .0, 5.0 Hz, 1 H), 7.34 (dd, J = 1 .0, 3.6 Hz, 1 H), 7.08 (dd, J = 3.7, 4.9 Hz, 1 H), 4.98 (td, J = 6.6, 13.2 Hz, 1 H), 4.47 (br d, J = 12.8 Hz, 2H), 3.45-3.27 (m, 3H), 2.28 (br dd, J = 3.4, 13.6 Hz, 2H), 2.15-2.01 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 422.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.07 (s, 1 H), 7.89-7.79 (m, 2H), 7.18 (d, J = 5.7 Hz, 1 H), 6.99 (d, J = 5.7 Hz, 1 H), 4.97 (td, J = 6.6, 13.4 Hz, 1 H), 4.66 (br d, J = 12.8 Hz, 1 H), 3.80 (br d, J = 13.5 Hz, 1 H), 3.43-3.16 (m, 3H), 2.40-2.17 (m, 2H), 2.17-1 .93 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 456.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (d, J = 0.6 Hz, 1 H), 8.16 (s, 1 H), 7.93-7.87 (m, 1 H), 7.86- 7.81 (m, 1 H), 5.89 (quin, J = 7.0 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.15 (t, J = 7.3 Hz, 2H), 4.32-3.96 (m, 2H), 3.20 (m, 1 H), 3.08-2.96 (m, 2H), 2.15 (br d, J = 12.5 Hz, 2H), 1 .99-1 .83 (m, 2H), 1 .59 (br s, 1 H), 1 .57 (s, 3H), 0.93-0.83 (m, 2H), 0.72-0.59 (m, 2H); LCMS (ESI) [M+H]+: 424.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.92-7.81 (m, 3H), 7.79-7.72 (m, 1 H), 7.57-7.52 (m, 1 H), 7.51 -7.43 (m, 2H), 7.26-7.17 (m, 1 H), 4.65-4.50 (m, 0.5H), 4.44-4.32 (m, 2.5H), 4.25 (dt, J = 5.7, 14.8 Hz, 0.5H), 4.09 (s, 3H), 4.04 (br d, J = 4.9 Hz, 0.5H), 3.96-3.69 (m, 2H), 3.68-3.50 (m, 1 H), 2.61 (s, 3H), 2.50-2.23 (m, 2H); LCMS (ESI) [M+H]+: 495.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.90-7.81 (m, 3H), 7.78-7.73 (m, 1 H), 7.58-7.51 (m, 1 H), 7.50-7.43 (m, 2H), 7.30-7.19 (m, 1 H), 4.65-4.49 (m, 0.5H), 4.45-4.31 (m, 2.5H), 4.25 (dt, J = 5.6, 14.8 Hz, 0.5H), 4.09 (s, 3H), 4.08-4.00 (m, 0.5H), 3.98-3.70 (m, 2H), 3.66-3.51 (m, 1 H), 2.61 (s, 3H), 2.50-2.31 (m, 2H); LCMS (ESI) [M+H]+: 495.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.10 (s, 1 H), 7.91 -7.83 (m, 2H), 6.77-6.62 (m, 1 H), 5.00 (td, J = 6.6, 13.2 Hz, 1 H), 4.58 (dt, J = 6.8, 14.5 Hz, 0.5H), 4.34 (br d, J = 13.9 Hz, 0.5H), 4.28-4.14 (m, 2.5H), 4.00 (br d, J = 13.6 Hz, 0.5H), 3.94-3.45 (m, 3H), 2.36 (br d, J = 16.4 Hz, 2H), 1 .66 (d, J = 6.7 Hz, 6H), 1 .57-1 .49 (m, 1 H), 1 .06-0.99 (m, 2H), 0.82 (td, J = 3.6, 7.4 Hz, 2H); LCMS (ESI) [M+H]+: 473.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.09 (s, 1 H), 7.87-7.79 (m, 2H), 7.48-7.43 (m, 1 H), 7.42-7.30 (m, 3H), 4.97 (td, J = 6.8, 13.2 Hz, 1 H), 4.13-4.00 (m, 1 H), 3.97-3.84 (m, 1 H), 3.72 (br s, 2H), 3.66-3.57 (m, 1 H), 3.56-3.41 (m, 2H), 3.38 (br d, J = 7.1 Hz, 1 H), 1 .64 (br d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 451 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.07 (s, 1 H), 7.83-7.78 (m, 1 H), 7.74-7.69 (m, 1 H), 4.19 (td, J 3.8, 13.6 Hz, 2H), 4.06 (s, 3H), 3.40-3.23 (m, 3H), 2.94-2.84 (m, 1 H), 2.58 (s, 3H), 2.27 (br dd, J = 3.3, 13.7 Hz, 2H), 2.15-2.02 (m, 2H), 1 .28 (d, J = 6.8 Hz, 6H); LCMS (ESI) [M+H]+: 408.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.37 (s, 1 H), 8.1 9 (s, 1 H), 7.95 (m, J = 8.6 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.54-7.37 (m, 5H), 5.1 5 (spt, J = 6.6 Hz, 1 H), 3.66 (br s, 4H), 3.58-3.50 (m, 4H), 1 .53 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 417.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1H), 8.11 (s, 1 H), 7.91 -7.86 (m, 1 H), 7.85-7.81 (m, 1H), 5.16-5.03 (m, 1H), 4.91 (dd, J = 7.9, 9.3 Hz, 0.5H), 4.82-4.76 (m, 1H), 4.67 (dd, J = 4.9, 9.4 Hz, 0.5H), 4.61 (brs, 1H), 4.04 (br d, J = 13.7 Hz, 1H), 3.36-3.24 (m, 2H), 2.97 (br t, J = 12.1 Hz, 1H), 2.32 (s, 2H), 2.27-2.17 (m, 2H), 2.05-1.89 (m, 2H), 1.66 (dd, J = 1.6, 6.8 Hz, 3H), 1.09 (s, 9H); LCMS (ESI) [M+H]+: 428.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.07 (s, 1 H), 7.90-7.81 (m, 2H), 4.98 (spt, J = 6.6 Hz, 1 H), 4.48-3.98 (m, 2H), 3.81 -3.68 (m, 1 H), 3.61 -3.47 (m, 1 H), 3.32 (br t, J = 10.1 Hz, 1 H), 2.42-2.20 (m, 2H), 1.64 (d, J = 6.7 Hz, 6H), 1.59 (s, 3H), 0.96-0.90 (m, 2H), 0.72-0.65 (m, 2H); LCMS (ESI) [M+H]+ 446.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.11 (s, 1 H), 7.92-7.86 (m, 1 H), 7.85-7.79 (m, 1 H), 5.16-5.03 (m, 1H), 4.90 (dd, J = 8.0, 9.4 Hz, 0.5H), 4.82-4.76 (m, 1H), 4.67 (dd, J = 4.9, 9.4 Hz, 0.5H), 4.60 (brd, J = 13.6 Hz, 1H), 3.97 (brd, J = 13.4 Hz, 1H), 3.34-3.24 (m, 2H), 2.98 (br t, J = 11.9 Hz, 1H), 2.40 (d, J = 3.2 Hz, 2H), 2.22 (br d, J = 13.1 Hz, 2H), 1.96 (quin, J = 11.9 Hz, 2H), 1.66 (dd, J = 1.5, 6.8 Hz, 3H), 1.18 (s, 3H), 0.50-0.44 (m, 2H), 0.44-0.38 (m, 2H); LCMS (ESI) [M+H]+: 426.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.57 (d, J = 2.0 Hz, 1 H), 8.22 (s, 1 H), 8.07 (s, 1 H), 7.89-7.78 (m, 3H), 7.69 (d, J = 8.3 Hz, 1H), 4.98 (td, J = 6.7, 13.4 Hz, 1H), 4.67 (brd, J = 13.1 Hz, 1H), 4.16 (brd, J = 13.4 Hz, 1H), 3.45-3.33 (m, 2H), 3.26 (br t, J = 10.8 Hz, 1H), 2.33 (brd, J = 10.9 Hz, 1H), 2.24-2.07 (m, 3H), 1.64 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 451.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (dd, J = 1.2, 4.6 Hz, 1H), 8.22 (s, 1H), 8.07 (s, 1H), 7.91- 7.75 (m, 3H), 7.33 (dd, J = 4.6, 8.2 Hz, 1 H), 4.98 (td, J = 6.6, 13.3 Hz, 1 H), 4.78-4.63 (m, 1 H), 3.53 (td, J = 3.8, 13.6 Hz, 1 H), 3.42-3.19 (m, 3H), 2.35 (br dd, J = 3.9, 13.6 Hz, 1 H), 2.25-2.03 (m, 2H), 2.25-2.03 (m, 1 H), 1.64 (d, J = 6.6 Hz, 6H); M+H]+: 451.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.71 (d, J = 4.6 Hz, 1 H), 8.22 (s, 1 H), 8.07 (s, 1 H), 7.89-7.79 (m, 2H), 7.68 (d, J = 4.9 Hz, 1H), 4.98 (td, J = 6.6, 13.4 Hz, 1H), 4.68 (br d, J = 13.5 Hz, 1H), 4.57 (br d, J = 13.9 Hz, 1H), 3.53-3.44 (m, 1H), 3.44-3.35 (m, 1H), 3.32-3.17 (m, 1H), 2.38-2.21 (m, 2H), 2.21-2.07 (m, 2H), 1.64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 423.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.07 (s, 1 H), 7.89-7.80 (m, 2H), 7.68 (s, 1 H), 5.41 (brd, J = 12.3 Hz, 1H), 4.97 (td, J = 6.6, 13.4 Hz, 1H), 4.60 (br d, J = 11.5 Hz, 1H), 3.75-3.62 (m, 1H), 3.49-3.35 (m, 1 H), 3.33-3.19 (m, 1 H), 2.30 (br s, 2H), 2.14 (br s, 2H), 1.64 (d, J = 6.6 Hz, 5H), 1.66-1.61 (m, 1 H); LCMS (ESI) [M+H]+: 457.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.27 (s, 1 H), 8.05 (dd, J = 1.1 , 8.2 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1H), 4.16 (br s, 2H), 3.20 (tt, J = 3.9, 10.8 Hz, 1H), 3.09-2.97 (m, 2H), 2.62 (s, 3H), 2.14 (brd, J = 11.4 Hz, 2H), 1.98-1.84 (m, 2H), 1.56 (s, 3H), 0.91 -0.85 (m, 2H), 0.67-0.61 (m, 2H); LCMS (ESI) [M+H]+: 383.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (s, 1 H), 8.05 (dd, J = 1.1 , 8.2 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 1H), 4.58 (brd, J = 13.7 Hz, 1H), 3.96 (brd, J = 13.5 Hz, 1H), 3.34-3.22 (m, 2H), 2.97 (br t, J = 11.2 Hz, 1 H), 2.63 (s, 3H), 2.39 (s, 2H), 2.21 (br d, J = 13.2 Hz, 2H), 2.03-1 .85 (m, 2H), 1 .16 (s, 3H), 0.48-0.38 (m, 4H); LCMS (ESI) [M+H]+: 381 .1 .

Ή NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.88-7.81 (m, 1 H), 7.79-7.70 (m, 1 H), 4.94 (t, J = 7.0 Hz, 2H), 4.52 (br d, J = 13.7 Hz, 1 H), 4.43 (t, J = 5.6 Hz, 2H), 4.09 (s, 3H), 3.98 (br d, J = 13.6 Hz, 1 H), 3.50-3.39 (m, 1 H), 3.33 (br s, 2H), 3.00 (br s, 1 H), 2.83 (d, J = 7.7 Hz, 2H), 2.61 (s, 3H), 2.25 (br t, J = 14.4 Hz, 2H), 2.09-1 .89 (m, 2H); LCMS (ESI) [M+H]+: 396.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (d, J = 0.7 Hz, 1 H), 8.05 (s, 1 H), 7.78 (d, J = 0.9 Hz, 2H), 4.95 (spt, J = 6.6 Hz, 1 H), 4.56 (q, J = 8.4 Hz, 2H), 3.78 (br s, 4H), 3.74-3.68 (m, 4H), 1 .63 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 439.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.84 (s, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 8.39 (dd, J = 8.4, 1 .6 Hz, 1 H), 6.22 (s, 1 H), 4.75-4.64 (m, 1 H), 4.13-4.05 (m, 1 H), 3.71 (s, 4H), 3.55-3.30 (m, 4H), 1 .93-1 .72 (m, 4H), 1 .56 (d, J = 6.8 Hz, 6H), 0.75-0.62 (m, 4H); LCMS (ESI) [M+H]+: 369.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (d, J = 0.9 Hz, 1 H), 8.05 (s, 1 H), 7.78 (d, J = 1 .0 Hz, 2H), 4.95 (td, J = 6.7, 13.3 Hz, 1 H), 4.17 (s, 2H), 3.84-3.68 (m, 8H), 3.51 -3.42 (m, 1 H), 3.46 (s, 2H), 1 .63 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 485.1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.26 (s, 1 H), 8.1 8 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.73 (dd, J = 1 .1 , 8.4 Hz, 1 H), 5.09 (spt, J = 6.6 Hz, 1 H), 3.16-3.05 (m, 2H), 2.24 (br d, J = 1 1 .4 Hz, 2H), 2.10 (br d, J = 10.0 Hz, 2H), 1 .76-1 .65 (m, 2H), 1 .54 (br dd, J = 2.8, 12.6 Hz, 2H), 1 .49 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 326.1 .

¹ H NMR (300 MHz, CHLOROFORM-d) δ 8.19 (dd, J = 14.6, 1 .0 Hz, 2H), 7.95-7.80 (m, 2H), 5.89 (p, J = 7.1 Hz, 1 H), 5.33 (t, J = 6.9, 6.2 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.51 (q, J = 6.7 Hz, 2H), 3.83 (s, 1 H), 3.37 (d, J = 10.6 Hz, 1 H), 3.32 (s, 1 H), 3.1 9-3.05 (m, 1 H), 2.80 (s, 1 H), 2.25 (s, 1 H), 1 .64 (d, J = 7.0 Hz, 1 H), 1 .57-1 .42 (m, 1 H), 1 .38 (dd, J = 8.8, 6.1 Hz, 3H), 1 .25 (s, 1 H), 1 .06 (s, 1 H); LCMS (ESI) [M+H]+: 398.3.

¹ H NMR (300 MHz, CHLOROFORM-d) δ 8.26-8.14 (m, 2H), 7.96-7.80 (m, 4H), 7.59-7.40 (m, 3H), 7.33 (s, 1 H), 5.88 (q, J = 6.8 Hz, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.3 Hz, 2H), 4.54 (d, J = 14.0 Hz, 1 H), 4.32 (d, J = 4.0 Hz, 2H), 3.93 (d, J = 13.8 Hz, 1 H), 3.43-3.28 (m, 2H), 3.1 5 (t, J = 12.1 Hz, 1 H), 2.02 (dd, J = 14.6, 1 0.7 Hz, 2H), 1 .47 (s, 1 H), 1 .25 (s, 2H); LCMS (ESI) [M+H]+: 487.3.

¹ H NMR (300 MHz, CHLOROFORM-d) δ 8.27-8.14 (m, 2H), 8.01 -7.81 (m, 4H), 7.55-7.40 (m, 2H), 5.90 (s, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.57 (t, J = 15.7 Hz, 1 H), 4.34 (dd, J = 9.5, 6.6 Hz, 1 H), 3.95 (t, J = 8.1 Hz, 2H), 3.62 (p, J = 8.2 Hz, 1 H), 3.40 (d, J = 8.2 Hz, 1 H), 3.37 (s, 1 H), 3.21 -2.87 (m, 3H), 2.28 (d, J = 13.1 Hz, 2H), 2.06 (s, 1 H), 1 .25 (s, 1 H); LCMS (ESI) [M+H]+: 538.3.

¹ H NMR (300 MHz, CHLOROFORM-d) δ 8.27-8.14 (m, 2H), 8.01 -7.81 (m, 4H), 7.55-7.40 (m, 2H), 5.89 (s, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.17 (t, J = 7.1 Hz, 2H), 4.57 (s, 1 H), 4.34 (dd, J = 9.5, 6.6 Hz, 1 H), 3.96 (t, J = 8.5 Hz, 2H), 3.68-3.56 (m, 1 H), 3.39 (s, 1 H), 3.12 (s, 1 H), 3.06-2.89 (m, 2H), 2.29 (s, 1 H), 2.06 (s, 1 H), 1 .25 (s, 1 H); LCMS (ESI) [M+H]+: 538.3.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1 H), 7.95 (d, J = 8.2 Hz, 2H), 7.83 (dd, J = 0.7, 8.4 Hz, 1 H), 7.79-7.71 (m, 3H), 7.42-7.29 (m, 1 H), 4.58 (dt, J = 6.5, 14.7 Hz, 0.5H), 4.44-4.30 (m, 2.5H), 4.29- 4.16 (m, 0.5H), 4.08 (s, 3H), 4.06-3.99 (m, 0.5H), 3.96-3.69 (m, 2H), 3.67-3.50 (m, 1 H), 2.60 (s, 3H), 2.49- 2.29 (m, 2H); LCMS (ESI) [M+H]+: 520.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.03 (s, 1 H), 7.76 (dd, J = 1 .1 , 8.4 Hz, 1 H), 7.70-7.64 (m, 1 H), 7.57-7.46 (m, 2H), 7.36 (dt, J = 5.6, 7.9 Hz, 1 H), 7.21 -7.1 1 (m, 2H), 4.57-4.42 (m, 0.5H), 4.34-4.22 (m, 2.6H), 4.21 -4.10 (m, 0.6H), 4.01 (s, 3H), 3.99-3.90 (m, 0.5H), 3.87-3.62 (m, 2H), 3.60-3.42 (m, 1 H), 2.53 (s, 3H), 2.41 -2.22 (m, 2H); LCMS (ESI) [M+H]+: 513.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (s, 1 H), 7.91 -7.85 (m, 2H), 7.81 -7.76 (m, 1 H), 7.74 (d, J = 7.7 Hz, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.46-7.40 (m, 1 H), 7.23 (br d, J = 19.8 Hz, 1 H), 4.60 (dt, J = 6.4, 14.7 Hz, 0.5H), 4.44-4.32 (m, 2.5H), 4.25 (dt, J = 5.3, 14.7 Hz, 0.5H), 4.13 (s, 3H), 4.06 (br d, J = 13.4 Hz, 0.5H), 3.97-3.71 (m, 2H), 3.69-3.52 (m, 1 H), 2.65 (s, 3H), 2.48-2.33 (m, 2H); LCMS (ESI) [M+H]+: 529.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.17 (br d, J = 5.3 Hz, 1H), 8.11 (s, 1H), 8.07 (brd, J = 7.9 Hz, 1 H), 7.87-7.80 (m, 2H), 7.76 (dd, J = 0.7, 8.4 Hz, 1 H), 7.64-7.59 (m, 1 H), 7.35-7.26 (m, 1 H), 4.58 (dt, J = 6.3, 14.9 Hz, 0.5H), 4.44-4.30 (m, 2.5H), 4.24 (dt, J = 5.6, 15.1 Hz, 0.5H), 4.09 (s, 3H), 4.04 (brd, J = 14.5 Hz, 0.5H), 3.96-3.84 (m, 1.5H), 3.82-3.70 (m, 0.5H), 3.70-3.49 (m, 1H), 2.61 (s, 3H), 2.47-2.31 (m, 2H); LCMS (ESI) [M+H]+: 520.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.32 (s, 1 H), 8.11 (s, 1 H), 7.95-7.79 (m, 2H), 5.00 (spt, J = 6.6 Hz, 1 H), 4.42-4.24 (m, 4H), 4.01 (tt, J = 6.1 , 8.8 Hz, 1 H), 1.66 (d, J = 6.6 Hz, 6H), 1.49 (s, 9H); LCMS (ESI) [M-55]+: 328.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.31 (s, 1 H), 8.11 (s, 1 H), 7.88 (m, 2H), 4.99 (spt, J = 6.7 Hz, 1H), 4.59-4.49 (m, 2H), 4.48-4.41 (m, 1H), 4.39-4.32 (m, 1H), 4.04 (tt, J = 6.0, 8.8 Hz, 1H), 2.14-2.02 (m, 2H), 1.66 (d, J = 6.6 Hz, 6H), 1.10 (s, 9H); LCMS (ESI) [M+H]+: 382.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1H), 8.11 (s, 1 H), 7.91 -7.86 (m, 1 H), 7.85-7.80 (m, 1H), 5.16-5.03 (m, 1H), 4.90 (t, J = 8.6 Hz, 0.5H), 4.82-4.74 (m, 1H), 4.67 (dd, J = 5.0, 9.4 Hz, 0.5H), 4.34-3.93 (brs, 2H), 3.21 (tt, J = 3.9, 10.8 Hz, 1H), 3.11-2.97 (m, 2H), 2.16 (brd, J = 12.0 Hz, 2H), 1.94 (brd, J = 9.7 Hz, 2H), 1.66 (dd, J = 1.5, 6.9 Hz, 3H), 1.58 (s, 3H), 0.95-0.84 (m, 2H), 0.69-0.60 (m, 2H); LCMS (ESI) [M+H]+: 428.1.

¹ H NMR (400 MHz, DMSO-de) δ 8.29 (s, 1 H), 8.19 (s, 1 H), 7.93 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1H), 6.95 (brd, J = 4.5 Hz, 1H), 5.14 (spt, J = 6.5 Hz, 1H), 4.65-4.43 (m, 1H), 3.20-3.12 (m, 1H), 2.58 (d, J = 4.5 Hz, 3H), 2.21 (br d, J = 11.4 Hz, 2H), 2.04 (br dd, J = 3.1 , 12.5 Hz, 2H), 1.82-1.71 (m, 2H), 1.57- 1.44 (m, 8H); LCMS (ESI) [M+H]+: 384.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.83 (dd, J = 1 .0, 8.4 Hz, 1 H), 7.76-7.70 (m, 1 H), 4.80-4.54 (m, 2H), 4.08 (s, 3H), 3.06-2.96 (m, 1 H), 2.82 (d, J = 4.8 Hz, 3H), 2.60 (s, 3H), 2.34-2.16 (m, 4H), 1 .94-1 .82 (m, 2H), 1 .60-1 .46 (m, 2H); LCMS (ESI) [M+H]+: 370.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (d, J = 7.7 Hz, 1 H), 7.66 (s, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), 4.72-4.65 (m, 1 H), 4.25-4.00 (m, 2H), 3.56 (s, 2H), 3.24-3.15 (m, 1 H), 3.03 (br t, J = 1 1 .1 Hz, 2H), 2.14 (br d, J = 1 1 .9 Hz, 2H), 1 .92 (br d, J = 9.5 Hz, 2H), 1 .57 (s, 3H), 1 .54 (d, J = 7.0 Hz, 6H), 0.92-0.87 (m, 2H), 0.68-0.63 (m, 2H); LCMS (ESI) [M+H]+: 425.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (d, J = 7.7 Hz, 1 H), 7.66 (s, 1 H), 7.35 (d, J = 7.7 Hz, 1 H), 4.72-4.65 (m, 1 H), 4.62 (br d, J = 14.1 Hz, 1 H),4.03 (br d, J = 14.1 Hz, 1 H), 3.56 (s, 2H), 3.34-3.22 (m, 2H), 2.95 (br t, J = 1 1 .5 Hz, 1 H), 2.32 (s, 2H), 2.20 (br d, J = 1 1 .5 Hz, 2H), 2.03-1 .84 (m, 2H), 1 .54 (d, J 6.8 Hz, 6H), 1 .08 (s, 9H); LCMS (ESI) [M+H]+: 425.2.

¹ H NMR (400 MHz, METHANOLS) δ 7.80 (d, J = 7.7 Hz, 1 H), 7.75 (s, 1 H), 7.54 (d, J = 7.7 Hz, 1 H), 7.49-7.35 (m, 4H), 4.70-4.63 (m, 2H), 3.60-3.53 (m, 1 H), 3.44-3.39 (m, 1 H), 3.52-3.37 (m, 1 H), 3.32-3.22 (m, 2H), 2.35 (br d, J = 1 1 .9 Hz, 1 H), 2.17 (br d, J = 13.0 Hz, 1 H), 2.10-1 .96 (m, 2H), 1 .95-1 .81 (m, 1 H), 1 .55 (d, J = 7.1 Hz, 6H). LCMS (ESI) [M+H]+: 465.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (s, 1 H), 7.70-7.61 (m, 2H), 3.99 (s, 3H), 3.67-3.49 (m, 8H), 2.51 (s, 3H), 1 .51 (s, 3H), 0.88-0.79 (m, 2H), 0.64-0.56 (m, 2H); LCMS (ESI) [M+H]+: 397.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (s, 1 H), 8.03 (s, 1 H), 7.81 -7.73 (m, 2H), 4.95 (m, 1 H), 4.30 (m, 2H), 3.49 (q, J = 7.1 Hz, 2H), 3.32 (d, J = 6.0 Hz, 2H), 3.15 (dt, J = 2.3, 12.8 Hz, 2H), 1 .96-1 .80 (m, 3H), 1 .61 (d, J = 6.6 Hz, 6H), 1 .46-1 .29 (m, 2H), 1 .21 (t, J = 6.9 Hz, 3H); LCMS (ESI) [M+H]+: 370.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.07 (s, 1 H), 7.90-7.78 (m, 3H), 7.28 (s, 1 H), 5.09- 4.91 (m, 2H), 4.65 (br d, J = 13.2 Hz, 1 H), 3.70-3.58 (m, 1 H), 3.47-3.36 (m, 1 H), 3.34-3.23 (m, 1 H), 2.30 (br d, J = 3.5 Hz, 2H), 2.23-2.05 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 407.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.08 (s, 1 H), 7.91 -7.79 (m, 2H), 4.98 (td, J = 6.6, 13.3 Hz, 1 H), 4.74-4.49 (m, 1 H), 4.25-4.03 (m, 1 H), 3.53-3.29 (m, 3H), 3.23-2.97 (m, 2H), 2.77 (s, 3H), 2.48 (br dd, J = 7.6, 17.0 Hz, 1 H), 2.38-2.21 (m, 2H), 2.1 1 -1 .92 (m, 2H), 1 .65 (d, J = 6.6 Hz, 6H), 1 .43 (s, 3H), 1 .1 7 (d, J = 5.0 Hz, 3H); LCMS (ESI) [M+H]+: 465.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.17 (s, 1 H), 7.94-7.89 (m, 1 H), 7.88-7.83 (m, 1 H), 5.90 (quin, J = 7.0 Hz, 1 H), 5.34 (t, J = 6.6 Hz, 2H), 5.1 6 (t, J = 7.3 Hz, 2H), 4.63 (br d, J = 13.4 Hz, 1 H), 4.05 (br d, J = 13.4 Hz, 1 H), 3.37-3.23 (m, 2H), 2.96 (br t, J = 1 1 .2 Hz, 1 H), 2.32 (s, 2H), 2.22 (br d, J = 12.8 Hz, 2H), 2.03-1 .88 (m, 2H), 1 .09 (s, 9H); LCMS (ESI) [M+H]+: 424.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.17 (s, 1 H), 7.94-7.88 (m, 1 H), 7.88-7.82 (m, 1 H), 5.90 (quin, J = 7.0 Hz, 1 H), 5.34 (t, J = 6.5 Hz, 2H), 5.1 6 (t, J = 7.3 Hz, 2H), 4.39-3.91 (m, 3H), 3.23 (tt, J = 3.9, 1 0.9 Hz, 1 H), 3.07 (ddd, J = 2.9, 1 1 .2, 13.8 Hz, 2H), 2.25-2.08 (m, 2H), 2.03-1 .85 (m, 2H), 0.76- 0.66 (m, 4H); LCMS (ESI) [M+H]+: 410.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (br d, J = 2.9 Hz, 2H), 7.86-7.78 (m, 2H), 5.93-5.84 (m, 1 H), 5.33 (m, 2H), 5.19-5.1 1 (m, 2H), 3.85-3.67 (m, 8H), 2.33 (d, J = 2.4 Hz, 2H), 1 .09 (d, J = 2.4 Hz, 9H); LCMS (ESI) [M+H]+: 425.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (d, J = 7.1 Hz, 2H), 7.84-7.78 (m, 2H), 5.88 (quin, J = 7.1 Hz, 1 H), 5.32 (t, J = 6.6 Hz, 2H), 5.14 (t, J = 7.3 Hz, 2H), 3.74-3.56 (m, 8H), 1 .58 (s, 3H), 0.93-0.88 (t, J 6.4 Hz, 2H), 0.70-0.65 (t, J = 6.4 Hz, 2H); LCMS (ESI) [M+H]+: 425.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.46 (s, 1 H), 8.21 -8.14 (m, 2H), 7.85 (d, J = 8.4 Hz, 1 H), 5.94 (m, 1 H), 5.37 (t, J = 6.6 Hz, 2H), 5.18 (t, J = 7.3 Hz, 2H), 4.26 (m, 2H), 3.38 (m, 1 H), 3.00 (m, 2H), 2.25 (m, 2H), 1 .87 (m, 2H), 1 .52 (s, 9H); LCMS (ESI) [M+H]+: 442.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.07 (s, 1 H), 7.89-7.80 (m, 2H), 5.02-4.93 (m, 1 H), 4.10 (br s, 2H), 3.75 (s, 3H), 3.42 (br t, J = 10.6 Hz, 2H), 2.41 -2.23 (m, 4H), 1 .63 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 388.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (s, 1 H), 8.09 (s, 1 H), 7.90-7.83 (m, 2H), 5.03-4.96 (m, 1 H), 4.56 (br d, J = 13.4 Hz, 1 H), 3.89 (br d, J = 13.9 Hz, 1 H), 3.62 (br t, J = 1 1 .4 Hz, 1 H), 3.29 (br t, J = 1 1 .2 Hz, 1 H), 2.48-2.24 (m, 6H), 1 .65 (d, J = 6.6 Hz, 6H), 1 .20 (s, 3H), 0.52-0.40 (m, 4H); LCMS (ESI) [M+H]+: 426.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (s, 1 H), 7.99 (s, 1 H), 7.80-7.73 (m, 2H), 4.95-4.84 (m, 1 H), 4.19-3.78 (m, 3H), 3.39-3.24 (m, 2H), 2.34-2.1 1 (m, 4H), 1 .55 (d, J = 6.7 Hz, 6H), 0.67-0.61 (m, 4H); LCMS (ESI) [M+H]+: 414.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, 1 H), 8.08 (s, 1 H), 7.89-7.82 (m, 2H), 4.98 (spt, J = 6.6 Hz, 1 H), 4.22-3.89 (m, 2H), 3.46-3.32 (m, 2H), 2.40-2.23 (m, 4H), 1 .65 (d, J = 6.6 Hz, 6H), 1 .59 (s, 3H), 1 .05-0.86 (m, 2H), 0.71 -0.65 (m, 2H); LCMS (ESI) [M+H]+: 428.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (d, J = 7.7 Hz, 1 H), 7.66 (s, 1 H), 7.35 (d, J = 7.5 Hz, 1 H), 4.72-4.65 (m, 1 H), 4.59 (br d, J = 13.5 Hz, 1 H), 3.96 (br d, J = 13.7 Hz, 1 H), 3.56 (s, 2H), 3.33-3.23 (m, 2H), 2.97 (br t, J = 1 1 .4 Hz, 1 H), 2.39 (d, J = 4.4 Hz, 2H), 2.21 (br d, J = 13.2 Hz, 2H), 2.01 -1 .87 (m, 2H), 1 .54 (d, J = 7.1 Hz, 6H), 1 .17 (s, 3H), 0.48-0.38 (m, 4H); LCMS (ESI) [M+H]+: 423.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (dd, J = 1 .0, 7.6 Hz, 1 H), 7.66 (s, 1 H), 7.35 (d, J = 7.7 Hz, 1 H), 4.68 (spt, J = 7.0 Hz, 1 H), 4.30-4.00 (m, 2H), 3.73 (s, 3H), 3.55 (s, 2H), 3.22 (tt, J = 4.0, 10.8 Hz, 1 H), 3.08 (br t, J = 1 1 .7 Hz, 2H), 2.16 (br d, J = 10.8 Hz, 2H), 2.03-1 .84 (m, 2H), 1 .54 (d, J = 7.1 Hz, 6H); LCMS (ESI) [M+H]+: 385.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.27 (s, 1 H), 8.10 (s, 1 H), 7.87 (m, 2H), 5.06-4.92 (m, 1 H), 4.37- 3.97 (m, 2H), 3.14-2.90 (m, 3H), 2.09 (br d, J = 10.8 Hz, 2H), 1 .88 (br d, J = 9.9 Hz, 2H), 1 .65 (d, J = 6.6 Hz, 6H), 1 .58 (s, 3H), 0.97-0.83 (m, 2H), 0.70-0.59 (m, 2H); LCMS (ESI) [M+H]+: 410.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (s, J = 0.6 Hz, 1 H), 8.10 (s, 1 H), 7.92-7.82 (m, 2H), 4.98 (spt, J = 6.7 Hz, 1 H), 4.22 (br s, 2H), 3.74 (s, 3H), 3.1 6-2.97 (m, 3H), 2.1 1 (m, J = 1 1 .7 Hz, 2H), 1 .99-1 .82 (m, 2H), 1 .65 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 370.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.09 (s, 1 H), 7.84 (m, 2H), 4.97 (spt, J

1 H), 3.76 (s, 3H), 3.69-3.44 (m, 8H), 1 .64 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 371 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (s, 1 H), 8.03-7.82 (m, 3H), 7.78-7.73 (m, 1 H), 7.53-7.43 (m, 2H), 4.65 (m 0.4H), 4.48 (m, 0.5H), 4.41 -4.24 (m, 2H), 4.1 0 (br d, J = 2.4 Hz, 3H), 4.00 (t, J = 9.0 Hz, 1 H), 3.95-3.75 (m, 2H), 3.73-3.45 (m, 2H), 3.07-2.89 (m, 2H), 2.62 (s, 3H), 2.49-2.32 (m, 2H); LCMS (ESI) [M+H]+: 546.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.85 (s, 1 H), 7.54 (d, J = 8.7 Hz, 1 H), 6.40 (dd, J = 1 .6, 8.7 Hz, 1 H), 6.23 (s, 1 H), 4.83-4.60 (m, 1 H), 3.73 (s, 4H), 3.69-3.44 (m, 4H), 2.30 (s, 2H), 1 .85 (br dd, J = 5.4, 8.8 Hz, 4H), 1 .57 (d, J = 6.6 Hz, 6H), 1 .08 (s, 9H); LCMS (ESI) [M+H]+: 383.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.38 (s, 1 H), 8.14-8.04 (m, 2H), 7.76 (d, J = 8.4 Hz, 1 H), 6.83 (br s, 1 H), 5.85 (t, J = 6.9 Hz, 1 H), 5.28 (t, J = 6.5 Hz, 2H), 5.09 (t, J = 7.3 Hz, 2H), 4.15 (d, J = 2.4 Hz, 2H), 3.64 (t, J = 5.4 Hz, 2H), 2.70 (m, 2H), 1 .44 (s, 9H) LCMS (ESI) [M+H]+: 440.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.08 (s, 1 H), 7.89-7.81 (m, 2H), 5.04-4.93 (m, 1 H), 3.84-3.73 (m, 1 H), 3.03 (tt, J = 3.7, 1 1 .9 Hz, 1 H), 2.33-2.26 (m, 2H), 2.24-2.15 (m, 2H), 1 .88-1 .77 (m, 2H), 1 .64 (d, J = 6.7 Hz, 6H), 1 .55-1 .44 (m, 2H); LCMS (ESI) [M+H]+: 327.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.17 (s, 1 H), 7.94-7.88 (m, 1 H), 7.87-7.81 (m, 1 H), 5.90 (quin, J = 7.0 Hz, 1 H), 5.34 (t, J = 6.5 Hz, 2H), 5.1 6 (t, J = 7.3 Hz, 2H), 4.31 -4.08 (m, 2H), 3.74 (s, 3H), 3.23 (tt, J = 3.9, 10.9 Hz, 1 H), 3.09 (br t, J = 1 1 .5 Hz, 2H), 2.18 (br dd, J = 2.8, 13.3 Hz, 2H), 2.02- 1 .89 (m, 2H); LCMS (ESI) [M+H]+: 384.1 .

¹ HNMR (400 MHz, CHLOROFORM-d) δ 8.14 (d, J = 4.5 Hz, 2H), 7.81 -7.81 (m, 2H), 5.87 (quin, J = 7.0 Hz, 1 H), 5.32 (t, J = 6.5 Hz, 2H), 5.14 (t, J = 7.3 Hz, 2H), 3.76 (s, 3H), 3.72 (m, 4H), 3.65 (m, 4H); LCMS (ESI) [M+H]+: 385.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (s, 1 H), 8.03 (s, 1 H), 7.81 -7.73 (m, 2H), 4.95 (m, 1 H), 4.33 (m, 2H), 3.57 (d, J = 6.2 Hz, 2H), 3.16 (dt, J = 2.8, 13.0 Hz, 2H), 1 .90 (br d, J = 12.6 Hz, 2H), 1 .84-1 .73 (m, 1 H), 1 .61 (d, J = 6.6 Hz, 6H), 1 .45-1 .33 (m, 2H); LCMS (ESI) [M+H]+: 342.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.08 (s, 1 H), 7.84-7.79 (m, 1 H), 7.75-7.71 (m, 1 H), 4.50 (br dd, J = 10.0, 13.3 Hz, 1 H), 4.37 (t, J = 8.5 Hz, 1 H), 4.19 (t, J = 9.3 Hz, 1 H), 4.07 (s, 3H), 3.92 (br d, J = 13.5 Hz, 1 H), 3.79 (dd, J = 5.6, 8.5 Hz, 1 H), 3.67 (br dd, J = 5.7, 9.5 Hz, 1 H), 3.31 (br t, J = 1 0.9 Hz, 2H), 3.06- 2.96 (m, 2H), 2.80-2.62 (m, 2H), 2.59 (s, 3H), 2.29-2.1 8 (m, 2H), 2.05-1 .91 (m, 2H), 1 .85 (s, 3H); LCMS (ESI) [M+H]+: 437.5.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.45 (s, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.65 (d, J = 8.8 Hz, 1 H), 4.16 (br s, 2H), 3.48 (td, J = 7.0, 14.0 Hz, 1 H), 3.28-3.13 (m, 1 H), 3.02 (br t, J = 1 1 .6 Hz, 2H), 2.1 5 (br d, J = 1 0.4 Hz, 2H), 2.03-1 .86 (m, 2H), 1 .54 (d, J = 7.0 Hz, 6H), 1 .49 (s, 9H).; LCMS (ESI) [M+H]+: 413.1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.29 (s, 1 H), 8.20 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.74 (dd, J = 1 .2, 8.5 Hz, 1 H), 4.46-4.29 (m, 1 H), 3.98 (br d, J = 13.2 Hz, 2H), 3.48-3.35 (m, 1 H), 2.99 (br s, 2H), 2.10 (br dd, J = 3.1 , 13.2 Hz, 2H), 1 .80-1 .64 (m, 2H), 1 .59 (d, J = 6.6 Hz, 3H), 1 .47-1 .36 (m, 10H), 0.64-0.55 (m, 1 H), 0.44 (qd, J = 4.8, 9.5 Hz, 1 H), 0.38-0.30 (m, 1 H), 0.25 (qd, J = 4.9, 9.6 Hz, 1 H); LCMS (ESI) [M+H]+: 438.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (s, 1 H), 8.07 (s, 1 H), 7.88-7.84 (d, J = 12 Hz, 1 H), 7.83- 7.79 (d, J = 12 Hz, 1 H), 5.15-5.01 (m, 1 H), 4.1 6 -4.13 (m, 2H), 3.64-3.62 (m, 1 H), 3.45-3.34 (m, 1 H), 3.21 -3. 18 (m, 1 H), 2.98-3.02 (m, 2H), 2.39- 2.36 (m, 1 H), 2.24-2.09 (m, 3H), 1 .99-1 .86 (m, 3H), 1 .63 (d, J = 6.6 Hz, 3H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 442.2.

Ή NMR (400 MHz, CHLOROFORM-d) δ 8.14 (d, J = 6.1 Hz, 2H), 7.84-7.78 (m, 2H), 5.88 (quin, J = 7.1 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.14 (t, J = 7.3 Hz, 2H), 4.16-4.10 (m, 1 H), 3.79-3.56 (m, 8H), 0.78-0.67 (m, 4H); LCMS (ESI) [M+H]+: 41 1 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.21 (s, 1 H), 7.98-7.83 (m, 2H), 5.91 (m, J = 7.0 Hz, 1 H), 5.40-5.30 (m, 2H), 5.24-5.1 1 (m, 2H), 4.29-4.06 (m, 2H), 3.06 (tt, J = 3.7, 1 1 .2 Hz, 1 H), 2.97 (br t, J = 1 1 .9 Hz, 2H), 2.16-2.01 (m, 2H), 1 .97-1 .79 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-55]+: 370.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (d, J = 8.4 Hz, 2H), 8.00-7.94 (m, 1 H), 7.92-7.83 (m, 1 H), 5.90-5.75 (m, 1 H), 5.16 (s, 2H), 4.25-4.1 0 (m, 2H), 3.29-2.96 (m, 3H), 2.80 (d, J = 4.8 Hz, 3H), 2.18 (br d, J = 1 1 .1 Hz, 2H), 2.05-1 .85 (m, 2H), 1 .51 (s, 9H); LCMS (ESI) [M-1 00+H]+: 341 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.32 (s, 1H), 8.08 (s, 1 H), 7.91 -7.88 (m, 1 H), 7.85-7.81 (m, 1H), 5.61 (brs, 1H), 4.92 (dd, J = 4.3, 14.4 Hz, 1H), 4.63 (dd, J = 8.5, 14.4 Hz, 1H), 4.17 (m, 2H), 3.39-3.16 (m, 3H), 3.14-2.95 (m, 3H), 2.31-2.07 (m, 4H), 2.02-1.89 (m, 2H); LCMS (ESI) [M+H]+: 367.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.45 (s, 1 H), 8.28 (dd, J = 1.6, 8.8 Hz, 1 H), 7.65 (d, J = 8.9 Hz, 1H), 4.19 (brs, 2H), 3.74 (s, 3H), 3.48 (td, J = 6.9, 14.0 Hz, 1H), 3.29-3.18 (m, 1H), 3.09 (br t, J = 12.5 Hz, 2H), 2.17 (br d, J = 13.6 Hz, 2H), 2.02-1.88 (m, 2H), 1.55 (s, 3H), 1.54 (s, 3H); LCMS (ESI) [M+H]+: 371.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.06 (s, 1 H), 7.89-7.80 (m, 2H), 5.04-4.93 (m, 2H) 4.65 (br s, 1 H), 3.18-3.09 (m, 1 H), 2.82 (d, J = 4.9 Hz, 3H), 2.23-1.97 (m, 6H), 1.77 (br d, J = 11.1 Hz, 2H), 1.63 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 384.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.11 (s, 1H), 8.01-7.83 (m, 3H), 7.79-7.73 (m, 1H), 7.52-7.43 (m, 2H), 4.64 (dt, J = 6.5, 14.2 Hz, 1H), 4.47 (br d, J = 13.3 Hz, 1H), 4.41-4.25 (m, 2H), 4.10 (br d, J = 2 Hz, 3H), 3.99 (t, J = 9.0 Hz, 1H), 3.94-3.75 (m, 2H), 3.71-3.43 (m, 2H), 3.05-2.87 (m, 2H), 2.61 (s, 3H), 2.48-2.30 (m, 2H); LCMS (ESI) [M+H]+: 546.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 7.98 (d, J = 8.4 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 5.55-5.48 (m, 1 H), 5.24-5.21 (m, 2H), 5.15-5.11 (m, 2H), 4.22-4.05 (m, 2H), 3.19 (tt, J = 3.8, 11.0 Hz, 1 H), 3.00 (br t, J = 11.8 Hz, 2H), 2.14 (br d, J = 10.6 Hz, 2H), 1.98-1.85 (m, 2H), 1.49 (s, 9H); LCMS (ESI) [M- 55]+: 387.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, 1 H), 8.08 (s, 1 H), 7.93-7.87 (m, 1 H), 7.86-7.79 (m, 1 H), 5.43-5.33 (m, 1 H), 4.34-4.12 (m, 5H), 4.05 (q, J = 7.3 Hz, 1 H), 3.21 (br t, J = 10.9 Hz, 1 H), 3.02 (br t, J = 1 1 .7 Hz, 2H), 2.55 (q, J = 6.7 Hz, 2H), 2.1 6 (br d, J = 13.0 Hz, 2H), 2.01 -1 .86 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 440.5.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (s, 1 H), 8.07 (s, 1 H), 7.88-7.84 (d, J = 8.4 Hz, 1 H), 7.82- 7.77 (d, J = 8.4 Hz, 1 H), 5.35-5.23 (m, 1 H), 4.18 -4.16 (m, 2H), 4.05-3.96 (m, 2H), 3.25-3.14 (m, 2H), 3.03 (br t, J = 1 1 .9 Hz, 2H), 2.93 (dd, J = 6.1 , 16.0 Hz, 1 H), 2.16 (br d, J = 10.8 Hz, 2H), 2.01 -1 .89 (m, 2H), 1 .64 (d, J = 6.6 Hz, 3H), 1 .50 (s, 9H), 1 .10 (t, J = 7.2 Hz, 3H); LCMS (ESI) [M+H]+: 484.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.17 (s, 1 H), 8.14 (s, 1 H), 7.93-7.87 (m, 1 H), 7.86-7.80 (m, 1 H), 5.54-5.42 (m, 1 H), 4.60-4.52 (m, 2H), 4.51 -4.43 (m, 2H), 4.22-4.07 (m, 2H), 3.20 (tt, J = 3.9, 10.9 Hz, 1 H), 3.01 (br t, J = 12.0 Hz, 2H), 2.15 (br dd, J = 2.6, 13.2 Hz, 2H), 2.00-1 .83 (m, 2H), 1 .49 (d, J = 2.6 Hz, 18H); LCMS (ESI) [M-100+H]+: 425.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (s, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.93-7.85 (m, 1 H), 7.07 (dd, J = 1 1 .5, 1 8.0 Hz, 1 H), 6.09 (d, J = 18.1 Hz, 1 H), 5.63-5.46 (m, 1 H), 5.05-4.85 (m, 1 H), 4.16 (br s, 2H), 3.21 (ddd, J = 4.2, 6.9, 10.8 Hz, 1 H), 3.02 (br t, J = 1 1 .6 Hz, 2H), 2.16 (br d, J = 1 1 .1 Hz, 2H), 2.00- 1 .88 (m, 2H), 1 .63 (d, J = 6.7 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 438.5.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.06 (s, 1 H), 7.90-7.80 (m, 2H), 4.98 (spt, J = 6.6 Hz, 1 H), 4.05 (br d, J = 2.9 Hz, 1 H), 3.19-3.03 (m, 1 H), 2.32-2.21 (m, 2H), 1 .98 (qd, J = 4.5, 13.7 Hz, 2H), 1 .91 -1 .77 (m, 4H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .43 (d, J = 3.4 Hz, 1 H); LCMS (ESI) [M+H]+: 327.1

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.51 (s, 1 H), 8.07 (s, 1 H), 7.80-7.76 (m, 1 H), 7.75-7.72 (m, 1 H), 5.36-5.26 (m, 1 H), 4.32-4.08 (m, 5H), 4.06-3.99 (m, 1 H), 3.24-3.14 (m, 1 H), 3.03 (br t, J = 1 1 .8 Hz, 2H), 2.69-2.58 (m, 1 H), 2.54-2.44 (m, 1 H), 2.15 (br d, J = 1 1 .4 Hz, 2H), 1 .99-1 .87 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 440.5.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.53 (d, J = 0.7 Hz, 1 H), 8.10 (s, 1 H), 7.82-7.77 (m, 1 H), 7.76- 7.71 (m, 1 H), 5.35 (m, 1 H), 4.55-4.45 (m, 4H), 4.21 -4.04 (m, 2H), 3.25-3.12 (m, 1 H), 3.02 (br t, J = 1 1 .7 Hz, 2H), 2.14 (br dd, J = 2.9, 13.2 Hz, 2H), 2.00-1 .83 (m, 2H), 1 .48 (d, J = 1 .5 Hz, 18H); LCMS (ESI) [M+23]+: 547.2, LCMS (ESI) [M-100+H]+: 425.2, LCMS (ESI) [M-100-55+H]+: 369.1 .

Ή NMR (400 MHz, CHLOROFORM-d) δ 8.15 (s, 1 H), 8.07 (s, 1 H), 7.79 (m, 2H), 5.04-4.88 (m, 1 H), 3.85 (m, 8H), 2.28 (s, 3H), 1 .64 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 395.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.98-7.90 (m, 2H), 7.46-7.36 (m, 2H), 4.22-4.05 (m, 4H), 3.94 (q, J = 7.9 Hz, 1 H), 3.80-3.73 (m, 1 H), 3.48 (quin, J = 7.8 Hz, 1 H), 3.17 (m, 1 H), 2.99 (br t, J = 1 1 .4 Hz, 2H), 2.41 (m, 1 H), 2.18-1 .99 (m, 3H), 1 .97-1 .83 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M-100+H]+: 300.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (d, J = 3.4 Hz, 2H), 7.85-7.78 (m, 2H), 5.88 (quin, J = 7.1 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.14 (t, J = 7.3 Hz, 2H), 3.83-3.62 (m, 8H), 2.35 (d, J = 6.7 Hz, 2H), 1 .12-1 .02 (m, 1 H), 0.65-0.58 (m, 2H), 0.25-0.18 (m, 2H); LCMS (ESI) [M+H]+: 409.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.43 (s, 1 H), 8.13 (s, 1 H), 7.96 (d, J = 8.3 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 1 H), 7.68-7.34 (t,J = 59.6 Hz, 1 H), 3.70 (m, 4H), 3.62-3.57 (m, 4H),1 .50 (s, 9H); LCMS (ESI) [M- 55]+: 365.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.04 (d, J = 0.7 Hz, 1 H), 7.91 -7.86 (m, 1 H), 7.84- 7.80 (m, 1 H), 4.85 (dd, J = 6.5, 7.5 Hz, 2H), 4.76 (d, J = 7.5 Hz, 2H), 4.62 (t, J = 6.1 Hz, 2H), 4.26-4.05 (m, 2H), 3.72-3.60 (m, 1 H), 3.21 (tt, J = 3.9, 1 1 .0 Hz, 1 H), 3.02 (br t, J = 1 1 .6 Hz, 1 H), 3.08-2.96 (m, 1 H), 2.16 (br dd, J = 2.4, 13.6 Hz, 2H), 2.01 -1 .87 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 440.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.76 (d, J = 7.7 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 1 H), 7.05 (s, 1 H), 5.22-5.09 (m, 1 H), 5.02 (t, J = 7.1 Hz, 2H), 4.70 (t, J = 7.3 Hz, 2H), 4.21 -4.08 (m, 2H), 3.1 7 (tt, J = 3.8, 10.9 Hz, 1 H), 3.06-2.94 (m, 4H), 2.62 (t, J = 7.2 Hz, 2H), 2.12 (br d, J = 1 1 .0 Hz, 2H), 1 .97-1 .83 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 455.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.34 (s, 1 H), 8.24 (s, 1 H), 8.00-7.89 (m, 2H), 5.93 (quin, J = 6.9 Hz, 1 H), 5.35 (t, J = 6.5 Hz, 2H), 5.20 (t, J = 7.2 Hz, 2H), 4.53-4.04 (m, 2H), 3.69-3.38 (m, 2H), 3.35-3.22 (m, 1 H), 2.41 -2.14 (m, 2H), 1 .53 (s, 9H); LCMS (ESI) [M+H]+: 462.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (d, J = 4.4 Hz, 2H), 7.85-7.78 (m, 2H), 5.88(quin, J = 7.1 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.14 (t, J = 7.3 Hz, 2H), 3.75-3.67 (m, 4H), 3.63-3.57(m, 4H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 427.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, 1 H), 8.02 (d, J = 7.7 Hz, 1 H), 7.64 (br d, J = 8.1 Hz,

1 H), 7.40-7.33 (m, 1 H), 4.14 (br s, 2H), 3.18 (tt, J = 3.8, 10.9 Hz, 1 H), 3.01 (br t, J = 1 1 .6 Hz, 2H), 2.13 (br d, J = 10.9 Hz, 2H), 1 .98-1 .82 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-55]+: 352.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.07 (s, 1 H), 7.84 (q, J = 8.4 Hz, 1 H), 7.90-7.80 (m, 1 H), 4.98 (td, J = 6.7, 13.4 Hz, 1 H), 4.86 (t, J = 6.8 Hz, 1 H), 3.93 (br t, J = 12.8 Hz, 2H), 3.59-3.41 (m, 2H), 3.34-3.22 (m, 1 H), 3.20-3.03 (m, 2H), 2.38-2.28 (m, 1 H), 2.36-1 .92 (m, 7H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 434.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.07 (s, 1 H), 7.90-7.79 (m, 2H), 4.98 (td, J = 6.7, 13.3 Hz, 1 H), 3.68 (br d, J = 13.4 Hz, 2H), 3.50 (t, J = 6.6 Hz, 2H), 3.19 (tt, J = 4.0, 11.1 Hz, 1 H), 2.99- 2.82 (m, 2H), 2.26-2.13 (m, 2H), 2.06-1.94 (m, 2H), 1.91-1.82 (m, 2H), 1.80-1.74 (m, 2H), 1.64 (d, J = 6.7 Hz, 6H), 1.46 (s, 6H); LCMS (ESI) [M+H]+: 437.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1H), 8.05 (s, 1H), 7.78 (s, 2H), 4.96 (td, J = 6.6, 13.3 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2H), 3.79-3.61 (m, 8H), 1.63 (d, J = 6.7 Hz, 6H), 1.31 (t, J = 7.1 Hz, 3H); LCMS (ESI) [M+H]+: 385.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1H), 8.05 (s, 1H), 7.78 (s, 2H), 4.95 (td, J = 6.6, 13.3 Hz, 1H), 3.92-3.68 (m, 8H), 3.18 (s, 2H), 2.31 (s, 6H), 1.63 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 398.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.45 (s, 1 H), 8.28 (dd, J = 1.4, 8.7 Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1H), 4.60 (brd, J = 13.3 Hz, 1H), 3.97 (br d, J = 13.6 Hz, 1H), 3.48 (td, J = 6.9, 14.0 Hz, 1H), 3.37-3.22 (m, 2H), 2.97 (br t, J = 11.1 Hz, 1H), 2.40 (d, J = 4.0 Hz, 2H), 2.22 (brd, J = 12.6 Hz, 2H), 2.04-1.86 (m, 2H), 1.55 (s, 6H), 1.18 (s, 3H), 0.49-0.40 (m, 4H); LCMS (ESI) [M+H]+: 409.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.20 (s, 1 H), 8.24 (s, 1 H), 8.09 (m, J = 8.2 Hz, 1 H), 7.85 (br d, J = 8.2 Hz, 1H), 4.58 (brd, J = 14.1 Hz, 1H), 4.03 (brd, J = 13.7 Hz, 1H), 3.28 (brd, J = 11.7 Hz, 3H), 2.98 (brt, J = 11.8 Hz, 1H), 2.32 (s, 2H), 2.21 (brd, J = 12.6 Hz, 2H), 2.05-1.80 (m, 2H), 1.37 (m, 2H), 1.18 (m, J = 4.0 Hz, 2H), 1.09 (s, 9H); LCMS (ESI) [M+H]+: 436.20.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.71 (d, J = 7.7 Hz, 1 H), 7.43-7.35 (m, 2H), 6.89 (dd, J = 2.5, 8.3 Hz, 1 H), 5.32-5.26 (m, 1 H), 5.02 (t, J = 6.8 Hz, 2H), 4.79 (dd, J = 5.3, 7.2 Hz, 2H), 4.13 (br d, J = 9.9 Hz, 2H), 3.17 (tt, J = 3.9, 1 0.9 Hz, 1 H), 3.00 (br t, J = 1 1 .8 Hz, 2H), 2.12 (br dd, J = 2.8, 13.3 Hz, 2H), 1 .94-1 .83 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-55]+: 346.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (s, 1 H), 8.04 (s, 1 H), 7.79 (s, 2H), 5.01 -4.90 (m, 1 H), 4.24 (br s, 2H),3.12-3.04 (m, 1 H), 2.99-2.88 (m, 2H), 2.15-2.06 (m, 2H), 1 .89-1 .80 (m, 2H), 1 .61 (d, J = 6.6 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 41 1 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.79 (s, 1 H), 8.54 (s, 1 H), 7.79 (m, 2H), 4.60 (m, J = 13.0 Hz, 1 H), 4.04 (m, J = 13.5 Hz, 1 H), 3.47 (s, 1 H), 3.39-3.22 (m, 2H), 3.00 (t, J = 1 1 .7 Hz, 1 H), 2.33 (m, 2H), 2.22 (m, J = 13.5 Hz, 2H), 2.07-1 .82 (m, 2H), 1 .44 (m, 2H), 1 .32 (m, 2H), 1 .09 (s, 9H); LCMS (ESI)

[M+H]+: 436.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.21 (s, 1 H), 8.01 -7.82 (m, 2H), 5.91 (quin, J = 7.0 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.19 (t, J = 7.2 Hz, 2H), 4.27 (m, 1 H), 4.1 6-3.98 (m, 2H), 3.18-2.93 (m, 3H), 2.08 (m, 2H), 1 .90 (m, 2H), 0.78-0.65 (m, 4H); LCMS (ESI) [M+H]+: 410.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.21 (s, 1 H), 7.98-7.86 (m, 2H), 5.97-5.81 (m, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.18 (t, J = 7.2 Hz, 2H), 4.21 (m, 2H), 3.74 (s, 3H), 3.20-2.92 (m, 3H), 2.1 1 (m, J = 1 1 .8 Hz, 2H), 1 .96-1 .79 (m, 2H); LCMS (ESI) [M+H]+: 384.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 7.97 (s, 1 H), 7.73-7.66 (m, 2H), 4.94-4.78 (m, 1 H), 4.19 (br s, 2H), 3.66 (s, 3H), 3.09-2.86 (m, 3H), 2.06 (br d, J = 10.9 Hz, 2H), 1 .87-1 .71 (m, 2H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 369.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) 5 8.54 (s, 1 H), 8.08 (s, 1 H), 7.91 -7.71 (m, 2H), 6.65 (br s, 1 H), 5.15 (s, 2H), 4.25-4.07 (m, 2H), 3.22 (br t, J = 10.8 Hz, 1 H), 3.12-2.97 (m, 2H), 2.83 (d, J = 4.9 Hz, 3H), 2.17 (br d, J = 1 1 .1 Hz, 2H), 2.04-1 .87 (m, 2H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 441 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 7.94 (s, 1 H), 7.73-7.62 (m, 2H), 7.37-7.25 (m, 5H), 4.84-4.64 (m, 2H), 3.87-3.67 (m, 1 H), 3.16-2.88 (m, 3H), 2.12-1 .74 (m, 4H), 1 .47 (br d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 415.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (br s, 1 H), 8.02 (s, 1 H), 7.77-7.72 (m, 1 H), 7.68-7.63 (m, 1 H), 4.38 (br d, J = 13.4 Hz, 1 H), 4.20-4.07 (m, 2H), 4.01 (s, 3H), 3.85 (br d, J = 14.4 Hz, 1 H), 3.66 (br s, 2H), 3.30-3.1 0 (m, 3H), 2.93 (br t, J = 10.5 Hz, 1 H), 2.84-2.73 (m, 2H), 2.52 (s, 3H), 2.21 -2.08 (m, 2H), 1 .96-1 .81 (m, 2H); LCMS (ESI) [M+H]+: 395.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.35 (s, 1 H), 8.21 (s, 1 H), 7.98-7.90 (m, 1 H), 7.89-7.81 (m, 1 H), 5.99-5.86 (m, 1 H), 5.35 (t, J = 6.6 Hz, 2H), 5.24-5.12 (m, 2H); LCMS (ESI) [M+H]+: 219.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.08 (s, 1 H), 7.82 (m, 2H), 5.08-4.88 (m, 1 H), 3.55 (m, 8H), 1 .63 (d, J = 6.6 Hz, 6H), 1 .57 (s, 3H), 0.96-0.85 (m, 2H), 0.68-0.60 (m, 2H); LCMS (ESI) [M+H]+: 41 1 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (d, J = 0.9 Hz, 1 H), 8.18 (s, 1 H), 7.94-7.90 (m, 1 H), 7.87- 7.84 (m, 1 H), 5.92 (quin, J = 7.1 Hz, 1 H), 5.35 (t, J = 6.7 Hz, 2H), 5.17 (t, J = 7.4 Hz, 2H), 4.61 (br s, 1 H), 3.76 (br s, 1 H), 3.26-3.16 (m, 1 H), 2.21 -2.10 (m, 2H), 2.06-1 .96 (m, 2H), 1 .92-1 .81 (m, 2H), 1 .77-1 .66 (m, 2H), 1 .46 (s, 9H); LCMS (ESI) [M+H]+: 440.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.06 (s, 1 H), 7.88-7.80 (m, 2H), 4.97 (quin, J = Hz, 1 H), 3.99-3.90 (m, 4H), 3.22 (tt, J = 3.9, 10.9 Hz, 1 H), 3.01 -2.92 (m, 2H), 2.16 (br dd, J = 3.2, 13.' Hz, 2H), 2.05-1 .95 (m, 4H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .53 (s, 6H); LCMS (ESI) [M+H]+: 423.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.49 (s, 1 H), 8.37 (s, 1 H), 8.03 (d, J = 8.6 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.50-7.39 (m, 5H), 6.28-6.15 (m, 1 H), 5.08 (d, J = 6.8 Hz, 4H), 4.07 (br s, 2H), 3.32-3.15 (m, 3H), 2.1 1 (br d, J = 1 1 .5 Hz, 2H), 1 .89-1 .74 (m, 2H); LCMS (ESI) [M+H]+: 430.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.07 (s, 1 H), 7.84 (q, J = 8.4 Hz, 2H), 4.97 (td, J = 6.5, 13.4 Hz, 1H), 4.54 (br d, J = 12.7 Hz, 1H), 4.22 (brd, J = 13.8 Hz, 1H), 3.31 (br t, J = 10.5 Hz, 2H), 3.25-3.10 (m, 2H), 3.01 (br t, J = 11.0 Hz, 1H), 2.33 (s, 6H), 2.23 (brd, J = 13.6 Hz, 2H), 2.07-1.89 (m, 2H), 1.64 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 397.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.06 (s, 1 H), 7.89-7.78 (m, 2H), 5.66 (dd, J = 1.7,

9.5 Hz, 1H), 4.97 (td, J = 6.6, 13.3 Hz, 1H), 3.80-3.67 (m, 3H), 3.63-3.45 (m, 3H), 3.23 (tt, J = 4.1, 10.9 Hz, 1 H), 3.07-2.90 (m, 2H), 2.22 (br t, J = 10.7 Hz, 2H), 2.13-1.91 (m, 2H), 1.90-1.73 (m, 4H), 1.63 (d, J

6.6 Hz, 6H), 1.43 (s, 3H); LCMS (ESI) [M+H]+: 453.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.28 (s, 1 H), 8.15 (s, 1 H), 7.91 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1H), 5.11 (td, J = 6.7, 13.1 Hz, 1H), 4.26 (brd, J = 13.9 Hz, 2H), 3.62-3.47 (m, 1H), 3.39-3.26 (m, 2H), 2.29-2.20 (m, 2H), 1.89 (q, J = 10.4 Hz, 2H), 1.62-1.56 (m, 2H), 1.53 (m, 8H); LCMS (ESI) [M+H]+: 405.1

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1 H), 8.05 (s, 1 H), 7.78 (d, J = 0.7 Hz, 2H), 4.95 (td, J 6.7, 13.3 Hz, 1H), 4.21-4.05 (m, 1H), 3.80-3.52 (m, 8H), 1.62 (d, J = 6.6 Hz, 6H), 0.79-0.67 (m, 4H); LCMS (ESI) [M+H]+: 397.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.11 (d, J = 4.5 Hz, 2H), 7.91-7.85 (m, 1H), 7.81-7.77 (m, 1H), 5.53-5.42 (m, 1H), 4.93-4.83 (m, 2H), 4.66-4.56 (m, 2H), 4.08 (br s, 2H), 3.14 (tt, J = 3.8, 10.9 Hz, 1H), 2.95 (br t, J = 11.6 Hz, 2H), 2.14-2.03 (m, 2H), 1.93-1.80 (m, 2H), 1.42 (s, 9H); LCMS (ESI) [M+H]+: 418.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.05 (s, 1 H), 7.87-7.76 (m, 2H), 4.96 (td, J = 6.6, 13.2 Hz, 1 H), 4.76 (br d, J = 13.3 Hz, 1 H), 4.03 (br d, J = 13.6 Hz, 1 H), 3.30-3.13 (m, 2H), 2.85 (br t, J = 1 1 .7 Hz, 1 H), 2.51 -2.35 (m, 2H), 2.28-2.10 (m, 2H), 2.02-1 .84 (m, 2H), 1 .61 (d, J = 6.6 Hz, 6H), 1 .19 (s, 2H), 1 .20-1 .1 7 (m, 1 H), 0.50-0.38 (m, 4H); LCMS (ESI) [M+H]+: 407.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.55 (dd, J = 1 .0, 4.7 Hz, 1 H), 8.29 (s, 1 H), 8.09 (s, 1 H), 7.86 (s, 2H), 7.78 (dd, J = 1 .0, 8.2 Hz, 1 H), 7.32 (dd, J = 4.6, 8.2 Hz, 1 H), 4.99 (td, J = 6.7, 13.3 Hz, 1 H), 4.78- 4.71 (m, 1 H), 3.55-3.46 (m, 1 H), 3.30-3.14 (m, 3H), 2.28 (br dd, J = 3.5, 13.6 Hz, 1 H), 2.14-2.02 (m, 3H), 1 .65 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 451 .1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.53 (s, 1 H), 8.41 (s, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.84 (dd, J = 1 .2, 8.5 Hz, 1 H), 7.55-7.47 (m, 1 H), 7.44 (br t, J = 6.7 Hz, 1 H), 7.35-7.27 (m, 2H), 6.29 (quin, J = 6.9 Hz, 1 H), 5.04 (d, J = 7.1 Hz, 4H), 4.53 (br d, J = 13.2 Hz, 1 H), 3.49 (br d, J = 13.7 Hz, 1 H), 3.31 -3.23 (m, 2H), 3.15-3.06 (m, 1 H), 2.16 (br d, J = 1 1 .5 Hz, 1 H), 2.02 (br d, J = 12.1 Hz, 1 H), 1 .82-1 .65 (m, 2H); LCMS (ESI) [M+H]+: 448.1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.53 (s, 1 H), 8.42 (s, 1 H), 8.03 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.55 (br d, J = 6.8 Hz, 1 H), 7.49-7.36 (m, 3H), 6.34-6.23 (m, 1 H), 5.04 (d, J = 6.8 Hz, 4H), 4.54 (br d, J = 12.1 Hz, 1 H), 3.37 (br d, J = 2.4 Hz, 1 H), 3.32-3.16 (m, 2H), 3.16-3.05 (m, 1 H), 2.20-2.09 (m, 1 H), 2.07-1 .95 (m, 1 H), 1 .85-1 .72 (m, 2H), 1 .72-1 .61 (m, 1 H); LCMS (ESI) [M+H]+: 464.1 .

¹ H NMR (400 MHz, DMSO-de) δ 8.48 (s, 1 H), 8.37 (s, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 5.3 Hz, 1 H), 7.10 (d, J = 5.3 Hz, 1 H), 6.21 (m, 1 H), 5.08 (d, J = 6.8 Hz, 4H), 4.15-3.95 (m, 2H), 3.35-3.23 (m, 3H), 2.14 (br dd, J = 3.2, 13.3 Hz, 2H), 1 .89-1 .75 (m, 2H); LCMS (ESI) [M+H]+: 470.0. H

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.17 (s, 1 H), 7.90-7.81 (m, 1 H), 7.79-7.67 (m, 1 H), 4.91 (td, J = 6.6, 13.3 Hz, 1 H), 4.16 (br s, 2H), 4.09 (q, J = 5.9 Hz, 2H), 3.28-3.18 (m, 3H), 3.1 1 (t, J = 6.3 Hz, 1 H), 3.02 (br t, J = 1 1 .7 Hz, 2H), 2.16 (br d, J = 1 1 .5 Hz, 2H), 2.02-1 .87 (m, 2H), 1 .60 (d, J = 6.6 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 456.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (s, 1 H), 8.17 (s, 1 H), 7.94-7.89 (m, 1 H), 7.88-7.82 (m, 1 H), 5.96-5.85 (m, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.1 7 (t, J = 7.3 Hz, 2H), 4.47-4.32 (m, 4H), 4.14-4.04 (m, 1 H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 398.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.46 (d, J = 0.9 Hz, 1 H), 8.18-8.1 1 (m, 1 H), 7.72 (m, 2H), 5.79- 5.71 (m, 1 H), 5.25-5.16 (m, 4H), 3.72-3.67 (m, 4H), 3.62-3.56 (m, 4H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 427.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (s, 1 H), 7.81 (s, 2H), 4.90 (quin, J = 6.7 Hz, 1 H), 4.15 (br s, 2H), 3.88-3.75 (m, 2H), 3.40 (s, 3H), 3.29 (t, J = 7.1 Hz, 2H), 3.24-3.14 (m, 1 H), 3.02 (br t, J = 1 1 .1 Hz, 2H), 2.1 5 (br d, J = 13.3 Hz, 2H), 2.01 -1 .88 (m, 2H), 1 .63-1 .57 (m, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 470.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.27 (s, 1 H), 8.1 5 (s, 1 H), 7.91 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 5.1 1 (td, J = 6.6, 13.2 Hz, 1 H), 4.56-4.37 (m, 2H), 3.97-3.85 (m, 1 H), 3.75 (q, J = 7.4 Hz, 1 H), 3.53- 3.41 (m, 1 H), 3.24-3.1 1 (m, 2H), 2.72-2.63 (m, 1 H), 2.1 6 (br s, 2H), 1 .91 -1 .71 (m, 4H), 1 .64-1 .56 (m, 1 H), 1 .53 (d, J = 6.6 Hz, 6H), 1 .42 (s, 3H); LCMS (ESI) [M+H]+: 424.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.06 (s, 1 H), 7.90-7.78 (m, 2H), 4.97 (td, J = 6.7, 13.3 Hz, 1 H), 4.06 (td, J = 3.8, 13.4 Hz, 2H), 3.36-3.22 (m, 3H), 2.42 (s, 3H), 2.29 (br dd, J = 3.4, 13.7 Hz, 2H), 2.20-2.05 (m, 2H), 1 .65-1 .62 (m, 6H); LCMS (ESI) [M+H]+: 394.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.07 (s, 1 H), 7.89-7.78 (m, 2H), 5.03-4.90 (m, 1 H), 4.51 (br d, J = 13.2 Hz, 1 H), 4.27 (br d, J = 13.4 Hz, 1 H), 3.40-3.24 (m, 2H), 3.03-2.90 (m, 1 H), 2.53 (s, 1 H), 2.27-2.1 5 (m, 8H), 2.03-1 .89 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 406.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.07 (s, 1 H), 7.92-7.77 (m, 2H), 4.97 (td, J = 6.6, 13.2 Hz, 1 H), 4.74-4.49 (m, 1 H), 4.40-4.16 (m, 1 H), 3.31 (br s, 2H), 3.23-2.91 (m, 3H), 2.38 (s, 3H), 2.30- 2.13 (m, 4H), 2.04-1 .76 (m, 5H), 1 .64 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 423.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (d, J = 0.7 Hz, 1H), 8.17 (s, 1H), 7.94-7.82 (m, 2H), 5.95- 5.83 (m, 1H), 5.33 (t, J = 6.5 Hz, 2H), 5.17 (t, J = 7.3 Hz, 2H), 4.66-4.36 (m, 4H), 4.18-4.07 (m, 1H), 2.05 (s, 2H), 1.09 (s, 9H); LCMS (ESI) [M+H]+: 369.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (s, 1H), 8.17 (s, 1H), 7.84-7.73 (m, 2H), 5.76 (m, 1H), 5.28- 5.14 (m, 4H), 4.45-4.30 (m, 4H), 4.14-4.03 (m, 1H), 1.48 (s, 9H); LCMS (ESI) [M+H]+: 398.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (d, J = 0.7 Hz, 1H), 8.17 (s, 1H), 7.94-7.90 (m, 1H), 7.88- 7.83 (m, 1 H), 5.96-5.85 (m, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.21 -5.11 (t, J = 7.3 Hz, 2H), 4.53-4.40 (m, 4H), 4.15 (m, 1H), 3.80 (s, 2H), 0.96 (s, 9H); LCMS (ESI) [M+H]+: 412.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.53 (s, 1 H), 8.07 (s, 1 H), 7.82-7.77 (m, 1 H), 7.77-7.71 (m, 1 H), 5.40 (m, 1H), 4.79 (dd, J = 5.3, 8.8 Hz, 1H), 4.73-4.65 (m, 1H), 4.63-4.55 (m, 2H), 4.13 (br d, J = 8.2 Hz, 2H), 3.25-3.13 (m, 1H), 3.02 (br t, J = 11.5 Hz, 2H), 2.14 (br d, J = 11.2 Hz, 2H), 1.99 (s, 3H), 1.97-1.85 (m, 2H), 1.48 (s, 9H); LCMS (ESI) [M-100+H]+: 367.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.16 (s, 2H), 7.95-7.89 (m, 1H), 7.87-7.82 (m, 1H), 5.54 (m, 1H), 4.80 (dd, J = 5.4, 8.7 Hz, 1H), 4.72-4.63 (m, 1H), 4.62-4.51 (m, 2H), 4.23-4.07 (m, 2H), 3.26-3.14 (m, 1H), 3.02 (br t, J = 1 1 .5 Hz, 2H), 2.15 (m, 2H), 1 .99 (s, 3H), 1 .98-1 .86 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M- 100+H]+: 367.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (s, 1 H), 8.20 (s, 1 H), 7.88 (m, 2H), 7.46 (s, 5H), 5.90 (quin, J = 6.9 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.18 (t, J = 7.3 Hz, 2H), 3.61 (m, 8H); LCMS (ESI) [M+H]+: 431 .1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, 1 H), 8.19 (s, 1 H), 7.94-7.82 (m, 2H), 5.90 (quin, J = Hz, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.18 (t, J = 7.2 Hz, 2H), 3.76 (s, 3H), 3.69-3.41 (m, 8H); LCMS (ESI) [M+H]+: 385.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.49 (d, J = 4.6 Hz, 1 H), 8.29 (s, 1 H), 8.10 (s, 1 H), 7.87 (s, 2H), 7.55-7.49 (m, 1 H), 7.40 (td, J = 4.4, 8.6 Hz, 1 H), 4.99 (spt, J = 6.7 Hz, 1 H), 4.78-4.68 (m, 1 H), 3.67 (br d, J = 13.8 Hz, 1 H), 3.32-3.17 (m, 3H), 2.27 (br dd, J = 3.5, 13.6 Hz, 1 H), 2.15-2.01 (m, 3H), 1 .65 (d, J = 6.7 Hz, 6H); LCMS (ESI) [M+H]+: 435.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.43 (s, 1 H), 8.1 9 (s, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.81 -7.75 (m, 2H), 7.08 (d, J = 5.3 Hz, 1 H), 5.22-5.1 0 (m, 1 H), 4.02 (br s, 2H), 3.33-3.20 (m, 3H), 2.13 (m, 2H), 1 .86-1 .75 (m, 2H), 1 .52 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 456.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.85 (d, J = 5.0 Hz, 2H), 8.30 (s, 1 H), 8.09 (s, 1 H), 7.86 (d, J = 0.9 Hz, 2H), 7.37 (t, J = 5.0 Hz, 1 H), 4.99 (spt, J = 6.6 Hz, 1 H), 4.78-4.68 (m, 1 H), 3.73-3.65 (m, 1 H), 3.33-3.17 (m, 3H), 2.29-2.21 (m, 1 H), 2.16-2.04 (m, 3H), 1 .65 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 418.2.

¹ H NMR (400 MHz, DMSO-de) δ 8.28 (s, 1 H), 8.1 6 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.6 Hz, 1 H), 5.12 (quin, J = 6.6 Hz, 1 H), 4.31 (br d, J = 14.1 Hz, 2H), 3.62-3.49 (m, 1 H), 3.33 (br t, J = 12.1 Hz, 2H), 2.25 (br d, J = 10.4 Hz, 2H), 1 .98-1 .82 (m, 2H), 1 .59 (s, 6H), 1 .54 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 407.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.18 (s, 1 H), 7.94-7.89 (m, 1 H), 7.88-7.83 (m, 1 H), 7.41 (d, J = 5.3 Hz, 1 H), 6.95 (d, J = 5.3 Hz, 1 H), 5.90 (quin, J = 7.1 Hz, 1 H), 5.34 (t, J = 6.5 Hz, 2H), 5.20-5.14 (m, 2H), 4.77-3.73 (m, 2H), 3.50-3.1 6 (m, 3H), 2.28 (br d, J = 1 1 .6 Hz, 2H), 2.18-2.03 (m, 2H); LCMS (ESI) [M+H]+: 470.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.51 (s, 1 H), 8.14 (s, 1 H), 7.79-7.73 (m, 2H), 4.69-4.61 (m, 1 H), 4.23 (dd, J = 4.0, 1 1 .4 Hz, 1 H), 4.14 (br d, J = 6.2 Hz, 2H), 4.03-3.91 (m, 2H), 3.72-3.63 (m, 1 H), 3.19 (tt, J = 3.9, 10.8 Hz, 1 H), 3.03 (br t, J = 1 1 .4 Hz, 2H), 2.41 -2.32 (m, 2H), 2.15 (br d, J = 1 0.3 Hz, 2H), 1 .98- 1 .79 (m, 4H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 454.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, 1 H), 8.06 (s, 1 H), 7.91 -7.86 (m, 1 H), 7.84-7.79 (m, 1 H), 4.79-4.68 (m, 1 H), 4.24-4.02 (m, 4H), 3.85 (t, J = 10.7 Hz, 1 H), 3.60-3.50 (m, 1 H), 3.22 (tt, J = 3.9, 10.9 Hz, 1 H), 3.03 (br t, J = 1 1 .6 Hz, 2H), 2.48-2.35 (m, 1 H), 2.27 (br d, J = 12.5 Hz, 1 H), 2.17 (br d, J = 1 0.6 Hz, 2H), 2.02-1 .89 (m, 4H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 454.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.1 1 (d, J = 0.9 Hz, 1 H), 8.06 (s, 1 H), 7.79-7.74 (m, 2H), 5.16 (quin, J = 8.3 Hz, 1 H), 3.77-3.65 (m, 4H), 3.63-3.53 (m, 4H), 2.89-2.75 (m, 2H), 2.61 -2.50 (m, 2H), 2.06- 1 .86 (m, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 425.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (br d, J = 2.6 Hz, 1 H), 8.10 (br d, J = 3.4 Hz, 1 H), 7.86 (br d, J = 4.2 Hz, 2H), 5.06-4.91 (m, 1 H), 4.60 (br d, J = 12.2 Hz, 2H), 3.36-3.03 (m, 3H), 2.27-2.13 (m, 2H), 2.05-1 .90 (m, 2H), 1 .70-1 .62 (m, 6H), 1 .17-1 .08 (m, 2H), 0.99 (br s, 2H); LCMS (ESI) [M+H]+: 396.2.

¹ H NMR (400 MHz, METHANOLS) δ 8.53 (s, 1 H), 8.35-8.27 (m, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 3.60-3.45 (m, 4H), 3.30-3.21 (m, 2H), 2.47 (br dd, J = 3.2, 14.4 Hz, 2H), 2.25-2.1 1 (m, 2H), 1 .51 (d, J = 7.1 Hz, 6H; LCMS (ESI) [M+H]+: 313.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, 1 H), 8.17 (s, 1 H), 7.94-7.89 (m, 1 H), 7.88-7.83 (m, 1 H), 5.90 (quin, J = 7.0 Hz, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.1 7 (t, J = 7.3 Hz, 2H), 4.50-4.31 (m, 4H), 4.18-4.03 (m, 1 H), 1 .57 (s, 3H), 0.96-0.85 (m, 2H), 0.68-0.61 (m, 2H); LCMS (ESI) [M+H]+: 396.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (s, J = 0.9 Hz, 1 H), 8.20 (s, 1 H), 7.88 (m, J = 0.9 Hz, 2H), 7.50-7.40 (m, 2H), 7.28 (d, J = 0.9 Hz, 0.3H), 7.26-7.22 (m, 0.7H), 7.14 (t, J = 9.2 Hz, 1 H), 5.96-5.81 (m, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.18 (t, J = 7.5 Hz, 2H), 3.98 (br s, 2H), 3.71 (br t, J = 4.8 Hz, 2H), 3.62-3.41 (m, 4H); LCMS (ESI) [M+H]+: 449.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (s, 1 H), 8.20 (s, 1 H), 7.88 (m, 2H), 7.48-7.42 (m, 1 H), 7.41 7.31 (m, 3H), 5.89 (quin, J = 7.0 Hz, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.23-5.14 (m, 2H), 4.13-4.02 (m, 1 H), 3.98-3.85 (m, 1 H), 3.78-3.69 (m, 2H), 3.68-3.57 (m, 1 H), 3.57-3.41 (m, 2H), 3.40-3.32 (m, 1 H); LCMS (ESI) [M+H]+: 465.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.23 (s, 1 H), 8.19 (d, J = 0.9 Hz, 1 H), 8.13 (dd, J = 1 .3, 8.3 Hz, 1 H), 7.86 (dd, J = 0.7, 8.3 Hz, 1 H), 6.22 (dd, J = 6.8, 9.0 Hz, 1 H), 4.93-4.76 (m, 2H), 4.57 (br d, J = 13.2 Hz, 1 H), 4.05 (br d, J = 12.2 Hz, 1 H), 3.41 -3.19 (m, 3H), 3.10-2.87 (m, 2H), 2.35 (s, 2H), 2.24 (br dd, J = 3.5, 13.4 Hz, 2H), 2.03 (m, 2H), 1 .09 (s, 9H); LCMS (ESI) [M+H]+: 452.2.

¹ H NMR (400 MHz, METHANOLS) δ 8.54 (br d, J = 4.3 Hz, 1 H), 8.36 (s, 1 H), 8.33 (s, 1 H), 7.97-7.89 (m, 2H), 5.98 (quin, J = 7.2 Hz, 1 H), 4.72-4.57 (m, 4H), 4.14 (m, 2H), 3.42-3.34 (m, 1 H), 3.20-3.01 (m, 2H), 2.19 (m, 2H), 1 .94-1 .79 (m, 2H), 1 .56-1 .46 (s, 9H); LCMS (ESI) [M+H]+: 425.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.43 (d, J = 1 .0 Hz, 1 H), 7.98 (s, 1 H), 7.68 (d, J = 0.9 Hz, 2H), 5.07 (quin, J = 8.4 Hz, 1 H), 3.71 -3.64 (m, 4H), 3.62-3.54 (m, 4H), 2.83-2.67 (m, 2H), 2.66-2.51 (m, 2H), 2.06-1 .89 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 425.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.19 (s, 1 H), 8.07 (s, 1 H), 7.88-7.74 (m, 2H), 5.17 (quin, J = Hz, 1 H), 4.15 (br s, 2H), 3.20 (tt, J = 3.9, 1 1 .0 Hz, 1 H), 3.01 (br t, J = 12.0 Hz, 2H), 2.91 -2.76 (m, 2H), 2.63-2.50 (m, 2H), 2.15 (br d, J = 10.8 Hz, 2H), 2.06-1 .84 (m, 4H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 424.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.52 (d, J = 1 .1 Hz, 1 H), 8.00 (s, 1 H), 7.77-7.70 (m, 2H), 5.08 (quin, J = 8.3 Hz, 1 H), 4.20-4.07 (m, 2H), 3.21 -3.12 (m, 1 H), 3.02 (br t, J = 1 1 .5 Hz, 2H), 2.82-2.58 (m, 4H), 2.14 (br d, J = 9.9 Hz, 2H), 2.06-1 .85 (m, 4H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 424.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 10.59 (br s, 1 H), 8.29 (s, J = 0.9 Hz, 1 H), 8.15 (s, J = 0.9 Hz, 1 H), 7.89 (m, J = 1 .0, 8.5 Hz, 2H), 4.62 (br d, J = 13.7 Hz, 1 H), 4.04 (br d, J = 13.9 Hz, 1 H), 3.45-3.20 (m, 2H), 2.99 (br t, J = 1 1 .0 Hz, 1 H), 2.33 (m, 2H), 2.22 (m, J = 13.5 Hz, 2H), 2.00-1 .85 (m, 2H), 1 .09 (s, 9H); LCMS (ESI) [M+H]+: 368.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (br s, 1 H), 8.07 (s, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 7.86 (d, J = 8.3 Hz, 1 H), 7.71 (dd, J = 1 .1 , 8.6 Hz, 1 H), 7.47 (br d, J = 8.8 Hz, 1 H), 4.99 (spt, J = 6.7 Hz, 1 H), 4.05- 3.90 (m, 1 H), 3.86-3.60 (m, 3H), 3.58-3.45 (m, 1 H), 2.51 -2.22 (m, 2H), 1 .64 (d, J = 6.6 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 408.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.55 (d, J = 5.1 Hz, 1 H), 8.00 (s, 1 H), 7.88 (dd, J = 1.3, 5.1 Hz, 1H), 4.18 (br s, 2H), 3.73 (s, 3H), 3.23 (tt, J = 3.9, 10.9 Hz, 1H), 3.08 (br t, J = 11.7 Hz, 2H), 2.20-2.12 (m, 2H), 1.99-1.86 (m, 2H); LCMS (ESI) [M+H]+: 323.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, J = 0.7 Hz, 1H), 8.20 (s, 1H), 7.88 (m, 2H), 5.90 (quin, J = 7.0 Hz, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.22-5.11 (m, 2H), 3.56 (br s, 8H), 1.58 (s, 3H), 0.95-0.85 (m, 2H), 0.72-0.61 (m, 2H); LCMS (ESI) [M+H]+: 425.1.

¹ H NMR (400 MHz, DMSO-de) δ 8.46 (d, J = 0.9 Hz, 1H), 8.15 (d, J = 0.9 Hz, 1H), 7.97-7.88 (m, 1H), 7.73 (dd, J = 1.2, 8.4 Hz, 1H), 5.07 (t, J = 5.7 Hz, 1H), 3.98 (brd, J = 13.0 Hz, 2H), 3.81 (d, J = 5.7 Hz, 2H), 3.43-3.36 (m, 1H), 2.98 (br s, 2H), 2.11 (br dd, J = 2.9, 13.3 Hz, 2H), 1.79-1.63 (m, 8H), 1.42 (s, 9H); LCMS (ESI) [M+H]+: 442.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.16-8.12 (m, 2H), 7.85-7.78 (m, 2H), 5.92-5.84 (m, 1H), 5.33 (t, J = 6.7 Hz, 2H), 5.14 (t, J = 7.3 Hz, 2H), 3.84-3.71 (m, 8H), 3.17 (s, 2H), 2.30 (s, 6H); LCMS (ESI)

[M+H]+: 412.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.31 (s, 1 H), 8.20 (s, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 13.7 Hz, 1H), 6.85-6.73 (m, 1H), 4.78 (dd, J = 2.9, 17.0 Hz, 1H), 4.67-4.52 (m, 1 H), 4.1 6 (br s, 2H), 3.21 (tt, J = 3.8, 1 0.9 Hz, 1 H), 3.01 (br t, J = 1 1 .4 Hz, 2H), 2.1 6 (br d, J = 1 1 .2 Hz, 2H), 2.00-1 .86 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 440.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.48 (s, 1 H), 8.07 (s, 1 H), 7.79-7.70 (m, 2H), 7.51 (d, J = 13.7 Hz, 1 H), 7.14-7.02 (m, 1 H), 4.92 (dd, J = 2.9, 16.3 Hz, 1 H), 4.81 -4.66 (d, J = 48 Hz, 1 H), 4.13 (br s, 2H), 3.25-3.14 (m, 1 H), 3.02 (br t, J = 1 1 .7 Hz, 2H), 2.14 (br d, J = 1 1 .0 Hz, 2H), 1 .98-1 .85 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M-55]+: 384.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (s, 2H), 7.93 (d, J = 3.2 Hz, 1 H), 7.86-7.79 (m, 2H), 7.60 (d, J = 3.2 Hz, 1 H), 5.93-5.84 (m, 1 H), 5.33 (t, J = 6.6 Hz, 2H), 5.15 (t, J = 7.3 Hz, 2H), 4.66 (m, 2H), 3.98 (m, 2H), 3.87 (br t, J = 4.9 Hz, 4H); LCMS (ESI) [M+H]+: 438.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (t, J = 1 .5 Hz, 1 H), 8.09 (td, J = 1 .4, 7.8 Hz, 1 H), 7.73 (td, J = 1 .4, 7.8 Hz, 1 H), 7.47 (t, J = 7.8 Hz, 1 H), 4.34-4.14 (m, 4H), 4.05 (br d, J = 9.0 Hz, 2H), 3.14-3.06 (m, 1 H), 2.94 (br t, J = 1 1 .7 Hz, 2H), 2.35-2.23 (m, 2H), 2.05 (br dd, J = 3.2, 13.3 Hz, 2H), 1 .88-1 .74 (m, 2H), 1 .41 (s, 9H); LCMS (ESI) [M-100+1 ]+: 313.1 , LCMS (ESI) [M+23]+: 435.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.17 (s, 1 H), 8.1 1 (s, 1 H), 7.92-7.88 (dd, J = 8.8, 1 H), 7.85-7.81 (d, J = 8.8, 1 H), 5.19-5.05 (m, 1 H), 4.14 (m, 2H), 3.51 -3.35 (m, 2H), 3.28-3.1 5 (m, 3H), 3.02 (br t, J = 1 1 .6 Hz, 2H), 2.15 (br dd, J = 2.6, 13.4 Hz, 2H), 2.00-1 .87 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-55]+: 404.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1 H), 8.04 (s, 1 H), 7.81 -7.74 (m, 2H), 4.95 (td, J = 6.6, 13.4 Hz, 1 H), 4.81 (dd, J = 6.2, 7.7 Hz, 2H), 4.51 (t, J = 6.3 Hz, 2H), 4.33 (br d, J = 13.2 Hz, 2H), 3.17 (dt, J = 2.6, 12.9 Hz, 2H), 2.86-2.74 (m, 1 H), 2.03-1 .91 (m, 1 H), 1 .77 (br d, J = 1 1 .9 Hz, 2H), 1 .62 (d, J = 6.6 Hz, 6H), 1 .25 (dq, J = 4.4, 12.5 Hz, 2H); LCMS (ESI) [M+H]+: 368.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (s, 1 H), 8.04 (s, 1 H), 7.80-7.75 (m, 2H), 4.95 (quin, J = 6.7 Hz, 1 H), 4.60 (t, J = 7.7 Hz, 2H), 3.85 (td, J = 4.9, 13.6 Hz, 2H), 3.68 (ddd, J = 3.3, 9.8, 13.3 Hz, 2H), 2.47 (t, J = 7.8 Hz, 2H), 2.13 (td, J = 4.2, 13.3 Hz, 2H), 1 .92 (ddd, J = 4.4, 9.6, 13.6 Hz, 2H), 1 .62 (d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 354.2.

¹ H NMR (400 MHz, DMSO-de) δ 9.44 (br s, 1 H), 8.25 (s, 1 H), 7.92 (br d, J = 8.3 Hz, 1 H), 7.76 (br d, J = 8.3 Hz, 1 H), 4.05 (s, 3H), 2.85 (br d, J = 3.5 Hz, 3H), 2.52 (br s, 3H); LCMS (ESI) [M+H]+: 272.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (s, 1 H), 8.06 (s, 1 H), 7.90-7.78 (m, 2H), 7.19 (br s, 1 H), 5.03-4.87 (m, 1 H), 3.21 -3.06 (m, 3H), 1 .63 (br d, J = 6.6 Hz, 6H); LCMS (ESI) [M+H]+: 286.1 .

¹ H NMR (300 MHz, Chloroform-d) δ 8.10 (d, J = 0.9 Hz, 1 H), 7.80 (dd, J = 8.4, 0.8 Hz, 1 H), 7.70 - 7.56 (m, 3H), 7.43 (dd, J = 8.4, 1 .4 Hz, 1 H), 7.38 - 7.28 (m, 2H), 5.93 - 5.77 (m, 1 H), 5.35 (dd, J = 6.9, 6.2 Hz, 2H), 5.1 5 (t, J = 7.4 Hz, 2H), 4.27 (s, 2H), 2.91 - 2.66 (m, 3H), 1 .88 (d, J = 13.0 Hz, 2H), 1 .70 (td, J = 12.5, 4.3 Hz, 2H), 1 .52 - 1 .42 (m, 9H); LCMS (ESI) [M+H]+: 433.4.

¹ H NMR (300 MHz, Chloroform-d) δ 8.43 (dd, J = 1 .6, 0.8 Hz, 1 H), 8.26 (dd, J = 8.8, 1 .6 Hz, 1 H), 7.64 (dd, J = 8.8, 0.8 Hz, 1 H), 4.55 (d, J = 13.9 Hz, 1 H), 3.81 (d, J = 14.1 Hz, 1 H), 3.47 (hept, J = 7.0 Hz, 1 H), 3.38 - 3.10 (m, 3H), 3.03 - 2.87 (m, 1 H), 2.48 - 2.29 (m, 2H), 2.19 (dd, J = 10.7, 7.2 Hz, 4H), 2.09 - 1 .80 (m, 4H), 1 .53 (d, J = 7.0 Hz, 6H); LCMS (ESI) [M+H]+: 395.6.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.31 (d, J=0.9 Hz, 1 H), 8.21 (s, 1 H), 7.95 - 7.87 (m, 2H), 5.96 5.86 (m, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.23 - 5.15 (m, 2H), 3.90 - 3.77 (m, 3H), 3.09 - 2.97 (m, 3H), 2.66 2.53 (m, 2H), 2.37 - 2.26 (m, 2H), 2.19 (br dd, J=3.6, 13.5 Hz, 2H), 2.10 - 1 .96 (m, 4H); LCMS (ESI) [M+H]+: 444.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.25 (d, J=0.8 Hz, 1 H), 8.19 (br s, 1 H), 7.91 - 7.85 (m, 2H),

5.92 -5.84 (m, 1 H), 5.32 (t, J=6.4 Hz, 2H), 5.17 (t, J=7.2 Hz, 2H), 3.85 (br s, 4H), 3.67 - 3.60 (m, 4H), 1 .40 - 1 .22 (m, 4H); LCMS (ESI) [M+H]+: 413.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 8.09 (s, 1 H), 7.89 - 7.79 (m, 2H), 5.37 (quin, J=5.9 Hz, 1 H), 4.33 - 4.10 (m, 5H), 4.09 - 4.00 (m, 1 H), 3.20 (tt, J=3.8, 1 1 .0 Hz, 1 H), 3.01 (br t, J=1 1 .6 Hz, 2H), 2.61 - 2.48 (m, 2H), 2.15 (br dd, J=2.8, 13.2 Hz, 2H), 2.00 - 1 .86 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M- 56+H]+: 384.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.48 (td, J=1 .2, 4.8 Hz, 1 H), 8.24 (d, J=0.8 Hz, 1 H), 8.1 8 (s, 1 H), 7.87 (d, J=0.8 Hz, 2H), 7.54 (dt, J=1 .2, 8.8 Hz, 1 H), 7.75 -7.40 (m, 1 H), 5.92 -5.84 (m, 1 H), 5.31 (t, J=6.4 Hz, 2H), 5.20 - 5.13 (t, J=6.8 Hz, 2H), 4.00 -3.98 (m, 2H), 3.77 - 3.70 (m, 2H), 3.63 - 3.57 (m, 2H), 3.52 - 3.46 (m, 2H); LCMS (ESI) [M+H]+: 450.2.

¹ H NMR (400MHz, METHANOL-d4) δ 8.74 (d, J=5.1 Hz, 1 H), 8.13 (s, 1 H), 7.93 (d, J=5.0 Hz, 1 H), 5.05 (t, J=6.9 Hz, 1 H), 4.20 - 4.09 (m, 3H), 4.00 (q, J=7.4 Hz, 1 H), 3.70 (s, 3H), 3.21 - 3.01 (m, 3H), 2.54 - 2.43 (m, 1 H), 2.13 - 1 .89 (m, 5H), 1 .86 - 1 .73 (m, 2H); LCMS (ESI) [M+H]+: 359.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.31 (s, 1 H), 8.1 1 (s, 1 H), 7.95 - 7.83 (m, 2H), 5.40 (quin, J=5.8 Hz, 1 H), 4.63 (br d, J=13.5 Hz, 1 H), 4.34 - 4.18 (m, 3H), 4.09 - 4.01 (m, 1 H), 3.96 (br d, J=13.2 Hz, 1 H), 3.26 (br t, J=1 1 .5 Hz, 1 H), 3.20 - 3.1 1 (m, 1 H), 2.92 (br t, J=1 1 .7 Hz, 1 H), 2.62 - 2.50 (m, 2H), 2.33 (d, J=6.8 Hz, 2H), 2.15 (br d, J=13.0 Hz, 2H), 1 .99 - 1 .83 (m, 2H), 1 .14 - 1 .02 (m, 1 H), 0.63 - 0.55 (m, 2H), 0.24 - 0.18 (m, 2H); LCMS (ESI) [M+H]+: 422.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.32 (s, 1 H), 8.12 (s, 1 H), 7.94 - 7.85 (m, 2H), 5.45 - 5.35 (m, 1 H), 4.63 (br d, J=13.7 Hz, 1 H), 4.35 - 4.18 (m, 3H), 4.09 - 4.02 (m, 1 H), 3.98 (br d, J=13.2 Hz, 1 H), 3.25 (br t, J=1 1 .6 Hz, 1 H), 3.21 - 3.1 1 (m, 1 H), 2.91 (br t, J=1 1 .1 Hz, 1 H), 2.63 - 2.51 (m, 2H), 2.41 (q, J=7.5 Hz, 2H), 2.15 (br s, 2H), 2.00 - 1 .81 (m, 2H), 1 .19 (t, J=7.4 Hz, 3H); LCMS (ESI) [M+H]+: 396.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.15 (s, 1 H), 8.03 (s, 1 H), 7.86 - 7.81 (m, 1 H), 7.78 - 7.72 (m, 1 H), 5.86 (m, 1 H), 5.32 (t, J=6.5 Hz, 2H), 5.1 6 (t, J=7.3 Hz, 2H), 3.61 (s, 8H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 427.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (dd, J=0.8, 4.8 Hz, 1 H), 7.49 (dd, J=1 .2, 4.0 Hz, 1 H), 7.44 -7.40 (m, 1 H), 5.69 - 5.62 (m, 1 H), 5.00 (t, J=6.4 Hz, 2H), 4.75 (t, J=7.2 Hz, 2H), 3.58 - 3.48 (m, 8H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 404.1 .

¹ H NMR (400MHz, CHLOROFORM-d-d) δ 8.25 (d, J=5.1 Hz, 1 H), 7.22 (br d, J=5.1 Hz, 1 H), 6.98 (s, 5.18 (br s, 1 H), 5.05 (br s, 3H), 4.58 (br s, 2H), 3.77 (br s, 2H), 3.65 - 3.44 (m, 6H), 2.41 (q, J=7.4 Hz, 2H), 1 .1 9 (t, J=7.3 Hz, 3H); LCMS (ESI) [M+H]+: 359.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 7.65 - 7.59 (m, 2H), 7.41 (t, J=8.0 Hz, 1 H), 7.12 (br d, J=8.0 Hz, 1 H), 4.28 - 4.05 (m, 2H), 3.93 - 3.86 (m, 4 H), 3.29 - 3.22 (m, 4H), 3.07 - 2.89 (m, 3H), 2.06 (br d, J=12.4 Hz, 2H), 1 .92 - 1 .78 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H-Boc]+: 31 5.2.

¹ H NMR (400MHz, METHANOL-d4) δ = 8.33 (s, 1 H), 8.27 (s, 1 H), 7.96 (d, J=7.8 Hz, 1 H), 7.85 (dd, J=1 .2, 8.3 Hz, 1 H), 6.14 (quin, J=6.8 Hz, 1 H), 5.28 - 5.15 (m, 4H), 4.1 0 (br s, 2H), 3.38 - 3.33 (m, 1 H), 3.1 0 (br s, 2H), 2.1 8 (br s, 2H), 1 .93 - 1 .77 (m, 2H), 1 .55 (s, 3H), 0.92 - 0.84 (m, 2H), 0.70 - 0.63 (m, 2H); LCMS (ESI) [M+H]+: 424.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.19 (s, 2H), 7.92 - 7.83 (m, 2H), 5.89 (br t, J=6.8 Hz, 1 H), 5.33 (t, J=6.4 Hz, 2H), 5.23 - 5.15 (m, 2H), 4.1 7 (br s, 2H), 3.21 (br t, J=10.8 Hz, 1 H), 3.03 (br s, 2H), 2.41 - 2.28 (m, 2H), 2.23 - 2.1 0 (m, 4H), 1 .94 (q, J=10.6 Hz, 2H), 1 .82 (br d, J=1 0.8 Hz, 1 H), 1 .76 - 1 .62 (m, 1 H), 1 .59 (br s, 3H); LCMS (ESI) [M+H]+: 438.2.

¹ H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=4.8 Hz, 1 H), 7.62 (dd, J=5.6, 1 .2 Hz, 1 H), 7.47 (s, 1 H) 5.67 5.59 (m, 1 H), 4.91 (t, J=7.2 Hz, 2H), 4.59 (dd, J=7.6, 5.4 Hz, 2H), 3.96 (br d, J=12.0 Hz, 2H), 3.14 (tt, J=1 1 .2, 3.6 Hz, 1 H), 3.05 - 2.85 (m, 2H), 2.00 (br dd, J=13.2, 2.4 Hz, 2H), 1 .68 - 1 .54 (m, 2H), 1 .41 (s, 9H); LCMS (ESI) [M+H]+: 403.1 .

¹ H NMR (400 MHz, DMSO-d6) δ 7.54 - 7.42 (m, 3H), 7.27 (dd, J=8.0, 1 .2 Hz, 1 H), 3.99 (br d, J=10.8 Hz, 2H), 3.79 - 3.72 (m, 4H), 3.60 (s, 3H), 3.24 - 3.16 (m, 4H), 3.1 5 - 2.94 (m, 3H), 2.04 - 1 .94 (m, 2H), 1 .69 - 1 .56 (m, 2H); LCMS (ESI) [M+H]+: 373.1 .

¹ H NMR (300 MHz, Chloroform-d) δ 8.84 (d, J = 0.9 Hz, 2H), 8.61 (q, J = 1 .1 Hz, 1 H), 8.30 (dd, J = 8.6, 1 .2 Hz, 1 H), 8.15 (d, J = 1 .0 Hz, 1 H), 7.84 (dd, J = 8.5, 0.9 Hz, 1 H), 6.25 (s, 1 H), 5.95 (p, J = 7.1 Hz, 1 H), 5.36 (t, J = 6.5 Hz, 2H), 5.22 - 5.05 (m, 2H), 4.16 (d, J = 3.2 Hz, 2H), 3.71 (t, J = 5.6 Hz, 2H), 2.58 (s, 2H), 1 .44 (s, 9H); LCMS (ESI) [M+H]+: 434.6.

¹ H NMR (300 MHz, Chloroform-d) δ 8.70 (s, 2H), 8.59 (s, 1 H), 8.28 (dd, J = 8.5, 1 .3 Hz, 1 H), 7.84 (dd, J 8.6, 0.8 Hz, 1 H), 5.95 (p, J = 7.0 Hz, 1 H), 5.36 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.31 (s, 2H), 2.83 (dd, J = 29.2, 14.6 Hz, 3H), 1 .91 (d, J = 13.2 Hz, 2H), 1 .80 - 1 .62 (m, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+: 436.6.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.10 (s, 1 H), 7.89 - 7.80 (m, 2H), 5.38 (quin, J=5.8 Hz, 1 H), 4.38 - 3.97 (m, 6H), 3.21 (tt, J=3.6, 10.9 Hz, 1 H), 3.03 (br t, J=1 1 .0 Hz, 2H), 2.59 - 2.52 (m, 2H), 2.16 (br d, J=12.3 Hz, 2H), 1 .98 - 1 .86 (m, 2H), 1 .58 (s, 3H), 0.93 - 0.87 (m, 2H), 0.69 - 0.63 (m, 2H); LCMS (ESI) [M+H]+: 438.2.

¹ H NMR (400MHz, CHLOROFORM-d) 5 8.15 (s, 1 H), 8.05 (d, J=0.9 Hz, 1 H), 7.87 - 7.81 (m, 1 H), 7.79 - 7.72 (m, 1 H), 5.94 - 5.79 (m, 1 H), 5.32 (t, J=6.7 Hz, 2H), 5.16 (t, J=7.4 Hz, 2H), 3.85 (m, 4H), 3.76 - 3.58 (m, 4H), 1 .78 (m, 1 H), 1 .08 - 1 .00 (m, 2H), 0.88 - 0.81 (m, 2H); LCMS (ESI) [M+H]+: 395.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.21 (d, J=2.2 Hz, 1 H), 7.82 (dd, J=5.6, 8.4 Hz, 1 H), 7.64 (d, J=8.6 Hz, 1 H), 6.17 - 6.07 (m, 1 H), 5.33 (t, J=6.4 Hz, 2H), 5.15 (t, J=7.0 Hz, 2H), 4.18 (br s, 2H), 3.09 (tt, J=3.8, 1 1 .2 Hz, 1 H), 2.97 (br t, J=1 1 .8 Hz, 2H), 2.10 (br d, J=10.8 Hz, 2H), 1 .95 - 1 .81 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H-56]+: 388.1 .

¹ H NMR (400MHz, METHANOL-d4) δ = 8.32 (d, J=2.2 Hz, 1 H), 7.86 - 7.78 (m, 1 H), 7.77 - 7.73 (m, 1 H), 6.23 - 6.13 (m, 1 H), 5.30 - 5.23 (m, 2H), 5.19 - 5.1 1 (m, 2H), 3.51 (td, J=3.8, 13.2 Hz, 2H), 3.40 - 3.32 (m, 1 H), 3.28 - 3.19 (m, 2H), 2.38 (br dd, J=3.4, 14.8 Hz, 2H), 2.19 - 2.06 (m, 2H); LCMS (ESI) [M+H]+: 344.1 .

¹ H NMR (400MHz, CHLOROFORM-d) 8.24 (d, J=3.3 Hz, 2H), 8.00 - 7.96 (m, 1 H), 7.94 - 7.90 (m, 1 H), 5.62 - 5.53 (m, 1 H), 5.03 - 4.95 (m, 2H), 4.77 - 4.68 (m, 2H), 4.18 (br s, 2H), 3.1 1 - 2.91 (m, 3H), 2.09 (br d, J=1 1 .2 Hz, 2H), 1 .94 - 1 .82 (m, 2H), 1 .50 (s, 9H); LCMS (ESI) [M-56+H]+: 418.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.18 (s, 1 H), 8.07 (s, 1 H), 7.88 - 7.83 (m, 1 H), 7.80 - 7.75 (m, 1 H), 5.95 - 5.82 (m, 1 H), 5.34 (m, 2H), 5.24 - 5.13 (m, 2H), 3.90 - 3.58 (m, 8H), 2.18 (dd, J=4.3, 7.4 Hz, 1 H), 1 .67 (m, 1 H), 1 .36 (dd, J=3.7, 7.4 Hz, 1 H), 1 .04 - 0.90 (m, 3H), 0.89 - 0.82 (m, 1 H); LCMS (ESI) [M+H]+: 421 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.71 (d, J=5.1 Hz, 1 H), 7.85 (s, 1 H), 7.78 (dd, J=1 .5, 5.0 Hz, 1 H), 4.27 - 4.08 (m, 4H), 4.02 - 3.92 (m, 2H), 3.68 (quin, J=7.7 Hz, 1 H), 3.20 (tt, J=3.8, 1 1 .0 Hz, 1 H), 3.07 - 2.92 (m, 2H), 2.50 - 2.36 (m, 1 H), 2.28 (qd, J=7.8, 12.3 Hz, 1 H), 2.13 (br dd, J=2.5, 13.1 Hz, 2H), 1 .96 - 1 .83 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 401 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) 6 8.15 (s, 1 H), 8.04 (s, 1 H), 7.87 - 7.80 (m, 1 H), 7.78 - 7.71 (m, 1 H), 5.86 (m, 1 H), 5.31 (m, 2H), 5.22 - 5.10 (m, 2H), 3.91 - 3.77 (m, 2H), 3.67 - 3.52 (m, 6H), 3.51 - 3.40 (m, 1 H), 2.70 - 2.54 (m, 2H), 2.27 - 2.17 (m, 2H), 0.56 - 0.37 (m, 4H); LCMS (ESI) [M+H]+: 435.2.

¹ H NMR (400MHz, CHLOROFORM-d) 5 8.15 (s, 1 H), 8.04 (s, 1 H), 7.86 - 7.81 (m, 1 H), 7.78 - 7.72 (m, 1 H), 5.86 (m, 1 H), 5.32 (m, 2H), 5.20 - 5.12 (m, 2H), 3.88 - 3.73 (m, 4H), 3.70 - 3.57 (m, 4H), 2.55 (s, 1 H), 2.21 (s, 6H); LCMS (ESI) [M+H]+: 421 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) 5 8.15 (s, 1 H), 8.05 (s, 1 H), 7.86 - 7.81 (m, 1 H), 7.78 - 7.72 (m, 1 H), 5.86 (m, 1 H), 5.32 (t, J=6.5 Hz, 2H), 5.1 6 (t, J=7.3 Hz, 2H), 3.82 (m, 2H), 3.66 (br s, 6H), 2.40 (s, 2H), 1 .1 7 (s, 3H), 0.51 - 0.37 (m, 4H); LCMS (ESI) [M+H]+: 423.2.

¹ H NMR (400MHz, CHLOROFORM-d) 5 8.15 (s, 1 H), 8.04 (s, 1 H), 7.86 - 7.80 (m, 1 H), 7.78 - 7.72 (m, 1 H), 5.92 - 5.79 (m, 1 H), 5.32 (m, 2H), 5.22 - 5.10 (m, 2H), 3.86 - 3.75 (m, 2H), 3.67 - 3.49 (m, 6H), 3.31 (m, 1 H), 2.46 - 2.32 (m, 2H), 2.26 - 2.14 (m, 2H), 2.09 - 1 .84 (m, 2H); LCMS (ESI) [M+H]+: 409.1 .

¹ H NMR (400MHz, CHLOROFORM-d) 5 8.22 (s, 1 H), 8.18 (s, 1 H), 7.96 - 7.87 (m, 2H), 5.62 - 5.52 (m, 1 H), 5.02 - 4.94 (m, 2H), 4.76 - 4.68 (m, 2H), 3.60 - 3.54 (m, 8H), 1 .51 (s, 9H); LCMS (ESI) [M+H]+: 419.0.

¹ H NMR (400MHz, CHLOROFORM-d) 5 8.21 (s, 1 H), 8.18 (s, 1 H), 7.95 - 7.86 (m, 2H), 5.61 - 5.52 (m, 1 H), 5.02 - 4.94 (m, 2H), 4.74 - 4.68 (m, 2H), 3.75 (s, 3H), 3.63 -3.62 (m, 4H), 3.59 -3.53 (m, 4H); LCMS (ESI) [M+H]+: 433.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.83 - 7.78 (m, 1 H), 4.27 - 4.08 (m, 4H), 4.03 - 3.91 (m, 2H), 3.71 (quin, J=7.6 Hz, 1 H), 3.1 1 - 3.01 (m, 1 H), 2.96 (br t, J=1 1 .4 Hz, 2H), 2.49 - 2.38 (m, 1 H), 2.34 - 2.22 (m, 1 H), 2.06 (br d, J=12.1 Hz, 2H), 1 .91 - 1 .78 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+: 401 .2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.24 (d, J=4.2 Hz, 2H), 8.00 - 7.95 (m, 1 H), 7.94 - 7.90 (m, 1 H), 5.62 - 5.53 (m, 1 H), 4.99 (br dd, J=6.6, 14.6 Hz, 2H), 4.73 (br dd, J=9.0, 14.6 Hz, 2H), 4.21 (br s, 2H), 3.74 (s, 3H), 3.14 - 2.99 (m, 3H), 2.1 1 (br d, J=12.6 Hz, 2H), 1 .97 - 1 .83 (m, 2H); LCMS (ESI) [M+H]+: 432.1 .

¹ H NMR (400MHz, CHLOROFORM-d-d) δ 8.26 (d, J=5.1 Hz, 1 H), 7.22 (dd, J=1 .3, 5.3 Hz, 1 H), 6.97 (s, 1 H), 5.1 5 (br d, J=5.3 Hz, 1 H), 5.10 - 4.98 (m, 3H), 4.65 - 4.50 (m, 2H), 3.84 - 3.70 (m, 2H), 3.58 - 3.44 (m, 6H), 3.31 (quin, J=8.7 Hz, 1 H), 2.48 - 2.30 (m, 2H), 2.30 - 2.1 0 (m, 2H), 2.08 - 1 .80 (m, 2H); LCMS (ESI) [M+H]+: 385.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.24 (d, J=5.2 Hz, 1 H), 7.49 (dd, J=1 .2, 5.2 Hz, 1 H), 7.42 (br s, 1 H), 5.66 (quin, J=5.6 Hz, 1 H), 5.00 (t, J=7.2 Hz, 2H), 4.75 (t, J=5.6 Hz, 2H), 3.75 (s, 3H), 3.65 - 3.58 (m, 4H), 3.53 -3.52 (m, 4H); LCMS (ESI) [M+H]+: 362.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.76 (d, J=5.0 Hz, 1 H), 8.12 (s, 1 H), 7.82 (d, J=5.0 Hz, 1 H), 5.15 - 5.07 (m, 1 H), 4.26 - 4.1 1 (m, 3H), 4.07 - 3.97 (m, 1 H), 3.12 - 3.01 (m, 1 H), 3.01 - 2.88 (m, 2H), 2.55 - 2.42 (m, 1 H), 2.10 - 1 .96 (m, 5H), 1 .92 - 1 .78 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+: 401 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.21 (d, J=2.4 Hz, 1 H), 7.81 (dd, J=5.6, 8.3 Hz, 1 H), 7.64 (d, J=8.4 Hz, 1 H), 6.1 1 (q, J=7.0 Hz, 1 H), 5.33 (t, J=6.4 Hz, 2H), 5.15 (t, J=7.6 Hz, 2H), 4.22 (br d, 2H), 3.73 (s, 3H), 3.1 8 - 3.09 (m, 1 H), 3.09 - 2.96 (m, 2H), 2.1 1 (br d, J=12.8 Hz, 2H), 1 .97 - 1 .82 (m, 2H); LCMS (ESI) [M+H]+: 402.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.29 (d, J=1 .2 Hz, 1 H), 8.03 (dd, J=2.0, 8.4 Hz, 1 H), 7.41 (d, J=8.4 Hz, 1 H), 5.59 - 5.45 (m, 1 H), 5.25 - 5.10 (m, 4H), 4.27 - 4.04 (m, 2H), 3.17 - 2.83 (m, 3H), 2.07 (br d, J=1 1 .2 Hz, 2H), 1 .94 - 1 .76 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H-56]+: 387.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.46 (dd, J=2.0, 8.4 Hz, 1 H), 7.02 (d, J=2.0 Hz, 1 H), 6.41 (d, J=8.4 Hz, 1 H), 5.33 (quin, J=5.6 Hz, 1 H), 5.08 (td, J=6.8, 18.0 Hz, 4H), 4.89 - 4.81 (m, 3H), 4.80 - 4.70 (m, 1 H), 4.61 (t, J=6.0 Hz, 2H), 4.14 (br s, 2H), 3.06 - 2.87 (m, 3H), 2.05 (br d, J=10.8 Hz, 2H), 1 .90 - 1 . (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H-56]+: 41 7.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.52 (d, J=6.8 Hz, 1 H), 7.30 (br s, 1 H), 6.82 (br d, J=6.8 Hz, 1 H), 4.1 9 (br d, J=5.2 Hz, 2H), 4.06 (br t, J=4.4 Hz, 1 H), 3.74 (s, 3H), 3.64 - 3.55 (m, 6H), 3.51 (br s, 4H) 3.30 -3.10 (m, 1 H); LCMS (ESI) [M+H]+: 380.1 . ¹ H NMR (400MHz, DMSO-d6) δ 8.18 (d, J=5.3 Hz, 1 H), 7.77 (d, J=6.0 Hz, 1 H), 7.10 (s, 1 H), 7.03 (dd, J=1 .3, 5.3 Hz, 1 H), 4.98 - 4.88 (m, 1 H), 4.82 (t, J=6.6 Hz, 2H), 4.44 (t, J=6.3 Hz, 2H), 3.42 (br d, J=13.5 Hz, 8H), 1 .49 (s, 3H), 0.86 - 0.76 (m, 2H), 0.67 - 0.56 (m, 2H); LCMS (ESI) [M+H]+: 401 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.48 (br s, 1 H), 7.96 (dd, J=1 .6, 8.4 Hz, 1 H), 7.86 (d, J=1 .2 Hz, 1 H), 7.35 (d, J=8.4 Hz, 1 H), 4.30 - 4.06 (m, 2H), 3.10 - 2.90 (m, 3H), 2.13 - 1 .99 (m, 2H), 1 .92 - 1 .80 (m, 1 H), 1 .92 - 1 .80 (m, 2H), 1 .60 - 1 .40 (m, 9H); LCMS (ESI) [M+H-56]+: 331 .0.

¹ H NMR (300 MHz, Chloroform-d) δ 8.76 (dd, J = 2.3, 1 .0 Hz, 1 H), 8.21 (q, J = 1 .0 Hz, 1 H), 8.14 (d, J 0.9 Hz, 1 H), 7.88 - 7.71 (m, 4H), 6.19 (s, 1 H), 6.00 - 5.84 (m, 1 H), 5.35 (dd, J = 6.9, 6.2 Hz, 2H), 5.21 5.09 (m, 2H), 4.14 (d, J = 3.2 Hz, 2H), 3.69 (t, J = 5.7 Hz, 2H), 2.58 (s, 2H), 1 .51 (d, J = 39.9 Hz, 9H), 1 .27 (d, J = 13.0 Hz, 1 H); LCMS (ESI) [M+H]+: 433.6.

¹ H NMR (300 MHz, Chloroform-d) δ 8.59 (d, J = 2.3 Hz, 1 H), 8.21 - 8.09 (m, 2H), 7.89 - 7.67 (m, 3H), 7.62 (dd, J = 8.2, 2.4 Hz, 1 H), 5.91 (ddd, J = 14.2, 7.7, 6.3 Hz, 1 H), 5.34 (dd, J = 6.9, 6.1 Hz, 2H), 5.14 (dd, J = 7.7, 6.8 Hz, 2H), 4.30 (d, J = 13.0 Hz, 2H), 2.93 - 2.68 (m, 3H), 1 .89 (d, J = 13.0 Hz, 2H), 1 .69 (tt, J = 13.2, 6.6 Hz, 2H), 1 .46 (d, J = 17.7 Hz, 9H); LCMS (ESI) [M+H]+: 435.6.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.20 (s, 1 H), 7.92 - 7.83 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.18 (t, J=7.3 Hz, 2H), 4.08 (br t, J=1 1 .9 Hz, 2H), 3.96 - 3.68 (m, 6H), 1 .50 (s, 9H); LCMS (ESI) [M-56+H]+: 421 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.70 (br d, J=7.6 Hz, 1 H), 7.44 - 7.39 (m, 1 H), 7.34 -7.31 (m, 1 H), 6.94 -6.92(m, 1 H), 5.29 (quin, J=5.6 Hz, 1 H), 5.01 (t J = 8.0, 2H), 4.77 (t J = 8.0, 12.0, 2H), 3.74 (s, 3H), 3.65 -3.60 (m, 4H), 3.55 3.50 (m, 4H); LCMS (ESI) [M+H]+:361 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.18 (d, J=5.7 Hz, 2H), 7.99 - 7.94 (m, 1 H), 7.89 - 7.85 (m, 1 H), 5.61 - 5.52 (m, 1 H), 5.02 - 4.95 (m, 2H), 4.74 - 4.66 (m, 2H), 4.19 (br s, 2H), 3.74 (s, 3H), 3.29 - 3.19 (m, 1 H), 3.1 0 (br t, J=12.1 Hz, 2H), 2.1 9 (br d, J=1 1 .0 Hz, 2H), 2.03 - 1 .89 (m, 2H); LCMS (ESI) [M+H]+: 432.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .1 , 5.0 Hz, 1 H), 4.31 - 4.08 (m, 4H), 4.03 - 3.93 (m, 2H), 3.76 - 3.66 (m, 4H), 3.14 - 2.97 (m, 3H), 2.49 - 2.38 (m, 1 H), 2.33 - 2.22 (m, 1 H), 2.08 (br d, J=12.2 Hz, 2H), 1 .94 - 1 .81 (m, 2H); LCMS (ESI) [M+H]+: 359.0.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.78 (d, J=5.0 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .3, 5.0 Hz, 1 H), 4.29 - 4.03 (m, 4H), 4.02 - 3.92 (m, 2H), 3.71 (quin, J=7.6 Hz, 1 H), 3.12 - 2.90 (m, 3H), 2.49 - 2.38 (m, 1 H), 2.28 (qd, J=7.6, 12.4 Hz, 1 H), 2.06 (br d, J=1 1 .0 Hz, 2H), 1 .91 - 1 .77 (m, 2H), 1 .57 (s, 3H), 0.93 0.86 (m, 2H), 0.69 - 0.61 (m, 2H); LCMS (ESI) [M+H]+: 399.1 .

Ή NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.21 (s, 1 H), 7.99 - 7.85 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.34 (dt, J=3.1 , 6.5 Hz, 2H), 5.18 (t, J=7.3 Hz, 2H), 4.22 (sxt, J=6.6 Hz, 1 H), 4.01 - 3.91 (m, 1 H), 3.31 (ddd, J=5.5, 10.7, 14.0 Hz, 1 H), 3.22 - 3.12 (m, 1 H), 2.23 - 2.00 (m, 4H), 1.49 (s, 9H), 1.09 (d, J=6.6 Hz, 3H); LCMS (ESI) [M-56+H]+: 384.1.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.21 (s, 1 H), 7.97 - 7.85 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.33 (t, J=6.5 Hz, 2H), 5.18 (t, J=7.3 Hz, 2H), 4.61 (br s, 1 H), 4.16 (br s, 1 H), 3.26 (tt, J=3.6, 12.4 Hz, 1H), 3.03 (br t, J=13.2 Hz, 1H), 2.16 - 1.91 (m, 3H), 1.80 (dq, J=4.7, 12.9 Hz, 1H), 1.49 (s, 9H), 1.27 (d, J=7.1 Hz, 3H); LCMS (ESI) [M-56+H]+: 384.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1H), 8.21 (s, 1H), 7.96 - 7.85 (m, 2H), 5.91 (quin, J=7.0 Hz, 1H), 5.33 (t, J=6.6 Hz, 2H), 5.24 - 5.14 (m, 2H), 4.60 (br s, 1H), 4.15 (br s, 1H), 3.26 (tt, J=3.6, 12.3 Hz, 1H), 3.03 (br t, J=12.8 Hz, 1H), 2.15 - 1.93 (m, 3H), 1.80 (dq, J=4.7, 12.9 Hz, 1H), 1.49 (s, 9H), 1.27 (d, J=6.8 Hz, 3H); LCMS (ESI) [M-56+H]+: 384.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.13 (s, 1 H), 7.84 (q, J=8.4 Hz, 2H), 5.83 (quin, J=7.0 Hz, 1H), 5.26 (t, J=6.5 Hz, 2H), 5.10 (t, J=7.2 Hz, 2H), 3.98 (s, 2H), 3.93 (s, 2H), 3.54 (quin, J=8.2 Hz, 1 H), 2.65 - 2.51 (m, 4H), 1.38 (s, 9H); LCMS (ESI) [M+H]+: 438.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.28 (d, J=1.2 Hz, 1 H), 8.03 (dd, J=1.6, 8.4 Hz, 1 H), 7.40 (d, J=8.4 Hz, 1H), 5.60 - 5.44 (m, 1H), 5.25 - 5.09 (m, 4H), 4.61 (brd, J=13.2 Hz, 1H), 3.83 (br d, J=13.6 Hz, 1 H), 3.45 (quin, J=8.4 Hz, 1 H), 3.22 - 3.06 (m, 2H), 2.99 - 2.83 (m, 1 H), 2.62 (td, J=7.6, 11.6 Hz, 2H), 2.25 - 2.16 (m, 2H), 2.16 - 2.04 (m, 2H), 1.93 - 1.78 (m, 2H), 0.52 - 0.45 (m, 2H), 0.45 - 0.37 (m, 2H); LCMS(ESI)[M+H]+:451.9.

¹ H NMR (400MHz, CHLOROFORM-d-d) δ 8.28 (d, J=4.8 Hz, 1 H), 7.20 (dd, J=0.9, 5.3 Hz, 1 H), 7.12 (s, 1 H), 5.51 (quin, J=7.1 Hz, 1 H), 4.94 (t, J=7.2 Hz, 2H), 4.80 (t, J=6.8 Hz, 2H), 3.64 - 3.41 (m, 8H), 3.16 (s, 3H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+:417.1 .

¹ H NMR (300 MHz, Chloroform-d) δ 8.28 - 8.12 (m, 2H), 7.96 - 7.79 (m, 2H), 5.89 (tt, J = 7.6, 6.3 Hz, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.60 (d, J = 13.6 Hz, 1 H), 4.04 (d, J = 14.0 Hz, 1 H), 3.30 (tt, J = 10.6, 3.6 Hz, 2H), 2.96 (t, J = 12.7 Hz, 1 H), 2.84 (h, J = 6.7 Hz, 1 H), 2.22 (s, 2H), 1 .97 (d, J = 14.9 Hz, 2H), 1 .27 - 1 .05 (m, 7H); LCMS (ESI) [M+H]+ 396.6.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.31 (d, J=1 .0 Hz, 1 H), 8.10 (s, 1 H), 7.93 - 7.84 (m, 2H), 5.44 -

5.35 (m, 1 H), 4.63 (br d, J=1 1 .1 Hz, 1 H), 4.34 - 4.25 (m, 1 H), 4.25 - 4.1 7 (m, 2H), 4.10 - 4.00 (m, 2H),

3.36 - 3.08 (m, 2H), 2.98 - 2.78 (m, 2H), 2.62 - 2.49 (m, 2H), 2.14 (m, 2H), 2.01 - 1 .79 (m, 2H), 1 .16 (br d, J=6.7 Hz, 6H); LCMS (ESI) [M+H]+: 41 0.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.28 (d, J=1 .2 Hz, 1 H), 8.03 (dd, J=1 .6, 8.4 Hz, 1 H), 7.40 (d, J=8.4 Hz, 1 H), 5.60 - 5.44 (m, 1 H), 5.25 - 5.09 (m, 4H), 4.61 (br d, J=13.2 Hz, 1 H), 3.83 (br d, J=13.6 Hz, 1 H), 3.45 (quin, J=8.4 Hz, 1 H), 3.22 - 3.06 (m, 2H), 2.99 - 2.83 (m, 1 H), 2.62 (td, J=7.6, 1 1 .6 Hz, 2H), 2.25 - 2.16 (m, 2H), 2.16 - 2.04 (m, 2H), 1 .93 - 1 .78 (m, 2H), 0.52 - 0.45 (m, 2H), 0.45 - 0.37 (m, 2H); LCMS (ESI) [M+H]+: 451 .9.

¹ H NMR (400MHz, CHLOROFORM-d-d) δ 8.28 (d, J=4.8 Hz, 1 H), 7.20 (dd, J=0.9, 5.3 Hz, 1 H), 7.12 (s, 1 H), 5.51 (quin, J=7.1 Hz, 1 H), 4.94 (t, J=7.2 Hz, 2H), 4.80 (t, J=6.8 Hz, 2H), 3.64 - 3.41 (m, 8H), 3.16 (s, 3H), 1 .50 (s, 9H); LCMS (ESI) [M+H]+:417.1 .

¹ H NMR (300 MHz, Chloroform-d) δ 8.28 - 8.12 (m, 2H), 7.96 - 7.79 (m, 2H), 5.89 (tt, J = 7.6, 6.3 Hz, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.60 (d, J = 13.6 Hz, 1 H), 4.04 (d, J = 14.0 Hz, 1 H), 3.30 (tt, J = 10.6, 3.6 Hz, 2H), 2.96 (t, J = 12.7 Hz, 1 H), 2.84 (h, J = 6.7 Hz, 1 H), 2.22 (s, 2H), 1 .97 (d, J = 14.9 Hz, 2H), 1 .27 - 1 .05 (m, 7H); LCMS (ESI) [M+H]+ 396.6.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.31 (d, J=1 .0 Hz, 1 H), 8.10 (s, 1 H), 7.93 - 7.84 (m, 2H), 5.44 -

5.35 (m, 1 H), 4.63 (br d, J=1 1 .1 Hz, 1 H), 4.34 - 4.25 (m, 1 H), 4.25 - 4.1 7 (m, 2H), 4.10 - 4.00 (m, 2H),

3.36 - 3.08 (m, 2H), 2.98 - 2.78 (m, 2H), 2.62 - 2.49 (m, 2H), 2.14 (m, 2H), 2.01 - 1 .79 (m, 2H), 1 .16 (br d, J=6.7 Hz, 6H); LCMS (ESI) [M+H]+: 41 0.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.31 (s, 1 H), 8.21 (s, 1 H), 7.97 - 7.87 (m, 2H), 5.91 (quin, J=6.9 Hz, 1 H), 5.34 (dt, J=3.0, 6.4 Hz, 2H), 5.23 - 5.14 (m, 2H), 4.22 (sxt, J=6.7 Hz, 1 H), 4.01 - 3.90 (m, 1 H), 3.31 (ddd, J=5.6, 10.6, 14.0 Hz, 1 H), 3.23 - 3.13 (m, 1 H), 2.24 - 2.00 (m, 4H), 1 .49 (s, 9H), 1 .09 (d, J=6.6 Hz, 3H); LCMS (ESI) [M-100+H]+: 340.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.06 (s, 1 H), 7.88 (s, 1 H), 7.75 (d, J=8.4 Hz, 1 H), 7.46 (d, J=8.4 Hz, 1H), 6.42 (s, 1H), 5.78 (quin, J=7.0 Hz, 1H), 5.25 (t, J=6.5 Hz, 2H), 5.10 (t, J=7.2 Hz, 2H), 4.12 (br s, 2H), 2.97-2.89 (m, 1H), 2.89 - 2.77 (m, 2H), 1.97 - 1.90 (m, 2H), 1.65 (dq, J=4.3, 12.3 Hz, 2H), 1.42 (s, 9H); LCMS (ESI) [M-56+H]+: 369.1.

H NMR (400MHz, CHLOROFORM-d) δ 8.07 (s, 1H), 7.88 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1 H), 6.42 (s, 1 H), 5.78 (quin, J=7.0 Hz, 1 H), 5.25 (t, J=6.5 Hz, 2H), 5.14 - 5.06 (m, 2H), 4.16 (br s, 2H), 3.66 (s, 3H), 3.00 - 2.86 (m, 3H), 1.96 (brd, J=10.9 Hz, 2H), 1.68 (dq, J=4.2, 12.4 Hz, 2H); LCMS (ESI) [M+H]+: 383.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.31 (d, J=0.7 Hz, 1H), 8.10 (s, 1H), 7.94 - 7.82 (m, 2H), 5.46 5.32 (m, 1H), 4.54 (brd, J=13.2 Hz, 1H), 4.36 - 4.14 (m, 3H), 4.11 - 3.95 (m, 2H), 3.32 - 3.11 (m, 2H), 3.01 (br t, J=12.2 Hz, 1 H), 2.90 - 2.65 (m, 2H), 2.61 - 2.32 (m, 4H), 2.24 - 2.06 (m, 2H), 2.03 - 1.85 (m, 3H), 1.79 - 1.61 (m, 1 H); LCMS (ESI) [M+H]+: 440.3.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.29 (s, 1 H), 8.20 (s, 1 H), 7.95 - 7.85 (m, 2H), 5.91 (quin, J=7.0 Hz, 1H), 5.33 (t, J=6.4 Hz, 2H), 5.22 - 5.14 (m, 2H), 4.55 (brd, J=13.5 Hz, 1H), 4.02 (brd, J=13.7 Hz, 1 H), 3.33 - 3.12 (m, 2H), 3.01 (br t, J=12.2 Hz, 1 H), 2.87 - 2.67 (m, 2H), 2.54 - 2.35 (m, 2H), 2.22 - 2.09 (m, 2H), 2.03 - 1.87 (m, 3H), 1.76 - 1.62 (m, 1 H); LCMS (ESI) [M+H]+: 426.2.

¹ H NMR (300 MHz, Chloroform-d) δ 8.38 (t, J = 1.1 Hz, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.96-7.82 (m, 7.77 (dd, J = 8.5, 1.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 5.90 (ddd, J = 14.1, 7.7, 6.3 Hz, 1H), 5.34 (t, J 6.5 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.30 (s, 2H), 3.1 8 (tt, J = 1 1 .9, 3.7 Hz, 1 H), 2.93 (t, J = 12.7 Hz, 2H), 2.04 (d, J = 12.1 Hz, 2H), 1 .85 (qd, J = 12.5, 4.3 Hz, 2H), 1 .49 (s, 9H); LCMS (ESI) [M+H]+ 436.6.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.29 (d, J=1 .2 Hz, 1 H), 8.03 (dd, J=1 .2, 8.4 Hz, 1 H), 7.41 (d, J=8.4 Hz, 1 H), 5.60 - 5.44 (m, 1 H), 5.25 - 5.10 (m, 4H), 4.36 - 4.05 (m, 2H), 3.73 (s, 3H), 3.15 - 2.92 (m, 3H), 2.08 (br d, J=12.3 Hz, 2H), 1 .96 - 1 .80 (m, 2H); LCMS (ESI) [M+H]+: 401 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.21 (s, 1 H), 8.13 (s, 1 H), 7.88 - 7.77 (m, 2H), 5.83 (quin, J 7.0 Hz, 1 H), 5.25 (t, J 6.5 Hz, 2H), 5.10 (t, J 7.2 Hz, 2H), 4.04 (s, 2H), 3.99 (s, 2H), 3.61 (s, 3H), 3.58 - 3.50 (m, 1 H), 2.66 - 2.53 (m, 4H); LCMS (ESI) [M+H]+: 396.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.32 (s, 1 H), 8.22 (s, 1 H), 8.00 - 7.89 (m, 2H), 5.92 (quin, J 7.0 Hz, 1 H), 5.35 (t, J 6.5 Hz, 2H), 5.20 (t, J 7.3 Hz, 2H), 4.42 (br s, 2H), 4.14 (br s, 2H), 3.66 (br t, J 7.9 Hz, 1 H), 2.76 - 2.65 (m, 4H), 1 .23 (s, 9H); LCMS (ESI) [M+H]+:422.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.20 (s, 1 H), 7.91 - 7.83 (m, 2H), 5.91 (quin, J=7.1 Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.19 (t, J=7.3 Hz, 2H), 4.12 (q, J=1 1 .2 Hz, 2H), 4.01 - 3.79 (m, 6H), 3.78 (s, 3H); LCMS (ESI) [M+H]+: 435.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, 1 H), 8.21 (s, 1 H), 7.91 - 7.83 (m, 2H), 5.91 (quin, J= Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.22 - 5.16 (m, 2H), 4.15 - 4.08 (m, 2H), 3.95 - 3.76 (m, 6H), 2.46 - 2. (m, 2H), 1 .20 - 1 .04 (m, 1 H), 0.68 - 0.53 (m, 2H), 0.22 - 0.16 (m, 2H); LCMS (ESI) [M+H]+: 459.3.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 7.89 (dd, J=1 .3, 8.4 Hz, 1 H), 7.76 (d, J=8.2 Hz, 1 H), 7.72 (d, J=3.3 Hz, 1 H), 6.72 (d, J=3.1 Hz, 1 H), 5.73 (quin, J=6.8 Hz, 1 H), 5.25 (t, J=7.4 Hz, 2H), 5.06 (t, J=6.6 Hz, 2H), 4.20 (br s, 2H), 3.73 (s, 3H), 3.12 - 2.97 (m, 3H), 2.1 1 (br d, J=12.1 Hz, 2H), 1 .97 - 1 .84 (m, 2H); LCMS (ESI) [M+H]+: 383.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.19 (s, 1 H), 7.84 (dd, J=1 .3, 8.2 Hz, 1 H), 7.72 (d, J=8.4 Hz, 1 H), 7.42 (d, J=3.1 Hz, 1 H), 6.60 (d, J=3.1 Hz, 1 H), 4.82 (td, J=6.6, 13.4 Hz, 1 H), 4.23 (br s, 2H), 3.73 (s, 3H), 3.1 1 - 2.97 (m, 3H), 2.1 1 (br d, J=12.3 Hz, 2H), 1 .97 - 1 .84 (m, 2H), 1 .58 (d, J=6.6 Hz, 6H); LCMS (ESI) [M+H]+: 369.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.20 (s, 1 H), 7.91 - 7.84 (m, 2H), 5.91 (quin, J= Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.22 - 5.15 (m, 2H), 4.15 - 4.05 (m, 2H), 3.96 - 3.75 (m, 6H), 2.53 - 2. (m, 2H), 1 .23 - 1 .14 (m, 3H); LCMS (ESI) [M+H]+: 433.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.20 (s, 1 H), 7.89 (dd, J=1 .2, 8.3 Hz, 1 H), 7.78 - 7.69 (m, 2H), 6.72 (d, J=3.3 Hz, 1 H), 5.73 (quin, J=6.8 Hz, 1 H), 5.24 (t, J=7.4 Hz, 2H), 5.06 (t, J=6.6 Hz, 2H), 4.1 8 (br d, J=6.2 Hz, 2H), 3.09 - 2.90 (m, 3H), 2.14 - 2.02 (m, 2H), 1 .94 - 1 .82 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M- 56+H]+: 369.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.25 (s, 1 H), 8.07 (s, 1 H), 7.83 (dd, J=0.7, 7.5 Hz, 1 H), 7.05 (dd, J=1 .5, 7.4 Hz, 1 H), 4.09 ( m, 2H), 3.34 (td, J=6.9, 13.8 Hz, 1 H), 3.03 - 2.78 (m, 3H), 1 .99 (br d, J=1 1 .0 Hz, 2H), 1 .86 - 1 .69 (m, 2H), 1 .41 (s, 9H), 1 .36 (d, J=7.0 Hz, 6H); LCMS (ESI) [M+H]+: 412.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.22 (s, 1 H), 8.20 (s, 1 H), 8.09 (d, J=0.8 Hz, 1 H), 5.92 - 5.82 (m, 1 H), 5.30 (t, J=6.4 Hz, 2H), 5.17 (t, J=7.2 Hz, 2H), 4.17 (br s, 2H), 3.10 - 3.00 (m, 1 H), 2.98 -2.93 (m, 2H), 2.08 -2.05 (m, 2H), 1 .93 - 1 .79 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M-56+H]+: 448.0.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.28 (d, J=0.8 Hz, 1 H), 8.06 (br s, 1 H), 7.86 -7.82 (m, 2H), 5.10 -5.06 (m, 1 H), 4.30 - 4.14 (m, 2H), 3.72 (s, 3H), 3.16 - 2.94 (m, 3H), 2.26 - 2.16 (m, 4H), 2.14 - 2.06 (m, 2H), 2.04 - 1 .97 (m, 2H), 1 .96 - 1 .84 (m, 2H), 1 .83 - 1 .72 (m, 2H); LCMS (ESI) [M+H]+: 396.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.22 (m, 1 H), 8.10 - 8.09 (m, 1 H), 8.08 (m, 1 H), 5.59 -5.82 (m, 1 H), 5.30 (t, J=6.8 Hz, 2H), 5.30 (t, J=7.6 Hz, 2H), 4.20 (br s, 2H), 3.72 (s, 3H), 3.1 0 - 3.00 (m, 3H), 2.1 0 - 2.03 (m, 2H), 1 .92 - 1 .86 (m, 2H); LCMS (ESI) [M+H]+: 462.0.

¹ H NMR (300 MHz, Chloroform-d) δ 8.19 (d, J = 12.9 Hz, 2H), 7.87 (qd, J = 8.5, 1 .1 Hz, 2H), 5.97 - 5.81 (m, 1 H), 5.33 (t, J = 6.5 Hz, 2H), 5.16 (t, J = 7.2 Hz, 2H), 4.56 (d, J = 13.5 Hz, 1 H), 3.82 (d, J = 14.0 Hz, 1 H), 3.39 - 3.12 (m, 3H), 3.04 - 2.89 (m, 1 H), 2.39 (p, J = 9.2 Hz, 2H), 2.26 - 2.14 (m, 4H), 2.09 - 1 .82 (m, 4H); LCMS (ESI) [M+H] 408.5+.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.25 (s, 1 H), 8.07 (s, 1 H), 7.83 (dd, J=0.7, 7.3 Hz, 1 H), 7.05 (dd, J=1 .5, 7.3 Hz, 1 H), 4.24 - 4.00 (m, 2H), 3.65 (s, 3H), 3.34 (td, J=6.9, 13.8 Hz, 1 H), 3.05 - 2.88 (m, 3H), 2.00 (br d, J=1 1 .4 Hz, 2H), 1 .88 - 1 .72 (m, 2H), 1 .36 (d, J=7.0 Hz, 6H); LCMS (ESI) [M+H]+: 370.1 .

¹ H NMR (400 MHz, DMSO) δ 8.45 (s, 1 H), 8.41 (s, 1 H), 8.00 (dd, J=1 .4, 8.5 Hz, 1 H), 7.79 (d, J=8.4 Hz, 1 H), 6.33 - 6.22 (m, 1 H), 5.03 (d, J=6.8 Hz, 4H), 4.22 - 3.87 (m, 4H), 3.83 - 3.73 (m, 2H), 3.68 (q, J=5.1 Hz, 2H), 3.46 - 3.40 (m, 1 H), 2.20 - 2.04 (m, 4H), 1 .96 - 1 .82 (m, 1 H), 1 .79 - 1 .65 (m, 1 H); LCMS (ESI) [M+H]+: 459.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 9.34 (d, J=1 .5 Hz, 1 H), 8.63 (s, 1 H), 8.46 (s, 1 H), 5.88 (quin, J=6.9 Hz, 1 H), 5.35 - 5.28 (m, 2H), 5.24 - 5.15 (m, 2H), 4.20 (br d, J=9.7 Hz, 2H), 3.08 (tt, J=3.7, 1 1 .2 Hz, 1 H), 2.97 (br s, 2H), 2.09 (br d, J=1 1 .0 Hz, 2H), 1 .95 - 1 .81 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-56+H]+: 371 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.19 (s, 1 H), 7.85 (dd, J=1 .3, 8.4 Hz, 1 H), 7.72 (d, J=8.4 Hz, 1 H), 7.42 (d, J=3.1 Hz, 1 H), 6.60 (d, J=3.1 Hz, 1 H), 4.87 - 4.76 (m, 1 H), 4.18 (br d, J=5.7 Hz, 2H), 3.09 2.88 (m, 3H), 2.15 - 2.04 (m, 2H), 1 .95 - 1 .82 (m, 2H), 1 .58 (d, J=6.6 Hz, 6H), 1 .49 (s, 9H); LCMS (ESI) [M-56+H]+: 355.1 .

¹ H NMR (400MHz, CHLOROFORM-d-d) δ 8.31 (d, J=0.9 Hz, 1 H), 8.1 1 (s, 1 H), 7.96 - 7.84 (m, 2H), 5.50 - 5.33 (m, 1 H), 4.63 (br d, J=13.4 Hz, 1 H), 4.36 - 4.17 (m, 3H), 4.09 - 4.02 (m, 1 H), 3.97 (br d, J=13.6 Hz, 1 H), 3.31 - 3.21 (m, 1 H), 3.16 (tt, J=3.9, 10.9 Hz, 1 H), 2.97 - 2.84 (m, 1 H), 2.60 - 2.51 (m, 2H), 2.41 (q, J=7.5 Hz, 2H), 2.21 - 2.09 (m, 2H), 1 .98 - 1 .79 (m, 2H), 1 .19 (t, J=7.5 Hz, 3H); LCMS (ESI) [M+H]+:396.2.

¹ H NMR (400MHz, CHLOROFORM-d -d) δ 8.32 (d, J=0.7 Hz, 1 H), 8.1 1 (s, 1 H), 7.94 - 7.84 (m, 2H), 5.44 - 5.34 (m, 1 H), 4.63 (br d, J=13.7 Hz, 1 H), 4.35 - 4.17 (m, 3H), 4.10 - 4.02 (m, 1 H), 3.97 (br d, J=13.2 Hz, 1 H), 3.32 - 3.21 (m, 1 H), 3.16 (tt, J=3.9, 10.9 Hz, 1 H), 2.91 (br t, J=1 1 .4 Hz, 1 H), 2.62 - 2.50 (m, 2H), 2.41 (q, J=7.5 Hz, 2H), 2.23 - 2.08 (m, 2H), 2.01 - 1 .78 (m, 2H), 1 .19 (t, J=7.5 Hz, 3H); LCMS (ESI)

[M+H]+:396.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.08 (s, 1 H), 7.91 - 7.79 (m, 2H), 4.99 (td, J=6.6, 13.3 Hz, 1 H), 3.32 - 3.1 7 (m, 1 H), 3.15 - 2.99 (m, 3H), 2.80 (br t, J=1 1 .1 Hz, 1 H), 2.62 (br t, J=1 1 .0 Hz, 1 H), 2.24 - 2.12 (m, 2H), 2.09 - 1 .94 (m, 2H), 1 .65 (d, J=6.7 Hz, 6H), 1 .30 (d, J=7.1 Hz, 3H); LCMS (ESI) [M+H]+:408.2.

¹ H NMR (400MHz,CHLOROFORM-d) δ 9.33 (d, J=1 .5 Hz, 1 H), 8.63 (s, 1 H), 8.45 (s, 1 H), 5.92 - 5.84 (m, 1 H), 5.31 (t, J=6.5 Hz, 2H), 5.24 - 5.17 (m, 2H), 4.21 (br s, 2H), 3.74 (s, 3H), 3.17 - 2.99 (m, 3H), 2.1 1 (br d, J=1 1 .2 Hz, 2H), 1 .97 - 1 .84 (m, 2H); LCMS (ESI) [M+H]+: 385.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.21 (s, 1 H), 7.96 - 7.86 (m, 2H), 5.91 (quin, J=6.9 Hz, 1 H), 5.33 (t, J=6.5 Hz, 2H), 5.18 (t, J=7.4 Hz, 2H), 5.06 - 4.78 (m, 1 H), 4.63 - 4.30 (m, 1 H), 3.42 (br s, 1 .5H), 3.04 (br s, 0.5H), 2.25 - 1 .78 (m, 4H), 1 .50 - 1 .1 8 (m, 7H); LCMS (ESI) [M+H]+: 426.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.21 (s, 1 H), 7.97 - 7.85 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.23 - 5.13 (m, 2H), 4.66 (br s, 1 H), 4.20 (br s, 1 H), 3.74 (s, 3H), 3.28 (tt, J=3.9, 12.2 Hz, 1 H), 3.1 0 (br t, J=12.9 Hz, 1 H), 2.17 - 1 .95 (m, 3H), 1 .81 (dq, J=4.6, 12.9 Hz, 1 H), 1 .30 (d, J=7.1 Hz, 3H); LCMS (ESI) [M+H]+: 398.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.21 (s, 1 H), 7.96 - 7.87 (m, 2H), 5.91 (quin, J=6.9 Hz, 1 H), 5.33 (t, J=6.5 Hz, 2H), 5.22 - 5.12 (m, 2.6H), 4.76 (br d, J=12.6 Hz, 0.4H), 4.45 (br s, 0.4H), 3.94 (br d, J=13.2 Hz, 0.6H), 3.44 - 3.28 (m, 1 .6H), 2.92 - 2.76 (m, 1 .4H), 2.23 - 1 .69 (m, 4H), 1 .44 - 1 .24 (m, 3H), 1 .22 - 1 .08 (m, 6H); LCMS (ESI) [M+H]+: 410.2.

Ή NMR (400 MHz, CHLOROFORM-d) δ 8.28 (s, H), 8. 9 (s, H), 7.94 - 7.84 (m, 2H), 5.89 (quin, J=6.9 Hz, 1 H), 5.32 (t, J=6.5 Hz, 2H), 5.17 (t, J=7.3 Hz, 2H), 5.13 - 5.06 (m, 0.5H), 4.69 (br d, J=14.3 Hz, 0.5H), 4.19 (br s, 0.5H), 3.67 (br d, J=13.9 Hz, 0.5H), 3.41 - 3.15 (m, 2.5H), 2.93 - 2.78 (m, 0.5H), 2.50 - 2.28 (m, 2H), 2.26 - 2.07 (m, 3H), 2.05 - 1 .68 (m, 5H), 1 .37 - 1 .23 (m, 3H); LCMS (ESI) [M+H]+: 422.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, 1 H), 8.21 (s, 1 H), 7.92 - 7.86 (m, 2H), 5.91 (quin, J=6.9 Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.19 (t, J=7.3 Hz, 2H), 4.30 - 3.86 (m, 8H), 1 .44 - 1 .25 (m, 4H); LCMS (ESI) [M+H]+: 463.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.21 (s, 1 H), 7.96 - 7.86 (m, 2H), 5.95 - 5.87 (m, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.23 - 5.12 (m, 2.6H), 4.76 (br d, J=1 5.4 Hz, 0.4H), 4.45 (br s, 0.4H), 3.94 (br d, J=13.7 Hz, 0.6H), 3.43 - 3.28 (m, 1 .6H), 2.93 - 2.77 (m, 1 .4H), 2.22 - 1 .69 (m, 4H), 1 .43 - 1 .25 (m, 3H), 1 .22 - 1 .10 (m, 6H); LCMS (ESI) [M+H]+: 410.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.21 (s, 1 H), 7.97 - 7.87 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.33 (t, J=6.5 Hz, 2H), 5.25 - 5.12 (m, 2H), 4.67 (br s, 1 H), 4.1 9 (br s, 1 H), 3.74 (s, 3H), 3.28 (tt, J=3.9, 12.1 Hz, 1 H), 3.1 5 - 3.02 (m, 1 H), 2.1 9 - 1 .94 (m, 3H), 1 .82 (dq, J=4.6, 12.9 Hz, 1 H), 1 .30 (d, J=7.1 Hz, 3H); LCMS (ESI) [M+H]+: 398.1 .

¹ H NMR (400MHz, DMSO-d6) δ 8.62 (s, 1 H), 8.43 (s, 1 H), 8.04 (d, J=8.4 Hz, 1 H), 7.87 (dd, J=1 .1 , 8.4 Hz, 1 H), 6.1 6 - 6.01 (m, 1 H), 4.93 - 4.84 (m, 2H), 4.81 - 4.73 (m, 2H), 4.1 1 - 3.83 (m, 2H), 3.20 - 3.10 (m, 1 H), 3.00 (br s, 2H), 2.02 (br d, J=1 1 .5 Hz, 2H), 1 .72 - 1 .58 (m, 2H), 1 .49 (s, 3H), 0.83 - 0.75 (m, 2H), 0.65 - 0.58 (m, 2H); LCMS (ESI) [M+H]+: 472.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.27 (s, 1 H), 8.10 (s, 1 H), 7.57 (d, J=9.9 Hz, 1 H), 5.89 (quin, J=7.0 Hz, 1 H), 5.31 (t, J=6.5 Hz, 2H), 5.24 - 5.10 (m, 2H), 4.60 (br d, J=13.7 Hz, 1 H), 3.82 (br d, J=13.5 Hz, 1 H), 3.31 (quin, J=8.6 Hz, 1 H), 3.22 - 3.04 (m, 2H), 2.96 - 2.83 (m, 1 H), 2.46 - 2.31 (m, 2H), 2.24 - 1 .78 (m, 8H); LCMS (ESI) [M+H]+: 426.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.27 (s, 1 H), 8.1 1 (s, 1 H), 7.58 (dd, J=0.7, 9.9 Hz, 1 H), 5.94 - 5.84 (m, 1 H), 5.32 (t, J=6.6 Hz, 2H), 5.23 - 5.14 (m, 2H), 4.45 (br s, 2H), 3.43 - 3.00 (m, 3H), 2.18 (br dd, J=3.1 , 13.5 Hz, 2H), 2.08 - 1 .89 (m, 2H), 1 .37 - 1 .19 (m, 4H); LCMS (ESI) [M+H]+: 430.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.23 (d, J=1 .0 Hz, 1 H), 8.20 (s, 1 H), 7.87 (d, J=1 .0 Hz, 2H), 5.94 - 5.86 (m, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.17 (t, J=7.4 Hz, 2H), 4.29 (s, 4H), 4.21 (s, 4H), 3.70 (s, 3H); LCMS (ESI) [M+H]+: 397.1 .

¹ H NMR (400MHz, DMSO-d6) δ 8.43 - 8.36 (m, 1 H), 7.62 (dd, J=1 .2, 5.3 Hz, 1 H), 7.47 (s, 1 H), 5.64 (q, J=5.6 Hz, 1 H), 4.92 (t, J=7.2 Hz, 2H), 4.60 (dd, J=5.2, 7.6 Hz, 2H), 3.99 (br d, J=12.2 Hz, 2H), 3.61 (s, 3H), 3.1 7 (tt, J=3.6, 1 1 .2 Hz, 1 H), 3.12 - 2.93 (m, 2H), 2.02 (br d, J=10.8 Hz, 2H), 1 .73 - 1 .57 (m, 2H); LCMS (ESI) [M+H]+: 361 .2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (d, J=0.7 Hz, 1 H), 8.21 (s, 1 H), 7.98 - 7.86 (m, 2H), 5.95 - 5.87 (m, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.23 - 5.14 (m, 2H), 5.08 - 4.80 (m, 1 H), 4.64 - 4.31 (m, 1 H), 3.41 (br s, 1 .5H), 3.04 (br s, 0.5H), 2.25 - 1 .76 (m, 4H), 1 .50 - 1 .19 (m, 7H); LCMS (ESI) [M+H]+: 426.1 .

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.21 (s, 1 H), 7.95 - 7.82 (m, 2H), 5.91 (quin, J=7.0 Hz, 1 H), 5.33 (t, J=6.5 Hz, 2H), 5.18 (t, J=7.3 Hz, 2H), 5.15 - 5.07 (m, 0.5H), 4.76 - 4.66 (m, 0.5H), 4.27 - 4.13 (m, 0.5H), 3.68 (br d, J=12.3 Hz, 0.5H), 3.41 - 3.20 (m, 2.5H), 2.88 (dt, J=2.9, 13.6 Hz, 0.5H), 2.51 - 2.31 (m, 2H), 2.26 - 2.09 (m, 3H), 2.06 - 1 .69 (m, 5H), 1 .37 - 1 .25 (m, 3H); LCMS (ESI) [M+H]+: 422.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.28 (s, 1 H), 8.1 1 (s, 1 H), 7.58 (d, J=9.9 Hz, 1 H), 5.89 (quin, J=7.0 Hz, 1 H), 5.32 (t, J=6.6 Hz, 2H), 5.22 - 5.15 (m, 2H), 4.59 (br s, 1 H), 4.33 (br s, 1 H), 3.36 (br s, 1 H), 3.18 (tt, J=3.9, 10.9 Hz, 1 H), 2.94 (br s, 1 H), 2.16 (br s, 2H), 2.06 - 1 .84 (m, 2H), 1 .84 - 1 .76 (m, 1 H), 1 .02 (br s, 2H), 0.80 (dd, J=3.0, 8.0 Hz, 2H); LCMS (ESI) [M+H]+: 412.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.27 (s, 1 H), 8.10 (s, 1 H), 7.58 (d, J=9.8 Hz, 1 H), 5.89 (quin, J=7.0 Hz, 1 H), 5.32 (t, J=6.5 Hz, 2H), 5.22 - 5.16 (m, 2H), 4.64 (br d, J=13.2 Hz, 1 H), 4.05 (br d, J=13.0 Hz, 1 H), 3.28 (br t, J=12.0 Hz, 1 H), 3.16 (tt, J=3.9, 1 1 .0 Hz, 1 H), 2.95 - 2.80 (m, 2H), 2.16 (br s, 2H), 1 .99 - 1 .79 (m, 2H), 1 .1 7 (br s, 6H); LCMS (ESI) [M+H]+: 414.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.27 (s, 1 H), 8.10 (s, 1 H), 7.62 - 7.54 (m, 1 H), 5.94 - 5.83 (m, 1 H), 5.32 (t, J=6.6 Hz, 2H), 5.22 - 5.14 (m, 2H), 4.35 - 3.99 (m, 2H), 3.12 - 2.91 (m, 3H), 2.08 (br d, J=1 1 .5 Hz, 2H), 1 .94 - 1 .79 (m, 2H), 1 .58 (s, 3H), 0.93 - 0.86 (m, 2H), 0.69 - 0.62 (m, 2H); LCMS (ESI) [M+H]+: 442.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.19 (s, 1 H), 8.10 (s, 1 H), 7.70 (s, 1 H), 5.87 (quin, J=6.8 Hz, 1 H), 5.32 (t, J=6.4 Hz, 2H), 5.16 (t, J=7.2 Hz, 2H), 4.21 (br s, 2H), 3.73 (s, 3H), 3.13 - 2.93 (m, 3H), 2.69 (s, 3H), 2.09 (br d, J=12.8 Hz, 2H), 1 .98 - 1 .79 (m, 2H); LCMS (ESI) [M+H]+: 398.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.27 (s, 1 H), 8.10 (s, 1 H), 7.57 (d, J=9.9 Hz, 1 H), 5.88 (quin, J=6.9 Hz, 1 H), 5.32 (t, J=6.6 Hz, 2H), 5.22 - 5.15 (m, 2H), 4.34 - 4.04 (m, 3H), 3.13 - 2.96 (m, 3H), 2.15 - 2.01 (m, 2H), 1 .88 (br d, J=9.5 Hz, 2H), 0.76 - 0.65 (m, 4H); LCMS (ESI) [M+H]+: 428.2.

¹ H NMR (400MHz, CHLOROFORM-d-d) δ 8.27 (s, 1 H), 8.10 (s, 1 H), 7.58 (dd, J=0.8, 9.8 Hz, 1 H), 6.01 - 5.80 (m, 1 H), 5.32 (t, J=6.6 Hz, 2H), 5.23 - 5.13 (m, 2H), 4.63 (br d, J=13.3 Hz, 1 H), 3.97 (br d, J=13.8 Hz, 1 H), 3.36 - 3.09 (m, 2H), 2.98 - 2.81 (m, 1 H), 2.41 (q, J=7.5 Hz, 2H), 2.23 - 2.05 (m, 2H), 1 .98 - 1 .76 (m, 2H), 1 .19 (t, J=7.5 Hz, 3H); LCMS (ESI) [M+H]+:400.1 .

¹ H NMR (400MHz, DMSO-d6) δ 8.09 (s, 1 H), 8.04 (s, 1 H), 7.47 (d, J=9.9 Hz, 1 H), 5.33 - 5.26 (m, 1 H), 4.25 - 4.16 (m, 2H), 4.14 (d, J=5.1 Hz, 2H), 4.12 - 3.94 (m, 2H), 3.66 (s, 3H), 3.05 - 2.99 (m, 1 H), 2.99 - 2.89 (m, 2H), 2.55 - 2.42 (m, 2H), 2.02 (br d, J=1 1 .4 Hz, 2H), 1 .88 - 1 .76 (m, 2H); LCMS (ESI) [M+H]+: 416.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.15 (s, 1 H), 8.12 (s, 1 H), 7.79 (d, J=0.9 Hz, 2H), 5.82 (quin, J=7.0 Hz, 1 H), 5.25 (t, J=6.6 Hz, 2H), 5.09 (t, J=7.3 Hz, 2H), 4.20 (s, 4H), 4.06 (s, 4H), 1 .38 (s, 9H); LCMS (ESI) [M+H]+: 439.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.10 (s, 1 H), 8.04 (s, 1 H), 7.48 (d, J=9.9 Hz, 1 H), 5.34 - 5.26 (m, 1 H), 4.26 - 4.16 (m, 2H), 4.15 - 4.12 (m, 2H), 3.98 (dt, J=6.1 , 8.2 Hz, 2H), 3.03 - 2.95 (m, 1 H), 2.89 (br s, 2H), 2.55 - 2.41 (m, 2H), 2.01 (br d, J=1 1 .7 Hz, 2H), 1 .85 - 1 .74 (m, 2H), 1 .42 (s, 9H); LCMS (ESI)

[M+23]+: 480.2, [M-56+H]: 402.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.16 (s, 1 H), 7.80 (s, 1 H), 7.14 (s, 1 H), 5.77 (quin, J=7.0 Hz, 1 H), 5.24 (t, J=6.5 Hz, 2H), 5.08 (t, J=7.2 Hz, 2H), 4.20 - 4.04 (m, 2H), 4.00 (s, 3H), 3.02 - 2.94 (m, 1 H), 2.89 (br t, J=1 1 .9 Hz, 2H), 2.01 (br d, J=1 1 .2 Hz, 2H), 1 .87 - 1 .73 (m, 2H), 1 .42 (s, 9H); LCMS (ESI) [M- 56+H]+: 400.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.26 (s, 1 H), 8.12 (s, 1 H), 7.94 - 7.85 (m, 2H), 5.27 (quin, J=7.6 Hz, 1 H), 4.21 (br s, 2H), 3.73 (s, 3H), 3.10 - 3.00 (m, 3H), 2.97 - 2.69 (m, 2H), 2.66 - 2.51 (m, 1 H), 2.44 (q, J=7.5 Hz, 2H), 2.37 - 2.20 (m, 1 H), 2.10 -2.04 (m, 2H), 1 .97 - 1 .83 (m, 2H); LCMS (ESI) [M+H]+: 446.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.26 (s, 1 H), 8.16 (s, 1 H), 7.97 - 7.74 (m, 2H), 5.56 (quin, J=7.2 Hz, 1 H), 4.20 (br s, 2H), 3.72 - 3.60 (m, 6H),3.30 - 3.1 1 (m, 1 H), 3.08 - 3.00 (m, 3H), 2.95 - 2.7(m, 2H), 2.20 - 1 .99 (m, 2H), 1 .97 - 1 .84 (m, 2H); LCMS (ESI) [M+H]+: 432.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.67 - 7.57 (m, 2H), 7.42 (t, J=7.9 Hz, 1 H), 7.13 (dd, J=2.1 , 8.3 Hz, 1 H), 4.58 (br d, J=13.3 Hz, 1 H), 3.97 - 3.86 (m, 4H), 3.81 (br d, J=13.7 Hz, 1 H), 3.36 - 3.24 (m, 5H), 3.20 - 3.07 (m, 2H), 2.94 - 2.83 (m, 1 H), 2.40 (quin, J=9.0 Hz, 2H), 2.25 - 2.15 (m, 2H), 2.15 - 2.07 (m, 2H), 2.05 - 1 .89 (m, 2H), 1 .89 - 1 .80 (m, 2H); LCMS (ESI) [M+H]+: 397.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.69 - 7.58 (m, 2H), 7.43 (t, J=7.9 Hz, 1 H), 7.14 (dd, J=2.0, 8.3 Hz, 1 H), 4.45 (br d, J=9.5 Hz, 2H), 3.96 - 3.87 (m, 4H), 3.39 - 3.04 (m, 7H), 2.18 (br d, J=1 0.8 Hz, 2H), 2.09 - 1 .89 (m, 2H), 1 .37 - 1 .21 (m, 4H); LCMS (ESI) [M+H]+: 401 .2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.77 (d, J=5.0 Hz, 1 H), 7.96 (s, 1 H), 7.80 (d, J=4.9 Hz, 1 H), 4.22 (br s, 2H), 3.75 (s, 3H), 3.1 7 - 2.97 (m, 3H), 2.86 (d, J=7.0 Hz, 2H), 2.10 (br d, J=12.8 Hz, 2H), 1 .99 - 1 .81 (m, 2H), 1 .26 - 1 .13 (m, 1 H), 0.71 - 0.58 (m, 2H), 0.38 - 0.27 (m, 2H); LCMS (ESI) [M+H]+:343.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.77 (d, J=5.1 Hz, 1 H), 7.96 (s, 1 H), 7.81 (d, J=4.8 Hz, 1 H), 4.20 (br s, 2H), 3.16 - 2.92 (m, 3H), 2.86 (d, J=7.1 Hz, 2H), 2.08 (br d, J=1 1 .2 Hz, 2H), 1 .97 - 1 .78 (m, 2H), 1 .50 (s, 9H), 1 .25 - 1 .13 (m, 1 H), 0.67 - 0.58 (m, 2H), 0.32 (q, J=4.8 Hz, 2H); LCMS (ESI)

[M+H]+:385.2.

¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (s, 1 H), 8.20 (s, 1 H), 7.91 - 7.85 (m, 2H), 5.91 (quin, J Hz, 1 H), 5.33 (t, J=6.6 Hz, 2H), 5.23 - 5.15 (m, 2H), 4.21 - 4.04 (m, 3H), 4.02 - 3.66 (m, 6H), 0.74 (d, J=3.5 Hz, 4H); LCMS (ESI) [M+H]+: 461 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.21 (s, 1H), 8.10 (s, 1H), 7.90 - 7.80 (m, 2H), 5.43 - 5.34 (m, 1 H), 4.97 (q, J=7.4 Hz, 1 H), 4.34 - 4.26 (m, 1 H), 4.25 - 4.15 (m, 4H), 4.11 - 4.00 (m, 1 H), 3.23 (tt, J=3.8, 11.0 Hz, 1 H), 3.06 (br s, 2H), 2.59 - 2.51 (m, 2H), 2.42 - 2.31 (m, 2H), 2.17 (br dd, J=2.8, 13.4 Hz, 2H), 2.13 - 2.02 (m, 2H), 2.01 - 1.88 (m, 2H), 1.79 (q, J=10.4 Hz, 1H), 1.69 - 1.56 (m, 1H); LCMS (ESI)

[M+H]+: 438.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.53 (s, 1 H), 8.40 (s, 1 H), 8.30 (s, 1 H), 5.96 -5.89 (m, 1 H), 5.30 (t, J=7.2 Hz, 2H), 5.20 (t, J=7.2 Hz, 2H), 4.21 (br s, 2H), 3.73 (s, 3H), 3.10 - 3.00 (m, 3H), 2.10-1.93 (m, 2H), 1.92 - 1.84 (m, 2H); LCMS (ESI) [M+H]+: 409.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.34 (s, 1 H), 7.20 (s, 1 H), 6.69 (br d, J=11.6 Hz, 1 H), 4.09 (br s, 2H), 3.84 - 3.78 (m, 4H), 3.20 - 3.15 (m, 4H), 2.99 - 2.93 (m, 1 H), 2.89 (br d, J=15.3 Hz, 2H), 1.98 (br d, J=12.2 Hz, 2H), 1.82 - 1.74 (m, 2H), 1.41 (s, 9H); LCMS (ESI) [M-100+H]+: 333.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.79 (d, J=5.1 Hz, 1 H), 7.89 (s, 1 H), 7.81 (dd, J=1.3, 5.1 Hz, 1H), 4.45 (br s, 2H), 4.23 (t, J=8.2 Hz, 1H), 4.13 (dt, J=5.2, 8.3 Hz, 1H), 4.04 - 3.93 (m, 2H), 3.71 (quin, J=7.6 Hz, 1H), 3.50 - 2.86 (m, 3H), 2.50 - 2.39 (m, 1H), 2.28 (qd, J=7.6, 12.3 Hz, 1H), 2.21 -2.14(m,2H), 1.96 (br d, J=10.8 Hz, 2H), 1.39 - 1.12 (m, 4H); LCMS (ESI) [M+H]+:387.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 9.12 (s, 1 H), 8.19 (s, 1 H), 8.15 (s, 1 H), 6.74 (s, 1 H), 4.92 (quin,

J=6.7 Hz, 1H), 4.22 (br s, 2H), 3.73 (s, 3H), 3.11 -2.94 (m, 3H), 2.13 (br d, J=11.2 Hz, 2H), 1.81 - 1.66 (m, 2H), 1.63 (d, J=6.6 Hz, 6H); LCMS (ESI) [M+H]+:370.1.

¹ H NMR (400MHz, CHLOROFORM-d) 5 9.12 (d, J=0.9 Hz, 1 H), 8.19 (s, 1 H), 8.15 (s, 1 H), 6.74 (s, 1 H), 4.92 (td, J=6.6, 13.4 Hz, 1 H), 4.67 (br d, J=13.9 Hz, 1 H), 3.96 (br d, J=14.1 Hz, 1 H), 3.23 (br t, J=1 1 .7 Hz, 1 H), 3.1 8 - 3.08 (m, 1 H), 2.85 (br t, J=1 1 .7 Hz, 1 H), 2.40 (q, J=7.4 Hz, 2H), 2.1 8 (br t, J=13.7 Hz, 2H), 1 .82 - 1 .69 (m, 2H), 1 .63 (d, J=6.6 Hz, 6H), 1 .18 (t, J=7.5 Hz, 3H); LCMS (ESI) [M+H]+:368.2.

¹ H NMR (400MHz, CHLOROFORM-d) 5 = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .3, 5.1 Hz, 1 H), 4.64 (br d, J=13.7 Hz, 1 H), 4.23 (t, J=8.0 Hz, 1 H), 4.13 (dt, J=5.2, 8.4 Hz, 1 H), 4.09 - 3.94 (m, 3H), 3.71 (quin, J=7.6 Hz, 1 H), 3.32 - 3.12 (m, 2H), 2.93 - 2.80 (m, 2H), 2.49 - 2.39 (m, 1 H), 2.33 - 2.23 (m, 1 H), 2.1 9 - 2.09 (m, 2H), 1 .97 - 1 .77 (m, 2H), 1 .16 (br d, J=5.1 Hz, 6H); LCMS (ESI) [M+H]+:371 .2.

¹ H NMR (400MHz, CHLOROFORM-d) 5 8.14 (s, 1 H), 8.09 (s, 1 H), 7.85 - 7.81 (d,J=8.4 1 H), 7.79 - 7.74 (d,J=8.4 1 H), 5.87 - 5.76 (m, 1 H), 5.26 (t, J=6.7 Hz, 2H), 5.08 (t, J=7.3 Hz, 2H), 3.21 - 3.08 (m, 1 H), 3.05 2.91 (m, 3H), 2.71 (br t, J=10.8 Hz, 1 H), 2.53 (br t, J=1 1 .1 Hz, 1 H), 2.15 - 2.01 (m, 2H), 1 .99 - 1 .83 (m, 2H), 1 .21 (d, J=7.1 Hz, 3H); LCMS (ESI) [M+H]+:422.2.

¹ H NMR (400MHz, CHLOROFORM-d) 5 = 8.31 (s, 1 H), 8.1 1 (s, 1 H), 7.95 - 7.85 (m, 2H), 5.46 - 5.36 (m, 1 H), 4.38 - 4.1 1 (m, 5H), 4.09 - 3.98 (m, 1 H), 3.15 - 2.89 (m, 3H), 2.63 - 2.49 (m, 2H), 2.09 (br d, J=1 1 .9 Hz, 2H), 1 .98 - 1 .81 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-56+H]+:384.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.31 (s, 1 H), 8.1 1 (s, 1 H), 7.94 - 7.83 (m, 2H), 5.45 - 5.34 (m, 1 H), 4.60 (br d, J=13.2 Hz, 1 H), 4.36 - 4.25 (m, 1 H), 4.25 - 4.17 (m, 2H), 4.10 - 4.01 (m, 1 H), 3.82 (br d, J=13.7 Hz, 1 H), 3.31 (quin, J=8.6 Hz, 1 H), 3.21 - 3.08 (m, 2H), 2.95 - 2.84 (m, 1 H), 2.59 - 2.51 (m, 2H), 2.46 - 2.32 (m, 2H), 2.24 - 2.08 (m, 4H), 2.05 - 1 .94 (m, 1 H), 1 .93 - 1 .80 (m, 3H); LCMS (ESI)

[M+H]+:422.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.31 (s, 1 H), 8.10 (s, 1 H), 7.93 - 7.83 (m, 2H), 5.43 (quin, J=7.2 Hz, 1 H), 4.40 - 4.09 (m, 4H), 3.73 (s, 3H), 3.19 - 2.91 (m, 3H), 2.54 - 2.35 (m, 2H), 2.10 (br d, J=1 1 .2 Hz, 2H),1 .96 - 1 .84 (m, 2H), 1 .52 (s, 3H), 1 .40 (s, 3H) ; LCMS (ESI) [M+H]+:426.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.55 (s, 1 H), 8.15 (s, 1 H), 7.77 (s, 2H), 5.37 - 5.26 (m, 1 H), 4.41 - 4.29 (m, 2H), 4.1 8 (br s, 2H), 3.72 (s, 3H), 3.13 - 2.94 (m, 3H), 2.59 - 2.46 (m, 1 H), 2.39 (br dd, J=5.2, 13.2 Hz, 1 H), 2.09 (br d, J=12.0 Hz, 2H), 1 .97 - 1 .77 (m, 2H), 1 .46 (s, 3H), 1 .37 (s, 3H); LCMS (ESI) [M+H]+:426.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.32 (d, J=0.6 Hz, 1 H), 8.1 1 (s, 1 H), 7.94 - 7.84 (m, 2H), 5.45 - 5.35 (m, 1 H), 4.46 (br d, J=8.8 Hz, 2H), 4.34 - 4.17 (m, 3H), 4.1 1 - 4.00 (m, 1 H), 3.51 - 2.91 (m, 3H), 2.63 - 2.49 (m, 2H), 2.1 9 (br dd, J=3.0, 13.5 Hz, 2H), 2.00 (br d, J=10.1 Hz, 2H), 1 .39 - 1 .17 (m, 4H); LCMS (ESI) [M+H]+:426.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .4, 5.0 Hz, 1 H), 4.54 (br d, J=12.6 Hz, 1 H), 4.23 (t, J=8.0 Hz, 1 H), 4.13 (dt, J=5.1 , 8.3 Hz, 1 H), 4.06 - 3.94 (m, 3H), 3.71 (quin, J=7.6 Hz, 1 H), 3.29 - 3.13 (m, 2H), 3.00 (br t, J=12.5 Hz, 1 H), 2.87 - 2.66 (m, 2H), 2.55 - 2.36 (m, 3H), 2.28 (qd, J=7.6, 12.4 Hz, 1 H), 2.20 - 2.06 (m, 2H), 2.00 - 1 .84 (m, 3H), 1 .69 (qd, J=8.9, 17.9 Hz, 1 H); LCMS (ESI) [M+H]+:401 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1.3, 5.1 Hz, 1 H), 4.23 (t, J=8.0 Hz, 2H), 4.17 - 4.03 (m, 3H), 4.02 - 3.94 (m, 2H), 3.71 (quin, J=7.6 Hz, 1 H), 3.16 - 2.93 (m, 3H), 2.50 - 2.38 (m, 1 H), 2.34 - 2.22 (m, 1 H), 2.07 (br d, J=11.2 Hz, 2H), 1.86 (br d, J=11.5 Hz, 2H), 0.75 - 0.67 (m, 4H); LCMS (ESI) [M+H]+:385.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.81 (dd, J=1.2, 5.0 Hz, 1H), 7.47-7.36 (m, 2H), 7.26 - 7.19 (m, 1H), 7.12 (t, J=9.0 Hz, 1H), 4.74 (brd, J=13.2 Hz, 1H), 4.23 (t, J=8.0 Hz, 1H), 4.13 (dt, J=5.1, 8.3 Hz, 1H), 4.03 - 3.93 (m, 2H), 3.78 - 3.64 (m, 2H), 3.38 - 3.05 (m, 3H), 2.51 - 2.38 (m, 1H), 2.35 - 2.18 (m, 2H), 2.12 - 1.80 (m, 3H); LCMS (ESI) [M+H]+:423.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.79 (d, J=4.9 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1.2, 5.2 Hz, 1H), 4.63 (brd, J=13.2 Hz, 1H), 4.23 (t, J=8.0 Hz, 1H), 4.13 (dt, J=5.1, 8.3 Hz, 1H), 3.97 (quin, J=7.6 Hz, 3H), 3.71 (quin, J=7.6 Hz, 1H), 3.31 - 3.10 (m, 2H), 2.91 (br t, J=12.1 Hz, 1 H), 2.50 - 2.39 (m, 1H), 2.33 (d, J=6.6 Hz, 2H), 2.31 - 2.22 (m, 1H), 2.20 - 2.07 (m, 2H), 1.97 - 1.79 (m, 2H), 1.14-1.02 (m, 1H), 0.63 - 0.55 (m, 2H), 0.25 - 0.18 (m, 2H); LCMS (ESI) [M+H]+:383.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.30 (s, 1 H), 8.13 (s, 1 H), 7.92 - 7.83 (m, 2H), 5.41 (t, J=8.4 Hz, 1 H), 4.20 (br s, 2H), 3.78 - 3.66 (m, 4H), 3.59 -3.53 (m, 1 H), 3.12 - 2.97 (m, 6H), 2.82 - 2.63 (m, 2H), 2.09 (br d, J=11.2 Hz, 2H), 1.96 - 1.82 (m, 2H); LCMS (ESI) [M+H]+:425.2. ¹ H NMR (400MHz, CHLOROFORM-d) δ 8.54 (d, J=0.9 Hz, 1 H), 8.22 (br s, 1 H), 7.82 - 7.73 (m, 2H), 5.27 -5.18(m, 1H), 4.18 (brs, 2H), 3.78 -3.73 (m, 1H), 3.72 (s, 3H), 3.61 -3.49 (m, 1 H), 3.11 -3.01 (m, 3H), 3.00 (s, 3H), 2.97 - 2.85 (m, 1 H), 2.85 - 2.71 (m, 1 H), 2.09 (br d, J=11.2 Hz, 2H), 1.96 - 1.81 (m, 2H); LCMS (ESI) [M+H]+:425.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.70 - 7.65 (m, 1H), 7.55 (d, J=7.3 Hz, 1H), 6.84 (d, J=8.6 Hz, 1 H), 4.57 (br d, J=13.0 Hz, 1 H), 3.89 - 3.85 (m, 4H), 3.81 (br d, J=13.3 Hz, 1 H), 3.68 - 3.63 (m, 4H), 3.31 (quin, J=8.6 Hz, 1 H), 3.19 - 3.09 (m, 2H), 2.96 - 2.86 (m, 1 H), 2.45 - 2.33 (m, 2H), 2.24 - 2.07 (m, 4H), 2.04 - 1.94 (m, 1 H), 1.93 - 1.80 (m, 3H); LCMS (ESI) [M+H]+:398.2.

Ή NMR (400MHz, CHLOROFORM-d) δ = 8.31 (s, 1H), 8.11 (s, 1 H), 7.94 - 7.84 (m, 2H), 5.45 - 5.35 (m, 1 H), 4.64 (br d, J=13.2 Hz, 1 H), 4.36 - 4.26 (m, 1 H), 4.25 - 4.17 (m, 2H), 4.11 - 4.01 (m, 1 H), 3.96 (br d, J=13.8Hz, 1H), 3.26 (br t, J=11.4 Hz, 1 H), 3.16 (tt, J=4.0, 10.9 Hz, 1H), 2.92 (br t, J=11.2 Hz, 1H), 2.60- 2.51 (m, 2H), 2.34 (d, J=6.8 Hz, 2H), 2.16 (br d, J=14.6 Hz, 2H), 2.00 - 1.85 (m, 2H), 1.14-1.02 (m, 1H), 0.65 - 0.55 (m, 2H), 0.26 - 0.17 (m, 2H); LCMS (ESI) [M+H]+:422.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.37 (d, J=5.1 Hz, 1 H), 7.29 (s, 1 H), 7.26 (br s, 1 H), 4.59 (br d, J=13.0 Hz, 1H), 3.89 - 3.75 (m, 5H), 3.65 - 3.57 (m, 4H), 3.30 (quin, J=8.7 Hz, 1H), 3.20 - 3.06 (m, 2H), 2.92 - 2.80 (m, 1 H), 2.46 - 2.30 (m, 2H), 2.22 - 1.77 (m, 8H); LCMS (ESI) [M+H]+: 398.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.37 (d, J=5.1 Hz, 1H), 7.29 (s, 1H), 7.27 - 7.25 (m, 1H), 4.20 (br s, 2H), 3.89 - 3.82 (m, 4H), 3.73 (s, 3H), 3.65 - 3.58 (m, 4H), 3.12 - 2.97 (m, 3H), 2.07 (br d, J=12.3 Hz, 2H), 1.92 - 1.81 (m, 2H); LCMS (ESI) [M+H]+: 374.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 9.06 (s, 1 H), 8.22 (s, 1 H), 7.92 (s, 1 H), 6.80 (s, 1 H), 5.80 - 5.72 (m, 1 H), 5.23 (t, J=6.5 Hz, 2H), 5.1 5 - 5.04 (m, 2H), 4.15-4.01 (m, 2H), 2.97 - 2.71 (m, 3H), 1 .94 (br d, J=12.3 Hz, 2H), 1 .75 - 1 .57 (m, 2H), 1 .41 (s, 9H); LCMS (ESI) [M+H]+:426.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.1 1 (s, 1 H), 8.04 (s, 1 H), 7.80 - 7.73 (m, 2H), 5.01 - 4.86 (m, 1 H), 4.35 - 4.17 (m, 2H), 4.00 (dd, J=2.8, 13.2 Hz, 1 H), 3.86 - 3.74 (m, 1 H), 3.51 (t, J=8.8 Hz, 1 H), 3.26 3.16 (m, 1 H), 3.15 - 3.03 (m, 3H), 2.85 (s, 3H), 1 .62 (d, J=6.8 Hz, 6H); LCMS (ESI) [M+H]+:382.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.06 (d, J=1 .0 Hz, 1 H), 8.23 (s, 1 H), 7.92 (s, 1 H), 6.79 (s, 1 H), 5.79 (quin, J=6.9 Hz, 1 H), 5.27 - 5.17 (m, 2H), 5.1 1 (t, J=7.3 Hz, 2H), 4.57 (br d, J=13.3 Hz, 1 H), 3.75 (br d, J=13.4 Hz, 1 H), 3.29 - 3.16 (m, 1 H), 3.12 - 2.95 (m, 2H), 2.79 - 2.68 (m, 1 H), 2.39 - 2.25 (m, 2H), 2.16 - 2.05 (m, 2H), 1 .99 (br d, J=13.1 Hz, 2H), 1 .95 - 1 .76 (m, 2H), 1 .70 - 1 .58 (m, 3H); LCMS (ESI)

[M+H]+:408.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.06 (d, J=1 .1 Hz, 1 H), 8.23 (s, 1 H), 7.93 (s, 1 H), 6.82 (s, 1 H), 5.86 - 5.72 (m, 1 H), 5.24 (t, J=6.6 Hz, 2H), 5.15 - 5.09 (m, 2H), 4.42 (br s, 2H), 3.36 - 2.75 (m, 3H), 2.06 (br d, J=1 1 .1 Hz, 2H), 1 .77 (br d, J=8.8 Hz, 2H), 1 .36 - 1 .06 (m, 4H); LCMS (ESI) [M+H]+:412.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.13 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 6.86 (s, 1H), 5.85 (quin, J=6.9 Hz, 1H), 5.30 (t, J=6.6 Hz, 2H), 5.21 - 5.14 (m, 2H), 4.22 (m, 2H), 3.72 (s, 3H), 3.10 - 2.86 (m, 3H), 2.03 (br d, J=12.6 Hz, 2H), 1.75 (dq, J=4.2, 12.3 Hz, 2H); LCMS (ESI) [M+H]+:384.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.21 (d, J=2.2 Hz, 1H), 7.82 (dd, J=5.6, 8.5 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 6.12 (quin, J=7.0 Hz, 1H), 5.33 (t, J=6.4 Hz, 2H), 5.15 (t, J=7.1 Hz, 2H), 4.64 (br d, J=13.7 Hz, 1 H), 4.05 (br d, J=12.8 Hz, 1 H), 3.36 - 3.13 (m, 2H), 2.98 - 2.78 (m, 2H), 2.17 (br s, 2H), 2.03 - 1.78 (m, 2H), 1.17 (br s, 6H); LCMS (ESI) [M+H]+:414.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.52 (d, J=2.4 Hz, 1H), 8.00 - 7.95 (m, 1H), 6.71 - 6.64 (m, 1 H), 5.86 - 5.76 (m, 1 H), 5.16 (t, J=7.6 Hz, 2H), 4.88 - 4.79 (m, 2H), 4.16 (br s, 2H), 3.08 - 2.85 (m, 3H), 2.11 - 1.94 (m, 2H), 1.90 - 1.74 (m, 2H), 1.48 (s, 9H); LCMS (ESI) [M-55+H]+:347.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.40 (d, J=2.4 Hz, 1H), 7.92 (dd, J=2.4, 9.5 Hz, 1H), 6.65 (d, J=9.6 Hz, 1 H), 5.71 - 5.62 (m, 1 H), 4.25 (dt, J=5.6, 8.7 Hz, 1 H), 4.20 - 4.03 (m, 3H), 3.99 - 3.84 (m, 2H), 3.04 - 2.86 (m, 3H), 2.65 (dtd, J=5.6, 8.4, 14.2 Hz, 1H), 2.11 - 1.95 (m, 3H), 1.88 - 1.74 (m, 2H), 1.53 - 1.42 (m, 1 H), 1.48 (s, 9H); LCMS (ESI) [M+H]+:417.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.28 (d, J=5.3 Hz, 1 H), 7.26 (d, J=1.3 Hz, 1 H), 7.03 (s, 1 H), 5.21 (brd, J=4.4 Hz, 1H), 5.10 - 5.02 (m, 3H), 4.63-4.55 (m, 3H), 4.30 (brd, J=12.8 Hz, 1H), 3.35 (br s, 1H), 3.17 (tt, J=3.9, 10.9 Hz, 1H), 2.92 (br s, 1H), 2.14 (br s, 2H), 2.01 - 1.75 (m, 3H), 1.01 (brs, 2H), 0.79 (dd, J=3.0, 8.0 Hz, 2H); ¹ H NMR (400MHz, METHANOL-d4) δ 8.17 (dd, J=0.6, 5.4 Hz, 1 H), 7.22 (s, 1 H), 7.1 9 (dd, J=1 .5, 5.4 Hz, 1 H), 5.08 - 5.01 (m, 1 H), 5.01 - 4.96 (m, 2H), 4.60 (t, J=6.0 Hz, 2H), 4.52 - 4.34 (m, 2H), 3.50 - 3.38 (m, 1 H), 3.28 - 3.21 (m, 1 H), 2.99 (br t, J=12.5 Hz, 1 H), 2.23 - 2.05 (m, 2H), 2.05 - 1 .97 (m, 1 H), 1 .88 (br d, J=10.1 Hz, 1 H), 1 .76 (br d, J=10.5 Hz, 1 H), 0.93 - 0.87 (m, 2H), 0.86 - 0.79 (m, 2H); LCMS (ESI) [M+H]+:370.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.28 (d, J=5.1 Hz, 1 H), 7.26 (br s, 1 H), 7.03 (s, 1 H), 5.19 (br d, J=5.1 Hz, 1 H), 5.10 - 5.02 (m, 3H), 4.62 - 4.55 (m, 2H), 4.46 (br s, 2H), 3.33 (br s, 1 H), 3.24 - 3.15 (m, 1 H), 3.05 (br s, 1 H), 2.20 - 2.12 (m, 2H), 1 .95 (br d, J=9.7 Hz, 2H), 1 .35 - 1 .21 (m, 4H); LCMS (ESI) [M+H]+: 388.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.30 - 8.21 (m, 1 H), 7.22 (dd, J=1 .1 , 5.3 Hz, 1 H), 6.98 (s, 1 H), 5.17 (br d, J=4.0 Hz, 1 H), 5.09 - 5.00 (m, 3H), 4.61 - 4.55 (m, 2H), 3.80 (br s, 4H), 3.57 (br s, 4H), 1 .83 - 1 .73 (m, 1 H), 1 .07 - 1 .01 (m, 2H), 0.86 - 0.78 (m, 2H); LCMS (ESI) [M+H]+: 371 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.61 (d, J=5.1 Hz, 1 H), 7.98 (s, 1 H), 7.85 (dd, J=1 .3, 5.1 Hz, 1 H), 3.81 (br s, 4H), 3.59 (br d, J=10.8 Hz, 4H), 1 .83 - 1 .73 (m, 1 H), 1 .08 - 1 .02 (m, 2H), 0.87 - 0.79 (m, 2H); LCMS (ESI) [M+H]+: 334.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.61 (d, J=5.1 Hz, 1 H), 7.97 (s, 1 H), 7.84 (dd, J=1 .2, 5.2 Hz, 1 H), 3.85 - 3.62 (m, 4H), 3.57 (br s, 4H), 2.84 (td, J=6.7, 13.5 Hz, 1 H), 1 .18 (d, J=6.8 Hz, 6H); [M+H]+: 336.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.61 (d, J=5.1 Hz, 1 H), 7.98 (s, 1 H), 7.85 (dd, J

1 H), 3.85 (br s, 4H), 3.66 - 3.58 (m, 4H), 1 .38 - 1 .23 (m, 4H); LCMS (ESI) [M+H]+: 352.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.80 (d, J=7.3 Hz, 1 H), 7.31 (d, J=1 .1 Hz, 1 H), 6.95 (dd, J=1 .8, 7.3 Hz, 1 H), 5.86 (quin, J=6.8 Hz, 1 H), 5.1 6 (t, J=7.5 Hz, 2H), 4.78 (t, J=6.7 Hz, 2H), 4.27 - 4.03 (m, 2H), 3.10 - 2.86 (m, 3H), 2.1 1 - 2.00 (m, 2H), 1 .89 - 1 .76 (m, 2H), 1 .49 (s, 9H); LCMS (ESI) [M-Boc+H]+:303.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.64 (d, J=5.0 Hz, 1 H), 8.03 (s, 1 H), 7.90 (dd, J=1 .3, 5.0 Hz, 1 H), 4.45 (br d, J=1 1 .5 Hz, 2H), 3.45 - 2.92 (m, 3H), 2.17 (br dd, J=3.3, 13.3 Hz, 2H), 1 .95 (br d, J=1 1 .0 Hz, 2H), 1 .37 - 1 .26 (m, 3H), 1 .24 (br d, J=3.1 Hz, 1 H); LCMS (ESI) [M+H]+:351 .0.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.63 (d, J=5.0 Hz, 1 H), 8.03 (s, 1 H), 7.90 (dd, J=1 .3, 5.1 Hz, 1 H), 4.58 (br s, 1 H), 4.31 (br d, J=7.3 Hz, 1 H), 3.35 (br s, 1 H), 3.19 (tt, J=4.0, 1 1 .0 Hz, 1 H), 2.93 (br s, 1 H), 2.14 (br s, 2H), 2.02 - 1 .84 (m, 2H), 1 .83 - 1 .74 (m, 1 H), 1 .07 - 0.94 (m, 2H), 0.79 (dd, J=3.0, 8.0 Hz, 2H); LCMS (ESI) [M+H]+:333.0.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.40 (d, J=5.3 Hz, 1 H), 7.86 (d, J=5.1 Hz, 1 H), 7.61 (s, 1 H), 4.59 (brd, J=12.5 Hz, 1H), 4.05 (br d, J=13.0 Hz, 1H), 3.41 -3.23 (m, 2H), 2.97 (br t, J=11.9 Hz, 1H), 2.85 (td, J=6.7, 13.5 Hz, 1H), 2.23 (brs, 2H), 2.03 - 1.82 (m, 2H), 1.17 (d, J=6.7 Hz, 6H); LCMS (ESI) [M+H]+:319.1.

¹ H NMR (400MHz, CHLOROFORM-d-d) δ 8.32 (d, J=5.1 Hz, 1 H), 7.26 (dd, J=1.3, 5.1 Hz, 1 H), 7.20 (s, 1H), 5.53 (quin, J=7.2 Hz, 1H), 4.96 (t, J=7.2 Hz, 2H), 4.84 (t, J=6.8 Hz, 2H), 4.69 - 4.51 (m, 1H), 4.31 (br s, 1 H), 3.36 (br s, 1 H), 3.19 (s, 4H), 2.94 (br s, 1 H), 2.16 (br s, 2H), 2.05 - 1.84 (m, 2H), 1.83 - 1.74 (m, 1 H), 1.03 (br s, 2H), 0.80 (dd, J=3.1 , 7.9 Hz, 2H); LCMS (ESI) [MS+H]+:384.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.28 (d, J=1.5 Hz, 1 H), 8.03 (dd, J=1.6, 8.4 Hz, 1 H), 7.41 (d, J=8.4 Hz, 1H), 5.58 - 5.48 (m, 1H), 5.23 - 5.12 (m, 4H), 4.63 (brd, J=12.7 Hz, 1H), 4.04 (brd, J=13.3 Hz, 1 H), 3.26 (br t, J=11.9 Hz, 1 H), 3.14 (tt, J=3.9, 11.0 Hz, 1 H), 2.96 - 2.79 (m, 2H), 2.16 (br d, J=13.1 Hz, 2H), 2.00 - 1.76 (m, 2H), 1.16 (br s, 6H); LCMS (ESI) [M+H]+:413.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.29 (d, J=1.3 Hz, 1 H), 8.04 (dd, J=1.6, 8.4 Hz, 1 H), 7.41 (d, J=8.4 Hz, 1H), 5.58 - 5.48 (m, 1H), 5.23 - 5.12 (m, 4H), 4.63 (brd, J=13.0 Hz, 1H), 4.04 (brd, J=13.2 Hz, 1H), 3.26 (brt, J=12.0 Hz, 1 H), 3.14 (tt, J=3.8, 11.0 Hz, 2H), 2.95 - 2.79 (m, 1H), 2.50-2.31 (m, 1H), 2.22 - 2.07 (m, 4H), 2.05 - 1.93 (m, 1 H), 1.92 - 1.76 (m, 3H); LCMS (ESI) [M+H]+:425.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.31 (d, J=5.1 Hz, 1 H), 7.78 (d, J=5.1 Hz, 1 H), 7.53 (s, 1 H), 4.54 - 4.13 (m, 2H), 3.39 - 3.17 (m, 2H), 2.93 (br s, 1H), 2.15 (br s, 2H), 1.98 - 1.77 (m, 2H), 1.75 - 1.66 (m, 1 H), 0.99 - 0.89 (m, 2H), 0.76 - 0.66 (m, 2H); LCMS (ESI) [M+H]+:317.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.63 (d, J=5.0 Hz, 1 H), 8.03 (s, 1 H), 7.90 (d, J=4.8 Hz, 1 H), 4.64 (brd, J=12.8 Hz, 1H), 4.04 (br d, J=13.8 Hz, 1H), 3.26 (br t, J=11.9Hz, 1 H), 3.17 (tt, J=3.9, 11.0 Hz, 1H), 2.94 - 2.80 (m, 2H), 2.14 (br s, 2H), 1.96 - 1.76 (m, 2H), 1.16 (brd, J=4.2 Hz, 6H); LCMS (ESI)

[M+H]+:335.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.63 (d, J=5.1 Hz, 1 H), 8.03 (s, 1 H), 7.89 (dd, J=1.2, 5.2 Hz, 1 H), 4.31 - 3.99 (m, 2H), 3.07 (tt, J=3.8, 11.2 Hz, 1 H), 2.97 (br t, J=12.1 Hz, 2H), 2.06 (br d, J=11.0 Hz, 2H), 1.83 (br d, J=10.4 Hz, 2H), 1.57 (s, 3H), 0.92 - 0.86 (m, 2H), 0.68 - 0.62 (m, 2H); LCMS (ESI)

[M+H]+:363.0.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.29 (d, J=1.5 Hz, 1 H), 8.04 (dd, J=1.6, 8.4 Hz, 1 H), 7.41 (d, J=8.3 Hz, 1H), 5.57 - 5.48 (m, 1H), 5.23 - 5.13 (m, 4H), 4.45 (brd, J=11.1 Hz, 2H), 3.48 - 2.95 (m, 3H), 2.23 - 2.10 (m, 2H), 1.97 (br d, J=10.9 Hz, 2H), 1.40 - 1.16 (m, 4H); LCMS (ESI) [M+H]+:429.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.64 (d, J=4.9 Hz, 1H), 8.05 - 8.02 (m, 1H), 7.90 (d, J=4.9 Hz, 1 H), 7.46 - 7.38 (m, 2H), 7.27 - 7.21 (m, 1 H), 7.17 - 7.08 (m, 1 H), 4.74 (br d, J=13.2 Hz, 1 H), 3.70 (br d, J=13.3 Hz, 1H), 3.33 - 3.08 (m, 3H), 2.23 (brd, J=13.3 Hz, 1H), 2.11 - 1.83 (m, 3H); LCMS (ESI)

[M+H]+:387.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.29 - 8.22 (m, 1 H), 7.22 (dd, J=1 .3, 5.3 Hz, 1 H), 6.98 (s, 1 H), 5.17 (br d, J=4.0 Hz, 1 H), 5.12 - 4.98 (m, 3H), 4.64 - 4.52 (m, 2H), 3.82 - 3.61 (m, 4H), 3.55 (br s, 4H), 2.89 - 2.77 (m, 1 H), 1 .17 (d, J=6.8 Hz, 6H); LCMS (ESI) [M+H]+:373.2.

¹ H NMR (400MHz, DMSO-d6) δ 8.50 (s, 1 H), 8.37 (s, 1 H), 7.94 - 7.79 (m, 2H), 6.58 (br s, 2H), 6.29 (quin, J=7.1 Hz, 1 H), 5.15 - 4.95 (m, 4H), 4.13 - 3.95 (m, 2H), 2.95 - 2.70 (m, 2H), 2.43 - 2.29 (m, 1 H), 1 .85 - 1 .55 (m, 4H), 1 .42 (s, 9H); LCMS (ESI) [M-56+H]+:388.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.29 (d, J=1 .5 Hz, 1 H), 8.04 (dd, J=1 .6, 8.3 Hz, 1 H), 7.41 (d, J=8.3 Hz, 1 H), 5.59 - 5.46 (m, 1 H), 5.25 - 5.10 (m, 4H), 4.58 (br s, 1 H), 4.30 (br s, 1 H), 3.35 (br s, 1 H), 3.16 (tt, J=3.9, 1 1 .0 Hz, 1 H), 2.93 (br s, 1 H), 2.15 (br s, 2H), 2.04 - 1 .86 (m, 2H), 1 .83 - 1 .76 (m, 1 H), 1 .02 (br s, 2H), 0.79 (dd, J=2.9, 7.9 Hz, 2H); LCMS (ESI) [M+H]+:41 1 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.78 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .3, 5.1 Hz, 1 H), 4.29 - 4.02 (m, 4H), 4.01 - 3.93 (m, 2H), 3.71 (quin, J=7.6 Hz, 1 H), 3.1 1 - 2.91 (m, 3H), 2.49 - 2.39 (m, 1 H), 2.28 (qd, J=7.6, 12.3 Hz, 1 H), 2.1 1 - 2.01 (m, 2H), 1 .84 (br d, J=1 0.4 Hz, 2H), 1 .57 (s, 3H), 0.94 - 0.86 (m, 2H), 0.69 - 0.61 (m, 2H); LCMS (ESI) [M+H]+:399.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.78 (d, J=4.9 Hz, 1 H), 7.87 (s, 1 H), 7.80 (dd, J=1 .5, 5.1 Hz, 1 H), 4.32 - 4.02 (m, 4H), 4.02 - 3.91 (m, 2H), 3.70 (quin, J=7.6 Hz, 1 H), 3.10 - 2.88 (m, 3H), 2.50 - 2.38 (m, 1 H), 2.28 (qd, J=7.6, 12.3 Hz, 1 H), 2.1 0 - 2.01 (m, 2H), 1 .84 (br d, J=1 0.1 Hz, 2H), 1 .57 (s, 3H), 0.94 - 0.81 (m, 2H), 0.67 - 0.62 (m, 2H); LCMS (ESI) [M+H]+:399.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.34 (d, J=1 .6 Hz, 1 H), 8.64 (s, 1 H), 8.46 (s, 1 H), 5.88 (quin, J=6.9 Hz, 1 H), 5.35 - 5.28 (m, 2H), 5.25 - 5.16 (m, 2H), 4.66 (br d, J=13.2 Hz, 1 H), 4.06 (br d, J=13.2 Hz, 1 H), 3.28 (br t, J=12.7 Hz, 1 H), 3.1 9 (tt, J=4.0, 1 1 .0 Hz, 1 H), 2.96 - 2.78 (m, 2H), 2.25 - 2.09 (m, 2H), 2.02 - 1 .79 (m, 2H), 1 .1 7 (br t, J=5.9 Hz, 6H); LCMS (ESI) [M+H]+:397.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.35 (d, J=1 .6 Hz, 1 H), 8.65 (s, 1 H), 8.47 (s, 1 H), 5.90 (quin, J=6.9 Hz, 1 H), 5.38 - 5.29 (m, 2H), 5.27 - 5.18 (m, 2H), 4.43 - 3.98 (m, 3H), 3.18 - 3.08 (m, 1 H), 3.08 - 2.98 (m, 2H), 2.1 1 (br s, 2H), 1 .91 (br d, J=9.9 Hz, 2H), 0.78 - 0.69 (m, 4H); LCMS (ESI) [M+H]+:41 1 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.34 (d, J=1 .7 Hz, 1 H), 8.64 (s, 1 H), 8.46 (s, 1 H), 5.96 - 5 (m, 1 H), 5.31 (t, J=6.6 Hz, 2H), 5.26 - 5.17 (m, 2H), 4.49 (br s, 2H), 3.57 - 2.87 (m, 3H), 2.20 (br dd, J=2.8, 13.4 Hz, 2H), 2.1 0 - 1 .89 (m, 2H), 1 .42 - 1 .18 (m, 4H); LCMS (ESI) [M+H]+:413.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.30 (d, J=0.9 Hz, 1 H), 8.20 (s, 1 H), 7.95 - 7.87 (m, 2H), 5.97 - 5.84 (m, 1 H), 5.33 (t, J=6.5 Hz, 2H), 5.23 - 5.1 1 (m, 2H), 3.60 - 3.53 (m, 2H), 3.51 - 3.36 (m, 2H), 3.34 - 3.27 (m, 1 H), 2.94 - 2.80 (m, 2H), 2.42 - 2.31 (m, 1 H), 2.29 - 2.15 (m, 1 H), 1 .09 - 0.96 (m, 1 H), 0.58 - 0.48 (m, 2H), 0.28 (q, J=5.0 Hz, 2H); LCMS (ESI) [M+H]+:394.1 .

¹ H NMR (400MHz, METHANOL-d4) δ 8.25 (s, 1H), 8.21 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.79 - 7.75 (m, 1H), 6.13 - 6.01 (m, 1H), 5.26 - 5.21 (m, 2H), 5.19 - 5.14 (m, 2H), 4.29 (dd, J=3.2, 12.8 Hz, 1H), 4.19 (br d, J=13.2 Hz, 1 H), 3.92 - 3.81 (m, 2H), 3.55 (t, J=8.8 Hz, 1 H), 3.25 - 3.10 (m, 4H), 2.82 (s, 3H); LCMS (ESI) [M+H]+:396.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.45 (s, 1 H), 8.14 (s, 1 H), 7.72 (s, 2H), 5.75 (quin, J=6.8 Hz, 1 H), 5.26 - 5.15 (m, 4H), 4.31 - 4.24 (m, 1 H), 4.18 (br d, J=13.2 Hz, 1 H), 4.03 - 3.95 (m, 1 H), 3.84 - 3.74 (m, 1H), 3.51 (t, J=8.6Hz, 1 H), 3.25 - 3.15 (m, 1 H), 3.14 - 3.11 (m, 1 H), 3.10 - 3.03 (m, 2H), 2.85 (s, 3H); LCMS (ESI) [M+H]+:396.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 9.16 (d, J=1.1 Hz, 1H), 8.30 (s, 1H), 8.16 (s, 1H),6.73 (s, 1H), 5.85 (quin, J=6.9 Hz, 1H), 5.31 (t, J=6.6 Hz, 2H), 5.20 - 5.13 (m, 2H), 4.19 (br s, 2H), 3.09 -3.00 (m, 1H), 2.99 - 2.87 (m, 2H), 2.11 (br d, J=11.0 Hz, 2H), 1.80 - 1.67 (m, 2H), 1.49 (s, 9H); LCMS (ESI)

[M+H]+:426.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.02 (dd, J=1.2, 7.7 Hz, 1H), 7.58 - 7.45 (m, 1H), 7.20 - 7.12 (m, 2H), 4.26 - 4.07 (m, 2H), 3.93 - 3.84 (m, 4H), 3.07 - 2.90 (m, 7H), 2.09 (br d, J=11.2 Hz, 2H), 1.92 - 1.80 (m, 2H), 1.49 (s, 9H); LCMS (ESI) [M+H]+:415.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.27 (s, 1 H), 8.09 (s, 1 H), 7.89 - 7.83 (m, 2H), 4.97 (td, J=6.7, 13.3 Hz, 1H), 3.59 - 3.52 (m, 2H), 3.50-3.26 (m, 3H), 2.97-2.79 (m, 2H), 2.36 (td, J=4.4, 9.0 Hz, 1H), 2.29 - 2.14 (m, 1H), 1.64 (d, J=6.7 Hz, 6H), 1.09 - 0.96 (m, 1H), 0.59 - 0.45 (m, 2H), 0.27 (q, J=4.9 Hz, 2H); LCMS (ESI) [M+H]+:380.2.

¹ H NMR (400MHz, CHLOROFORM-d) 59.17 (d, J=0.7 Hz, 1H), 8.32 (s, 1H), 8.17 (s, 1H),6.75 (s, 1H), 5.86 (quin, J=7.0 Hz, 1H), 5.32 (t, J=6.6 Hz, 2H), 5.23 - 5.12 (m, 2H), 4.68 (br d, J=13.3 Hz, 1H), 3.97 (br d, J=13.3 Hz, 1H), 3.30 -3.19 (t, 1H), 3.19- 3.09 (m, 1H), 2.86 (br t, J=11.4 Hz, 1H), 2.41 (q, J=7.5 Hz, 2H), 2.19 (brt, J=14.2 Hz, 2H), 1.76 (q, J=12.0 Hz, 2H), 1.21 - 1.17 (t,3 H); LCMS (ESI) [M+H]+:382.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.26 (d, J=5.3 Hz, 1 H), 7.22 (dd, J=1.1 , 5.3 Hz, 1 H), 6.98 (s, 1 H), 5.18 (br d, J=4.4 Hz, 1 H), 5.11 - 4.98 (m, 3H), 4.64 - 4.53 (m, 2H), 3.98 - 3.69 (m, 4H), 3.65 - 3.50 (m, 4H), 1.39 - 1.21 (m, 4H); LCMS (ESI) [M+H]+:389.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.74 (ddd, J=2.1 , 4.4, 8.3 Hz, 1 H), 7.68 (dd, J=2.1 , 8.3 Hz, 1 H), 7.17 (dd, J=8.4, 12.1 Hz, 1 H), 4.15 (br s, 2H), 3.93 - 3.88 (m, 4H), 3.20 - 3.15 (m, 4H), 3.06 - 2.89 (m, 3H), 2.05 (br d, J=12.1 Hz, 2H), 1.91 -1.78 (m, 2H), 1.49 (s, 9H); LCMS (ESI) [M-100+H]+:333.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.00 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 4.15 (br d, J=6.8 Hz, 2H), 3.91 - 3.86 (m, 4H), 3.35 - 3.30 (m, 4H), 3.04 - 2.89 (m, 3H), 2.09 - 2.01 (m, 2H), 1 .90 - 1 .78 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M-56+H]+:359.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.27 (d, J=5.3 Hz, 1 H), 7.25 (br d, J=1 .2 Hz, 1 H), 7.03 (s, 1 H), 5.19 (br d, J=4.9 Hz, 1 H), 5.09 - 5.02 (m, 3H), 4.62 - 4.55 (m, 2H), 4.33 - 3.98 (m, 2H), 3.1 1 - 2.91 (m, 3H), 2.05 (br d, J=1 1 .7 Hz, 2H), 1 .83 (br d, J=10.6 Hz, 2H), 1 .57 (s, 3H), 0.92 - 0.86 (m, 2H), 0.68 - 0.62 (m, 2H); LCMS (ESI) [M+H]+:400.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.19 (s, 1 H), 8.07 (d, J=7.8 Hz, 1 H), 7.70 (d, J=7.7 Hz, 1 H), 7.62 - 7.54 (m, 1 H), 5.91 (t, J=7.5 Hz, 1 H), 4.95 - 4.85 (m, 1 H), 4.73 (td, J=5.8, 9.2 Hz, 1 H), 4.1 7-4.07 (m, 2H), 3.17 - 2.92 (m, 4H), 2.77 - 2.62 (m, 1 H), 2.08 (br d, J=1 1 .0 Hz, 2H), 1 .96 - 1 .83 (m, 2H), 1 .50 (s, 9H); LCMS (ESI) [M+Na]+:408.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.28 (d, J=5.3 Hz, 1 H), 7.26 (s, 1 H), 7.03 (s, 1 H), 5.20 (br s, 1 H), 5.10 - 5.02 (m, 3H), 4.67 - 4.55 (m, 3H), 4.04 (br d, J=13.7 Hz, 1 H), 3.26 (br t, J=1 1 .7 Hz, 1 H), 3.20 - 3.10 (m, 1 H), 2.93 - 2.79 (m, 2H), 2.20 - 2.07 (m, 2H), 1 .96 - 1 .76 (m, 2H), 1 .17 (br s, 6H); LCMS (ESI) [M- Boc+H]+:333.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.71 - 7.65 (m, 1 H), 7.25 - 7.20 (m, 1 H), 7.1 9 - 7.1 1 (m, 1 H), 4.16 (br s, 2H), 3.93 - 3.87 (m, 4H), 3.18 - 3.12 (m, 4H), 3.06 (tt, J=3.8, 1 1 .2 Hz, 1 H), 2.95 (br t, J=1 1 .5 Hz, 2H), 2.07 (br d, J=12.1 Hz, 2H), 1 .94 - 1 .77 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M-Boc+H]+:333.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.31 (dd, J=0.7, 5.1 Hz, 1 H), 7.25 (dd, J=1 .2, 5.1 Hz, 1 H), 7.18 (s, 1 H), 5.52 (quin, J=7.1 Hz, 1 H), 4.95 (t, J=7.3 Hz, 2H), 4.81 (t, J=6.9 Hz, 2H), 4.63 (br d, J=12.3 Hz, 1 H), 4.04 (br d, J=13.1 Hz, 1 H), 3.26 (br t, J=13.0 Hz, 1 H), 3.18 (s, 3H), 3.16 - 3.10 (m, 1 H), 2.94 - 2.80 (m, 2H), 2.22 - 2.07 (m, 2H), 1 .97 - 1 .73 (m, 2H), 1 .19 - 1 .15 (m, 6H); LCMS (ESI) [M+H]+:386.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.54 (dd, J=3.2, 5.6 Hz, 1 H), 7.20 - 7.14 (m, 1 H), 7.13 - 7.07 (m, 1 H), 4.1 5 (br s, 2H), 3.90 - 3.86 (m, 4H), 3.20 - 3.15 (m, 4H), 3.05 - 3.01 (m, 1 H), 2.97- 2.91 (m, 2H), 2.06 (br d, J=1 0.8 Hz, 2H), 1 .91 - 1 .79 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+23]+:455.1 , [M+H-1 00]+:333.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.28 (d, J=5.3 Hz, 1 H), 7.45 - 7.38 (m, 2H), 7.26 - 7.20 (m, 2H), 7.15 - 7.08 (m, 1 H), 7.04 (s, 1 H), 5.22 (br d, J=5.1 Hz, 1 H), 5.08 - 5.02 (m, 3H), 4.73 (br d, J=13.2 Hz, 1 H), 4.63 - 4.53 (m, 2H), 3.70 (br d, J=13.7 Hz, 1 H), 3.30 - 3.08 (m, 3H), 2.28 - 2.16 (m, 1 H), 2.1 1 - 1 .85 (m, 3H); LCMS (ESI) [M+H]+:424.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.30 (dd, J=0.7, 5.1 Hz, 1 H), 7.24 (dd, J=1 .3, 5.1 Hz, 1 H), 7.17 (t, J=1 .0 Hz, 1 H), 5.52 (quin, J=7.2 Hz, 1 H), 4.94 (t, J=7.3 Hz, 2H), 4.80 (t, J=6.9 Hz, 2H), 4.37 - 3.90 (m, 2H), 3.1 7 (s, 3H), 3.10 - 2.87 (m, 3H), 2.13 - 1 .99 (m, 2H), 1 .84 (br d, J=9.9 Hz, 2H), 1 .57 (s, 3H), 0.92 - 0.85 (m, 2H), 0.68 - 0.61 (m, 2H); LCMS (ESI) [M+H]+:414.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.67 (t, J=6.3 Hz, 1 H), 7.25 - 7.1 9 (m, 1 H), 7.1 8 - 7.1 1 (m, 1 H), 4.59 (br d, J=13.0 Hz, 1 H), 4.00 - 3.84 (m, 5H), 3.27 - 3.09 (m, 6H), 2.88 (br t, J=1 1 .2 Hz, 1 H), 2.38 (q, J=7.5 Hz, 2H), 2.19 - 2.06 (m, 2H), 1 .96 - 1 .76 (m, 2H), 1 .17 (t, J=7.4 Hz, 3H); LCMS (ESI) [M+H]+:389.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.72 - 7.66 (m, 1 H), 7.26 - 7.20 (m, 1 H), 7.1 9 - 7.13 (m, 1 H), 4.62 (br d, J=13.0 Hz, 1 H), 4.03 (br d, J=13.5 Hz, 1 H), 3.94 - 3.85 (m, 4H), 3.32 - 3.12 (m, 6H), 2.96 - 2.79 (m, 2H), 2.22 - 2.07 (m, 2H), 1 .99 - 1 .78 (m, 2H), 1 .19 - 1 .12 (m, 6H); LCMS (ESI) [M+H]+:403.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.73 (ddd, J=2.1 , 4.3, 8.4 Hz, 1 H), 7.68 (dd, J=2.0, 8.1 Hz, 1 H), 7.17 (dd, J=8.4, 12.1 Hz, 1 H), 4.20 (br s, 2H), 3.94 - 3.87 (m, 4H), 3.73 (s, 3H), 3.20 - 3.16 (m, 4H), 3.09 2.97 (m, 3H), 2.07 (br d, J=12.7 Hz, 2H), 1 .93 - 1 .81 (m, 2H); LCMS (ESI) [M+H]+:391 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.74 (ddd, J=2.1 , 4.4, 8.4 Hz, 1 H), 7.68 (dd, J=2.1 , 8.2 Hz, 1 H), 7.18 (dd, J=8.4, 12.2 Hz, 1 H), 4.63 (br d, J=13.6 Hz, 1 H), 4.03 (br d, J=13.6 Hz, 1 H), 3.94 - 3.88 (m, 4H), 3.25 (br t, J=1 1 .6 Hz, 1 H), 3.21 - 3.16 (m, 4H), 3.15 - 3.08 (m, 1 H), 2.92 - 2.80 (m, 2H), 2.18 - 2.07 (m, 2H), 1 .97 - 1 .77 (m, 2H), 1 .16 (br t, J=5.7 Hz, 6H) ; LCMS (ESI) [M+H]+:403.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.00 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 4.18 (br s, 2 3.92 - 3.85 (m, 4H), 3.72 (s, 3H), 3.35 - 3.29 (m, 4H), 3.01 (tdd, J=3.7, 7.4, 1 1 .0 Hz, 3H), 2.07 (br d, J=1 1 .9 Hz, 2H), 1 .93 - 1 .80 (m, 2H); LCMS (ESI) [M+H]+:373.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.73 (ddd, J=2.1 , 4.3, 8.4 Hz, 1 H), 7.68 (dd, J=2.1 , 8.2 Hz, 1 H), 7.17 (dd, J=8.4, 12.2 Hz, 1 H), 4.61 (br d, J=13.2 Hz, 1 H), 3.95 (br d, J=14.4 Hz, 1 H), 3.93 - 3.89 (m, 4H), 3.27 - 3.22 (m, 1 H), 3.21 - 3.16 (m, 4H), 3.1 1 (tt, J=4.0, 1 1 .0 Hz, 1 H), 2.93 - 2.83 (m, 1 H), 2.40 (q, J=7.5 Hz, 2H), 2.16 - 2.06 (m, 2H), 1 .95 - 1 .79 (m, 2H), 1 .18 (t, J=7.5 Hz, 3H); LCMS (ESI) [M+H]+:389.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.03 - 7.97 (m, 2H), 6.98 - 6.92 (m, 2H), 4.61 (br d, J=13.1 Hz, 1 H), 4.02 (br d, J=14.2 Hz, 1 H), 3.91 - 3.85 (m, 4H), 3.35 - 3.30 (m, 4H), 3.24 (br t, J=1 1 .6 Hz, 1 H), 3.10 (tt, J=3.9, 1 1 .0 Hz, 1 H), 2.92 - 2.80 (m, 2H), 2.12 (br t, J=10.3 Hz, 2H), 1 .96 - 1 .77 (m, 2H), 1 .16 (br t, J=5.7 Hz, 6H); LCMS (ESI) [M+H]+:385.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.00 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 4.60 (br d, J=12.8 Hz, 1 H), 3.95 (br d, J=13.0 Hz, 1 H), 3.91 - 3.86 (m, 4H), 3.35 - 3.30 (m, 4H), 3.27 - 3.18 (m, 1 H), 3.09 (tt, J=3.9, 1 1 .0 Hz, 1 H), 2.93 - 2.84 (m, 1 H), 2.40 (q, J=7.4 Hz, 2H), 2.10 (br d, J=3.9 Hz, 2H), 1 .95 - 1 .78 (m, 2H), 1 .1 8 (t, J=7.5 Hz, 3H); LCMS (ESI) [M+H]+:371 .2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.94 (dd, J=1 .4, 7.8 Hz, 1 H), 7.50 - 7.40 (m, 1 H), 7.12 - 7.03 (m, 2H), 4.56 (br d, J=13.4 Hz, 1 H), 3.96 (br d, J=13.4 Hz, 1 H), 3.85 - 3.74 (m, 4H), 3.19 (br t, J=1 1 .8 Hz, 1 H), 3.07 (tt, J=3.9, 1 1 .0 Hz, 1 H), 2.98 - 2.89 (m, 4H), 2.86 - 2.73 (m, 2H), 2.08 (br t, J=1 1 .0 Hz, 2H), 1 .90 - 1 .70 (m, 2H), 1 .08 (br d, J=5.4 Hz, 6H); LCMS (ESI) [M+H]+:385.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.94 (dd, J=1 .4, 7.9 Hz, 1 H), 7.50 - 7.40 (m, 1 H), 7.12 - 7.04 (m, 2H), 4.54 (br d, J=13.2 Hz, 1 H), 3.88 (br d, J=13.6 Hz, 1 H), 3.84 - 3.77 (m, 4H), 3.21 - 3.13 (m, 1 H), 3.1 1 - 3.03 (m, 1 H), 2.99 - 2.91 (m, 4H), 2.88 - 2.77 (m, 1 H), 2.33 (q, J=7.5 Hz, 2H), 2.13 - 2.01 (m, 2H), 1 .88 - 1 .71 (m, 2H), 1 .1 1 (t, J=7.5 Hz, 3H); LCMS (ESI) [M+H]+:371 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.94 (dd, J=1 .4, 7.9 Hz, 1 H), 7.48 - 7.41 (m, 1 H), 7.1 1 - 7.05 (m, 2H), 4.27 - 3.95 (m, 2H), 3.86 - 3.77 (m, 4H), 3.65 (s, 3H), 3.02 - 2.91 (m, 7H), 2.03 (br d, J=1 1 .2 Hz, 2H), 1 .86 - 1 .74 (m, 2H); LCMS (ESI) [M+H]+:373.1 .

¹ H NMR (400MHz, METHANOL-d4) δ = 8.32 (d, J=5.3 Hz, 1 H), 7.31 (d, J=5.3 Hz, 1 H), 7.19 (s, 1 H), 4.54 (br d, J=13.4 Hz, 1 H), 4.16 (br d, J=13.8 Hz, 1 H), 3.93 (t, J=13.0 Hz, 2H), 3.78 (t, J=7.3 Hz, 2H), 3.43 - 3.35 (m, 1 H), 3.30 - 3.20 (m, 1 H), 3.07 - 2.90 (m, 2H), 2.59 (tt, J=7.1 , 13.9 Hz, 2H), 2.24 - 2.08 (m, 2H), 1 .92 - 1 .70 (m, 2H), 1 .14 (t, J=6.5 Hz, 6H); LCMS (ESI) [M+H]+:406.1 .

¹ H NMR (400MHz, METHANOL-d4) δ = 8.31 (dd, J=0.7, 5.3 Hz, 1 H), 7.28 (dd, J=1 .3, 5.3 Hz, 1 H), 7.16 (s, 1 H), 4.09 (br s, 2H), 3.91 (t, J=13.0 Hz, 2H), 3.76 (t, J=7.3 Hz, 2H), 3.20 - 2.97 (m, 3H), 2.64 - 2.51 (m, 2H), 2.12 - 2.00 (m, 2H), 1 .84 - 1 .69 (m, 2H), 1 .54 (s, 3H), 0.91 - 0.84 (m, 2H), 0.69 - 0.61 (m, 2H); LCMS (ESI) [M+H]+:434.2. ¹ H NMR (400MHz, CHLOROFORM-d) δ 7.40 (s, 1 H), 5.39 (quin, J=6.8 Hz, 1 H), 5.03 (d, J=7.2 Hz, 4H), 4.67 (s, 2H), 4.1 1 (br s, 2H), 3.92 (t, J=6.0 Hz, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.89 - 2.82 (m, 2H), 2.79 - 2.72 (m, 1 H), 1 .93 (br d, J=1 1 .2 Hz, 2H), 1 .78 - 1 .67 (m, 2H), 1 .46 (s, 9H); LCMS (ESI) [M+H]+:431 .2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.48 (s, 1 H), 5.41 - 5.28 (m, 1 H), 5.23 - 5.14 (m, 2H), 5.04 - 4.95 (m, 2H), 4.63 (br s, 2H), 4.12 (br s, 2H), 4.01 - 3.86 (m, 2H), 2.86 (br s, 1 H), 2.85 - 2.78 (m, 3H), 2.77 - 2.71 (m, 1 H), 1 .92 (br d, J=10.2 Hz, 2H), 1 .77 - 1 .60 (m, 2H), 1 .48 - 1 .41 (m, 9H); LCMS (ESI)

[M+1 ]+:431 .2, [M+H-100]+:331 .1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.75 (br s, 1 H), 8.18 (br s, 1 H), 7.96 (br s, 1 H), 4.36 (br s, 2H), 4.02 - 3.71 (m, 4H), 3.30 - 2.92 (m, 3H), 2.86 (td, J=6.7, 13.5 Hz, 1 H), 2.70 (br s, 2H), 2.14 (br d, J=10.8 Hz, 2H), 1 .85 (br d, J=12.8 Hz, 2H), 1 .17 (d, J=6.8 Hz, 6H); LCMS (ESI) [M+H]+:406.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.82 - 8.76 (m, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .3, 5.1 Hz, 1 H), 4.41 (br d, J=13.7 Hz, 2H), 4.23 (t, J=8.2 Hz, 1 H), 4.13 (dt, J=5.1 , 8.3 Hz, 1 H), 4.04 - 3.93 (m, 2H), 3.71 (quin, J=7.6 Hz, 1 H), 3.24 - 3.10 (m, 3H), 2.50 - 2.37 (m, 1 H), 2.28 (qd, J=7.6, 12.4 Hz, 1 H), 2.15 (br dd, J=3.3, 13.7 Hz, 2H), 1 .98 - 1 .86 (m, 2H), 1 .57 (s, 6H); LCMS (ESI) [M+H]+:439.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1 .3, 5.1 Hz, 1 H), 4.59 (br d, J=12.6 Hz, 1 H), 4.23 (t, J=8.0 Hz, 1 H), 4.13 (dt, J=5.2, 8.2 Hz, 1 H), 4.02 - 3.92 (m, 2H), 3.80 - 3.65 (m, 2H), 3.24 - 3.11 (m, 2H), 2.99 (br t, J=11.9 Hz, 1 H), 2.79 - 2.66 (m, 2H), 2.56 (br s, 2H), 2.50 - 2.38 (m, 1H), 2.28 (qd, J=7.6, 12.3 Hz, 1H), 2.20 - 2.06 (m, 3H), 1.97 - 1.81 (m, 3H); LCMS (ESI) [M+H]+:451.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1.3, 5.1 Hz, 1H), 4.44 (br s, 2H), 4.22 (t, J=8.0 Hz, 1H), 4.13 (dt, J=5.3, 8.3 Hz, 1H), 4.05 - 3.92 (m, 2H), 3.71 (quin, J=7.6 Hz, 1H), 3.41 -2.92 (m, 3H), 2.49 - 2.38 (m, 1H), 2.28 (qd, J=7.6, 12.3 Hz, 1 H), 2.16 (br dd, J=3.0, 13.6 Hz, 2H), 1.98 - 1.82 (m, 2H), 1.40 - 1.33 (m, 2H), 1.24 - 1.15 (m, 2H); LCMS (ESI) [M+H]+:437.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1.3, 5.1 Hz, 1H), 4.48 (brd, J=13.5 Hz, 2H), 4.23 (t, J=8.0 Hz, 1H), 4.13 (dt, J=5.2, 8.3 Hz, 1H), 4.03-3.93 (m, 2H), 3.71 (quin, J=7.6 Hz, 1H), 3.25 - 2.95 (m, 3H), 2.51 - 2.38 (m, 1H), 2.28 (qd, J=7.6, 12.4 Hz, 1H), 2.14 (br dd, J=2.6, 13.5 Hz, 2H), 1.95 - 1.80 (m, 2H), 1.35 (s, 3H), 1.01 - 0.93 (m, 2H), 0.66 - 0.57 (m, 2H); LCMS (ESI) [M+H]+:383.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1.3, 5.1 Hz, 1H), 4.58 (brd, J=11.0 Hz, 1H), 4.22 (t, J=8.0 Hz, 1H), 4.13 (dt, J=5.1, 8.3 Hz, 1H), 4.03-3.92 (m, 2H), 3.81 -3.65 (m, 2H), 3.14 (tdd, J=3.9, 7.3, 14.7 Hz, 2H), 2.87 (br t, J=11.1 Hz, 1 H), 2.63 - 2.51 (m, 2H), 2.49 - 2.38 (m, 1H), 2.28 (qd, J=7.6, 12.4 Hz, 1H), 2.17 - 2.05 (m, 2H), 2.04 - 1.81 (m, 5H), 1.80 - 1.70 (m, 1 H), 1.47 (s, 3H); LCMS (ESI) [M+H]+:397.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.79 (d, J=5.1 Hz, 1 H), 7.88 (s, 1 H), 7.80 (dd, J=1.5, 5.1 Hz, 1H), 4.59 (brd, J=13.0 Hz, 1H), 4.23 (t, J=8.0 Hz, 1H), 4.13 (dt, J=5.1, 8.3 Hz, 1H), 4.03-3.93 (m, 2H), 3.81 (br d, J=13.5 Hz, 1 H), 3.71 (quin, J=7.6 Hz, 1 H), 3.30 (quin, J=8.6 Hz, 1 H), 3.20 - 3.09 (m, 2H), 2.94 - 2.82 (m, 1 H), 2.49 - 2.33 (m, 3H), 2.33 - 2.24 (m, 1 H), 2.24 - 2.06 (m, 4H), 2.05 - 1 .76 (m, 4H); ¹ H NMR (400MHz, METHAN0L-d4) δ = 8.97 (d, J=6.4 Hz, 1 H), 8.58 (s, 1 H), 8.54 (dd, J=1 .5, 6.2 Hz, 1 H), 4.49 (br d, J=13.0 Hz, 1 H), 4.21 (dt, J=4.9, 8.5 Hz, 1 H), 4.17 - 4.08 (m, 2H), 4.03 - 3.87 (m, 3H), 3.47 (quin, J=8.5 Hz, 1 H), 3.36 - 3.33 (m, 1 H), 3.29 - 3.22 (m, 1 H), 2.96 (br t, J=1 1 .5 Hz, 1 H), 2.73 - 2.61 (m, 1 H), 2.37 - 2.1 1 (m, 7H), 2.09 - 1 .98 (m, 1 H), 1 .90 - 1 .71 (m, 3H); LCMS (ESI) [M+H]+:383.2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.76 (d, J=1 .6 Hz, 1 H), 8.17 (d, J=2.9 Hz, 1 H), 7.46 (dd, J=1 .8, 2.8 Hz, 1 H), 4.17 (br s, 2H), 3.80 (t, J=12.8 Hz, 2H), 3.67 (t, J=7.2 Hz, 2H), 3.13 - 2.87 (m, 3H), 2.58 (tt, J=7.0, 13.7 Hz, 2H), 2.07 (br d, J=1 1 .7 Hz, 2H), 1 .92 - 1 .78 (m, 2H), 1 .49 (s, 9H); LCMS (ESI)

[M+H]+:436.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.74 (dd, J=0.8, 5.2 Hz, 1 H), 8.08 (s, 1 H), 8.06 (s, 1 H), 8.01 (s, 1 H), 7.75 - 7.70 (m, 1 H), 4.25 -4.10 (br s, 2H), 3.99 (s, 3H), 3.06 -3.02 (m, 1 H), 2.96 -2.90 (m, 2H), 2.08 - 2.05 (m, 2H), 1 .92 - 1 .80 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+:41 1 .2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.82 (d, J=5.2 Hz, 1 H), 8.57 (s, 1 H), 7.83 (dd, J=1 .6, 5.2 Hz, 1 H), 7.46 (d, J=2.4 Hz, 1 H), 6.93 (d, J=2.0 Hz, 1 H), 4.1 8 (br d, J=8.4 Hz, 2H), 4.02 (s, 3H), 3.06 -3.02 (m, 1 H), 3.00 - 2.87 (m, 2H), 2.1 1 - 2.01 (m, 2H), 1 .91 - 1 .79 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+:41 1 .2. ¹ H NMR (400MHz, METHANOL-d4) δ 9.00 (d, J=0.9 Hz, 1 H), 8.90 (d, J=6.4 Hz, 1 H), 8.48 (dd, J=1.6, 6.4 Hz, 1H), 7.93 (d, J=2.2 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 4.55 (br d, J=13.5 Hz, 1H), 4.17 (brd, J=13.7 Hz, 1 H), 4.11 (s, 3H), 3.44 - 3.32 (m, 2H), 3.06 - 2.92 (m, 2H), 2.29 - 2.11 (m, 2H), 1.97 - 1.72 (m, 2H), 1.13 (t, J=6.0 Hz, 6H); LCMS (ESI) [M+H]+:381.2.

¹ H NMR (400MHz, METHAN0L-d4) δ 8.78 (d, J=5.2 Hz, 1 H), 8.60 (s, 1 H), 7.94 (dd, J=1.2, 5.2 Hz, 1 H), 7.69 (d, J=2.0 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 4.21 - 4.04 (m, 2H), 4.01 (s, 3H), 3.18-3.14 (m, 1H), 3.06 (br s, 2H), 2.17 - 2.00 (m, 2H), 1.79 (br d, J=11.0 Hz, 2H), 1.54 (s, 3H), 0.92 - 0.85 (m, 2H), 0.69 - 0.62 (m, 2H); LCMS (ESI) [M+H]+:409.2.

¹ H NMR (400MHz, METHAN0L-d4) δ 8.71 (d, J=5.2 Hz, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.81 (dd, J=1.6, 5.2 Hz, 1H), 4.12 (brd, J=14.8 Hz, 2H), 3.97 (s, 3H), 3.17 (tt, J=3.6, 11.2 Hz, 1H), 3.05 (br s, 2H), 2.13 - 2.03 (m, 2H), 1.88 - 1.71 (m, 2H), 1.54 (s, 3H), 0.91 - 0.85 (m, 2H), 0.68 - 0.63 (m, 2H); LCMS (ESI) [M+H]+:409.1.

¹ H NMR (400MHz, METHAN0L-d4) δ 8.72 (d, J=5.2 Hz, 1 H), 8.28 (s, 1 H), 8.26 (s, 1 H), 8.11 (s, 1 H), 7.83 (dd, J=1.6, 5.2 Hz, 1H), 4.53 (brd, J=13.2 Hz, 1H), 4.15 (brd, J=13.6 Hz, 1H), 3.97 (s, 3H), 3.41 - 3.33 (m, 1H), 3.29 - 3.23 (m, 1H), 3.10-2.88 (m, 2H), 2.29 - 2.04 (m, 2H), 1.95 - 1.69 (m, 2H), 1.13 (t, J=6.8 Hz, 6H); LCMS (ESI) [M+H]+:381.2.

¹ H NMR (400MHz, DMS0-d6) δ = 8.10 - 7.99 (m, 2H), 7.65 (dd, J=1.0, 7.7 Hz, 1 H), 4.39 (br d, J=12.8 Hz, 1 H), 4.11 (t, J=7.9 Hz, 1 H), 4.06 - 3.92 (m, 2H), 3.87 - 3.74 (m, 2H), 3.74 - 3.65 (m, 1 H), 3.27 - 3.18 (m, 2H), 2.96 - 2.79 (m, 2H), 2.40 - 2.29 (m, 1H), 2.18 (qd, J=7.7, 12.1 Hz, 1H), 2.12 - 1.96 (m, 2H), 1.78 - 1.50 (m, 2H), 1.02 (br d, J=6.4 Hz, 6H); LCMS (ESI) [M+H]+:371.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.98 (dd, J=0.7, 7.7 Hz, 1H), 7.77 (t, J=7.8 Hz, 1H), 7.39 (dd, J=0.6, 7.8 Hz, 1 H), 4.18 - 4.01 (m, 4H), 3.93 - 3.85 (m, 1 H), 3.93 - 3.85 (m, 1 H), 3.70 (quin, J=7.3 Hz, 1H), 3.00 (tt, J=3.8, 11.2 Hz, 1H), 2.88 (br t, J=11.6 Hz, 2H), 2.44 - 2.31 (m, 1 H), 2.18 (qd, J=7.4, 12.5 Hz, 1 H), 2.00 (br d, J=10.9 Hz, 2H), 1.85 - 1.72 (m, 2H), 1.41 (s, 9H); LCMS (ESI) [M+H]+:401.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.20 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.2 Hz, 1H), 8.26 (t, J=2.0 Hz, 1H), 4.22 - 4.10 (m, 4H), 4.01 - 3.92 (m, 1H), 3.82 (dd, J=6.5, 8.7 Hz, 1H), 3.58 - 3.48 (m, 1H), 3.12 2.87 (m, 3H), 2.54 - 2.44 (m, 1 H), 2.12-1.98 (m, 3H), 1.92 - 1.78 (m, 2H), 1.48 (s, 9H); LCMS (ESI) [M+H]+:401.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.19 (s, 1H), 8.10 - 8.05 (m, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.61 - 7.54 (m, 1H), 5.91 (t, J=7.5 Hz, 1H), 4.90 (dt, J=6.0, 7.9 Hz, 1H), 4.74 (td, J=5.8, 9.2 Hz, 1H), 4.32-4.10 (m, 2H), 3.75 (s, 3H), 3.19 - 3.00 (m, 4H), 2.70 (tdd, J=7.5, 9.1 , 11.0 Hz, 1 H), 2.10 (br d, J=11.2 Hz, 2H), 1.98 - 1.82 (m, 2H); LCMS (ESI) [M+Na]+:366.1.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.74 (d, J=5.1 Hz, 1H), 8.08 (s, 1H), 7.41 - 7.38 (m, 1H), 4.25 - 4.09 (m, 4H), 3.99-3.92 (m, 1H), 3.85 (dd, J=6.2, 8.8 Hz, 1H), 3.52 (quin, J=7.1 Hz, 1H), 3.13 - 3.03 (m, 1 H), 3.01 - 2.88 (m, 2H), 2.54 - 2.44 (m, 1 H), 2.1 1 - 2.00 (m, 3H), 1 .96 - 1 .83 (m, 2H), 1 .48 (s, 9H); LCMS (ESI) [M+H]+:401 .2.

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.46 (s, 1 H), 5.37 - 5.26 (m, 1 H), 5.16 (t, J=6.4 Hz, 2H), 4.96 (t, J=7.2 Hz, 2H), 4.61 (s, 2H), 4.23 - 3.95 (m, 2H), 3.90 (t, J=5.6 Hz, 2H), 2.87 (br t, J=1 1 .2 Hz, 2H), 2.79 (br t, J=5.6 Hz, 2H), 2.76 - 2.70 (m, 1 H), 1 .91 (br d, J=1 1 .2 Hz, 2H), 1 .80 - 1 .61 (m, 2H), 1 .53 (s, 3H), 0.94 - 0.80 (m, 2H), 0.65 - 0.55 (m, 2H); LCMS (ESI) [M+H]+:429.1 .

¹ H NMR (400MHz, CHLOROFORM-d) δ 7.48 (s, 1 H), 5.33 (quin, J=7.2 Hz, 1 H), 5.17 (t, J=6.4 Hz, 2H), 4.97 (t, J=7.2 Hz, 2H), 4.63 (s, 2H), 4.55 (br d, J=12.8 Hz, 1 H), 4.05 - 3.81 (m, 3H), 3.17 (br t, J=1 1 .6 Hz, 1 H), 2.95 - 2.69 (m, 5H), 1 .99 (br s, 2H), 1 .84 - 1 .68 (m, 2H), 1 .17 - 1 .08 (m, 6H); LCMS (ESI)

[M+H]+:401 .1 . ¹ H NMR (400MHz, CHLOROFORM-d) δ 7.39 (s, 1 H), 5.38 (quin, J=6.8 Hz, 1 H), 5.04 -4.99 (m, 4H), 4.67 (s, 2H), 4.61 - 4.45 (m, 1 H), 4.01 - 3.83 (m, 3H), 3.17 (br t, J=12.0 Hz, 1 H), 2.92 (t, J=6.0 Hz, 2H), 2.89 - 2.75 (m, 3H), 2.01 -1 .96 (m, 2H), 1 .80 - 1 .67 (m, 2H), 1 .16 -1 .07 (m, 6H); LCMS (ESI) [M+H]+:401 .1 .

Example 157. Description of yeast models

a-synuclein and ApoE4 yeast strains were previously engineered to express the human a- synuclein or ApoE4 genes under control of the yeast galactose-regulated promoter, GAL 1, as described in International Patent Publication No. WO2016/040794 and U.S. Patent Nos. 7,452,670 and 7,045,290, the procedures for the production of such strains of which are herein incorporated by reference. The induced expression of a-synuclein and ApoE4 confers cytotoxicity, thus enabling the identification of compounds that can restore cell viability. This instantaneous/synchronous induction of α-synuclein and ApoE4 can be achieved due to the following expression control. In glucose-containing media, gene expression from the GAL 1 promoter is 'off and actively repressed by additional epigenetic factors. In raffinose, expression is 'off, but the promoter not actively repressed. Upon transition to galactose- containing media, the promoter is instantaneously turned On' to achieve robust and synchronous induction of a-synuclein or ApoE4 expression. This highly regulated induction provides a robust window for the determination of both efficacy (amplitude of protective effect) and potency (concentration of protective effect) of cytoprotective compounds.

Compound Profiling

Fresh powders (~5 mg) of newly synthesized compounds were dissolved to 10 mM in 100% DMSO using a Janus (Perkin Elmer) robotic workstation. Re-suspended compound stocks were subsequently arrayed into 384 well compound plates using automated pipetting. All other wells not receiving stock compound were filled with 10 μΙ_ of 100% DMSO using an automated plate filler (Multidrop Combi). An 1 1 point, 2-fold serial dilution was then performed using the robotic platform. Compound assay plates were covered with foil and stored at -20°C until use.

Each strain was handled according to standard protocols and cultured in media composed of CSM (complete synthetic media), YNB (yeast nitrogenous base), and a 2% (w/v) carbon source (either glucose, raffinose, or galactose). Single use frozen aliquots of each strain were generated by growing cells in CSM/glucose media to an Οϋβοο of 0.6-0.8, concentrating the yeast to 12.5 Οϋβοο units per 30 μΙ_ of CSM/glucose media supplemented with 20% glycerol, and freezing 30 μΙ_ aliquots at -80°C.

In a standard yeast assay, a single-use aliquot of cells was thawed on ice and diluted into CSM/glucose (5 mL). Cultures were grown for 8 hours at 30°C. This pre-growth enables the yeast to exit the thaw and begin to grow without expressing aSyn or ApoE4. After 8 hours, cell density (Οϋβοο) was determined and cultures diluted to an Οϋβοο of 0.01 in CSM/raffinose for an overnight culture phase at 30°C. During this period, the active glucose repression of the GAL 1 promoter was relieved; however, expression of the a-Syn/ApoE4 genes were not yet induced. After -16 hours of growth, cultures attain an OD600 of 0.4-0.8 and were ready to apply to assay plates containing compound.

Compound profiling assays were executed in clear-bottom 384 well plates. First, compound plates were thawed at room temperature for 45', centrifuged at 1 ,000xg for 1 minute, and the foil removed. Clear 384 well assay plates were then filled with 15 μΙ_ of CSM/galactose. Both compound and media-containing plates were arranged on the Janus workstation and a compound pin tool (384 x 1 00 nL slotted pins) used to deliver 100 nL of compounds to each well according to the well map of the compound plate. Based on the previous serial dilution, the final concentration of compound ranged from 33.3 μΐ to 12.5 nM. The pin tool was washed iteratively with both 50% DMSO and 100% ethanol between each assay plate. After delivering compound to each assay plate, the overnight CSM/raffinose aSyn or ApoE4 cultures were added at a 2X cell density (0.04 for aSyn and 0.08 for ApoE4) in CSM/galactose to achieve a final assay Οϋβοο of 0.02 and 0.04 for aSyn and ApoE, respectively. The cultures (15 μί per well) were then dispensed to the compound-containing 384 well assay plates using an automated plate filler. Plates were incubated in a humidified 30°C incubator for 40 or 24 hours for aSyn and ApoE4, respectively. The ODeoo of each assay plate was then read with a microplate reader (e.g., Perkin Elmer Envision).

The efficacy and potency of compounds were calculated according to the following. Raw data

(OD600 values) were first background corrected to account for Οϋβοο contributed by the plate and media itself. The efficacy (percent above DMSO, herein referred to as "Emax") was calculated according to the equation: (Experimental well - DMSO control well)/(DMSO control well) ^* 100. For each individual compound with positive activity (>30% above DMSO - or 3 standard deviations from the DMSO negative control wells), the dose-response data were normalized to a scale of 0 - 1 00% to enable potency (herein referred to as "EC50") determination. Normalized dose-response data was fit with a logistic regression curve using Spotfire (TIBCO), or similar curve-fitting software package. EC50 values were then reported along with EMax to provide both efficacy and potency measures for each analog and enable further compound design. As shown in Table 3, compounds of the invention are able to reduce the toxicity of the expressed alpha-synuclein and/or ApoE4 proteins.

Table 3: Yeast rescue data for examples 1 -155 showing that compounds of the invention were able to reduce toxicity in yeast strains expressing the human proteins a-synuclein and/or ApoE4.

ApoE4 Emax

Compound # α-Syn EC50 (nM) a-Syn Emax (%) ApoE4 EC50 (nM)

(%)

28 66 576 1594 836

29 13928 38

31 7506 438 9813 721

32 9883 41

33 1 1 1 260 717 281

34 1 1 1 12 562 n/a 596

35 52 626 1 122 91 1

36 1757 629 2154 908

37 2205 608 6530 849

38 3296 336 6014 750

39 18143 216

40 86 443

41 10899 21 1 n/a 400

42 12462 255 n/a 399

43 14607 222 17730 517

44 10870 579 13312 676

45 2601 9 121 29268 19

46 10930 35

47 16513 88

48 1471 615 2944 874

49 1469 636 4336 942

50 7857 85 n/a 133

51 10924 137 n/a 286

52 9059 82 14485 154

53 6603 81 16643 296

54 9095 95 17308 240

55 2381 6 47 7902 29

56 1665 549 8325 793

57 9005 503 12060 797

58 7943 23

59 15667 82 n/a 47

60 32 605 1 19 795

61 19706 229 19380 465

62 21699 204 21427 430

63 17170 68 13385 250

64 13746 228 15275 330

65 36 643 987 779

66 1 1067 350 21212 790 ApoE4 Emax

Compound # α-Syn EC50 (nM) a-Syn Emax (%) ApoE4 EC50 (nM)

(%)

67 7377 255 17364 420

68 1864 652 3123 775

69 n/a 294 n/a 387

70 n/a 605 n/a 580

71 8093 151 8969 235

72 12665 35

73 15760 151 n/a 303

74 17866 155 n/a 41 1

76 9921 76 14827 162

77 n/a 345 n/a 436

78 14604 38

79 9907 627 18845 631

80 3322 188 6014 262

82 16773 40

83 9309 151 n/a 567

84 60 463 956 866

85 1261 0 486 17049 602

86 18 772 64 633

87 1929 579

88 9037 130

89 165 580

90 1646 281

91 107 452

92 2499 187

93 1800 626

94 40 1083

95 91 827

96 26 343 228 840

97 707 132 3884 704

98 8009 386 9747 650

99 1032 209 2749 663

100 1 191 385 2106 651

101 1 175 122

102 284 41 1

103 2023 75

104 1872 253

105 3180 391

106 100 415 ApoE4 Emax

Compound # α-Syn EC50 (nM) a-Syn Emax (%) ApoE4 EC50 (nM)

(%)

107 2899 312

108 11149 316

109 3041 35

110 4493 374

111 339 289

112 320 258

113 15628 55

114 17316 373

115 887 326

116 9038 345

117 7502 124

118 15667 65

119 20897 61

120 19502 139

121 15527 388

122 139 414

123 69 343

124 17661 395

125 16712 200

127 7416 349

128 252 306

129 47 360

130 1443 328

131 167 352

132 1006 253

133 6381 281

134 13976 357

135 593 144

136 4080 67

137 1052 376

138 1280 353

139 21 437

140 49 322

141 19 259

142 7644 319

143 16891 73

144 521 537

145 100 432 ApoE4 Emax

Compound # α-Syn EC50 (nM) a-Syn Emax (%) ApoE4 EC50 (nM)

(%)

146 1941 516

147 17902 453

148 13652 258

149 60 458

150 99 473

151 45 405

152 134 474

153 20 271

154 57 410

155 1 1 556 2159 865

Example 158: U20S transient overexpression induced cytotoxicity assay

U20S (Sigma-Aldrich), a human bone osteosarcoma epithelial cell line, is regularly maintained in McCoy's 5A medium (ATCC) supplemented with 10% FBS (ThermoFisher) between passage 1 1 -21 and sub-cultured twice a week for the assay.

On the day of experiment, cells are about 80% confluence and trypsinized using 0.25% trypsin-EDTA (ThermoFisher Inc.) for 5 minutes at 37c. Based on a ratio of 2ug DNA/2e5 cells, required cells are spun down at 800 rpm for 5 minutes at room temperature. Cells are then re-suspended in SE solution (Lonza Inc.) at a density of 2e4 cells/μΙ. Nucleofection is performed using 4D-Nucleofector™ System (Lonza Inc.) under program code CM130. Cells are allowed to recover in the cuvette at room temperature for 10-15 minutes before further handling. Pre-warmed medium is added and cells suspension is thoroughly but gently mixed before plating. Cells are seeded at 2e4 cells/1 ΟΟμΙ/well into 96 well PLD-coated white plate (Corning) using customized Viaflow program (Integra Biosciences). Serial dilution of drugs is carried out in DMSO. Drug solution is prepared at 6x fold, 20ul of which is added to cells 4 hours after

transfection. The final DMSO concentration is 0.3%. Microclimate lid (Labcyte) is strongly recommended to reduce evaporation and variation. Seventy-two hours post transfection, cells are lysed using CellTiter- Glow (Promega) and ATP content is determined using a luminescence plate reader (Perkin Elmer). %Maximum fold rescue at each concentration is calculated as follows:

FK506 (tacrolimus), a macrolide calcineurin inhibitor, is used as reference compound in the assay. FK506 has been shown to rescue aSyn toxicity in yeast models, and this activity has translated to rodent in vivo models of neurodegeneration.

% Rescue (normalized by max fold rescue of FK506) =(%Fold ^aS y ⁿ drug-100) ^* 100/(%Max fold ^aS y ⁿ FK506- 100).

As shown in Table 4, the compounds of the invention were able to rescue human bone osteosarcoma epithelial U20S cells that were transiently overexpressing the toxic alpha-synuclein protein, reducing the level of induced cytotoxicity: Table 4.

% Rescue (normalized by FK506 max rescue)

Example 159: Stearoyl-CoA desaturase (SCD) is the target of 1 ,2,4-oxadiazoles

A. Materials and Methods

Strain Construction and OLE 1 Replacement with SCD 1 or SCD5

Strain GMYF was constructed from the ABC1 6/Green monster strain described in Suzuki et al. Nat. Methods 8(2):159-164, 201 1 . In this strain, YAP1 was deleted using a HIS3-MX6 cassette, and FLR1 was deleted using a NAT-MX6 cassette using standard methods. The knockout cassettes were PCR-amplified from plasmid templates (see, e.g., Bahler et al. Yeast 14(1 0):943-951 , 1 998; Longtine et al. Yeast 14(1 0):953-961 , 1 998) and transformed into yeast using lithium acetate-based transformation (Gietz et al. Methods Mol. Biol. 1205:1 -12, 2014). The yap1::his3 deletion strain was selected on media lacking histidine and flr1::NAT on plates containing 100 μg/mL nourseothricin. All strains were confirmed by diagnostic PCR. Strain W303 pdrl . pdr3k was constructed from W303-1 A (American Type Culture Collection (ATCC) 208352) by deleting PDR1 and PDR3 with kan-MX6 cassettes separately in MATa and MATa W303a isolates, mating, sporulating, and identifying double deletion haploids by tetrad dissection and identification of non-parental ditype tetrads. Strain W-erg3 was derived from W303 pdrIA pdr3A by deleting SNQ2 with NAT-MX6, YAP1 with HIS3-MX6, and ERG3 with BleMX.

Strain ApoE-mga2A was generated by amplifying 1000 base pairs (bp) upstream and downstream of the MGA2 ORF in a strain in which MGA2 was deleted using a G418 (GENETICIN®) resistance cassette (kanMX) (Piotrowski et al. Proc. Natl. Acad. Sci. USA 1 12(12):E1490-1497, 2015) and transforming the resulting deletion cassette into the ApoE4 strain in the BY4741 (ATCC 201388) genetic background. The ApoE strain is described, for example, in International Patent Application Publication No. WO 2016/040794, which is incorporated herein by reference in its entirety.

The alpha-synuclein expression strain was made in the same manner as described in Su et al. Dis. Model Mech. 3(3-4):194-208, 2010, except that the alpha-synuclein construct lacked the green fluorescent protein (GFP) tag.

Strain o/e/Δ (yeast olel deletion mutant) was constructed by deleting OLE1 with NAT-MX6 in BY4741 , amplifying the deletion cassette from the genomic DNA of the resulting strain with primers flanking the ORF by 1000 bp upstream and downstream, transforming the resulting deletion cassette into W303 pdrIA pdr3A, and plating transformants on YPD media containing G418 (200 g/mL) and nourseothricin (100 g/mL) with 0.01 % TWEEN®-20 and 0.5 mM oleic and palmitoleic acids.

To generate yeast strains expressing SCD1 or SCD5 as the sole desaturase, the human SCD1 and SCD5 genes were cloned from cDNAs (Harvard PlasmID database Clone ID HsCD00340237 for SCD1 and HsCD00342695 for SCD5) into yeast plasmid pRS316 (ATCC 77145) between the yeast TDH3 promoter and the CYC1 terminator. The coding sequence of yeast OLE1 was also cloned into this plasmid). These clones were then transformed into the olelA strain and plated on CSM-Ura media (CSM lacking uracil) with 2% glucose (w/v) and independent colonies were isolated and amplified.

Compound Profiling Methods

All compound profiling experiments were performed using the same basic protocol. Different genetic backgrounds (e.g., gene deletions) or conditions (e.g., addition of oleic and palmitoleic acid) were replaced as indicated below.

Yeast were cultured using standard techniques in complete synthetic media (CSM) and yeast nitrogen base supplemented with 2% (w/v) carbon source (glucose, raffinose, or galactose) to regulate the expression of the toxic disease protein. An initial starter culture was inoculated in 3 mL CSM-Glucose media and incubated overnight in a 30°C shaker incubator (225 rpm). Saturated morning cultures were then diluted 1 :20 in fresh CSM-Raffinose media and grown for 6 h to an Οϋβοο (optical density) of -0.4- 0.8 at 30°C with shaking.

Compound stocks (10 mM in 100% DMSO) were arrayed into 384 round well, v-bottom polypropylene plates and diluted according to indicated dilution factors. Compound administration was performed in two separate steps. First, 1 5 μΙ_ of CSM-Galactose (induces expression of toxic protein) was dispensed into clear 384 well assay plates using a MULTIDROP™ Combi reagent dispenser. The diluted compound stock plates were then applied to the assay plates using an automated workstation (Perkin Elmer JANUS™) outfitted with a 384 pin tool containing slotted pins that deliver 100 nL of compound. The cultures described above were then diluted to a 2x concentration (0.03 and 0.08 for alpha-synuclein and ApoE, final Οϋβοο of 0.01 5 and 0.04) in CSM-Galactose. For wild-type and

Ole1 /SCD1 /SCD5 plasmid-containing strains, the 2x cell density was 0.02. In all experiments, 15 μΙ_ culture was then dispensed into the pinned assay plate to achieve 30 μΙ_ of the 1 x Οϋβοο culture and a top drug concentration of 33.3 μΜ. For 96-well assays (Figs. 1 A and 1 B), compound dilutions in DMSO were generated in 96 well plates and 1 μΙ_ was manually pipetted into 96 well clear bottom assay plates.

For experiments with oleic and palmitoleic acid supplementation (Figs. 2A, 2B, 4, and 5), TWEEN®-20 was first added to culture media at a concentration of 0.01 %. Oleic and palmitoleic acid were both then added at the indicated concentrations (0.08 to 0.5 mM) and mixed thoroughly prior to compound pinning or the addition of yeast.

For experiments using a plasmid-borne copy of Ole1 , SCD1 , or SCD5 (Figs. 3B, 6, and 7), media lacking uracil (SX-Ura, where X is glucose, raffinose, or galactose), was used for all steps of the compound profiling protocol to ensure its maintenance throughout the assay.

After yeast delivery, assay plates were incubated under humidified conditions at 30°C for 24 to 40 h. ApoE4 rescue experiments were stopped at 24 h, aSyn experiments at 40 h, Ole1 at 24 h, and SCD1 /SCD5 at 40 h. The growth of yeast was monitored by reading the Οϋβοο of each well using a microplate reader (Perkin Elmer EnVision™). Data were analyzed as follows. For model rescue experiments, raw data were processed by background subtracting and calculating a fold-change relative to DMSO control [(EXP-0.035)/(DMSO-0.035) - where 0.035 is the ODeoo contributed by an empty well containing 30 μΙ_ of media alone]. For growth inhibition of wild-type cells, raw data were processed by background subtracting and converting values to a percent of the nontreated condition for that strain [(EXP-0.035)/(DMSO-0.035) x 100%]. Compound Sources

Compounds were sourced as follows: cycloheximide (Sigma Aldrich), A939572 (Abeam), CAY10566 (Abeam), MF-438 (Calbiochem), MK-8245 (Selleckchem), oleic acid (Sigma Aldrich), palmitoleic acid (Acros organics), mycophenolic acid (Sigma Aldrich), and tunicamycin (Cayman

Chemical).

Drug Resistant Mutant Selection

Strains GMYF and W-erg3 were grown to saturation in CSM-glucose, centrifuged, resuspended in phosphate-buffered Saline (PBS), and plated at a density of 10 ⁷ cells/plate on solid 15cm petri dishes containing CSM with 2% galactose (w/v), 2% (w/v) agar, and 10 μΜ Compound 155, and incubated at 30°C. Resistant colonies were isolated after 5-7 days, re-streaked on the same media, and resistance reconfirmed. Cultures of validated strains were then inoculated for genomic DNA isolation using a YeaStar™ yeast genomic DNA kit (Zymo Research).

Libraries were prepared for sequencing using the lllumina NEXTERA™ library prep kit and sequenced via lllumina HiSeq™ 2500 1 X50 bp (single end reads). Sequences were aligned to the S. cerevisiae reference genome (S288CCR64-1 -1 , Saccharomyces Genome Database (SGD)) using Burrows-Wheeler Aligner (BWA, see, e.g., Li et al. Bioinformatics 25:1754-1 760, 2009; Li et al.

Bioinformatics 2010, Epub (PMID 20080505)). The BWA output SAI files were converted to SAM files using BWA. The SAM files were sorted using SAMtools 1 .3.1 (Li et al. Bioinformatics 25:2079-2079,

2009). Variants (single-nucleotide polymorphisms (SNPs), indeis) were identified using Freebayes (see, e.g., arXiv:1207.3907). Variant locations were summarized using snpEFF (Cingolani et al. Fly (Austin) 6(2):80-92, 2012). Quantitative Lipid Profiling

Overnight cultures of yeast strain W303 pdrIA pdr3A were diluted into CSM media with 2% (w/v) raffinose, Οϋβοο 0.25, and grown for 4 h before resuspending at an Οϋβοο of 0.2 in CSM media with 2% (w/v) galactose and adding Compound 95 or DMSO at the indicated concentrations. Cells were grown for the indicated timepoints before centrifugation, washing once in PBS, and freezing pellets. Lipids were extracted from pellets by resuspending the pellets in 600 μί methanol, 300 μί water, and 400 μί chloroform, followed by cell lysis by vortexing with glass beads for 1 min. Samples were then centrifuged at 10,000 x g for 10 min, and the bottom layer that formed (organic/lipids) was moved into a new tube and evaporated. Samples were then analyzed by LC/MS/MS using a Thermo Scientific Q Exactive™

Orbitrap™ coupled to a Dionex UltiMate® 3000 ultra-high performance liquid chromatography system, following the method described in Tafesse et al. PLoS Pathog. 1 1 (1 0): e1005188, 2015.

B. Results

The effect of 1 ,2,4-oxiadiazoles on cell growth was assessed in a control condition and in a yeast model for ApoE4 toxicity (see International Patent Application Publication No. WO 2016/040794). The control condition was growth of the ApoE4 strain under non-inducing conditions using raffinose as the carbon source. The 1 ,2,4-oxadiazoles exhibited a bell-shaped rescue curve in the ApoE4 model (Fig. 1 A, top panel). At higher concentrations, these compounds inhibited the growth in the control condition (Fig. 1 B, bottom panel). The potency of model rescue correlated well with the potency of growth inhibition across the entire series of 1 ,2,4-oxadiazoles tested (Fig. 1 B). These relationships indicate that the growth inhibition arises from an "on-target" activity, i.e., over activation or inhibition of a target that results in slowed growth.

Drug-resistant mutants can be used to identify the target of the compounds, for example, by preventing or reducing drug binding, and therefore allowing growth under inhibitory doses of 1 ,2,4- oxadiazole concentrations. Twenty drug-resistant mutants were isolated, and the mutants were subjected to whole-genome sequencing in order to identify genetic lesions associated with the drug resistance. Surprisingly, all mutations identified in the drug resistant mutants localized to OLE1 (YGL055W), the sole stearoyl-CoA desaturase (SCD; also referred to as A9-desaturase) in yeast (Fig. 9). The drug resistant mutants specifically conferred resistance to 1 ,2,4-oxadiazoles, but were not cross-resistant to other toxic compounds. The ole l mutations identified included indels and substitution mutations, including A305V, L1 18Δ, S190T, A305T, 1301 N, A91 T, S190T, P123T, and E1 18Q. These mutations are relative to the wild-type OLE1 sequence provided below.

MPTSGTTIELIDDQFPKDDSASSGIVDEVDLTEANILATGLNKKAPRIVNGFGSLMGSKE MVSVEFDKKGNEKKSNLDRLLEKDNQEKEEAKTKIHISEQPWTLNNWHQHLNWLNMVLVC GMPMIGWYFALSGKVPLHLNVFLFSVFYYAVGGVSITAGYHRLWSHRSYSAHWPLRLFYA IFGCASVEGSAKWWGHSHRIHHRYTDTLRDPYDARRGLWYSHMGWMLLKPNPKYKARADI TDMTDDWTIRFQHRHYILLMLLTAFVIPTLICGYFFNDYMGGLIYAGFIRVFVIQQATFC INSLAHYIGTQPFDDRRTPRDNWITAIVTFGEGYHNFHHEFPTDYRNAIKWYQYDPTKVI IYLTSLVGLAYDLKKFSQNAIEEALIQQEQKKINKKKAKINWGPVLTDLPMWDKQTFLAK SKENKGLVIISGIVHDVSGYISEHPGGETLIKTALGKDATKAFSGGVYRHSNAAQNVLAD MRVAVIKESKNSAIRMASKRGEIYETGKFF (SEQ ID NO: 1 )

These data strongly suggest that Ole1 is the target of 1 ,2,4-oxadiazoles. Additionally, addition of exogenous oleic acid reversed both growth inhibition of wild-type cells and rescue of toxicity in a yeast disease model of alpha-synuclein toxicity (Figs. 2A and 2B, respectively). Likewise, these effects were specific for 1 ,2,4-oxadiazoles, but not other toxic compounds.

Drug-resistant Ole1 mutations reduced 1 ,2,4-oxadiazole-induced growth inhibition in control conditions (Fig. 3A). The same mutations also increased the EC50 (concentration that gives half-maximal response) in the context of the alpha-synuclein model, which is consistent with reduced binding to the target. These shifts in does response were specific for 1 ,2,4-oxadiazoles. These data further support that Ole1 /SCD is the target for both growth inhibition and rescue of toxicity in disease models.

The OLE1 gene is essential in Saccharomyces cerevisiae. However, strains deleted for OLE1

(olel ) are viable if their growth media is supplemented with oleic/palmitoleic acid. The o/e/Δ strain supplemented with exogenous fatty acids was fully resistant to 1 ,2,4-oxadiazoles (Fig. 4). In other words, in the absence of the target, Ole1 , the 1 ,2,4-oxadiazoles do not have growth inhibition activity.

Independently, a chemical genetics approach identified MGA2, the transcription factor that regulates Ole1 . Genetic deletion of MGA2 (mga2A) phenocopied the effects of 1 ,2,4-oxadiazoles (Fig. 5). mga2A cells have reduced Ole1 levels, which itself rescues toxicity in the yeast disease models (e.g., the ApoE4 model). Supplementation of the growth media with oleic acid reversed this effect, similar to the results described above. Consistent with these data, treatment of yeast cells with the 1 ,2,4-oxadiazole

Compound 95 inhibited lipid desaturation (Figs. 8A-8D). Overall, these data provide still further evidence that Ole1 /SCD is the target of 1 ,2,4-oxadiazoles.

Humanized yeast strains expressing the human SCD proteins SCD1 or SCD5 were generated by genetic deletion of OLE1 and expressing human SCD1 or SCD5 on a plasmid. Yeast expressing OLE1 were resistant to known SCD1 /SCD5 inhibitors such as A939572, CAY10566, MF-438, and MK-8245 (Fig. 6), suggesting that they do not target the yeast enzyme. In marked contrast, in the SCD1 and SCD5 humanized strains, the known SCD1 /SCD5 inhibitors were extremely potent, with low nanomolar half- maximal inhibitory concentration (IC50) values (Fig. 6).

The effect of 1 ,2,4-oxadiazoles was also evaluated in both of the humanized SCD1 and SCD5 models. 1 ,2,4-oxadiazoles inhibited the growth of the SCD1 and/or SCD1 yeast strains, and differences in the structure-activity relationship (SAR) between the three SCD proteins was observed (Fig. 7). Some compounds inhibited the growth of both the SCD1 and the SCD5 strains. Other compounds appeared to target only the yeast enzyme. Out of a total of 250 1 ,2,4-oxadiazoles tested, approximately 50% exhibited activity against the human enzymes. The divergent SAR provides additional strong evidence for SCD being the target of 1 ,2,4-oxadiazoles.

Finally, treatment of yeast cells with the 1 ,2,4-oxadiazole Compound 95 inhibited lipid desaturation (Figs. 8A-8D), providing additional confimatory evidence that SCD is the target of 1 ,2,4- oxadiazoles.

Taken together, these data demonstrate that Ole1 /SCD is the target of 1 ,2,4-oxadiazoles, and that these compounds inhibit Ole1 /SCD.

Example 160. Inhibition of Ole1, SDC1, and SCD5 by Compounds of the Invention

Using the methods described above, the inhibition of Ole1 , SCD1 , and SCD5 was tested for compounds of the invention. The results are shown in Table 5.

Table 5. Inhibition of Ole1 , SCD1 , and SCD5 by Compounds of the Invention

OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

12 98.37 >45 70.29 >45 77.40 >45

13 5.69 >45 70.42 >45 25.88 >45

14 14.56 >45 90.98 >45 51 .85 27.53

15 9.81 >45 21 .78 >45 0.80 >45

16 82.88 >45 66.57 37.1 1 3.55 >45

17 94.17 >45 71 .38 >45 23.21 >45

18 5.70 >45 74.70 41 .00 22.66 >45

19 12.81 >45 28.21 >45 4.13 >45

20 1 12.10 >45 38.25 >45 6.14 >45

21 105.47 >45 87.64 39.94 12.90 >45

22 51 .46 40.47 64.47 41 .00 74.04 30.02

23 92.36 >45 61 .05 33.58 40.64 >45

24 99.70 >45 66.31 >45 67.98 30.03

25 3.45 >45 70.78 >45 51 .67 39.44

26 23.82 >45 82.66 >45 50.25 24.46

27 1 .78 >45 0.90 >45 -0.86 >45

27 2.82 >45 13.09 >45 3.95 >45

28 4.80 >45 98.15 >45 79.98 >45

29 91 .00 >45 69.52 >45 74.1 0 >45

30 100.46 >45 80.58 >45 74.1 7 >45

31 79.60 >45 81 .19 >45 24.26 25.37

32 108.22 >45 84.16 >45 80.1 7 >45

33 1 .55 >45 8.14 >45 24.1 0 >45

34 76.89 >45 42.55 >45 5.37 >45

35 3.66 >45 79.23 >45 68.57 >45

36 17.70 >45 64.67 30.02 63.86 >45

37 9.99 >45 81 .44 >45 74.1 8 >45

38 20.26 >45 72.81 >45 64.24 41 .03

39 1 10.89 >45 77.01 >45 79.1 0 >45

40 1 .26 >45 41 .70 >45 0.43 >45

40 0.80 >45 47.19 >45 4.73 >45

40 4.9 >45 57.7 >45 13.7 >45

41 85.45 >45 55.28 38.72 43.51 >45

42 95.43 >45 90.77 >45 47.40 >45

43 107.35 >45 76.52 >45 65.66 >45

44 93.69 >45 17.96 >45 10.99 >45

46 87.95 >45 70.27 >45 72.35 >45

47 109.20 >45 73.30 >45 74.25 >45

48 8.16 >45 63.58 39.27 75.26 >45

49 34.89 >45 61 .29 >45 63.1 8 >45

50 98.10 >45 67.05 41 .00 46.80 >45

51 102.56 >45 76.83 >45 6.59 >45 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

52 1 1 .78 >45 1 .65 >45 -1 .01 >45

53 98.51 >45 79.96 >45 2.94 >45

54 85.34 >45 82.41 >45 47.60 >45

55 1 14.12 >45 74.99 33.67 74.78 >45

56 10.04 >45 59.58 >45 70.33 30.00

57 82.47 >45 80.82 >45 63.1 7 41 .1 0

58 92.35 >45 101 .47 >45 66.93 >45

59 105.25 >45 79.13 >45 59.32 >45

60 2.91 >45 72.03 >45 57.1 9 41 .1 0

61 71 .50 40.87 2.37 >45 13.1 8 >45

62 86.77 >45 28.73 >45 5.75 >45

63 101 .06 >45 62.04 33.67 9.39 >45

64 1 15.95 >45 32.39 >45 42.05 >45

65 4.02 >45 83.43 >45 73.43 >45

66 99.71 >45 94.04 >45 19.53 >45

67 85.79 >45 54.45 40.71 4.32 >45

68 9.74 >45 22.28 >45 3.75 >45

69 105.31 >45 60.59 >45 8.06 >45

70 74.02 >45 39.36 >45 22.44 >45

71 97.50 >45 67.35 >45 46.73 >45

72 85.17 >45 41 .97 27.27 52.89 32.98

73 83.83 >45 61 .02 33.67 5.84 >45

74 85.96 >45 51 .32 31 .26 5.68 >45

75 91 .51 >45 80.18 >45 63.65 30.05

78 87.89 38.34 86.39 >45 86.12 >45

79 104.92 >45 81 .83 >45 76.87 >45

80 46.71 >45 98.34 >45 15.53 >45

81 13.12 >45 13.86 >45 3.39 >45

82 107.01 >45 83.67 >45 75.72 >45

83 3.73 >45 7.65 >45 1 .65 >45

85 64.87 >45 88.05 >45 16.38 >45

86 2.85 >45 84.44 >45 66.85 33.33

88 16.29 >45 63.82 33.46 5.70 >45

89 1 19.71 >45 106.83 >45 87.41 >45

90 23.20 >45 107.22 >45 3.66 >45

91 3.64 >45 97.20 >45 32.20 >45

92 107.87 >45 80.31 >45 83.38 >45

93 5.46 >45 97.21 >45 8.16 >45

94 29.00 >45 90.84 >45 61 .78 39.28

95 5.72 >45 58.05 39.20 7.46 >45

96 3.94 >45 12.37 >45 1 .38 >45

97 10.45 >45 81 .79 >45 78.75 30.01 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

98 92.44 >45 74.79 >45 52.40 41.10

99 64.73 >45 13.74 >45 8.85 >45

100 23.98 >45 54.37 32.84 6.56 >45

101 12.74 >45 29.81 >45 29.09 >45

102 24.90 >45 60.33 >45 6.56 >45

103 5.27 >45 93.33 >45 68.60 >45

104 110.40 >45 76.89 >45 77.11 >45

105 34.19 >45 41.38 >45 13.93 >45

106 35.35 >45 78.19 >45 71.22 >45

107 4.55 >45 73.32 >45 74.80 >45

108 72.04 >45 72.79 >45 64.66 >45

109 87.87 >45 84.36 >45 89.75 >45

110 96.31 >45 66.85 >45 65.07 >45

111 38.26 >45 76.39 >45 32.73 >45

112 3.16 >45 66.76 >45 21.21 >45

113 5.55 >45 55.33 40.72 27.28 >45

114 90.17 >45 74.54 >45 77.66 >45

115 101.68 >45 77.36 >45 77.85 >45

116 12.75 >45 71.12 >45 8.35 >45

117 92.97 >45 95.94 >45 54.63 36.14

118 87.29 >45 93.37 >45 32.21 27.53

119 111.86 >45 86.22 >45 93.93 >45

120 119.08 >45 99.80 >45 96.39 >45

121 111.12 >45 94.06 >45 98.38 >45

122 109.89 >45 92.73 >45 90.04 >45

123 3.12 >45 73.59 >45 9.69 >45

124 4.55 >45 88.87 >45 96.23 >45

125 92.36 >45 77.68 >45 94.83 >45

126 73.29 >45 69.80 >45 79.08 30.00

127 99.27 >45 66.46 >45 88.59 >45

128 81.43 >45 1.12 >45 1.89 >45

128 60.60 45 23.56 >45 3.32 >45

129 3.25 >45 75.60 >45 93.05 >45

130 2.75 >45 97.82 >45 99.82 >45

131 39.81 25.79 96.48 >45 98.92 >45

132 7.45 >45 115.10 >45 94.34 >45

133 26.72 >45 61.21 37.29 74.75 >45

134 93.94 >45 107.77 >45 98.55 >45

135 99.53 >45 92.42 >45 91.64 >45

136 73.60 >45 34.33 >45 17.07 >45

137 96.83 >45 90.19 >45 50.61 22.33

138 3.94 >45 54.49 37.32 4.57 >45 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

139 25.30 >45 87.50 >45 75.1 1 >45

140 3.96 >45 77.37 >45 3.46 >45

140 4.98 >45 75.00 45 10.1 6 1 .30

141 1 .77 >45 86.53 >45 78.91 >45

142 1 .1 1 >45 80.83 >45 26.00 >45

143 95.01 >45 79.38 >45 96.06 >45

144 100.96 >45 79.00 >45 84.27 >45

145 51 .17 15.85 78.31 >45 86.51 >45

146 3.28 >45 60.81 37.75 25.62 >45

147 9.34 >45 74.14 >45 86.70 >45

148 99.90 >45 79.55 >45 86.53 >45

149 90.68 >45 69.75 >45 38.72 >45

150 5.16 >45 74.48 >45 86.1 5 >45

151 2.67 >45 75.63 >45 20.68 >45

152 2.37 >45 83.39 >45 60.91 >45

153 2.75 >45 75.76 >45 87.51 >45

154 1 .20 >45 68.90 >45 3.25 >45

155 1 .65 >45 98.25 >45 67.35 33.77

156 63.63 37.08 72.58 >45 22.37 >45

157 91 .55 >45 80.54 >45 72.54 >45

158 89.93 >45 78.34 >45 91 .96 >45

159 46.92 >45 70.17 38.85 10.25 13.86

160 71 .55 36.23 63.44 40.70 28.51 24.31

162 100.35 >45 84.54 >45 76.89 >45

163 71 .84 >45 55.99 36.51 24.77 >45

164 96.96 >45 102.20 >45 73.90 >45

165 2.01 >45 94.44 >45 80.23 >45

166 105.73 >45 90.07 >45 68.87 >45

167 57.28 38.39 6.1 1 >45 2.38 >45

168 4.90 >45 1 14.58 >45 1 .99 >45

168 8.34 >45 74.07 45 14.85 >45

169 99.67 >45 78.78 >45 84.20 >45

170 67.97 40.39 103.19 >45 85.13 >45

171 6.77 >45 74.21 40.42 -0.14 >45

172 3.99 >45 89.39 >45 68.80 41 .1 0

173 99.75 >45 78.07 >45 42.09 29.77

174 89.17 >45 79.07 >45 10.95 >45

175 3.00 >45 77.47 >45 77.96 >45

176 3.62 >45 107.22 >45 83.50 >45

177 40.70 >45 97.88 >45 86.13 >45

178 7.39 >45 1 14.07 >45 85.67 >45

179 76.70 38.71 106.53 >45 85.02 >45 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

180 107.78 >45 102.85 >45 82.28 >45

181 20.70 >45 88.32 >45 81 .40 >45

182 124.27 >45 1 13.27 >45 79.82 >45

183 101 .71 >45 101 .67 >45 84.88 >45

184 3.07 >45 86.33 >45 2.41 >45

184 0.87 >45 50.65 45 1 1 .92 >45

185 93.51 >45 97.91 >45 72.91 >45

186 35.40 >45 86.16 >45 73.51 30.01

187 97.42 >45 72.13 >45 2.91 >45

188 4.70 >45 78.63 >45 4.51 >45

189 98.14 >45 88.10 >45 68.58 >45

190 100.94 >45 83.53 >45 19.31 >45

191 89.31 >45 81 .79 >45 6.72 >45

192 95.03 >45 84.60 >45 76.82 >45

193 89.35 >45 80.72 >45 85.76 >45

194 60.71 >45 74.07 >45 63.24 >45

195 3.86 >45 75.08 >45 9.78 >45

196 93.87 >45 86.58 >45 75.88 >45

197 4.80 >45 66.87 >45 61 .44 >45

198 2.96 >45 71 .25 >45 36.45 >45

199 24.34 >45 27.85 >45 3.87 >45

200 2.69 >45 79.67 >45 64.72 41 .1 0

201 85.29 >45 79.67 >45 65.14 32.88

202 94.93 >45 74.09 >45 74.20 >45

203 100.03 >45 84.83 >45 80.12 >45

204 79.30 >45 30.36 >45 0.25 >45

204 50.38 >45 21 .99 >45 2.95 >45

205 94.02 >45 31 .70 >45 1 .01 >45

206 5.25 >45 93.66 >45 19.89 >45

207 5.39 >45 86.42 >45 72.56 >45

208 96.63 >45 14.04 >45 5.68 >45

209 3.74 >45 101 .51 >45 78.88 >45

210 2.27 >45 30.48 >45 3.39 >45

21 1 2.65 >45 39.99 >45 6.95 >45

212 100.82 >45 76.79 >45 76.28 >45

213 94.72 >45 86.35 >45 85.33 >45

214 15.08 >45 65.73 41 .00 74.58 >45

215 48.68 >45 88.23 >45 78.96 >45

216 61 .84 35.1 1 83.82 >45 75.59 >45

217 10.39 >45 57.90 36.93 12.62 >45

218 4.63 >45 48.31 >45 25.1 5 >45

219 3.50 >45 95.22 >45 89.83 >45 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

220 3.10 >45 87.27 >45 13.65 >45

221 1 13.54 >45 100.56 >45 93.1 8 >45

222 3.59 >45 40.42 >45 1 .92 >45

223 2.22 >45 68.23 40.65 67.37 40.97

224 2.54 >45 26.70 >45 1 .12 >45

225 20.97 >45 94.06 >45 88.95 >45

226 1 .24 >45 33.20 >45 0.69 >45

227 1 .24 >45 63.76 38.33 6.17 >45

228 21 .30 >45 51 .80 41 .00 2.72 >45

229 89.56 >45 66.51 >45 71 .1 8 >45

230 2.63 >45 78.48 >45 44.00 >45

231 29.53 >45 80.00 >45 3.1 1 >45

232 4.20 >45 81 .04 >45 51 .1 7 41 .1 0

233 18.46 >45 73.65 >45 74.91 >45

234 84.80 >45 68.91 >45 76.83 >45

235 84.04 >45 74.46 >45 87.47 >45

236 8.46 >45 77.23 >45 3.14 >45

237 18.53 >45 71 .76 >45 45.34 32.63

238 4.93 >45 70.06 >45 69.63 30.00

239 29.21 >45 75.58 >45 6.02 >45

240 4.30 >45 66.85 >45 12.95 >45

241 6.15 >45 91 .61 >45 16.97 >45

242 95.59 >45 101 .23 >45 79.22 >45

243 94.60 >45 94.50 >45 72.1 1 >45

244 3.34 >45 15.54 >45 2.85 >45

244 1 .29 >45 8.51 >45 2.47 >45

245 95.26 >45 77.70 >45 66.96 >45

246 13.06 >45 77.22 >45 66.03 >45

247 98.49 >45 79.89 >45 72.46 >45

248 73.12 >45 3.09 >45 13.59 >45

249 88.69 >45 80.12 >45 61 .88 41 .67

250 4.41 >45 86.09 >45 14.48 >45

251 7.80 >45 83.15 >45 20.59 >45

252 27.85 >45 80.73 >45 39.69 >45

253 106.42 >45 62.07 >45 63.1 1 >45

254 92.77 >45 69.80 >45 83.13 >45

255 96.25 >45 72.70 >45 64.50 30.02

256 4.16 >45 76.04 >45 72.1 1 >45

261 94.41 >45 73.42 >45 82.31 >45

262 23.99 >45 41 .84 >45 10.38 >45

263 8.71 >45 18.81 >45 7.20 >45

264 15.52 >45 56.37 40.76 7.97 >45 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

265 103.04 >45 76.74 >45 10.96 >45

265 83.99 45 54.38 45 3.97 >45

266 7.17 >45 12.42 >45 9.90 >45

267 4.64 >45 58.58 37.75 1 1 .33 >45

268 4.39 >45 79.03 >45 8.68 >45

268 0.14 >45 65 45 2.67 >45

269 6.62 >45 38.78 >45 8.38 >45

269 4.57 >45 25.1 1 >45 5.30 >45

270 63.00 41 .85 82.42 >45 12.30 >45

271 1 1 .7 >45 67.9 >45 53.6 >45

272 40.3 >45 70.8 >45 51 .9 >45

273 78.7 >45 67.9 >45 55.0 >45

274 75.9 >45 75.3 >45 67.0 >45

275 1 1 .24 >45 76.51 >45 78.05 >45

276 6.27 >45 61 .16 >45 18.81 14.51

277 94.36 >45 76.49 >45 74.99 >45

278 21 .08 >45 32.22 >45 10.55 >45

279 83.07 >45 43.86 >45 21 .97 >45

280 17.18 >45 1 1 .48 >45 8.86 >45

281 60.23 33.84 84.97 >45 18.03 >45

281 32.09 >45 68.90 45 12.39 >45

282 1 10.18 >45 90.54 >45 56.23 28.87

283 24.43 >45 34.91 34.65 9.83 >45

284 12.40 >45 4.81 >45 6.80 >45

285 105.26 >45 45.62 >45 30.09 >45

286 5.18 >45 13.04 >45 8.76 >45

286 4.35 >45 14.44 >45 9.55 >45

287 93.89 >45 72.51 >45 66.81 >45

288 7.14 >45 8.71 >45 7.52 >45

289 45.87 >45 62.01 >45 77.71 >45

290 20.6 >45 3.3 >45 8.8 >45

291 15.6 >45 5.0 >45 8.5 >45

291 3.95 >45 0.30 >45 3.29 >45

292 13.6 >45 9.5 >45 10.2 >45

293 66.4 34.9 12.3 >45 1 1 .9 >45

294 4.5 >45 16.6 >45 7.8 >45

294 2.84 >45 23.31 >45 6.57 >45

295 18.4 >45 14.4 >45 9.2 >45

296 99.1 >45 86.6 >45 22.6 >45

297 42.0 25.2 5.7 >45 9.2 >45

298 6.6 >45 92.3 >45 21 .3 >45

299 17.5 >45 89.6 >45 30.1 >45 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

299 13.58 >45 62.80 45 22.61 >45

300 79.7 >45 78.1 >45 36.0 >45

301 99.4 >45 96.2 >45 21 .0 >45

302 6.7 >45 71 .1 36.1 9.4 >45

302 5.26 >45 50.17 45 10.64 >45

303 14.2 >45 94.3 >45 15.6 >45

303 8.50 >45 65 45 20.68 >45

304 14.7 >45 74.9 >45 51 .6 >45

305 6.6 >45 73.2 >45 18.4 >45

305 4.23 >45 55.27 45 5.95 >45

306 33.2 >45 67.6 >45 17.6 >45

306 36.88 >45 63.32 45 5.23 >45

307 7.8 >45 78.2 >45 52.5 >45

307 4.08 >45 70.58 45 27.45 >45

308 63.7 >45 81 .6 >45 15.5 >45

308 49.30 27.20 61 .05 45 6.81 >45

309 8.0 >45 80.6 >45 14.7 >45

310 7.1 >45 71 .2 >45 66.6 >45

31 1 90.8 >45 72.9 >45 60.5 >45

316 89.26 45 69.01 45 80 45

317 8.3 >45 30.0 >45 20.6 >45

318 89.1 >45 77.6 >45 33.7 >45

319 74.25 >45 97.10 >45 4.96 >45

319 63.83 >45 89.16 >45 10.94 >45

319 86.3 >45 81 .7 >45 19.6 >45

319 84.75 45 75.42 45 4.56 >45

320 28.5 >45 74.7 >45 76.0 >45

321 14.0 >45 71 .6 >45 74.1 >45

322 9.0 >45 73.6 >45 29.8 >45

323 89.1 >45 76.1 >45 73.5 >45

324 90.5 >45 74.9 >45 68.7 >45

325 79.2 >45 73.7 >45 67.2 >45

326 7.5 >45 77.1 >45 26.5 >45

327 74.8 >45 66.5 >45 68.0 >45

328 21 .9 >45 86.6 >45 80.5 >45

329 12.5 >45 16.2 >45 13.4 >45

331 13.7 >45 41 .9 >45 24.9 >45

332 77.0 >45 59.7 >45 31 .5 >45

333 81 .2 >45 55.6 >45 62.3 >45

334 84.4 >45 49.3 >45 66.7 >45

335 81 .5 >45 54.0 >45 61 .2 >45

336 86.7 >45 56.9 >45 74.1 >45 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

337 86.4 >45 49.6 >45 61 .6 >45

338 85.2 >45 60.0 >45 76.3 >45

339 85.7 >45 56.1 >45 75.4 >45

340 88.9 >45 55.0 >45 65.9 >45

341 91 .7 >45 45.2 »45 45.6 >45

342 80.9 >45 75.9 >45 43.5 >45

343 84.7 >45 59.1 >45 23.2 >45

344 7.14 >45 n/a n/a 1 .1 >45

345 6.63 >45 n/a n/a 2.2 >45

346 12.12 >45 n/a n/a 1 .1 >45

348 74.78 >45 n/a n/a 59.2 45

349 84.00 >45 n/a n/a 0.2 >45

350 71 .00 >45 n/a n/a 56.3 45

351 68.60 >45 n/a n/a 57.3 45

352 71 .57 >45 n/a n/a 44.5 >45

354 NT NT 30.16 >45 4.29 >45

355 NT NT 71 .31 >45 3.68 >45

356 NT NT 51 .18 >45 2.88 >45

357 NT NT 64.32 >45 2.31 >45

358 NT NT 59.61 >45 4.53 >45

359 NT NT 55.70 >45 0.81 >45

360 NT NT 64.03 >45 2.38 >45

361 NT NT 67.22 >45 0.95 >45

362 NT NT 67.00 >45 2.26 >45

363 NT NT 64.44 >45 1 .99 >45

364 NT NT 70.82 >45 2.22 >45

365 NT NT 58.08 >45 23.74 >45

484 92.09 >45 75.84 >45 81 .46 >45

485 75.19 >45 62.60 >45 65.42 30.03

486 103.51 >45 76.95 >45 72.76 >45

487 103.20 >45 83.76 >45 70.73 40.1 9

488 90.53 >45 75.87 >45 72.82 >45

489 94.30 >45 68.84 41 .00 61 .1 1 41 .1 0

490 96.38 >45 63.84 38.76 50.39 35.13

491 107.15 >45 1 18.81 >45 83.61 >45

492 106.45 >45 83.92 >45 75.64 >45

493 91 .16 >45 68.84 >45 60.28 30.20

494 92.28 >45 79.67 >45 73.76 >45

495 NT NT - >45 - 1 .91 7

496 NT NT - >45 - 0.445

497 NT NT - >45 - 1 1 .33

498 NT NT - >45 - >45 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

499 NT NT - >45 - 1 .103

500 NT NT - >45 - >45

501 NT NT - 12.16 - 21 .27

502 NT NT - >45 - 38.94

503 NT NT - >45 - 0.31 6

504 NT NT - >45 - 14.84

505 NT NT - >45 - 0.669

506 NT NT - >45 - 0.81

507 NT NT - >45 - 2.443

508 NT NT - >45 - >45

509 NT NT - >45 - >45

510 NT NT - >45 - 4.16

51 1 NT NT - >45 - 3.39

512 NT NT - >45 - >45

513 NT NT - >45 - >45

514 NT NT - >45 - >45

515 NT NT - 16.53 - >45

516 NT NT - >45 - >45

517 NT NT - >45 - >45

518 NT NT - >45 - 2.95

519 NT NT - >45 - >45

520 NT NT - >45 - >45

521 NT NT - >45 - 8.794

522 NT NT - >45 - >45

523 NT NT - >45 - >45

524 NT NT - >45 - 2.499

525 NT NT - >45 - >45

526 NT NT - >45 - >45

527 NT NT - 0.958 - 1 .46

528 NT NT - >45 - >45

529 NT NT - >45 - >45

530 NT NT - >45 - >45

531 NT NT - >45 - >45

532 NT NT - >45 - 2.15

533 NT NT - >45 - 3.331

534 NT NT - >45 - 36.8

535 NT NT - >45 - >45

536 NT NT - >45 - >45

537 NT NT - >45 - >45

538 NT NT - >45 - >45

539 NT NT - >45 - >45

540 NT NT - >45 - >45 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

541 NT NT - >45 - >45

542 NT NT - >45 - 7.331

543 NT NT - >45 - 45

544 NT NT - >45 - 10.03

545 NT NT - >45 - 18.95

546 NT NT - >45 - 0.01 9

547 NT NT - >45 - 44.3

548 NT NT - >45 - 0.01

549 NT NT - >45 - 1 .21 1

550 NT NT - >45 - >45

551 NT NT - >45 - >45

552 NT NT - >45 - >45

553 NT NT - 5.708 - 0.885

554 NT NT - 4.079 - 1 .071

555 NT NT - >45 - >45

556 NT NT - >45 - >45

557 NT NT - >45 - 6.03

558 NT NT - >45 - 1 .072

559 NT NT - >45 - 1 .191

560 NT NT - >45 - >45

561 NT NT - >45 - 29.43

562 NT NT - >45 - 1 .496

563 NT NT - >45 - >45

564 NT NT - >45 - 4.234

565 NT NT - >45 - >45

567 NT NT - >45 - >45

568 NT NT - >45 - >45

569 NT NT - >45 - >45

570 NT NT - >45 - 26.35

571 NT NT - >45 - >45

572 NT NT - >45 - 14.99

573 NT NT - >45 - 5.601

574 NT NT - >45 - 2.282

575 NT NT - >45 - 4.681

576 NT NT - >45 - 0.028

577 NT NT - >45 - >45

578 NT NT - 8.457 - 1 .487

579 NT NT - >45 - >45

580 NT NT - 14.08 - 0.022

581 NT NT - >45 - >45

582 NT NT - >45 - 0.176

583 NT NT - >45 - 0.989 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

584 NT NT - >45 - 5.338

585 NT NT - >45 - 1 .807

586 NT NT - >45 - 3.768

587 NT NT - >45 - 4.92

588 NT NT - >45 - 1 .861

589 NT NT - >45 - 0.356

590 NT NT - >45 - >45

591 NT NT - >45 - >45

592 NT NT - >45 - >45

593 NT NT - >45 - >45

594 NT NT - >45 - 1 1 .8

595 NT NT - >45 - >45

596 NT NT - >45 - >45

597 NT NT - >45 - >45

598 NT NT - >45 - >45

599 NT NT - >45 - >45

600 NT NT - >45 - >45

601 NT NT - >45 - 5.686

602 NT NT - 15.94 - 2.744

603 NT NT - 7.258 - 2.41 1

604 NT NT - >45 - 6.12

605 NT NT - 31 .84 - 0.513

606 NT NT - >45 - 0.737

607 NT NT - >45 - 0.51 1

608 NT NT - >45 - >45

609 NT NT - >45 - >45

610 NT NT - >45 - 2.157

61 1 NT NT - >45 - 7.479

612 NT NT - >45 - 2.385

613 NT NT - >45 - >45

614 NT NT - >45 - 13.92

615 NT NT - 0.848 - 1 .878

616 NT NT - >45 - >45

617 NT NT - >45 - 0.121

618 NT NT - >45 - 0.101

619 NT NT - >45 - 0.291

620 NT NT - >45 - 0.013

621 NT NT - >45 - 0.042

622 NT NT - >45 - 1 .614

623 NT NT - >45 - 0.854

624 NT NT - >45 - 0.222

625 NT NT - >45 - 0.122 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

626 NT NT - >45 - 2.75

627 NT NT - >45 - 6.686

628 NT NT - >45 - 0.01

629 NT NT - >45 - 0.03

630 NT NT - 10.24 - 0.014

631 NT NT - >45 - >45

632 NT NT - >45 - >45

633 NT NT - >45 - 0.214

634 NT NT - >45 - 45

635 NT NT - >45 - 0.397

636 NT NT - >45 - 1 .801

637 NT NT - >45 - >45

638 NT NT - >45 - >45

639 NT NT - >45 - 4.791

640 NT NT - >45 - 3.98

641 NT NT - >45 - 6.72

642 NT NT - >45 - 0.21 1

643 NT NT - >45 - 0.01

644 NT NT - >45 - >45

645 NT NT - 17.92 - 4.473

646 NT NT - >45 - 1 .184

647 NT NT - >45 - 9.371

648 NT NT - >45 - >45

649 NT NT - >45 - 0.259

650 NT NT - 4.359 - 0.013

651 NT NT - >45 - 18.43

652 NT NT - >45 - >45

653 NT NT - >45 - >45

654 NT NT - >45 - >45

655 NT NT - >45 - >45

656 NT NT - >45 - >45

657 NT NT - >45 - 9.109

658 NT NT - >45 - 0.089

659 NT NT - >45 - 4.201

660 NT NT - >45 - 14.62

661 NT NT - >45 - 1 .541

662 NT NT - >45 - >45

663 NT NT - >45 - 0.01

664 NT NT - 23.48 - 0.023

665 NT NT - >45 - 5.006

666 NT NT - >45 - >45

667 NT NT - >45 - 0.87 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

668 NT NT - >45 - 0.71 9

669 NT NT - >45 - >45

670 NT NT - >45 - 3.789

671 NT NT - >45 - >45

672 NT NT - >45 - 0.441

673 NT NT - >45 - 33.85

674 NT NT - >45 - >45

675 NT NT - >45 - 0.01

676 NT NT - >45 - 0.013

677 NT NT - >45 - >45

678 NT NT - >45 - 3.868

679 NT NT - >45 - >45

680 NT NT - >45 - >45

681 NT NT - >45 - >45

682 NT NT - >45 - 0.01

683 NT NT - >45 - 10.1 5

684 NT NT - >45 - >45

685 NT NT - >45 - 0.184

686 NT NT - >45 - >45

687 NT NT - >45 - >45

688 NT NT - >45 - 1 .504

689 NT NT - >45 - 0.657

690 NT NT - >45 - 0.131

691 NT NT - >45 - >45

692 NT NT - >45 - 0.492

693 NT NT - >45 - 1 .666

694 NT NT - >45 - >45

695 NT NT - >45 - 2.394

696 NT NT - >45 - 0.08

697 NT NT - >45 - 0.059

698 NT NT - >45 - 0.026

699 NT NT - >45 - 7.647

700 NT NT - >45 - 0.703

701 NT NT - >45 - >45

702 NT NT - >45 - >45

703 NT NT - >45 - 0.121

704 NT NT - >45 - 1 .677

705 NT NT - 14.37 - 0.174

706 NT NT - >45 - >45

707 NT NT - >45 - 14.53

708 NT NT - >45 - >45

709 NT NT - >45 - 4.774 OLE1 SCD1 SCD1 SCD5 SCD5

Compound OLE1

% Max % Max IC50 % Max IC50 # IC50

Inhibition Inhibition (μΜ) Inhibition (μΜ)

710 NT NT - >45 - 0.05

71 1 NT NT - >45 - >45

712 NT NT - >45 - 0.01 6

713 NT NT - 5.583 - 0.01

714 NT NT - >45 - 0.23

715 NT NT - >45 - 0.048

716 NT NT - >45 - >45

717 NT NT - >45 - 1 .698

718 NT NT - >45 - 0.635

719 NT NT - >45 - >45

720 NT NT - >45 - 1 .966

721 NT NT - >45 - 1 .653

722 NT NT - >45 - 1 .374

723 NT NT - >45 - >45

724 NT NT - >45 - 1 .249

725 NT NT - 5.99 - 0.01 1

726 NT NT - 5.65 - 0.01

727 NT NT - >45 - >45

728 NT NT - >45 - 0.126

729 NT NT - >45 - >45

730 NT NT - >45 - 0.71 8

731 NT NT - >45 - >45

732 NT NT - >45 - 31 .82

733 NT NT - >45 - 2.727

734 NT NT - >45 - >45

735 NT NT - 3.99 - 0.01

736 NT NT - 32.65 - 0.26

737 NT NT - >45 - >45

738 NT NT - >45 - >45

739 NT NT - >45 - >45

740 NT NT - >45 - 1 .43

741 NT NT - >45 - 7.756

742 NT NT - >45 - 5.048

743 NT NT - >45 - 14.78

744 NT NT - >45 - >45

745 NT NT - >45 - >45

Table 6. Inhibition of SCD1 and SCD5 by Compounds of the Invention

# SCD1 IC50 (μΜ) SCD5 IC50 (μΜ) # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ)

747 >45 26.801 858 >45 0.262

748 >45 2.140 859 >45 >4

749 >45 20.798 860 >45 0.478 # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ) # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ)

750 3.25 0.010 861 14.96 0.01 0

751 >45 >45 862 33.83 0.01 0

752 >45 >45 863 >45 >45

753 >45 0.585 864 >45 >45

754 >45 16.472 865 >45 0.01 0

755 >45 5.413 866 >45 4.607

756 >45 4.363 867 >45 1 .91 5

757 >45 4.951 868 >45 0.967

758 >45 5.271 869 >45 1 .64

759 >45 >45 870 >45 4.26

760 >45 >45 871 >45 9.54

761 >45 >45 872 >45 8.06

762 >45 5.253 873 >45 41 .27

763 29.49 18.001 874 >45 0.05

764 >45 16.700 875 >45 0.02

765 32.91 19.277 876 >45 0.01

766 >45 >45 877 >45 0.08

767 >45 0.010 878 >45 0.005

768 >45 >45 879 5.50 0.01

769 >45 >45 880 >45 0.01 0

770 >45 >45 881 >45 0.01

771 >45 >45 882 6.56 1 .91

772 >45 >45 883 >45 1 .00

773 >45 21 .475 884 >45 0.01

774 >45 >45 885 25.38 0.01

775 >45 0.022 886 10.62 0.06

776 >45 0.025 887 >45 0.01

777 4.16 0.010 888 >45 0.01

778 >45 0.012 889 13.31 1 .90

779 >45 15.285 890 22.69 0.01

780 >45 0.027 891 >45 0.01

781 >45 4.800 892 >45 0.01

782 >45 0.149 893 >45 0.01

783 >45 >45 894 >45 0.07

784 0.95 0.010 895 >45 0.01

785 9.21 0.041 896 >45 0.01

786 >45 >45 897 >45 0.06

787 31 .50 0.108 898 >45 0.07

788 >45 6.218 899 >45 25.98 # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ) # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ)

789 >45 0.010 900 >45 13.08

790 >45 0.053 901 >45 >45

791 >45 0.010 902 >45 0.01

792 8.83 0.010 903 >45 0.01

793 >45 >45 904 >45 7.62

794 >45 >45 905 >45 >45

795 >45 0.010 906 >45 0.89

796 >45 1 .589 907 >45 0.04

797 >45 0.133 908 >45 0.19

798 >45 >45 909 >45 2.85

799 >45 0.010 910 >45 0.01

801 >45 0.363 91 1 >45 >45

802 >45 14.209 912 >45 1 .98

803 12.88 0.679 913 >45 13.79

804 >45 >45 914 >45 6.17

805 >45 9.360 915 >45 10.12

806 >45 >45 916 1 .96 0.01

807 >45 0.247 917 >45 0.10

808 >45 5.816 918 >45 0.80

809 >45 0.124 919 >45 0.18

810 >45 2.497 920 1 1 .67 0.10

81 1 >45 0.679 921 >45 3.40

812 >45 0.010 922 >45 6.56

813 >45 0.010 923 >45 >45

814 >45 >45 924 >45 4.09

815 >45 >45 925 >45 >45

816 >45 7.186 926 >45 >45

817 4.13 0.010 927 >45 0.14

818 >45 0.560 928 >45 0.01

819 >45 3.725 929 >45 4.42

820 >45 3.744 930 >45 0.20

821 >45 5.058 931 >45 >45

822 >45 0.1 1 1 932 >45 0.01

823 >45 0.1 19 933 >45 0.20

824 >45 0.932 934 >45 0.01

825 >45 9.490 935 >45 >45

826 >45 1 .990 936 >45 3.45

827 >45 >45 937 >45 >45

828 >45 0.067 938 >45 >45 # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ) # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ)

829 >45 2.202 939 >45 10.91

830 >45 >45 940 >45 31 .1 8

831 >45 1 .202 941 >45 20.36

832 >45 1 1 .644 942 >45 9.16

833 >45 >45 943 >45 >45

834 >45 >45 944 >45 2.22

835 >45 >45 945 >45 5.29

836 >45 1 .438 946 >45 4.1 1

837 >45 12.527 947 >45 >45

838 >45 0.021 948 >45 >45

839 >45 0.035 949 >45 >45

840 >45 20.683 950 >45 >45

841 >45 0.209 951 >45 >45

842 >45 0.010 952 15.60 9.22

843 >45 0.033 953 >45 0.01

844 >45 0.015 954 >45 2.86

845 >45 0.637 955 >45 >45

846 >45 0.040 956 >45 2.46

847 >45 >45 957 27.91 0.01

848 >45 0.010 958 >45 34.53

849 >45 0.644 959 >45 >45

850 >45 0.010 960 20.36 0.01

851 >45 0.065 961 >45 >45

852 >45 5.358 962 >45 0.01

853 >45 0.010 963 >45 0.16

854 14.57 0.010 964 0.31 0.03

855 >45 >45 965 >45 0.01

856 >45 >45 966 >45 0.15

857 >45 26.801

Table 7. Inhibition of SCD1 and SCD5 by Compounds of the Invention

# SCD1 IC50 (μΜ) SCD5 IC50 (μΜ) # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ)

967 >45 1 .52 1082 >45 0.359

968 >45 2.83 1083 >45 0.033

969 >45 1 .42 1084 >45 0.027

970 8.50 0.00196 1085 >45 0.532

971 >45 0.089 1086 >45 0.019

972 >45 4.44 1087 >45 0.041

973 >45 >45 1088 >45 2.52 # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ) # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ)

974 >45 0.010 1089 >45 4.68

975 >45 0.010 1090 >45 0.540

976 >45 5.33 1091 >45 3.62

977 >45 5.94 1092 32.333 0.010

978 >45 >45 1093 >45 0.00253

979 >45 0.168 1094 >45 17.4

980 >45 0.877 1095 >45 11.1

981 >45 0.045 1096 >45 0.00101

982 0.010 0.327 1097 >45 0.020

983 >45 1.51 1098 >45 0.062

984 >45 >45 1099 >45 1.88

985 >45 2.56 1100 >45 0.738

986 >45 0.048 1101 27.15 16.6

987 >45 >45 1102 >45 >45

988 >45 0.024 1103 >45 23.397

989 >45 >45 1104 >45 0.01

990 >45 0.010 1105 >45 0.54915098

991 >45 >45 1106 >45 2.955

992 >45 0.081 1107 >45 0.01

993 >45 3.81 1108 >45 >45

994 >45 >45 1109 >45 0.0500

995 >45 >45 1110 >45 0.01

996 >45 5.04 1111 >45 0.179

997 >45 0.022 1112 >45 0.193

998 >45 4.13 1113 >45 0.494

999 >45 0.010 1114 >45 0.116

1000 >45 0.650 1115 >45 10.609

1001 >45 15.6 1116 >45 1.409

1002 >45 5.05 1117 >45 >45

1003 >45 0.457 1118 >45 >45

1004 >45 0.297 1119 >45 >45

1005 >45 0.010 1120 >45 32.764

1006 >45 0.637 1121 >45 15.516

1007 >45 >45 1122 >45 13.164

1008 >45 2.02 1123 >45 6.640

1009 >45 9.51 1124 >45 >45

1010 >45 0.816 1125 >45 0.523

1011 1126 >45 2.738 # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ) # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ)

1012 15.0 0.010 1127 >45 1.465

1013 >45 0.367 1128 >45 >45

1014 >45 4.82 1129 >45 >45

1015 >45 0.429 1130 >45 9.898

1016 >45 0.0614 1131 >45 0.207

1017 17.1 0.010 1132 >45 >45

1018 20.3 0.010 1133 >45 >45

1019 12.2 0.010 1134 >45 0.0269

1020 14.6 0.170 1135 >45 0.188

1021 >45 0.223 1136 >45 0.01

1022 >45 0.010 1137 >45 0.0522

1023 >45 0.295 1138 >45 0.761

1024 >45 0.010 1139 >45 0.0960

1025 >45 0.010 1140 >45 0.0613

1026 3.98 0.200 1141 >45 0.865

1027 >45 3.16 1142 >45 >45

1028 0.953 0.010 1143 >45 >45

1029 >45 0.010 1144 1.78 0.01

1030 >45 11.0 1145 >45 11.139

1031 >45 1.13 1146 >45 0.380

1032 >45 4.10 1147 >45 5.461

1033 >45 3.91 1148 >45 19.415

1034 >45 0.639 1149 >45 0.01

1035 >45 0.265 1150 >45 >45

1036 >45 0.010 1151 >45 1.0917

1037 10.23 0.457 1152 >45 0.01

1038 >45 2.30 1153 1.939 0.840

1039 15.68 0.010 1154 >45 0.0157

1040 >45 0.791 1155 >45 >45

1041 >45 0.010 1156 >45 0.493

1042 >45 0.079 1157 >45 >45

1043 >45 0.011 1158 >45 3.501

1044 >45 0.593 1159 >45 >45

1045 45 0.935 1160 >45 >45

1046 45 0.010 1161 >45 0.0363

1047 45 0.010 1162 17.236 0.0206

1048 >45 0.016 1163 >45 >45

1049 >45 0.012 1164 >45 0.540 # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ) # SCD1 IC50 (μΜ) SCD5 IC50 (μΜ)

1050 >45 0.020 1165 >45 >45

1051 >45 7.50 1166 >45 >45

1052 >45 0.253 1167 >45 >45

1053 >45 0.00118 1168 >45 >45

1054 >45 0.010 1169 15.362 >45

1055 >45 0.00488 1170 >45 0.402

1056 >45 0.00469 1171 1.140 0.0311

1057 >45 0.023 1172 45 9.893

1058 >45 0.00367 1173 45 23.382

1059 >45 0.00223 1174 >45 10.38

1060 >45 0.184 1175 >45 0.21

1061 >45 0.010 1176 >45 0.14

1062 29 0.010 1177 >45 0.84

1063 >45 3.44 1178 >45 0.63

1064 >45 3.44 1179 >45 0.11

1065 >45 0.000386 1180 >45 0.06

1066 >45 0.000681 1181 >45 0.47

1067 >45 0.00498 1182 0.83 0.72

1068 >45 0.00375 1183 >45 >45

1069 >45 0.000862 1184 >45 >45

1070 >45 0.081 1185 >45 >45

1071 >45 0.00303 1186 10.00 6.08

1072 >45 0.021 1187 >45 >45

1073 8.36 0.00252 1188 >45 >45

1074 5.43 1.96 1189 >45 7.72

1075 4.40 0.010 1190 >45 0.06

1076 >45 1.030 1191 >45 1.36

1077 >45 0.300 1192 >45 0.04

1078 >45 0.033 1193 >45 >45

1079 >45 0.911 1194 >45 >45

1080 >45 0.501 1195 >45 >45

1081 >45 2.43

Other Embodiments

While the present invention has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the invention is not limited to the disclosed examples. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

Other embodiments are in the claims.

What is claimed is: